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The cardiovascular centre is a part of the human brain responsible for the regulation of the rate at which the

heart beats. It is found in the medulla. Normally, the heart beats without nervous control, but in some situations (e.g., exercise, body trauma), the cardiovascular centre is responsible for altering the rate at which the heart beats. It also mediates respiratory sinus arrhythmia. The cardiovascular centre effects changes to the heart rate via sympathetic fibres (to speed up the heart rate) and the vagus nerve (to slow down the heart rate). The accelerator and vagus nerves both connect to the sinoatrial node (SA node). The cardiovascular centre also increases the stroke volume of the heart (that is, the amount of blood it pumps). These two changes help to regulate the cardiac output, so that a sufficient amount of blood reaches tissue. Hormones like adrenaline can affect the cardiovascular centre and cause it to increase the rate of impulses sent to the sinoatrial node, or "cardiac pacemaker", thus increasing the rate of the heart beat. Chemoreceptors may also prompt this regulation.

Cardiovascular system, physiology: cardiovascular physiology


Heart

Stroke volume = End-diastolic volume End-systolic volum Cardiac output = Heart rate Stroke volume Volumes Afterload Preload

FrankStarling law of the heart Cardiac function curve V curve

Aortic valve area calculation Ejection fraction Cardiac in Dimensions

Fractional shortening = (End-diastolic dimension End-sys / End-diastolic dimension

Interaction diagramsCardiac cycle Wiggers diagram Pressure volume diagram

Chronotropic (Heart rate) Dromotropic (Conduction veloc Tropism (Contractility) Bathmotropic (Excitability) Lusitropic (R

Cardiac action potential (Atrial action potential, Ventricula Conduction system /potential) Effective refractory period Pacemaker potentia Cardiac electrophysiologywave, PR interval, QRS complex, QT interval, ST segment wave) Hexaxial reference system

Chamber pressureCentral venous pressure/right atrial pressure Right ventr Pulmonary artery pressure Pulmonary wedge pressur

pressure Left ventricular pressure Aortic pressure OtherVentricular remodeling

Blood flowCompliance Vascular resistance (Total peripheral resistance) Pulse Pulse pressure (Systolic - Diastolic) Mean arterial pressure Blood pressureJugular venous pressure Vascular system/ Hemodynamics Portal venous pressure

Baroreflex Kininkallikrein system Reninangiotensin system Vasoconstrictors/Vasodilators Autoregulation (Myogenic mechanis Regulation of BP Tubuloglomerular feedback, Cerebral autoregulation) Paraganglia (A Carotid body, Glomus cell) M: HRT anat/phys/devp

noco/cong/tumr, proc, drug sysi/epon, injr (C1A/1B/1C/1D), b M: VAS anat(a:h/u/t/a/l,v:h/u/t/a/l)/phys/devp/cell/prot noco/syva/cong/lyvd/tumr, sysi/epon, injr drug(C2s Retrieved from "http://en.wikipedia.org/w/index.php? title=Cardiovascular_centre&oldid=441917185" Categories:

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The heart is a myogenic muscular organ found in all animals with a circulatory system (including all vertebrates), which pumps blood throughout the blood vessels by repeated, rhythmic contractions. The term cardiac (as in cardiology) means "related to the heart" and comes from the Greek , kardia, for "heart". The vertebrate heart is principally composed of cardiac muscle and connective tissue. Cardiac muscle is an involuntary striated muscle tissue found only in this organ and responsible for the ability of the heart to pump blood. The average human heart, beating at 72 beats per minute, will beat approximately 2.5 billion times during an average 66 year lifespan. It weighs approximately 250 to 300 grams (9 to 11 oz) in females and 300 to 350 grams (11 to 12 oz) in males.[1]

In invertebrates that possess a circulatory system, the heart is typically a tube or small sac and pumps fluid that contains water and nutrients such as proteins, fats, and sugars. In insects, the "heart" is often called the dorsal tube and insect "blood" is almost always not oxygenated since they usually respirate (breathe) directly from their body surfaces (internal and external) to air. However, the hearts of some other arthropods (including spiders and crustaceans such as crabs and shrimp) and some other animals pump hemolymph, which contains the copper-based protein hemocyanin as an oxygen transporter similar to the ironbased hemoglobin in red blood cells found in vertebrates.

Contents
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1 Early development 2 Structure o 2.1 In humans o 2.2 In fish o 2.3 In double circulatory systems o 2.4 The fully divided heart 3 Functioning 4 History of discoveries 5 Additional Images 6 See also 7 References 8 External links

[edit] Early development


Main article: Heart development The mammalian heart is derived from embryonic mesoderm germ-layer cells that differentiate after gastrulation into mesothelium, endothelium, and myocardium. Mesothelial pericardium forms the outer lining of the heart. The inner lining of the heart, lymphatic and blood vessels, develop from endothelium. Heart muscle is termed myocardium.[2] From splanchnopleuric mesoderm tissue, the cardiogenic plates develops cranially and laterally to the neural plate. In the cardiogenic plates, two separate angiogenic cell clusters form on either side of the embryo. The cell clusters coalesce to form an endocardial tube continuous with a dorsal aorta and a vitteloumbilical vein. As embryonic tissue continues to fold, the two endocardial tubes are pushed into the thoracic cavity, begin to fuse together, and complete the fusing process at approximately 22 days.[3]

At 22 days after conception, the human heart begins beating at 70 to 80 beats per minute and accelerates linearly for the first month of beating. The human embryonic heart begins beating at around 22 days after conception, or five weeks after the last normal menstrual period (LMP). The first day of the LMP is normally used to date the start of the gestation (pregnancy). The human heart begins beating at a rate near the mothers, about 7580 beats per minute (BPM). The embryonic heart rate (EHR) then accelerates linearly by approximately 100 BPM during the first month to peak at 165185 BPM during the early 7th week afer conception, (early 9th week after the LMP). This acceleration is approximately 3.3 BPM per day, or about 10 BPM every three days, which is an increase of 100 BPM in the first month.[4][5][6] After 9.1 weeks after the LMP, it decelerates to about 152 BPM (+/-25 BPM) during the 15th week post LMP. After the 15th week, the deceleration slows to an average rate of about 145 (+/-25 BPM) BPM, at term. The regression formula, which describes this linear acceleration before the embryo reaches 25 mm in crown-rump length, or 9.2 LMP weeks, is: the Age in days = EHR(0.3)+6. There is no difference in female and male heart rates before birth.[7]

[edit] Structure
The structure of the heart varies among the different branches of the animal kingdom. (See Circulatory system.) Cephalopods have two "gill hearts" and one "systemic heart". In vertebrates, the heart lies in the anterior part of the body cavity, dorsal to the gut. It is always surrounded by a pericardium, which is usually a distinct structure, but may be continuous with the peritoneum in jawless and cartilaginous fish. Hagfishes, uniquely among vertebrates, also possess a second heart-like structure in the tail.[8]

[edit] In humans
Main article: Human heart

Structure diagram of the human heart from an anterior view. Blue components indicate deoxygenated blood pathways and red components indicate oxygenated pathways. The human heart has a mass of between 250 and 350 grams and is about the size of a fist.[9] It is located anterior to the vertebral column and posterior to the sternum[10]. It is enclosed in a double-walled sac called the pericardium. The superficial part of this sac is called the fibrous pericardium. This sac protects the heart, anchors its surrounding structures, and prevents overfilling of the heart with blood. The outer wall of the human heart is composed of three layers. The outer layer is called the epicardium, or visceral pericardium since it is also the inner wall of the pericardium. The middle layer is called the myocardium and is composed of cardiac muscle which contracts. The inner layer is called the endocardium and is in contact with the blood that the heart pumps[11]. Also, it merges with the inner lining (endothelium) of blood vessels and covers heart valves.[12] The human heart has four chambers, two superior atria and two inferior ventricles. The atria are the receiving chambers and the ventricles are the discharging chambers. The pathway of blood through the human heart consists of a pulmonary circuit[13] and a systemic circuit. Deoxygenated blood flows through the heart in one direction, entering through the superior vena cava into the right atrium and is pumped through the tricuspid valve into the right ventricle before being pumped out through the pulmonary valve to the pulmonary arteries into the lungs. It returns from the lungs through the pulmonary veins to the left atrium where it is pumped through the mitral valve into the left ventricle before leaving through the aortic valve to the aorta.[14][15]

[edit] In fish

Schematic of simplified fish heart Primitive fish have a four-chambered heart, but the chambers are arranged sequentially so that this primitive heart is quite unlike the four-chambered hearts of mammals and birds. The first chamber is the sinus venosus, which collects de-oxygenated blood, from the body, through the hepatic and cardinal veins. From here, blood flows into the atrium and then to the powerful muscular ventricle where the main pumping action will take place. The fourth and final chamber is the conus arteriosus which contains several valves and sends blood to the ventral aorta. The ventral aorta delivers blood to the gills where it is oxygenated and flows, through the dorsal aorta, into the rest of the body. (In tetrapods, the ventral aorta has divided in two; one half forms the ascending aorta, while the other forms the pulmonary artery).[8]

In the adult fish, the four chambers are not arranged in a straight row but, instead form an S-shape with the latter two chambers lying above the former two. This relatively simpler pattern is found in cartilaginous fish and in the ray-finned fish. In teleosts, the conus arteriosus is very small and can more accurately be described as part of the aorta rather than of the heart proper. The conus arteriosus is not present in any amniotes, presumably having been absorbed into the ventricles over the course of evolution. Similarly, while the sinus venosus is present as a vestigial structure in some reptiles and birds, it is otherwise absorbed into the right atrium and is no longer distinguishable.[8]

[edit] In double circulatory systems


In amphibians and most reptiles, a double circulatory system is used but the heart is not completely separated into two pumps. The development of the double system is necessitated by the presence of lungs which deliver oxygenated blood directly to the heart. In living amphibians, the atrium is divided into two separate chambers by the presence of a muscular septum even though there is only one ventricle. The sinus venosus, which remains large in amphibians but connects only to the right atrium, receives blood from the vena cavae, with the pulmonary vein by-passing it entirely to enter the left atrium. In the heart of lungfish, the septum extends part-way into the ventricle. This allows for some degree of separation between the de-oxygenated bloodstream destined for the lungs and the oxygenated stream that is delivered to the rest of the body. The absence of such a division in living amphibian species may be at least partly due to the amount of respiration that occurs through the skin in such species; thus, the blood returned to the heart through the vena cavae is, in fact, already partially oxygenated. As a result, there may be less need for a finer division between the two bloodstreams than in lungfish or other tetrapods. Nonetheless, in at least some species of amphibian, the spongy nature of the ventricle seems to maintain more of a separation between the bloodstreams than appears the case at first glance. Furthermore, the conus arteriosus has lost its original valves and contains a spiral valve, instead, that divides it into two parallel parts, thus helping to keep the two bloodstreams separate.[8] The heart of most reptiles (except for crocodilians; see below) has a similar structure to that of lungfish but, here, the septum is generally much larger. This divides the ventricle into two halves but, because the septum does not reach the whole length of the heart, there is a considerable gap near the openings to the pulmonary artery and the aorta. In practice, however, in the majority of reptilian species, there appears to be little, if any, mixing between the bloodstreams, so the aorta receives, essentially, only oxygenated blood.[8]

[edit] The fully divided heart

Human heart removed from a 64-year-old man Surface anatomy of the human heart. The heart is demarcated by: -A point 9 cm to the left of the midsternal line (apex of the heart) -The seventh right sternocostal articulation -The upper border of the third right costal cartilage 1 cm from the right sternal line -The lower border of the second left costal cartilage 2.5 cm from the left lateral sternal line.
[16]

Archosaurs (crocodilians and birds) and mammals show complete separation of the heart into two pumps for a total of four heart chambers; it is thought that the four-chambered heart of archosaurs evolved independently from that of mammals. In crocodilians, there is a small opening, the foramen of Panizza, at the base of the arterial trunks and there is some degree of mixing between the blood in each side of the heart, during a dive underwater[17] [18] ; thus, only in birds and mammals are the two streams of blood those to the pulmonary and systemic circulations permanently kept entirely separate by a physical barrier.[8] In the human body, the heart is usually situated in the middle of the thorax with the largest part of the heart slightly offset to the left, although sometimes it is on the right (see dextrocardia), underneath the sternum. The heart is usually felt to be on the left side because the left heart (left ventricle) is stronger (it pumps to all body parts). The left lung is smaller than the right lung because the heart occupies more of the left hemithorax. The heart is fed by the coronary circulation and is enclosed by a sac known as the pericardium; it is also surrounded by the lungs. The pericardium comprises two parts: the fibrous pericardium, made of dense fibrous connective tissue, and a double membrane structure (parietal and visceral pericardium) containing a serous fluid to reduce friction during heart contractions. The heart is located in the mediastinum, which is the central sub-division of the thoracic cavity. The mediastinum also contains other structures, such as the esophagus and trachea, and is flanked on either side by the right and left pulmonary cavities; these cavities house the lungs.[19]

The apex is the blunt point situated in an inferior (pointing down and left) direction. A stethoscope can be placed directly over the apex so that the beats can be counted. It is located posterior to the 5th intercostal space just medial of the left mid-clavicular line. In normal adults, the mass of the heart is 250350 grams (912 oz), or about twice the size of a clenched fist (it is about the size of a clenched fist in children), but an extremely diseased heart can be up to 1000 g (2 lb) in mass due to hypertrophy. It consists of four chambers, the two upper atria and the two lower ventricles.

[edit] Functioning
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Circulation of blood through the heart The conduction system of the heart In mammals, the function of the right side of the heart (see right heart) is to collect deoxygenated blood, in the right atrium, from the body (via superior and inferior vena cavae) and pump it, through the tricuspid valve, via the right ventricle, into the lungs (pulmonary circulation) so that carbon dioxide can be dropped off and oxygen picked up (gas exchange). This happens through the passive process of diffusion. The left side (see left heart) collects oxygenated blood from the lungs into the left atrium. From the left atrium the blood moves to the left ventricle, through the bicuspid valve (mitral valve), which pumps it out to the body (via the aorta). On both sides, the lower ventricles are thicker and stronger than the upper atria. The muscle wall surrounding the left ventricle is thicker than the wall surrounding the right ventricle due to the higher force needed to pump the blood through the systemic circulation. Starting in the right atrium, the blood flows through the tricuspid valve to the right ventricle. Here, it is pumped out the pulmonary semilunar valve and travels through the pulmonary artery to the lungs. From there, oxygenated blood flows back through the pulmonary vein to the left atrium. It then travels through the mitral valve to the left ventricle, from where it is pumped through the aortic semilunar valve to the aorta. The aorta forks and the blood is divided between major arteries which supply the upper and

lower body. The blood travels in the arteries to the smaller arterioles and then, finally, to the tiny capillaries which feed each cell. The (relatively) deoxygenated blood then travels to the venules, which coalesce into veins, then to the inferior and superior venae cavae and finally back to the right atrium where the process began. The heart is effectively a syncytium, a meshwork of cardiac muscle cells interconnected by contiguous cytoplasmic bridges. This relates to electrical stimulation of one cell spreading to neighboring cells. Some cardiac cells are self-excitable, contracting without any signal from the nervous system, even if removed from the heart and placed in culture. Each of these cells have their own intrinsic contraction rhythm. A region of the human heart called the sinoatrial (SA) node, or pacemaker, sets the rate and timing at which all cardiac muscle cells contract. The SA node generates electrical impulses, much like those produced by nerve cells. Because cardiac muscle cells are electrically coupled by inter-calated disks between adjacent cells, impulses from the SA node spread rapidly through the walls of the artria, causing both artria to contract in unison. The impulses also pass to another region of specialized cardiac muscle tissue, a relay point called the atrioventricular node, located in the wall between the right atrium and the right ventricle. Here, the impulses are delayed for about 0.1s before spreading to the walls of the ventricle. The delay ensures that the artria empty completely before the ventricles contract. Specialized muscle fibers called Purkinje fibers then conduct the signals to the apex of the heart along and throughout the ventricular walls. The Purkinje fibres form conducting pathways called bundle branches. This entire cycle, a single heart beat, lasts about 0.8 seconds. The impulses generated during the heart cycle produce electrical currents, which are conducted through body fluids to the skin, where they can be detected by electrodes and recorded as an electrocardiogram (ECG or EKG).[20] The events related to the flow or blood pressure that occurs from the beginning of one heartbeat to the beginning of the next can be referred to a cardiac cycle. [21] The SA node is found in all amniotes but not in more primitive vertebrates. In these animals, the muscles of the heart are relatively continuous and the sinus venosus coordinates the beat which passes in a wave through the remaining chambers. Indeed, since the sinus venosus is incorporated into the right atrium in amniotes, it is likely homologous with the SA node. In teleosts, with their vestigial sinus venosus, the main centre of coordination is, instead, in the atrium. The rate of heartbeat varies enormously between different species, ranging from around 20 beats per minute in codfish to around 600 in hummingbirds.[8] Cardiac arrest is the sudden cessation of normal heart rhythm which can include a number of pathologies such as tachycardia, an extremely rapid heart beat which prevents the heart from effectively pumping blood, which is an irregular and ineffective heart rhythm, and asystole, which is the cessation of heart rhythm entirely. Cardiac tamponade is a condition in which the fibrous sac surrounding the heart fills with excess fluid or blood, suppressing the heart's ability to beat properly. Tamponade is treated by pericardiocentesis, the gentle insertion of the needle of a syringe into the pericardial sac

(avoiding the heart itself) on an angle, usually from just below the sternum, and gently withdrawing the tamponading fluids.

[edit] History of discoveries

Heart and its blood vessels, by Leonardo da Vinci, 15th century The valves of the heart were discovered by a physician of the Hippocratean school around the 4th century BC, although their function was not fully understood. On dissection, arteries are typically empty of blood because blood pools in the veins after death. Ancient anatomists subsequently assumed they were filled with air and served to transport it around the body. Philosophers distinguished veins from arteries, but thought the pulse was a property of arteries themselves. Erasistratos observed that arteries cut during life bleed. He ascribed the fact to the phenomenon that air escaping from an artery is replaced with blood which entered by very small vessels between veins and arteries. Thus he apparently postulated capillaries, but with reversed flow of blood. The Greek physician Galen (2nd century AD) knew blood vessels carried blood and identified venous (dark red) and arterial (brighter and thinner) blood, each with distinct and separate functions. Growth and energy were derived from venous blood created in the liver from chyle, while arterial blood gave vitality by containing pneuma (air) and originated in the heart. Blood flowed from both creating organs to all parts of the body, where it was consumed and there was no return of blood to the heart or liver. The heart did not pump blood around, the heart's motion sucked blood in during diastole and the blood moved by the pulsation of the arteries themselves. Galen believed the arterial blood was created by venous blood passing from the left ventricle to the right through 'pores' in the interventricular septum, while air passed from

the lungs via the pulmonary artery to the left side of the heart. As the arterial blood was created, "sooty" vapors were created and passed to the lungs, also via the pulmonary artery, to be exhaled. For more recent technological developments, see Cardiac surgery.

Cardiac Centers
The cardioinhibitor and cardioaccelerator centers in the medulla control the heart rate and the force of contraction. These centers are regulated by signals from the carotid sinus as well as from stretch receptors in the heart. Follow the interactions beginning with increased arterial blood pressure.

Cardioinhibitor Center
The carotid sinus (CS) is stimulated as blood pressure (BP) increases --a direct relationship (solid arrow). Stimulatory impulses (solid line) from the sinus lead to the cardioinhibitor centers (CI). This center sends simultaneous inhibitory signals (dashed lines) to two locations: to the pacemaker (heart rate (HR)) via the vagus nerve (V) and to the medullary cardioaccelerator center (CA).

Heart Rate
Notice that the pacemaker (HR) has dual innervation. It has inhibitory neurons (dashed line) from the cardioinhibitor center (CI) via the vagus nerve(V). It also has stimulatory neurons (solid line) from the cardioaccelerator center (CA) center via the cardiac nerves (CN). Simultaneous stimulation does indeed occur but they do not rise and fall together-- this could stop the heart! Instead, as the carotid sinus (CS) increases heart rate (HR) it simultaneously decreases impulses from the cardioaccelerator center (CA). When the cardioinhibitor center is decreasing heart rate it is also decreasing the ability of the cardioaccelerator center to increase heart rate! Decreased heart rate leads to deceased cardiac output which then leads to decreased arterial blood pressure. We've returned to the beginning where arterial blood pressure was increasing-- negative feedback, homeostasis at work.

Cardioaccelerator Center

Stimulatory neurons (solid lines) simultaneously increase the heart rate (HR) and the contractility (C). The neurons involved run from the cardioaccelerator center (CA) via the cardiac nerves (CN) .

Contractility
The number of cross-bridges that can form within myofilaments in cardiac contractile cells is dependent on the concentration of calcium ions. About 80% of cytoplasmic calcium is pumped into the sarcoplasmic reticulum between each contraction. The actual amount stored is increased by allowing more calcium into the cell from the interstitial fluid. (This is discussed in detail in the 'Cardiac Contractile Cell Tutorial'.) The end effect is that increased contractility (C) empties the heart more completely leaving less residual blood-- end systolic volume (ESV) behind.

Heart Stretch Receptors


Increased venous return (VR) stretches the heart causing stretch receptors to send stimulatory signals to the cardioaccelerator center (CA) via the glossopharyngeal nerve (GP) (solid line). This results in increased activity of this center resulting in increased heart rate and force of contraction (contractility).

The systemic circulation


The systemic blood vessels are divided into arteries, arterioles, capillaries and veins. Arteries supply blood to the organs at high pressure, whereas arterioles are smaller vessels with muscular walls which allow direct control of flow through each capillary bed. Capillaries consist of a single layer of endothelial cells, and the thin walls allow exchange of nutrients between blood and tissue. Veins return blood from the capillary beds to the heart, and contain 70% of the circulating blood volume, in contrast to the 15% in the arterial system. Veins act a reservoir, and venous tone is important in maintaining the return of blood to the heart, for example in severe haemorrhage, when sympathetic stimulation causes venoconstriction.

Blood flow
The relationship between flow and driving pressure is given by the Hagen-Poisseuille formula. This states that flow rate in a tube is proportional to:

Driving pressure x Radius4 Length x Viscosity

In blood vessels flow is pulsatile rather than continuous, and viscosity varies with flow rate, so the formula is not strictly applicable, but it illustrates an important point; small changes in radius result in large changes in flow rate. In both arterioles and capillaries changes in flow rate are brought about by changes in tone and therefore vessel radius. Viscosity describes the tendency of a fluid to resist flow. At low flow rates the red blood cells stick together, increasing viscosity, and remain in the centre of the vessel. The blood closest to the vessel wall (which supplies side branches) therefore has a lower haematocrit. This process is known as plasma skimming. Viscosity is reduced in the presence of anaemia, and the resulting increased flow rate helps maintain oxygen delivery to the tissues.

Control of the systemic circulation


Arteriolar tone determines blood flow to the capillary beds. A number of factors influence arteriolar tone, including autonomic control, circulating hormones, endothelium derived factors and the local concentration of metabolites.

Autonomic control is largely by the sympathetic nervous system, which supplies all
vessels except capillaries. Sympathetic fibres arise from the thoracic and lumbar segments of the spinal cord. These are under the control of the vasomotor centre in the medulla, which has distinct vasoconstrictor and vasodilator areas. Although there is a baseline sympathetic discharge to maintain vascular tone, increased stimulation affects some organs more than others (Figure 4). This tends to redistribute blood from skin, muscle and gut to brain, heart and kidney. Increased sympathetic discharge is one of the responses to hypovolaemia, for example in severe blood loss, with the effect of protecting blood supply to the vital organs. The predominant sympathetic influence is vasoconstriction via alphaadrenergic receptors. However, the sympathetic system also causes vasodilation via beta adrenergic and cholinergic receptor stimulation, but only in skeletal muscle. This increased blood flow to muscle is an important part of the "fight or flight" reaction, when exercise is anticipated. Circulating hormones such as adrenaline and angiotensin II are potent vasoconstrictors, but they probably have little effect on acute cardiovascular control. In contrast, endothelium derived factors play an important role in controlling local blood flow. These substances are either produced or modified in the vascular endothelium, and include prostacyclin and nitric oxide, both potent vasodilators. An accumulation of metabolites such as CO2, K+, H+,

adenosine and lactate causes vasodilation. This response is probably an important mechanism of autoregulation, the process whereby blood flow through an organ is controlled locally, and remains constant over a wide range of perfusion pressure. Autoregulation is a particular feature of the cerebral and renal circulations.

Control of arterial pressure


Systemic arterial pressure is controlled closely in order to maintain tissue perfusion. The mean arterial pressure (MAP) takes account of pulsatile blood flow in the arteries, and is the best measure of perfusion pressure to an organ. MAP is defined:

MAP = Diastolic arterial pressure + (pulse pressure / 3)


where pulse pressure is the difference between systolic and diastolic arterial pressure. MAP is the product of cardiac output (CO) and systemic vascular resistance (SVR):

MAP = CO x SVR
If cardiac output falls, for example when venous return decreases in hypovolaemia, MAP will also fall unless there is a compensatory rise in SVR by vasoconstriction of the arterioles. This response is mediated by baroreceptors, which are specialised sensors of pressure located in the carotid sinus and aortic arch, and connected to the vasomotor centre. A fall in blood pressure causes reduced stimulation of the baroreceptors, and consequent reduced discharge from the baroreceptors to the vasomotor centre. This causes an increase in sympathetic discharge leading to vasoconstriction, increased heart rate and contractility, and secretion of adrenaline. Conversely, rises in blood pressure stimulate the baroreceptors, which leads to increased parasympathetic outflow to the heart via branches of the vagus nerve, causing slowing of the heart. There is also reduced sympathetic stimulation to the peripheral vessels causing vasodilation. Baroreceptor responses provide immediate control of blood pressure; if hypotension is prolonged, other mechanisms start to operate, such as the release of angiotensin II and aldosterone from the kidneys and adrenal glands, which leads to salt and water being retained in the circulation. Teaching Point The valsalva manoeuvre is a simple test of the baroreceptor reflex. The patient tries to breathe out forcefully against a closed larynx - "straining" - resulting in an increased intrathoracic pressure. This causes decreased venous return, cardiac output and a fall in blood pressure leading to reduced baroreceptor discharge to the vasomotor centre. This then causes peripheral vasoconstriction, and an increase in heart rate which is the normal response. This has the effect of maintaining systolic pressure, although the pulse pressure is

reduced due to vasoconstriction. (Continued ...)

Cardiovascular responses to anaesthesia


All anaesthetic agents have a direct depressant effect on the myocardium. Therefore they reduce myocardial contractility, and many also reduce sympathetic stimulation of the vascular system. The result is a decreased cardiac output accompanied by vasodilation, causing hypotension. This fall in blood pressure can compromise perfusion of vital organs, especially at induction of anaesthesia in the hypovolaemic patient. In contrast, agents such as ketamine and ether increase sympathetic activity, which opposes the direct depressant effect. Thus cardiac output and blood pressure are maintained despite the direct myocardial depressant action. Volatile anaesthetic agents reduce discharge from the sinoatrial node. This can lead to junctional rhythms, when the atrioventricular node takes over as pacemaker, associated with an absent P wave on the ECG. Local anaesthetic agents depress conduction of the cardiac impulse. This effect can be therapeutic, for example in the treatment of ventricular arrhythmias with lignocaine. However, at higher concentrations local anaesthetics can cause cardiac arrest - it is vital to avoid accidental intravenous injection when using these agents. Controlled ventilation in a paralysed patient has many effects. Firstly it increases intrathoracic pressure which reduces venous return and preload, causing a fall in cardiac output. Secondly, changes in the partial pressure of carbon dioxide (PaCO2) resulting from changes in ventilation will also have cardiovascular effects. A low PaCO2, which commonly occurs during controlled ventilation, causes peripheral vasoconstriction by a direct effect. This increases systemic vascular resistance, increases afterload and can result in a fall in cardiac output. It also causes cerebral vasoconstriction, reducing cerebral blood volume ( Cerebral blood flow, Update in Anaesthesia 1998;8). A high PaCO2 usually occurs in the anaesthetised patient during spontaneous breathing, and causes vasodilation and increased sympathetic activity, leading to increased cardiac output. However, the heart will be more likely to develop arrhythmias, particularly when using volatile agents. Spinal and epidural anaesthesia blocks sympathetic nerves as well as sensory and motor fibres. This can lead to marked hypotension due to arteriolar and venous dilation because the sympathetic nerves to the lower extremities are blocked. Cardiac sympathetic nerve fibres, which arise from the high thoracic spinal cord, may also be blocked, allowing an unopposed vagal action on the heart. In this case there will not be an appropriate increase in cardiac output, and blood pressure will fall further with a bradycardia. For patients with coronary artery disease, it is important to use an anaesthetic technique which does not cause further myocardial ischaemia. The important principle is to ensure that myocardial oxygen supply is greater than myocardial oxygen demand. The balance between these two variables is influenced by the following factors:

Myocardial oxygen supply Heart rate Diastolic time Coronary perfusion pressure Aortic diastolic blood pressure Ventricular end-diastolic blood pressure Arterial oxygen content Arterial oxygen partial pressure Haemoglobin concentration Coronary artery diameter

Myocardial oxygen demand Heart rate Ventricular wall tension Preload Afterload Contractility

Introduction
In order to survive humans have to be able to extract oxygen from the atmosphere and transport it to their cells where it is utilised for essential metabolic processes. Some cells can produce energy without oxygen (anaerobic metabolism) for a short time, although it is inefficient. Other organs (e.g.brain) are made up of cells that can only make the energy necessary for survival in the presence of a continual supply of oxygen (aerobic metabolism). Tissues differ in their ability to withstand anoxia (lack of oxygen). The brain and the heart are the most sensitive. Initially a lack of oxygen affects organ function but with time irreversible damage is done (within minutes in the case of the brain) and revival is impossible.

OXYGEN TRANSPORT FROM AIR TO TISSUES


Oxygen is transported from the air that we breathe to each cell in the body. In general, gases move from an area of high concentration (pressure) to areas of low concentration (pressure). If there are a mixture of gases in a container, the pressure of each gas (partial pressure) is equal to the pressure that each gas would produce if it occupied the container alone.

Atmosphere to alveolus
The air (atmosphere) around us has a total pressure of 760 mmHg (1 atmosphere of pressure = 760mmHg = 101kPa = 15lbs/sq. in). Air is made up of 21% oxygen, 78% nitrogen and small quantities of CO2, argon and helium. The pressure exerted by the main two gases individually, when added together, equals the total surrounding pressure or atmospheric pressure. The pressure of oxygen (PO2) of dry air at sea level is therefore 159 mmHg (21/100 x 760=159). However by the time the inspired air reaches the trachea it has been warmed and humidified by the upper respiratory tract. The humidity is formed by

water vapour which as a gas exerts a pressure. At 37oC the water vapour pressure in the trachea is 47 mmHg. Taking the water vapour pressure into account, the PO2 in the trachea when breathing air is (760-47) x 21/100 = 150 mmHg. By the time the oxygen has reached the alveoli the PO2 has fallen to about 100 mmHg. This is because the PO2 of the gas in the alveoli (PAO2) is a balance between two processes: the removal of oxygen by the pulmonary capillaries and its continual supply by alveolar ventilation (breathing).

Alveolus to blood
Blood returning to the heart from the tissues has a low PO2 (40 mmHg) and travels to the lungs via the pulmonary arteries. The pulmonary arteries form pulmonary capillaries, which surround alveoli. Oxygen diffuses (moves through the membrane separating the air and the blood) from the high pressure in the alveoli (100 mmHg) to the area of lower pressure of the blood in the pulmonary capillaries (40 mmHg). After oxygenation blood moves into the pulmonary veins which return to the left side of the heart to be pumped to the systemic tissues. In a 'perfect lung' the PO2 of pulmonary venous blood would be equal to the PO2 in the alveolus. Three factors may cause the PO2 in the pulmonary veins to be less than the PAO2: ventilation/perfusion mismatch, shunt and slow diffusion.

Ventilation/perfusion mismatch
In a 'perfect lung' all alveoli would receive an equal share of alveolar ventilation and the pulmonary capillaries that surround different alveoli would receive an equal share of cardiac output ie.ventilation and perfusion would be perfectly matched. Diseased lungs may have marked mismatch between ventilation and perfusion. Some alveoli are relatively overventilated while others are relatively overperfused (the most extreme form of this is shunt where blood flows past alveoli with no gas exchange taking place (figure 1). Well ventilated alveoli (high PO2 in capillary blood) cannot make up for the oxygen not transferred in the underventilated alveoli with a low PO2 in the capillary blood. This is because there is a maximum amount of oxygen which can combine with haemoglobin (see haemoglobin-oxygen dissociation curve figure 2a). The pulmonary venous blood (mixture of pulmonary capillary blood from all alveoli) will therefore have a lower PO2 than the PO2 in the alveoli (PAO2). Even normal lungs have some degree of ventilation/perfusion mismatch; the upper zones are relatively overventilated while the lower zones are relatively overperfused and underventilated.

Shunt occurs when deoxygenated venous blood from the body passes unventilated alveoli to enter the pulmonary veins and the systemic arterial system with an unchanged PO2 (40 mmHg). (Figure 1.) Atelectasis (collapsed alveoli), consolidation of the lung, pulmonary oedema or small airway closure (see later) will cause shunt.

Diffusion
Oxygen diffuses from the alveolus to the capillary until the PO2 in the capillary is equal to that in the alveolus. This process is normally complete by the time the blood has passed about one third of the way along the pulmonary capillary. In the normal lung, the diffusion of oxygen into the blood is vary rapid and is complete, even if the cardiac output is increased (exercise) and the blood spends less time in contact with the alveolus. This may not happen when the alveolar capillary network is abnormal (pulmonary disease). However, the ability of the lung to compensate is great and problems caused by poor gas diffusion are a rare cause for hypoxia, except with diseases such as alveolar fibrosis. In order to decrease the detrimental effect that shunt and ventilation/perfusion mismatch have on oxygenation, the blood vessels in the lung are adapted to vasoconstrict and therefore reduce blood flow to areas which are underventilated. This is termed hypoxic pulmonary vasoconstriction and reduces the effect of shunt.

Oxygen carriage by the blood


Oxygen is carried in the blood in two forms. Most is carried combined with haemoglobin (figure 2b) but there is a very small amount dissolved in the plasma. Each gram of haemoglobin can carry 1.31 ml of oxygen when it is fully saturated. Therefore every litre of blood with a Hb concentration of 15g/dl can carry about 200 mls of oxygen when fully saturated (occupied) with oxygen (PO2 >100 mmHg). At this PO2 only 3 ml of oxygen will dissolve in every litre of plasma.

If the PO2 of oxygen in arterial blood (PAO2) is increased significantly (by breathing 100% oxygen) then a small amount of extra oxygen will dissolve in the plasma (at a rate of 0.003 ml O2/100ml of blood /mmHg PO2) but there will normally be no significant increase in the amount carried by haemoglobin, which is already >95% saturated with oxygen. When considering the adequacy of oxygen delivery to the tissues, three factors need to be taken into account, haemoglobin concentration, cardiac output and oxygenation.

Oxygen cascade
Oxygen moves down the pressure or concentration gradient from a relatively high level in air, to the levels in the respiratory tract and then alveolar gas, the arterial blood, capillaries and finally the cell. The PO2 reaches the lowest level (4-20 mmHg) in the mitochondria (structures in cells responsible for energy production). This decrease in PO2 from air to the mitochondrion is known as the oxygen cascade and the size of any one step in the cascade may be increased under pathological circumstances and may result in hypoxia (figure 3).

Oxygen delivery
The quantity of oxygen made available to the body in one minute is known as the oxygen delivery and is equal to the cardiac output x the arterial oxygen content (see previously) ie. 5000ml blood/min x 200 mlO2/1000 ml blood = 1000ml O2/min. Oxygen delivery (mls O2/min) = Cardiac output (litres/min) x Hb concentration (g/litre) x 1.31 (mls O2/g Hb) x % saturation

Oxygen consumption
Approximately 250 ml of oxygen are used every minute by a conscious resting person (oxygen consumption) and therefore about 25% of the arterial oxygen is used every minute. The haemoglobin in mixed venous blood is about 70% saturated (95% less 25%). In general there is more oxygen delivered to the cells of the body than they actually use. When oxygen consumption is high (eg. during exercise) the increased oxygen requirement is usually provided by an increased cardiac output - see formula above for how this works. However, a low cardiac output, a low haemoglobin concentration (anaemia) or a low haemoglobin O2 saturation will result in an inadequate delivery of oxygen, unless a compensatory change occurs in one of the other factors. Alternatively, if oxygen delivery falls relative to oxygen consumption the tissues extract more oxygen from the haemoglobin (the saturation of mixed venous blood falls below 70%)(a-b in figure 4). A reduction below point 'c' in figure 4 cannot be compensated for by an increased oxygen extraction and results in anaerobic metabolism and lactic acidosis. (Continued ...)

OXYGEN STORES
In spite of the great importance of oxygen, the stores of oxygen in the body are small and would be unable to sustain life for more than a few minutes. If breathing ceases, oxygen stores are limited to the oxygen in the lung and in the blood. The amount of oxygen in the blood depends on the blood volume and haemoglobin concentration. The amount of oxygen in the lung is dependent on the lung volume at functional residual capacity (FRC) and the alveolar concentration of oxygen. The FRC is the volume of air (about 3 litres in an adult) that is present in the lungs at the end of a normal expiration ie when the elastic recoil of the lung is balanced by the relaxed chest wall and diaphragm. While breathing air the total stores (oxygen in blood and lung) are small and because the major component of this store is the oxygen bound to haemoglobin (see Table 1) only a small part of these stores can be released without an unacceptable reduction in PaO2 (when haemoglobin is 50% saturated with oxygen the PaO2 will have fallen to 26 mmHg). Breathing 100% oxygen causes a large increase in the total stores as the FRC fills with oxygen. The major component of the store is now in the lung and 80% of this oxygen can be used without any reduction in haemoglobin saturation (PAO2 still about 100mmHg). This is the reason why pre-oxygenation is so effective. (see later) Table 1. Principle stores of oxygen in the body

While breathing AIR In the lungs (FRC) 450ml In the blood 850ml Dissolved or bound in tissues(FRC) 250ml Total 1550ml

While breathing 100% O2 3000ml 950ml 300ml 4250ml

OXYGEN TRANSPORT - THE EFFECTS OF ANAESTHESIA


Hypoventilation may occur during anaesthesia due to airway obstruction, the effects of volatile anaesthetic agents, opioids and other sedatives. In contrast, ketamine and ether anaesthesia (less than 1 MAC) cause less respiratory depression than other anaesthetic agents. Alveolar PO2 is a balance between the oxygen supplied by breathing and that used by metabolic processes in the body. Hypoventilation and a decreased inspired oxygen concentration will therefore cause a reduction in alveolar PO2(PAO2). The increased utilisation of oxygen when metabolic rate is raised such as with postoperative shivering or malignant hyperpyrexia also causes a reduction in alveolar PO2. If the PaO2 falls to less than 60mmHg the aortic and carotid body chemoreceptors respond by causing hyperventilation and increasing cardiac output through sympathetic nervous system stimulation. This normal protective response to hypoxia is reduced by anaesthetic drugs and this effect extends into the post-operative period. Following induction of anaesthesia there is a rapid reduction in FRC that results in airway closure - small airways, particularl in dependant parts of the lung, collapse and remain closed throughout the respiratory cycle. This results in some alveoli not being ventilated at all (true shunt). Ventilation/perfusion (V/Q) mismatch is also increased. Atelectasis (collapsed alveoli) also develops rapidly in the dependant lung regions and results in true shunt. As explained earlier, airway closure, V/Q mismatch and shunt will cause the oxygen saturation in the pulmonary veins to be less than in the pulmonary capillaries of ventilated alveoli. This 'venous admixture' increases from 1% to around 10% following induction of anaesthesia. With the possible exception of patients spontaneously breathing while anaesthetised with ketamine, this increase in venous admixture occurs irrespective of the anaesthetic agent used and whether muscle relaxants are used or not. It should be viewed as an unavoidable adverse effect of anaesthesia. Volatile anaesthetic agents suppress hypoxic pulmonary vasoconstriction, and blood flow to underventilated or collapsed alveoli is not reduced. Many anaesthetic agents depress cardiac output and therefore decrease oxygen delivery. Anaesthesia causes a 15% reduction in metabolic rate and therefore a reduction in oxygen requirements. Artificial ventilation causes a further 6% reduction in oxygen requirements

as the work of breathing is removed. Anaesthetic agents do not affect the carriage of oxygen by haemoglobin.

THE PRACTICAL USE OF OXYGEN


Inspired oxygen concentration The efficiency of oxygenation during anaesthesia is reduced due to hypoventilation and venous admixture. An inspired oxygen in the range of 25%-30% is usually effective in restoring the PaO2 to normal when hypoxaemia is due to hypoventilation. (figure 6)

When hypoxaemia is due to venous admixture it is only possible to restore the PaO2 by increasing the inspired oxygen concentration if the venous admixture does not exceed the equivalent of a 30% shunt. (figure 7) The inspired oxygen concentration during maintenance of anaesthesia should routinely be increased to 30% whenever possible to compensate for hypoventilation and shunt which normally accompany anaesthesia. Additional oxygen may need to be administered to patients at risk of decreased oxygen delivery (anaemia or decreased cardiac output) or increased oxygen consumption (fever). Pre-oxygenation The small volume of the oxygen stores in the FRC of a patient breathing air means that there will be a rapid fall in oxygen saturation during apnoea (e.g. following induction of anaesthesia, during laryngospasm or during upper airway obstruction). Pre-oxygenation involves the breathing of 100% oxygen for three minutes through an anaesthetic circuit with a face mask firmly applied to the face. This is the time taken to replace the nitrogen in the FRC with oxygen using normal tidal ventilation. Although FRC falls on induction of anaesthesia the extra oxygen contained within the FRC provides an essential store of oxygen for periods of apnoea, such as may occur during rapid sequence induction or difficult intubation. Patients with a small FRC (infants, pregnancy, obesity) or a low haemoglobin concentration and therefore smaller oxygen stores desaturate more rapidly and pre-oxygenation is especially indicated in these patients. Anoxic gas mixtures

If, during the course of an anaesthetic 100% nitrous oxide is given to the patient in error, the fall in alveolar PO2 will be much more rapid than during apnoea. The alveolar PO2 can fall to dangerously low levels in as little as 10 seconds. This is because the oxygen in the patient's lungs and blood (oxygen stores) is being actively washed out with each breath that contains no oxygen. The fall in PO2 is therefore more rapid than would occur if it was only being used up by the metabolic needs of the body (250ml/min). Crisis management When managing emergencies during anaesthesia consideration should always be given to the immediate administration of 100% oxygen while the cause is found and rectified. It is the most appropriate treatment for acute deterioration in cardiorespiratory function. Diffusion hypoxia Nitrous oxide is forty times more soluble in blood than nitrogen. When nitrous oxide is discontinued at the end of anaesthesia, nitrous oxide diffuses out of the blood into the alveoli in large volumes during the next 2 - 3 minutes. If the patient is allowed to breathe air at this time the combination of nitrous oxide and nitrogen in the alveoli reduces the alveolar PO2. This is called diffusion hypoxia and is avoided by increasing the inspired concentration of oxygen by the administration of 100% oxygen for 2 - 3 minutes after discontinuing nitrous oxide. Postoperative oxygen The causes of increased venous admixture (ventilation/perfusion mismatch, shunt and airway closure) and the abnormal response to hypoxia continue into the postoperative period for a number of days following major surgery. Postoperative hypoventilation is common and may be due to the residual effect of anaesthesia, the use of opioid analgesia, pain or airway obstruction. Shivering in the immediate postoperative period causes an increase in oxygen consumption. Additional oxygen should therefore be given to all unconscious patients in recovery and to those awake patients who either shiver, hypoventilate, desaturate or who are considered to be at special risk (eg. ishaemic heart disease). Postoperatively, on the ward, episodes of airway obstruction during sleep are common and may aggravate borderline oxygenation due to the above factors. This is due to the use of opioid analgesia and a change in sleep pattern that occurs on the second and third postoperative nights. It is clear that after major surgery the risk of hypoxaemia extends well into the postoperative period. Small degrees of cyanosis are not easy to detect clinically, especially in anaemic patients, and therefore oxygen should be given to these patients wherever possible. It is especially important to give it overnight to patients at special risk (ischaemic heart disease). Postoperative pain should be effectively treated (see Update 7) as patients in pain following abdominal or thoracic surgery will be reluctant to breathe deeply. If opioid analgesics are indicated, hypoventilation should be anticipated, and oxygen given.

PROBLEMS ASSOCIATED WITH OXYGEN ADMINISTRATION


It is has been suggested that high concentrations of oxygen (90-100%) administered to patients for a prolonged period (several days) may cause pulmonary damage. There is little evidence to support this and should never prevent its use in treating severe hypoxia. High concentrations of oxygen will encourage collapse of alveoli with low ventilation/perfusion ratios. Oxygen is rapidly and completely absorbed from these alveoli, and when it is the only gas being given, these underventilated alveoli collapse. When air and oxygen is used, the nitrogen present is absorbed more slowly and prevents the alveolus from collapsing. Oxygen therapy may rarely depress ventilation in patients suffering from severe chronic obstructive airways disease. Some of these patients lose their sensitivity to carbon dioxide and rely on hypoxia to stimulate breathing. In these patients, when high concentrations of oxygen are given, serious hypoventilation and hypercapnia can result due to the fact that their hypoxia is reversed. This is extremely rare. In the second part of this article we plan to discuss the more practical aspects of oxygen production and storage and the equipment needed to safely administer oxygen to patients.

References
1. Nunn JF. Applied Respiratory Physiology (3rd Edition). Butterworths 1987 2. West JB. Respiratory Physiology (4th Edition). Williams and Wilkins 1990 World Federation of Societies of Anaesthesiologists WWW implementation by the NDA Web

Pharmacology of Vasopressors and Inotropes


Dr Karen Gilmore,
Frenchay Hospital, Bristol, UK

Christine Nanyanzi,
Gihundwe Hospital, Rwanda Introduction Vasopressors and Inotropes Adrenaline Ephedrine Methoxamine Metaraminol Phenylephrine Dopamine Dobutamine Dopexamine Salbutamol Isophrenaline Phosphodiesterase Inhibitors Clinical Study

Inotropes given by infusion Noradrenaline

Summary

Introduction
A "vasopressor" causes vasoconstriction and an "inotrope" increases the force of cardiac contraction. Vasopressors and inotropes work via the Autonomic Nervous System. Neurotransmission at postganglionic receptors. The postganglionic receptors of the Parasympathetic Nervous System PNS are termed muscarinic, and acetylcholine (Ach) is the neurotransmitter. The equivalent receptors in the Sympathetic Nervous System (SNS) are noradrenergic receptors and noradrenaline (Norad) is the endogenous (naturally occurring) neurotransmitter (table 1). Table 1 Preganglionic receptor type (and neurotransmittor) PNS Nicotinic (Ach) SNS Nicotinic (Ach) Post ganglionic receptor type (and neurotransmittor) Muscarinic (Ach) Noradrenergic (Norad)

These noradrenergic receptors are further subdivided, the subdivisions relevant to this article are Alpha1 (1), Beta1 (1), Beta2 (2) and Dopamine (D). The main actions of each receptor subtype are as shown in table 2. Table 2 1 Peripheral arteriolar vasoconstriction 1 Cordiac increased heart rate and force of conctraction 2 D Bronchial smooth muscle dilation. Vasodilation in skeletal muscle. Also some cardiac effects Increased renal blood flow.

Vasopressors And Inotropes


This group of drugs is useful for resuscitation of seriously ill patients, and for the treatment of hypotension in theatre. All of these drugs act directly or indirectly on the SNS, but the effect of each varies according to which sympathetic receptor the drug has greatest affinity for. The duration of action also varies. Direct acting drugs act by stimulating the SNS

receptor whereas indirect acting drugs cause the release of noradrenaline from the receptor which produces the effect. Some drugs have a mixed effect.

Adrenaline (Epinephrine)
Adrenaline acts on 1, 1 and 2 receptors. It is said to prepare the body for a "fight or flight" response. Actions CVS: Increased heart rate and force of contraction produce an increase in cardiac output. Systolic blood pressure (SBP) rises, but with low doses diastolic blood pressure (DBP) may fall due to vasodilation and increased blood flow through skeletal muscle beds (2). At higher doses the vasoconstrictor effects of 1 stimulation become more apparent, causing the cool pale extremities of a frightened person. RS: Bronchial smooth muscle is relaxed resulting in bronchodilation (2). Other: Adrenaline mobilises glucose from glycogen and raises blood sugar. Pupillary dilation (mydriasis) occurs. Side effects Ventricular arrhythmias, hypertension. Care with halothane anaesthesia as arrhythmias may occur. Preparation 1:1000 i.e. 1mg in 1 ml.

1:10,000 i.e. 1mg in 10ml Indications and doses Cardiac Arrest - see 2000;10:6 Resuscitaion from Cardiac Arrest, Update in Anaesthesia

Anaphylactic shock - 1:10,000 adrenaline given iv in 1 ml doses until effective. If no iv access available then 0.5ml of 1:1,000 im. Additive to local anaesthetic - add adrenaline to local anaesthetic to make a concentration of 1:200,000 - see Toxicity from Local Anaesthetic Drugs, Update in Anaesthesia 2000;10:8 Acute severe asthma attack unresponsive to normal treatment may require infusions of adrenaline, though 0.5ml of 1:1000 s/c may be used. Septic shock - require infusions of adrenaline

Length of action Short, few minutes only with intravenous bolus.

Ephedrine
Ephedrine acts directly on 1 and 2 receptors, and indirectly on 1 receptors by causing noradrenaline release. Action It causes a rise in blood pressure and heart rate, and some bronchodilation. Side effects May cause tachycardia and hypertension. Possible arrhythmias if used with halothane. Preparation 3% or 5% solution: 1 ml ampoules. Indications Low blood pressure due to vasodilation e.g. following spinal or epidural anaesthesia and drug overdoses. Best vasopressor to use in pregnancy as it does not reduce placental blood flow. Dose 3-10 mg boluses iv, repeat until effective. Maximum dose is 60mg. Length of action 5-15 minutes, repeated doses less effective (i.e. it demonstrates tachyphylaxis).

Methoxamine
Methoxamine acts on 1 receptors. Actions Increases blood pressure. There may be a reflex decrease in heart rate, and therefore it is good for hypotension with tachycardia. Useful during spinal anaesthesia. Side effects May produce bradycardia Dose 2-4mg boluses IV, repeated as necessary.

Metaraminol
Acts directly on 1 receptors and also causes noradrenaline and adrenaline release. Actions Increases blood pressure and cardiac output. Less likely to cause a reflex bradycardia than methoxamine or phenylephrine. Dose - 1mg boluses iv, 2-10mg s/c or im, by infusion at 1-20mg/hr.

Phenylephrine

Acts directly on 1 receptors. Action Hypertension and a reflex decrease in heart rate. Dose 2-5mg im or sc, 0.1-0.5mg iv, by infusion 20-50mcg/min. (Continued ...)

World Federation of Societies of Anaesthesiologists WWW implementation by the NDA Web Team, Oxford

Inotropes Given By Infusion


Adrenaline is the most commonly available inotrope, and in many cases the most appropriate drug to maintain blood pressure. When other inotropes are available, some may offer advantages in certain situations. The inotropes listed below are only given by infusion unless a bolus dose is stated. They are mostly very short acting, their effects lasting from a few seconds to one or two minutes and should be given via a central line (except for aminophylline and salbutamol) via an infusion controller. The patient must be closely monitored, particularly the ECG and blood pressure. Tachycardia, arrhythmias, and hypertension or hypotension are side effects of these drugs. Although called inotropes some of these drugs also have vasoconstrictor properties.

Noradrenaline
Acts mainly on 1 receptors with few effects on receptors. Actions Increases blood pressure by vasoconstriction. Less likely to cause tachycardia than adrenaline. Indications Septic shock where peripheral vasodilation may be causing hypotension. Cautions Acts by increasing afterload and therefore not appropriate for use in patients in cardiogenic shock. Blood supply to kidneys and peripheries may be reduced. Dose - 1-30mcg/min

Add 4mg to 250ml 0.9% NaCl or 5% dextrose to give 16mcg/ml. Run at 0112ml/hr

Dopamine

Acts on D, 1, 2 and 1 receptors, depending on the dose administered. Actions Dose dependent. It used to be popular to increase urine output via its effect on the D receptors in the kidney. However, less commonly used for this purpose as it does not prevent renal failure. Indications Hypotension. Dose

1-2mcg/kg/min - acts on D receptors usually increasing urine output 2-10mcg/kg/min - also acts on receptors to increase cardiac output >10mcg/kg/min - additionally has effects on 1 receptors to vasoconstrict. o Add 3mg/kg (body weight) to 50mls 0.9%NaCl or 5% glucose o 1ml/hr = 1mcg/kg/min

Dobutamine
Acts on 1 and 2, with minimal action on 1 receptors. Actions It increases cardiac output and reduces afterload (2effects on skeletal muscle). Indications Cardiogenic shock. Dose 2-30mcg/kg/min

Add 3mg/kg to 50mls 0.9%NaCl or 5% glucose 1ml/hr = 1mcg/kg/min

Dopexamine
Acts on 2 and D receptors. Actions It increases cardiac output and reduces afterload. Increases blood supply to the kidneys and possibly also the gastrointestinal tract. Dose 0.5-6mcg/kg/min

Salbutamol
Acts on 2 receptors Actions Relaxes bronchial smooth muscle i.e. bronchodilation, may increase heart rate

Indications Severe acute asthma. Dose By infusion 5-20mcg/min.Can also be given in bolus form iv in the initial treatment of an attack at a dose of 5mcg/kg over several minutes.

Isoprenaline
Acts on 1 and 2 receptors Actions Main action is increased heart rate. Also increased force of contraction, and bronchodilation. Indications Complete heart block, overdose of beta blocker or severe bradycardia unresponsive to atropine. Can be used to treat asthma, but less suitable than drugs that act only on 2 receptors e.g. salbutamol Dose

0.02-0.2mcg/kg/min by infusion 5-20mcg bolus iv

Phosphodiesterase inhibitors (e.g. aminophylline, enoximone)


Prevent breakdown of cAMP by enzyme phosphodiesterase: this produces effects at 1 and 2 receptors. Actions Inodilation i.e. increased rate and force of contraction, vasodilation in skeletal muscle. Also bronchodilation. Indications Aminophylline: asthma, cardiac failure. Enoximone: cardiac failure in patients failing to respond to dobutamine

Clinical Case Study - Use Of Vasopressors


Lower segment Caesarean section (LSCS) under spinal anaesthesia A patient is scheduled for LSCS under spinal anaesthesia. An iv ifusion is set up and 1000 mls of Hartmanns run in whilst the spinal is performed. The patient is placed supine with a 15-degree left-lateral tilt to minimise aortocaval compression (i.e. pressure from the uterus on the inferior vena cava reducing venous return to the heart).

Despite good positioning and iv fluids, hypotension is very likely at this stage because of vasodilation due to the spinal. The patient should be given ephedrine in boluses of 6-9mg, which may need to be repeated several times. Alternatively, 30-60mg of ephedrine can be added to the intravenous infusion, and the rate titrated according to the BP. The SBP should be maintained above 100mmHg. (A hazard of adding ephedrine to the infusion is that the anaesthetist may forget to reduce the rate of infusion when the BP has returned to normal, and the patient may become dangerously hypertensive.) Once the baby has been delivered aortocaval compression is no longer a problem, and further ephedrine is not usually required. If hypotension persists, ensure that hypovolaemia is not the cause. Intravenous fluids should be given to restore blood volume, rather than vasopressors. Ephedrine is the best vasopressor for LSCS because it has fewest effects on placental blood supply. If ephedrine is not available another vasopressor should be used. Alternatively small doses of adrenaline (20-50mcg) can be given, in a dilute preparation.

Summary
The common causes of hypotension during LSCS under spinal anaesthesia are:

Vasodilation - treat with fluids and ephedrine Aortocaval compression - tilt patient 15 degrees to left Bleeding - replace blood loss with intravenous fluids

Chapter 4: REFLEX REGULATION OF CARDOVASCULAR FUNCTIONS

The above discussions on factors regulating cardiac output and peripheral resistance indicate that autonomic nervous activity, especially that of the sympathetic system, exerts important influences on cardiovascular function. These neural control mechanisms are discussed below in terms of the three major components of a reflex arc: the efferent system, the integration center, and the afferent system. 4.1 THE EFFERENT SYSTEM The efferent control of the cardiovascular system is exerted through the autonomic nerves. The main parasympathetic influence on the cardiovascular system is a slowing of the heart rate by vagal impulses. The sympathetic adrenergic system, on the other hand, has a much wider variety of actions. These include the acceleration of heart rate, increase of cardiac contractility, reduction of venous capacitance and constriction of resistance vessels. The first three effects cause an increase in cardiac output, whereas the last action raises the peripheral resistance. Therefore, sympathetic adrenergic impulses cause an elevation of

arterial pressure, which causes an increase in blood flow through regions (the brain and the heart) not constricted by the adrenergic influence.

4.2 THE INTEGRATING CENTER Circulatory reflexes are integrated at various levels of the central nervous system. A certain degree of integration of sympathetic reflexes can be achieved in the spinal cord. For example, sensory impulses from thermal or pain receptors in the skin can directly excite the sympathetic neurons in the lateral horn of the thoracolumbar cord. The most important level of integration of autonomic efferent activities to the cardiovascular system, howevcr, resides in the medulla oblongata. The cell bodies for the vagal efferents are located in the dorsal motor nuclei of the vagus in the dorsal aspects of the medulla. The neurons controlling the spinal sympathetic efferents are situated in the dorsolateral reticular formation of the medulla (see the following diagram). Electrical stimulation of these areas causes an enhancement of sympathetic adrenergic activity and an elevation of arterial pressure. Therefore, these bilateral areas are designated as the pressor areas. More medially and ventrally located is the depressor area. Stimulation of neurons in the depressor area causes an inhibition of sympathetic adrenergic activity and a decrease in arterial pressure. There exists a reciprocal relationship between the pressor area and the depressor area in response to afferent impulses, such that whenever one is activated the other is reciprocally inhibited. The pressor area and the dorsal motor nuclei of the vagus together constitute the cardiovascualr center. When we speak of an excitation of the cardiovascular center, however, we usually mean an excitation of the pressor area, while the other two areas may be reciprocally inhibited. The pressor and depressor areas send descending fibers through multisynaptic pathways to regulate the activity of sympathetic neurons located in the thoracolumbar cord.

In addition to the medulla oblongata, there are also neurons in the higher parts of the central nervous system which can modify sympathetic influences on the cardiovascular system. These include the neurons in the cerebral cortex (especially the limbic system) and the hypothalmus. They are particularly important in the activation of sympathetic cholinergic efferents in response to emotional excitement and anticipation of exercise. The hypothalamus not only contains neurons which can modify sympathetic adrenergic efferents via their influence on the medullary cardiovascular center, but also has neurons

which send fibers directly to the sympathetic cholinergic neurons in the spinal cord. This hypothalamus-sympathetic cholinergic pathway plays a significant role in inducing sudden vasodilation in the skeletal muscle in response to certain stimuli (e.g., that occurring during fainting at the sight of blood in some individuals).

4.3 THE AFFERENT SYSTEM There are many receptors which send afferent fibers to the cardiovascular center. Some of these receptors reside within the cardiovascular system, whereas others are located outside of the circulation. A. THE ARTERIAL BARORECEPTORS In the systemic arterial system there are two sets of receptors which respond to changes in arterial pressure level. One set is the carotid baroreceptors located in the wall of the carotid sinus, which is situated at the origin of the internal carotid artery at the carotid bifurcation. The other set is the aortic baroreceptors located in the wall of the arch of the aorta (see diagram on cardiovascular reflex pathway). The afferent impulses from the carotid sinus travel in the glossopharyngeal (IXth cranial) nerve, whereas those from the aortic arch are conveyed by the vagus (Xth cranial) nerve. The baroreceptors are stretch receptors which are activated when the vessel wall is stretched by the arterial pressure. These receptors are not only sensitive to the absolute pressure level, but also to the rate of change of arterial pressure. Thus, the frequency of afferent impulses increases when the pressure is rising during systole and decreases when the pressure is falling during diastole (see diagram below).

When the carotid sinus is perfused at various levels of steady pressures (no pulsation), the impulse frequency shows an S-shaped relation to the pressure level (see diagram below). The baroreceptor impulses cease completely at pressure below 50 mmHg, rise progressively between 60 and 180 mmHg, and reach a maximum frequency at pressures higher than approximately 180 mmHg.

A very important feature of the arterial baroreceptor impulses is that they are inhibitory to the cardiovascular center (i.e., inhibition of the pressor area and excitation of the depressor area and the dorsal motor nuclei of the vagus). The normal arterial pressure of 120/80 mmHg causes a low-level stimulation of the baroreceptors,which send in inhibitory impulses to keep the sympathetic adrenergic impulses partially in check. A decrease of arterial pressure, e.g., due to blood loss, would reduce the inhibitory baroreceptor impulses and hence increase sympathetic adrenergic activity, thus tending to raise the arterial

pressure. An increase in arterial pressure, e.g., due to cold induced vasoconstriction, would increase the inhibitory baroreceptor impulses and hence reduce sympathetic adrenergic activity, thus tending to lower the arterial pressure. Pa Baroreceptor imp. Symp. imp. Pa Pa Baroreceptor imp. Symp. imp. Pa Therefore, the baroreceptor reflexes provide a negative feedback system to buffer any significant changes in arterial pressure. These reflexes are very important in maintaining the arterial pressure within narrow limits on a short term basis. Because of the tendency of the baroreceptors to adapt to a static level of arterial pressure, they have lesser importance in long term regulation of arterial pressure.

B. THE ARTERIAL CHEMORECEPTORS The arterial chemoreceptors are located in areas very close to the baroreceptors: The carotid bodies are situated at the carotid bifurcation, and the aortic bodies are located near the aortic arch. These chemoreceptors are connected to the main arterial tree by arterial branches which carry a very high rate of blood flow considering the small size of the chemoreceptors. The afferent impulses from the carotid bodies travel in the glossopharyngeal (IXth cranial) nerve and those from the aortic bodies are conveyed by the vagus (Xth cranial) nerve. The chemoreceptors are sensitive to their local metabolic environment when altered. Thus, these receptors are stimulated by decreases in local pO2 and pH and an increase in local pCO2. Because of the existence of a very high rate of blood flow per unit weight of chemoreceptors normally (approximately 2,000 ml/min/100 gm), these local metabolic factors are sensitive primarily to variations in the corresponding parameters in the arterial blood. Thus, a decrease in arterial pO2, an increase in arterial pCO2, or a reduction in arterial pH, which are changes occurring after suppression of respiration, may cause stimulation of the chemoreceptors. The chemoreceptors can also be activated when there is a severe reduction in chemoreceptor blood flow, e.g., following a large volume of blood loss. The primary effect of chemoreceptor impulses is to stimulate the respiratory center and increase ventilation, but they also cause excitation of the cardiovascular center. The increase in sympathetic adrenergic activity resulting from chemoreceptor stimulation is mainly exerted on the resistance vessels to cause vasoconstriction. When circulatory and respiratory functions are normal, the existence of a high chemoreceptor blood flow and normal values for blood gases and pH provides a local metabolic environment which gives rise to the normal chemoreceptor firing rate. When the arterial pO2 is reduced due to hypoventilation, the chemoreceptors become increasingly activated. The resulting chemoreceptor reflex causes a stimulation of respiratory

movements to improve arterial pO2 and a selective constriction of resistance vessels to provide the brain and the heart with sufficient blood flow and oxygen delivery.

C. OTHER CARDIOVASCULAR RECEPTORS (1) Mechanoreceptors. There are receptors located in the atria and ventricles which are sensitive to mechanical stretch. The afferent fibers travel in the vagus nerves and in the sympathetic nerves. There are several types of atrial receptors. The type that has the clearest physiological function is the receptors which fire upon atrial distention. An expansion in blood volume would cause atrial distention. The impulses from these atrial receptors inhibit the medullary cardiovascular center to cause dilation of the resistance vessels and also inhibit the release of antidiuretic hormone by the hypothalamico-hypophyseal system. This latter effect would cause an increased urine flow, thus tending to reduce the blood volume toward normal. A reduction in blood volume would reduce the impulse discharge from these atrial receptors, thus causing sympathetic vasoconstriction and release of ADH. Atrial distention can also directly cause release of atrial peptide from the atrial myocytes. The atrial peptide would cause vasolidation and renal sodium excretion. The ventricular mechanoreceptors are located in the ventricular myocardium. These impulses cause reflex bradycardia and vasolidation, leading to a decrease in arterial pressure. (2) Chemoreceptors. Injection of several drugs (e.g., veratrum alkaloids and nicotine) into the coronary arteries of the dog causes reflex bradycardia and hypotension, together with some degree of respiratory inhibition. This is referred to as the Bezold-Jarish reflex, the significance of which is not known in man.

D. RECEPTORS IN THE SOMATIC SYSTEM In addition to the above receptors which are found in the cardiovascular system, there are also receptors in the skin, periosteum, skeletal muscles and joints which send afferent impulses to modify the activity of the cardiovascular center. (1) Thermoreceptors. Upon exposure to cold, the receptors in the skin send afferent impulses to stimulate the cardiovascular center and enhance sympathetic adrenergic impulses. Therefore, the arterial

pressure rises in a cold environment. This can be demonstrated by the cold pressor test in which an individual immerses his forearm in a bucket of cold water (e.g., 10C) for several minutes. The vasoconstriction in the immersed hand is due to a combination of the direct effect of low temperature on the vascular smooth muscle and the reflex activation of the sympathetic adrenergic system. The vasoconstriction in the contralateral, un-immersed hand and other parts of the body is due to the reflex action alone. The afferent impulses resulting from exposure to warmth causes an inhibition of the cardiovascular center. (2) Pain receptors. Superficial, sharp pain, e.g., that inflicted by a cut in the skin, is associated with afferent impulses which stimulate the cardiovascular center and sympathetic adrenergic nerves. Deep, dull pain, e.g., that elicited by scraping of priosteum by an orthopedic surgeon, is associated with afferent impulses which inhibit the cardiovascular center. Therefore, this type of deep, dull pain is often accompanied by a precipitous fall in arterial pressure. (3) Proprioceptors in muscle and joints. During muscular exercise, the rhythmic activation of propiroceptors in the exercising limb leads to afferent impulses which are excitatory to the cardiovascular center and the respiratory center.

E. CEREBRAL ISCHEMIC RESPONSE The cardiovascular center is stimulated by local accumulation of CO2 and acid metabolites. This occurs when cerebral blood flow is reduced as the arterial pressure falls below 50 mmHg. The cerebral ischemic response involves intense sympathetic adrenergic discharge, leading to a marked rise of arterial pressure as a last line of attempt to defend against cerebral ischemia.

F. HIGHER CENTERS The activity of the medullary cardiovascular center can be modified by descending impulses from the cerebral cortex and hypothalamus. Emotional stimuli can activate these higher centers, which in turn excite the medullary cardiovascular center, giving rise to increases in heart rate and arterial pressure. These higher centers are also responsible for the activation of sympathetic system that occurs in anticipation of exercise.

4.4 SUMMARY DIAGRAM A diagram summarizing reflex control of the circulatory system is shown below.