The Physiology Viva Questions & Answers Revised edition Kerry Brandis MB,BS FANZCA Director of Anaesthesia Gold Coast Hospital Queensiand, AustraliaThe Physiology Viva: Questions & Answers Revised edition Copyright (C) 2002 by Kerry Brandis First edition copyright (C) 1997 All rights reserved. No part of this book may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system without the written permission of the copyright holder. Published in Australia by the author Printed by: Australia Print & Copy 5 Young Street Southport, Queensland 4215. National Library of Australia Cataloguing-in-Publication: Brandis, Kerry. ‘The physiology viva: questions and answers. ISBN 0 646 31506 4. i. Human physiology - Examinations, questions, etc. 2, Anaesthetics - Physiological effect ~ Examinations, questions, ete. 1. Title 612.0076 ed j‘Thanks & Appreciation to John Stokes, Anaesthetist, Townsville Mater Hospital, Queensland (formerly at Palmerston North Hospital) Andrew Spiers, Anaesthetist, Palmerston North Hospital, NZ Brian Crichton, Anaesthetist, Palmerston North Hospital, NZ. for their guidance, support and encouragement when I started Anaesthetic trainingContents Preface .. - cee = vit Suggested Books .... er ix Chapter I Fluid & Electrolyte Physiology voces I Distribution of Body Water, 1 Control of Body water, 3 ‘Measurement of Compartment Volumes, 5 Contol of Iavacellular Volume, 7 Osmotic pressure, 8 Osmolality and Tonicity, 9 Oncatic p By Sodium con: Potassium, 15 Functions of Magnesium, 17 Gibbs-Donnan Relationship, 18 Lymph, 19 Sweat, 21 Infusion of 1000mls of 3N Saline rations, 13 Chapter 2 Acid-Base Physiology . . 2 Butfers, 24 Respiratory Regulation of Acid-Base Balance, 27 Renal Regulation of Acid-Base Balance Effects of Hypercapnia, Adverse Effects of Hypocapnia, Interpretation of Arterial Blood Gases Infusion of IN Hydrochloric Acid Infusion of & 4% Sodium Bicarbonate Chapter 3 Cardiovascular Physiology 39 Ventricular Pressure Curve, 39 Pressure-Volume Lopp, 42 erminants of Myocardial Performance, 46 Cardiac Output, 49 Myocardial Oxygen Valsalve Manoew CVS Response to Standing, 56 CVS Response to Rapid Loss of 1000mis of Blood, 37 Consumption, $2Hepatic Blood Flow, 72 Renal Blood Flow, 73, Microcirculation, 76 Pulmonary Microcirculation, 81 Autoregulation, 83 ‘Myocardial Action Potentials, 83 Properties of Cardiac Muscle, 88 ‘Mixed Venous Blood, 90 Distribution of Blood Volume, 92 Effects of Anaemia, 95 Venous Retum, 98 Physiology of CPR, 100 Arterial Pulse Contours, 101 Cardiac and Vascular Function Curves, 103 Hyperventilation with Chest Compression, 105 Chapter 4 Respiratory Physiology Dead Space, 106 Lung Volumes, 110 Functional Residual Copacity, 111 Compliance, 115 Closing Capacity, 118 Oxygen Cascade, 119 Oxygen Transport, 121 Oxygen Dissociation Curve, 122 Carbon Dioxide Transport, 128 Differences between the Base and Apex of the Lung, 130 Volume, Pressure & Flow during Normal Breathing, 131 Physiology of Preoxygenation, 132 Breathing 100% Oxygen, 134 Resorption of a Pneumothorax, 136 Cyanosis, 137 Fiow-Volume Loop, 138 Surfactant, 140 Non-Respiratory Functions of the Lung, 142 Respiratory Response to High Altitude, 144 Functions of the Nose, 145 Functions of the Red Blood Cell, 146 Mechanics of Breathing, 148 Alveolar-arterial pO2 gradient, 149 Hypoxaemia and Hypoxia, 152 Shunt, 154 Pulmonary Vascular Resistance, 156 Chapter 5 Renal Physiology Formation of Urine, 15 Glomerular Filtration Rate, 160 Preoperative Tests of Renal Function, 162 Juxtaglomerular Apparatus, 163, Excretion of Bicarbonate by the Kidney, 164 Renal Clearance, 165 Endocrine Functions of the Kidney, 166 Excretion of Urea, 168 106 158vi Chapter 6 Endocrine Physiology & Metabolism Hormones, 169 Insulin, 171 Regulation of te Blood Glucose Level, 173 Synthesis ofthe Thyroid Hormones, 177 The Pituitary, 178 Contzol of Caleium Level, 179 Mechanisms by which Hormones Interact with Cells, 180 Metabolic Rate, 183 Chapter 7 Physiology of Blood Storage of Blood, 184 Compatibitity Testing of Blood, 186 Plasma Proteins, 188 The Immune System, 190 Haemostasis, 194 Iron, 198 Blood Groups, 202 Complement, 204 ‘Vitamin K, 206 Erythropoietin, 208 Platelets, 209 ‘The Death of s Red Cell, 211 Chapter 8 Gastrointestinal Physiology . Gastric Acid Secretion, 212 Bite Acids, 214 Functions ofthe Liver, 216 Vomiting, 218 Digestion end Absorption of Carbohydrates, 220 Abdominal Pressure, 222 Chapter 9 Neurophysiology wee Cerebrospinal Fluid, 22: Blood-Brain Barrier, 225 Propagetion of an Action Potential, 226 Oculocardiae Reflex, 227 Peripheral Nerves, 228 Functions of the Hypothelamus, 230 Resting Membrane Potential, 232 Chapter 10 Physiology of Muscle & the Neuromuscular Junction Muscle Spindles, 233, Physiology of Neuromuscular Transmission, 235 Physiology of Muscle Contraction, 237 Smooth Muscle, 239 ‘Types of Skeletal Muscle, 241 - 169 . 184 22 223 233Chapter 11 Maternal, Foetal & Neonatal Physiology ..... 243 Cardiorespiratory Changes at Birth, 243 Functions of the Placenta, 244 Neonatal Temperature Regulation, 246 Maternal Cardiorespiratory Changes during Pregnancy, 248 Neonatal Respiratory Physiology, 250 Placental Gas Exchange, 252 ‘The First Breath, 257 Amniotic Fluid, 258 Chapter 12 Clinical Measurement . = 259 Exponential Functions, 259 Invasive Pressure Measurement, 261 Gauge Pressure & Pressure Gauges, 265 Strain Gauges, 267 Oscillometric BP Measurement, 268 Oxygen Analysis, 269 Carbon Dioxide Analysis, 270 Volatile Agent Monitoring, 272 Pressure Changes during Insertion of s Pulmonary Artery Catheter, 274 Temperature Measurement, 276 Measurement of Humidity, 278 Measurement of the Oxygen Content of « Blood Sample, 279 Physical Principles of Vaporisers, 281 Rotameters, 283, Gas Laws, 284 Chapter 13 Miscellaneous Topics ...... 5 cece 285 ‘Body Temperature Regulation, 285 Functions of the Skin, 287 Intraocular Pressure, 289 Physiological Principles inthe Care of a Trachyostomy, 291 Physiology of Anaphylaxis, 292 Appendix A Physiology Quick Quis Questions ..... 293 B: Answers 0 . - 306 Abbreviations ...0.....2. 005+ 38 Index . 322Preface to Revised Edition This book is designed to be useful for study end revision for those sining the physiology component of the Primary examination of the Australian and New Zealand College of Anaesthetists, I have structured the topics in the question and answer format that is used ic the actual viva examination. Some topics are considered important by the examiners and are asked frequently & I have tried t0 include as many of these topics as possible. Many of the common diagrams that you may be asked to draw and explain are included. The maverial may also be useful for registrars in other disciplines (such as Surgery and Emergency Medicine) which have a physiology exam component. This book will be most useful 10 you if you use it as a Workbook (ie write notes in the specially wide margins, use highlighters on text passages ete) Ihave included minimal reference material 2s you should be able to check most of the ‘answers and enlarge on the material in the standard texts. Some material is not covered very well in these books so this book will be your best source for this information. ! have included ‘mote recent material on some of the topics. I have not continued into excessive depth in many of the topics because, even though interesting, this evel of knowledge is not necessary for the vivas. You will pass if you have 2 good general knowledge end understanding rather than by knowing the minute details of any particular topic. There is a quiz section (with answers) in the appendix which will give you some practice and feedback on your study progress. ‘Thank you to Bart McKenzie (Brisbane) and John Martin (Cairns) who read through much of the original draft of this book and provided eriical advice in 1996, Thanks also to many of ‘my past registrars (in particular: Frank Daday, Penny Wilton, lan Cooper, Pamela DeWitt, ‘Simon Maffey, Pau! Wrigley, Helen Crilly, Paul Gray, Monique Maher, Brian McKinney, Danni Gerber, Richard McLean, Sonia Misso, Graham Mapp, Sarah Lindsay & Toni Stephen) who read and commented on various pars of the draft versions, mostly while studying for the primary themselves. I take full responsibility for any errors which remain. Finally, @ special thanks to Richard McLean for the many excellent ideas that developed in our discussions. More recently, | am grateful to Daniel Tsui for listing the many minor typos and. then sending them along to me for correction in this revised edition. On behalf on everyone who sits the primary exam, I would like to thank all the many registrars who have contributed to the various ‘Black Banks’ and to the website. Lam keen to receive your feedback and advice (comments, criticisms, suggestions, notification of errors). I can be contacted by email ( Kbrandis@bigponé.net.au ) or via the Queensland Anaesthesia website ( httpi/iwww.qldanaesthesia.com ). The site now has 2 Discussion Group where questions & comments can be made Best wishes for your exam, Kerry Brandis Department of Anaesthetics Gold Coast Hospital Southport, 4217 Queensland, Australia Revised August, 2002,Suggested Books General Physiology Ganong WF. Review of Medical Physiology (Lange) This is the best core text in general physiology for the Anaesthetic primary. Pertinent, relevant & up-fo-date, Most areas are not covered as well as in the specialist single system ext. Brey JI , Cragg PA et al, Lecture Notes on Human Physiology (Blackwell) An excellent general text from staff of the Physiology Departmnent at Dunedin Hospital. NZ. Now on the ANZCA recommended text list. Guyton AC & Hall JE, Textbook of Medical Physiology. (WB Saunders) A good text especially for undergraduate study. Many sections are not adequate for primary candidates, Respiratory Physiology West J. Respiratory Physiology: The Essentials (Williams & Wilkins) Exeellent text, Clear & concise. Essential to have your own copy. You must read and know this information. (John West graduated MB,BS from Adelaide University in 1951). Lumb AB, Nunn Applied Respiratory Physiology (Butterworth-Heinemann) A great reference but can be difficult to lea from without some background knowledge Best to use as a referen Cardiovascular Physiology Beme RM & Levy MN. Cardiovascular Physiology (CV Mosby) A good coverage of this area of physiology, Essential to have yous own copy Renal Physiology Vander AJ. Renal Physiology (McGraw-Hill) A good introductory renal text which contains more than is required for the primary. Worth a look. al | Measurement Sykes MK, Vickers MD & Hull CJ. Principles of Measurement and Monitoring in Anaesthesia and Intensive Care. (Blackwell) Excellent book, Highly recommended Davis PD, Parbrook GD & Kenny GN. Basic Physics and Measurement in Anaesthesia al for the primary exam.Additional material on companion websites: http:/www.qidanaesthesia.com http:/Avww.theblackbank.com These sites include: + Muhtple choice questions + On-line tutorials (eg on acid-base physiology, fluid physiology) + Discussion group - Various FANZCA exam materials + Links to useful educational materials on the web 4Chapter 1 Fluid & Electrolyte Physiology Distribution of Body Water What is the total body water in an adult male? 42 litres in the 70 kg man. This is 60% of total body weight (ie 600 mls H.O/kg body wt) What is meant by the term ‘body fluid compartment’? The water in the body is considered to exist in physiologically significant collections referred to as compartments. The major division is into Intracellular fluid (ICF) and Extracellular fluid (ECF) based on which side of the cell membrane the uid lies. Its easy to appreciate the idea of compartments but it should be noted that most of the compartments are actually “virtual compartments’. Consider the ICF: this docs not exist as a single united body of water but is represented by about 10" discrete little packets (cells) of solution. How can this large a number of separate Atuid coliections be considered as though it was a single entity? The answer has to do with physiological relevance, This virtual fuid collection is easily defined. has similar composition throughout nearly all cells and behaves in a generally predictable way to certain interventions. ‘The ECF is divided into several smaller compartments. These are + Interstitial fluid (ISF) + Intravascular fluid + Water of dense connective tissue (CT) and water of bone + Transcellular fluid What are the sices of the body's fluid compartments? ‘The sizes of the compartments as a percent of the 42 litres of total body water are: 1CF 35% G3 ues) ECF 45% (19 litres) made up of, Interstitial uid Intravascular fluid ‘Water in dense CT ‘Water in bone Transcellular fluid ‘The water of bone and the water of dense connective tissue is substantial (15% of total body water) but is kinetically a very slow compartment, The rest of the ECF makes up 30% of the total body water and is called the fimnerional ECF. The ratio of fluid in ICF to fluid in the kinetically active functional ECF is almost 2:1 (55% to 30%). This ratio is importamt in considering the compartmental distribution of acute fluid infusions rather than using the actual ratio of 35:45, (For example, see p60)2 Chapter What is ‘transcellular fluid’? ‘Transcellular fiuid is a term used to refer to a virtual compartment consisting of a diverse group of smaller fluid collections. The unifying factor for all these fluids is that they are formed from the transport activities of cells and are found in epithelial lined spaces. ‘Together they account for only 2.5% of total body water but they are important because of the special roles they play in the body. What fluids are included in this compartment? Some important transcellular fluids are: + cerebrospinal fluid Joint uid ‘aqueous humour bile fluid in the bowel fluid in body cavities. bladder urine Transcellular fluid is in contact with intracellular water (across the epithelial cell membrane) rather than ISF. What are the factors which control the distribution of water beoween the intracellular and the extracellular compartments? ‘The cell membrane separates these two fluid compartments, Water can cross nearly all cell membranes with great ease but most solutes cannot. Water moves across the cell membrane until the osmolality is the same on both sides of the membrane. The ECF to ICF distribution can be considered to be dependent on the osmolality of the ECF. This of course will be equal to ICF osmolality but as ECF is easier to sample, osmolality is measured in the ECF. Water moving into or out of the body effectively does so via the ECF. So we can conclude that whatever sets or determines ECF osmolality is effectively controlling the distribution of total body water between ECF and ICF (and thus also ceil volume). Ifthe osmolality of the ECF is increased then there would be net water movernent out of cells and this would continue until ICF osmolality equalled ECF osmolality. The reverse applies if ECF osmolality is decreased Sodium is the major cation present in extracellular fluid, For electrical neutrality, it must be associated with anions of equal total (but opposite) charge. Sodium and its abligatorily associated anions account for about 86% of ECF osmolality and for about 92% of the ECF tonicity, The contribution to tonicity is higher because the ineffective osmoles (such as ures and glucose) are not counted, Under usual physiological conditions, the distribution of TBW between ECF and ICF can be considered as being effectively determined by the [Ne’] in the ECF (and controlled indirectly by the system that controls ECF [Na] ), Is there any addirional control mechanism that operates at the local level? Yes. An additional factor not considered so far is that many if not all cells have the ability to regulete their intrecellular solute content. This allows a cell to adjust its cell volume against extracellular tonicity. This isa form of local control which allows independent fine adjustment atthe cellular level Iti especially important inthe brain which is constrained to fixed volume by the bony skull Neurones can produce extra osmoles (‘idiogenic osmoles’) when their cell volume decreases ue to extracellular hypertonicity: These exira osmoles draw water back into the cell and re- stores cell volume to normal. (See: *Contro! of Intracellular Volume’ on p7.)Control of Body Water Can you outline the control of total body water? Total body water is maintained fairly constant from day to day. The system is often said to be controlied by the thirst-ADH mechanism, Thirst affects input and ADH regulates output of Itis easy to model and understand water control mechanisms as a classical simple control system withthe three components af sensors, central integrator and effector mechsnisms, The system is a closed loop because changes in water balance have effects which are monitored by the sensors (ie negative feedback is present to complete the control loop). T! ‘components of his control system are + Sensors: Osmoreceptors, volume receptors, high pressure baroreceptors + Central controller: Hypothalamus + Effectors: Thirst and ADH + The osmoreceptors are specialised cells in the hypothalamus which respond to changes, in ECF tonicity, The exact details ofthe receptor mechanism have not been determined but may involve changes in neurone firing rare in response to cell volume changes. Sodium (and its obligatorily associated anions) account for 92% of ECF tonicity so the receptors have been called ‘osmo-sodium’ receptors. Changes in water balance cause a change in tonicity. + The volume receptors ot low-pressure baroreceptors are stretch receptors located in the walls of the large veins and right atrium. They monitor effective intravascular volume by assessing central venous pressure. (This is also what clinician does with a central line.) + Additionally, the high pressure baroreceptors in the carotid sinus and aortic arch monitor arterial blood pressure whichis affected if intravascular volume changes are large enous to affect systemic blood pressure ‘There is no single anatomically discrete water balance center in the hypothalamus but overall the hypothalamus acts the the central coordinator of water balance. Note that: + the osmoreceptors for monitoring water balance are located here + the other receptors input into the hypothalamus via nervous pathways + the effector mechanisms are also controlled by the parts of the hypothalamus (eg thirst originates here and ADH is synthetised in the hypothalamus). What is ‘thirst’? Thirst bas been described as the physiological wge to drink. Itis a conscious sensation which is stimulated by four major factors: + hypertonicity + hypovolaemia + hypotension + angiotensin IL ‘Thirst originates in the thirst center in the hypothalamus. Water intake is not normally due to thirst as most drinking and eating occurs because of social and behavioural factors. Thirst provides potent backup mechanism to stimulate water intake when the usual factors result in inadequate intake. The social and behavioural factors are responsible for the nonregulatory ‘or ‘hedonistic’ water intake. Thirst is responsible for the regulstory water intake In summary, water intake can be considered as consisting of: + non-regulatory intake: due to habit, social or behavioural factors and this represents the ‘majority of water intake under usual circumstances + regulatory intake: backup mechanism by which thirst provides a drive o increase intake if the nonregulatory intake is insufficient.Chapter t What is the role of ADH? Antidjuretic hormone (ADH) is 2 nonapeptide produced in the hypothalamus and secreted from the posterior pituitary It acts on the kidneys to increase water reabsorption. Increased water reabsorption decreases plasma [Na"] and increases intravascular volume, ‘This completes the loop in the negative feedback control system as both the fall in plasma tonicity and the rise in intravascular volume can be sensed. Overall: ADH appropriately regulates renal water excretion in response to changes in ECF tonicity or intravascular volume, Can you tell me more about ADH? How does it act on the kidney ADH is produced predominently in the supraoptic and the paraventricular nuciei of the hypothalamus. The secretory granules containing ADH travel down the neuronal axons to the posterior pituitary. ADH is secreted from the posterior pituitary into the systemic circulation in response to several stimuli + increased plasma tonicity + hypovolaemia + hypotension + angiotensin Il + swess (including stress response to surgery or trauma) + certain drugs (eg chlorpropamide, barbiturates. ADH has a short intravascular halflife: about 15 minutes. It is inactivated in the liver and kidney: ADH acts on cells ofthe cortical and medullary collecting ducts inthe kidney. There are two ‘major cell types in this part of the tubule: +” Principal ceils: responsible for water reabsorption, sodium reabsorption and potassium excretion. Both ADH and aldosterone act on the principal cells + Imtercalated cells: responsible for hydrogen ion secretion. ADH combines with the V2 receptors on the basolateral membrane of the principal cells in the collecting duct. This activates adenyl cyclase and cyclic AMP is formed as the second messenger. The end result is that specific vesicles present in the cytoplasm move towards and fuse with the luminal membrane. Water channels present in the vesicles are now incorporated into the luminal membrane, Water is now reabsorbed down its osmotic gradient, When ADH is not present, the luminal membrane is impermeable to water, Whar is the nature of the water channels in these vesicles? A protein called ‘aquaporin 2" is the water channel. This protein is present in the membrane of the vesicles. The channels are inserted into the apical membrane under the influence of eyelic AMP. They are removed and the vesicles reform when cyclic AMP levels fel. What cell membranes in the body are not permeable to water? Water crosses most cell membranes easily. There are several membranes which heve a very low water solubility because of their functional requirements: + Bladder epithelium (This is necessary otherwise water will move to isosmotic), + Ascending limb of the Loop of Henle (This is necessary so that Nav and Cl trenspor: out of the tubule can produce hypotonic fluid to enter the distal ubule). + Comtical and medullary collecting ducts in the absence of ADH (This is necessary 10 ellow production of a hypotanie urin der the urineFluid & Electrolyte Physiology Measurement of Compartment Volumes What is the principle used in the measurement of the body fluid compartments? ‘The principle is to measure the Volume of Disuribution of a tracer which is distributed ‘throughout only the compartment being measured. This is sometimes called ‘the dilution principle’ and is really based on the law of conservation of matter. The formula is simple: Volume = A@OUD* / Concentration ‘The tracer should be nontoxic, rapidly distributed, confined to the compartment being measured, not metabolised or excreted, easy to measure and should not alter body fluid distribution, Distribution through the compartment being measured must be uniform. If the tracer is metabolised, it can often still be used if the elimination follows first order Kinetics as concentration at time zero can be determined by extrapolation. If the tracer is ‘excreted and this amount can be measured (eg in the urine), the amount remaining in the ‘body at the time of measuring the concentration is easy to calculate. How is the volume of the extracellular fluid compartment measured? ‘Two types of tracers are used here: + Tonics (eg "Br, SOsand chloride isotopes) + Crystalloids (¢g inulin, mannitol) The ionic tracers are very small. They distribute throughout the whole ECF but unfortunately some tracer also enters cells. The concentration in the ECF is lower because of this and the ECF volume is consequently over-estimated when using these tracers. ‘The crystalloid tracers are larger molecules end do not diffuse equally throughout the whole of the ECF. They do not enter cells but the lack of full and equal distribution results in # higher plasma concentration. The ECF volume is under-estimated with these tracers, Because of these distribution problems, the volume measured with any of the tracers is not the true ECF volume. The volume is usually referred to by noting the tracer used and equilibration time prior to measurement: for example, the 24 hour bromide space. ‘The different components of the ECF have different kinetic characteristics, The water of bone and dense connective tissue is a slow compartment and tracers tend to be slow penetrating it. A long equilibration time is needed especially when crystalloid tracers are used. Some of the components of the ECF can also be determined separately (eg use of radio-iodide labelled serum albumin to measure plasma volume). How is blood volume measured? Blood volume can be determined indirectly from separate measurements of the haematocrit and the plasma volume ‘The plasma volume is calculated as the volume of distribusion of a tracer that distributes throughout the intravascular compartment and remains within it. Suitable tracers are the d Evan's blue or radioiodine. Both these tracers bind to serum albumin and this restricts their distribution to the intravascular plasma compartment, Some albumin is lost to the ISF and this loss causes an exponential decline in plasma tracer concentration. The method is to take ‘multiple samples of plasma (after allowing for the mixing phase) and extrapolate to tracer concentration in plasma at time zero.6 chapter Biood volume is calculated as: 100 Blood Volume = Plasma volume x “59 where: Hict is haematocrit (expressed as 2 percent) ‘An altemative technique to measure blood volume is to use radio-chromium (*1Cx) labelled red cells as the tracer. The patient's own red cells are used after incubation with the Ia ‘The tacer red cells are washed before reinfusion to remove eny unbound label inthe plasma What is the volume measured when "Cr labelled red cells are used - the whole blood volume or the red cell mass? (ie. In what compartment does this tracer distribute?) The labelled red cells distribute txoughout the whole blood volume but distribution is uneven (ie haematocrit is different in different parts of the circulation). Blood volume can be calculated by measuring the amount of label in 2 given volume of blood. For more accurate results, the amount of label in a known volume of red cells is measured (ie red cell mass) and blood volume is then calculated indirectly. Mixing occurs rapidly so the sample can be collected at 10 minutes. What are the problems with using venous blood to estimate the haematocrit? A red cell in the veins is larger than 2 red cell im the aneries because the various reactions involved in carbon dioxide transport lead to an increase in the number of particles in the venous red cell. Red cell water content increases due to osmotic forces and the measured ‘haematocrit increases because of this. Also, when determining the haematocrit about 4 t0 8 percent of the plasma remains trapped with the red cells. This means that the measured haematocrit is higher than the real haematocrit, Accounting for these factors, an estimated ‘true’ or ‘whole body’ haematocrit is substituted in the calculations. The equation for haematocrit is: Whole body haematocrit= 0.91 x Venous haematocrit Red cell volume and plasma volume can be measured simultaneously because the radioactive als from "I and “'Cr can be distinguished. This permits calculation of blood volume without using haematoert. What is the value for haematocrit in skeletal muscle capillaries? Why? Low: typically about 20%! This low value occurs because of axial streaming. Note that if this capillary blood with an actual haematocrit of 20% could be collected in a test tube over 2 minute oF $0, then the haematocrit measured in this sample would be much higher (eg normally about 40 t0 45%)! (Why?) What is the effect of pregnancy on blood volume, red cell mass and plasma volume? They all increase but by differing amounts: + Blood volume: 40 to 45% increase by term, + Plasma volume: 50% increase by term. This results in haemodilution and [Hb] falis (physiological anaemia of pregnancy). The increase in red cell mass is about 250 mis (18% increase) without iron supplementation, or 450 mis (30% increase) with iron supplementation Are there any particular problems encountered when measuring these volumes during pregnancy? In the third trimester, care should be taken to evoid the supine position during the measurement phase, Aorocaval compression can cause sequestering of blood in the pelvic veins resulting in inadequate mixingFluid & Electoiyte Physicioay z Control of Intracellular Volume Whac is the volume of the intracellular fluid? About 23 litres. This is 55% of the 42 litres of total body water in the 70 kg adult mate Can you outline the factors involved in the control of cell volume? ‘Most cell membranes are freely permeable to water and do not possess water pumps. If ECF tonicity changes, then cell volume will change, This is undesirable for cells which generally need a stable cellular volume for optimum function Cells contain a significant concentration of colloids (mostly proteins and organic phosphates? ‘which are not diffusible across the cell membrane, These charged nondiffusable anions set up a Gibbs-Donnan effect across the membrane. Now if Gibbs-Donnan equilibrium was ‘obtained there would be an excess of particles inside the cell. This would cause entry of more ‘water which would alter the Gibbs-Donnan equilibrium. This would result in more particles being retained intracellularly which would cause more water to enter the cell... and so on. This is clearly an unstable situation which would lead to cell rupture. As this does not occur, then clearly a counterbalancing mechanism must exist. Sodiurn isthe main extracellular cation, Itis effectively excluded from the cell because of the combination of low membrane permeability and active extrusion by the sodium pump. Sodium being effectively non-diffusable sets up a Gibbs-Donnan equilibrium which tends to ‘cause an extracellular excess of anions as compared to the intracellular environment. This ceauses water to move out ofthe cell, ‘This second Gibbs-Donnan equilibrium (due to extracellular sodium) opposes the actions of the first (due to intraceliular colloids). The balance between these two opposing effects (dou- ble Donnan effect) allows maintenance of a stable cell volume, Note in particular the critical role of the sodium pump in maintenance of cell volume. If the pump was blocked, the cell ‘would swell and rupture, [Note that there is both a sinall excess of cations intracellularly and a small excess of anions extracellularly: What is the consequence of this?] How do cells respond to acute changes in extracellular tonicity? .. & to chronic changes? Ifextracellular tonicity changes acutely, cell volume will change rapidly to maintain osmotic ‘equilibrium. Hypertonicity invariably causes intracellular dehydration, and conversely hhypotonicity causes cells to swell. These acute changes are predictable and can be utilised clinically. Mannitol is infused in certain clinical circumstances to increase extracellular tonicity and decrease cerebral cell volume. All cells in the body will be affected Cells possess mechanisms to minimise the disruption caused by changes in extracellular tonicity. They do this by altering their intracellular solute content, either gaining or losing solute so that changes in their cell volume is minimised. For example, in response 10 extracellular hypertonicity, cells may gain solute either from the extracellular fluid or from an increased production of intracellular solute particles. ‘This second mechanism is particularly important in the brain, Brain cell metabolic pathways alter to produce more intracellular particles. This increase in these idiogenic osmoles increases intracellular tonicity and draws water back into the cell to help restore intracellular volume towards normal. Because of this mechanism, chronic hypotonicity (ie chronic ‘hyponatraemia) is much better tolerated than acute hypotonicity (acute hyponatraemia). In general, cells possess a capacity 10 either gain or lose solute over 2 period of time to vary intracellular tonicity s0 that cell volume changes due to extracellular tonicity changes are minimised. The source of the extra solute may be extracellular (ions mosily; end to interfere ‘with metabolism) or intracellular (‘idiogenic’ solutes; minimal effect on metabolism).8 Chapter 1 Osmotic Pressure What are the ‘colligative properties’ of a solution? ‘These are the properties of @ solution that depend only on the particle concentration (ie osmolality). The important point is that only the number of particles per unit volume is imporant and not the type of particles, (Note that this is often stated as ‘the number of particles present’ but this should really be stated as no. of particles per unit volume.) The colligative properties are: + Vapour pressure depression + Freezing point depression + Boiling point elevation + Osmotic pressure What is ‘osmotic pressure"? Consider the situation with two aqueous solutions separated by a semipermeable membrane through which only water (the solvent) can pass. Let one of the solutions be pure water (the reference solution) and the other be a test solution containing dissolved particles. Water ‘would tend to pass across the membrane from the pure water to the test solution due 10 osmosis. The osmotic pressure is a measure of this osmotic tendency for water to cross the membrane Ifa hydrostatic pressure were applied to the test solution it would cause water molecules 10 move through the membrane in the opposite direction. The hydrostatic pressure could be increased until the number of water molecules moving one way due to the hydrostatic pressure gradient would equal the number of water molecules moving in the opposite Girection due to the difference in osmolaiity. This particular hydrostatic pressure is a measure of the osmolality of the solution and is referred to as the ‘osmotic pressure’. It is dependent only on the particle concentration present in the solution. Note that as considered here the hydrostatic pressure required to balance the osmotic movement of water is dependent on the difference in osmolality between the two solutions. However since the reference solution here is pure water, the hydrostatic pressure is a measure of the osmolaliry ‘of the test solution alone, What is the total osmotic pressure of plasma? For an osmolality of 287 mOsmolesrkg, the total plasma osmotic pressure is about 5545 mmHg. This is about 7.3 atmospheres! (Note that this pressure is not the hydrostatic pressure present in che plasma but is the pressure required to oppose water movement across a membrane - see answer to previous question}. How is this caleulated? The osmotic pressure can be calculated by using the van? Hoff equation: Osmotic pressure=n x (c/M) x RT where nis the no. of pantcles into which the substance dissociates Cis the concentration in of Mis the molecular weight ofthe molecules Ris the Universal Gas Constant = 0.082 Tis the Absolute Temperature (K) Substituting typical values for plasma at 37°C: Osmotic pressure = 1 x 0,082 x 310 x 0.001 x 760 x 287 = 5 (Note that this requires measurement of the osmolality of the plasma so this value can be substituted in the equation )Osmolality and Tonicity What is the difference between ‘molality’ and osmolality"? ‘The molality of a solution is the number of moles of a solute per kilogram of solvent. The mole is the SI unit for amount ofa substance. Molality represents the number of panicles of| the particular substance which are present. One mole of substance contains about 6 x 10° particles. This number is known as Avogadro’s number. ‘The osmotaligy ofa solution is the number of osmoles of solute per kilogram of solvent. One osmole contains Avogadro's number of particles but no distinction is made about the type of particle present: specifically, many different types of particles may be present. What is the normal osmolality of the ECF? About 285 to 290 mOsmales/kg. Js the osmolality the same in the ICF? Wh Water crosses nearly all cell membranes very easily. An osmotic gradient will not continue to exist across a cell membrane as water will move until the gradient is abolished. The significance is that intracellular osmolality must equal extracellular osmolality, Intracellular ‘osmolality can therefore be determined as itis the same as the osmolality of # blood sample. Do the terms ‘osmolality’ and ‘osmolarity? mean the same? No. Osmolality is the number of osmoles of solute per kilogram of solvent, This is independent of temperature Osmotarity is the number of osmoles of solute per litre of solution. This is altered by temperature changes because of the expansion of the solution. However, because a litre of water weighs about a kilogram, the numerical values of osmolality and osmolarity obtained for dilute aqueous solutions are almost the same. The units are different though (ie Osmvkg versus Ost), Define tonicity. Tonicity is the effective osmolality of a solution. What is the importance of tonicity (as compared t0 osmolality) in the body? Consider the following two facts: + Water crosses nearly all cell membranes easily (and quickly), + Most solutes do not cross cell membranes easily We could conclude that water alone will move between the intracellular and extracellular compartments until the osmolality on both sides of the membrane isthe same. This is not the case! Some solutes present in plasma (eg urea) can themselves cross the membrane easily. If excess urea was added to the extracellular fluid sufficient to raise the extracellular ‘osmolality, we would expect that there would be net movement of water out of the cell until there was no osmolar gradient across the cell membrane. The problem here is that urea itself crosses the cell membrane (until the urea concentrations are the same on both sides of the cell membrane). Any water that we predicted would have moved out ofthe cell in response to10 the initial increased extracellular osmol cell. The final result of adding urea extracellularly is an increased urea concentration, extracellularly and intracellularly but no change in the final luid distribution across the cell membrane. From this example it can be seen thet the osmolality needs to be ‘corrected’ to account for this type of solute. Most solutes (eg Na’, CI, Ca) do not cross cell membranes easly and are effective at exerting an osmotic force across a cell memibrane. Other solutes (eg urea) can cross membranes easily and are ineffective at exerting an osmotic force across cell membranes. Osmolality measures the concentration of all the particles (solutes) present in the solution. Tonicity is 2 measure of only those particles which are capable of exerting an osmotic force across the cell membrane. Tonicity is the effective osmolality of the solution and is that part of the total osmolality that is due to the effective osmoles. Tonicity is whet is important in determining fluid distribution across the cell membrane because it allows for those solutes which can cross the membrane. The osmoreceptors in the hypothalamus respond 10 extracellular tonicity rather than 10 ‘osmolality. Osmolality is however easy to measure. Tonicity of physiological body fluids can be estimated as osmolality minus the concentrations of urea and glucose as these are the only ‘wo ineffective solutes ordinarily present in any significant concentration. Why is glucose an ‘ineffective’ osmole? Is it ever an ‘effective’ osmole? In normal circumstances, glucose crosses cell membranes relatively easily In fat and muscle cells its entry into cells is greatly increased by facilitated diffusion stimulated by insulin. Glucose is not an ‘effective’ osmole in this situation. Tonicity of plasma can be estimated as the measured osmolality less the concentrations of urea and glucose. Other ineffective osmoles are normally present only in much lower concentrations. In diabetic patients, the situation is different. Insulin is absent and entry of glucose into fat and muscle cells is difficult. It is now an effective osmole and can exert an osmotic effect across the cell membrane in fat and muscle cells, These two tissues make up @ major part of body mass so are quantitatively very important in body metabolism. Hyperglycaemia in untreated diabetics causes hypertonicity. Five percent dextrose solution is isosmolar when first infused but the glucose is rapidly taken up by cells and metabolised. The net effect of an infusion of 5% dexzrose is of giving pure ‘water. Note that five percent dextrose is isosmolar when initially infused but is not isotonic. Indeed it is markedly hypotonic. If urea can cross cell membranes easily, then why is hypertonic urea effective as a cerebral dehydrating solution? (in the same way as hypertonic mannitol solutions) Hypertonic urea is effective for this purpose and has been used in the past o acutely reduce an elevated intracerebral pressure The membrane of most relevance here is the blood-brain barrier rather than the cell membrane, Urea crosses this barrier much more slowly than water, An acute increase in blood osmolality due to the rapid IV administration of hypertonic urea will acutely withdraw water from the brain and ceuse a decrease in intracerebral pressure, [Strictly speaking, tonicity of a solution should always be defined in relation to a particular membrane whereas osmolelity is independent of membrane properties. The blood-brain barrier is the membrane of concer here and its urea permeability is much less than its water permeability. So, in relation to this membrane, the hyperosmolar urea solution is certainly quite hypertonic as well so the term ‘hypertonic ures" is correct here.)Fd & Electolyte Physiology u Oncotic Pressure What is meant by the term ‘oncotic pressure"? Oncotic pressure or ‘colloid osmotic pressure” is that component of the total osmolality which is due to the colloids Colloids are large molecular weight (nominally MW > 30,000) particles. In plasma, proteins are the major colloid present and are responsible for the majority of the oncotic pressure of plasma, What is a typical value for plasma oncotic pressure? About 25 10 28 mmHg. This is about 0.5% of the total plasma osmotic pressure of 5545 mmEg. Why is this low value so important? COncotie pressure in exwemely important because of its role in capillary fluid dynamics (Starling's hypothesis). It is important here because the capillary membrane is impermeable to proteins but permeable to most other substances present in plasma, The proteins are the only effective solutes present and are important for retsining water in the capillaries (and thus for maintaining the circulating volume). The plasma oncotic pressure is the only force retaining intravascular volume in the capillaries, What is the value of oncotic pressure predicted from the van't Hoff equation? Why is the actual osmotic pressure higher than this value? ‘The value that can be calculated from this equation is about 15 mmHg. This is based on a protein concentration of 0.9 mOsmoles!l ‘The actual value of about 25 mmHg is significantly higher. The reasons for this are: + the Gibbs-Donnan effect, + the "Excluded volume’ effect ‘The major factor is the net negative charge on the proteins. The proteins are large and not, readily diffusible across the capillary membrane. The net effect is to lead to the retention of an increased number of sodium ions in the plasma in accordance with the Gibbs-Donnan equilibrium. The net increase in the particle concentration in the plasma is about 0.4 mOsmolesil, The increase in oncotic pressure due to this effect is sometimes referred to as the ‘Donnan excess pressure’, The retained sodium ions are not bound to the albumin but provide an excess of extra particles Another factor isthe ‘excluded volume’ effect. This refers to the effect of the large size of the proteins. The van't Hoff equation is based on ‘ideal’ (je infinitely dilute) solutions. The volume occupied by the large molecular weight proteins is significant and the consequence of this in chemical terms is to be an additional factor that is responsible for some of the discrepancy from the van't Hoff equation. How is oncotic pressure measured? By use of an instrument called an oncomerer. ‘The principle of this instrament is 10 have two chambers separated by a serni-permeable ‘membrane which is permeable to water and all solutes except those with a molecular weight ‘greater than about 30,000 (ie colloids). The colloids are the only solutes present which can exert an osmotic force across the membrane. The reference chamber contains isotonic saline and the second chamber contains the test solution.2 Chapters If the test solution contains colloids, then water moves across the membrane into the test solution. The pressure change in the test chamber is measured by a sensitive pressure transducer and is used to calculate the oncotic pressure Which proteins contribute most to the plasma oncotic pressure? Albumin is the major contributor to the plasma oncotic pressure accounting for about 65 to 75% of the total value ‘The plasma proteins may be considered as albumin, globulins and fibrinogen. The albumin thas @ concentrstion (45g/l) about double that of the globulins and has a molecular weight (MW) about half that of the average globulin (eg MW 69.000 vs 150,000). So there are almost four albumin molecules per globulin molecule. The net negative charge of albumin ‘means that itis also the major protein responsible for the Donnan excess pressure. Fibrinogen has @ large MW (340,000) and # low concenteation (3g/). It makes minimsl contribution 10 plasma oncotic pressure. What are the effects of a sudden decrease in plasma oncotic pressure? This will cause an increased loss of water from ihe capillaries (due to increased filation) w a decrease in intravascular volume. Ifhis volume decrease is sufficient to stimulate the volume receptors and high pressure baroreceptors this will lead to renal salt and water ret. minimises the intravascular valume change. sa whieh nterstitial fluid volume will increase and oedema may result if severe enough. In absence of additional factors, clinically evident oedema does not appear until the plasma oncotic pressure has decreased to quite low values (typically below 1] mmHg). The normal plasma oncotic pressure is 25 to 28 mmHg so there is clearly quite a large safety margin What are the factors that protect against development of oedema when albumin levels are ow? + Increased lymph flow can remove much of the excess interstitial fluid and return it to the circulation + Increase init factors are essure which tends to stitial fluid volume increases tissue hydrostatic ‘oppose further excess filtration + Decrease in interstitial protein concentration (due to decressed amounts of albumti leaking out of the capillary) which decreases interstitial oncotic pressure Clinically, itis found that oedema usually does not occur until albumin levels are less thenFlue & Blecroiye Physiotogy 2 Sodium Concentrations What would be a typical value for [Na‘] in the blood plasma? 140 mmols!l. (The reference range is typically quoted as 135 to 145 mmols!t but varies in different laboratories) What is a typical value for intracellular [Na*]? Does this value vary between different cell pes? Intracellular (Na’] is very low, Values of about 12 mmolsil (or less) are quoted for muscle cells. Some cells have higher levels: [Na"] in red cells can be as high as 20 mmolsil. Why is the intracellular sodium concentration so low? Intracellular levels are kept low by two factors: + the sodium pump (Na-K: ATPase} + the low sodium permeability of the membrane, ‘The membrane Na-K> ATPase transports two K> into the cell for every three Na pumped out, The low membrane permeability prevents re-entry of appreciable amounts of sodium. What would be a typical value for [Net] of interstitial fluid (ISF) ? This is usually very close to the plasma value: say 140 mmols/| Why is this value so similar t0 the [Na"] for plasma? Doesn't the Gibbs-Donnan ‘equilibrium predict thar it should be different? Plasma consists of plasma water (93%) and plasma solids (79). Plasma solids are mostly plasma proteins. The Gibbs-Donnan effect causes the (Na"] in plasma water to be higher than {Na"] in interstitial uid by about 6 or 7 mmols/. Sodium is present only inthe plasme ‘water component but is measured as though it was present in the whole plasme sample. This means that the value as measured is decreased by & small amount: this is Known as the “plasma solids effect’ ‘The decrease in measured plasma (Na"] due to the plasma solids effect is about the same ‘magnirude as the increase in [Na"] in plasma water that occurs due to the Gibbs-Donnan effect. The result is that measured plasma (Na"] is about the same as [Na] in interstitial uid. [ Note: The common laboratory methods for measuring [Na] are flame emission spectro- hotomesry and the indirect ISE technique. Effectively these give a measure of the amount of Na* present in the sample and (Na"] is determined because the total volume used in the analysis is known, This volume is whole serum (and essentially includes all plasma proteins except fibrinogen) racher than plasma water. So the amount of Na” is considered ro be present in the whole volume and not justin he plasma water component. The presence of the ‘plasma proteins in the volume means that the [Na*] as reported by the machine (ie the ‘measured’ value) is lower than the ‘real" concentration in plasma water ] Colloid osmotic pressure is about 25 mmflg in plasma. This is higher than predicted by the van't Hoff equation for the actual protein concentration (about 0.9 mOsmotes/)) that is present. The reason the actual oncotic pressure is higher is because the Gibbs-Donnan equibrium results in an increase in the [Na‘] in plasma and the increased number of particles contribute an extra 0.4 mOsmolesil which increases the oncotic pressure. If the increase in [Na‘] in plasma due to the Gibbs-Donnan effect is really of the order of“ chastert 6 t0 7 mmolsf (see previous question), why does this increased [Na’] contribute only 0.4 ‘mmols/ to the oncotic pressure? ‘The actual [Na"] in plasma water really is increased by ebout 6 or 7 mmols/ but this is not the only change in electrolyte concentrations that is occurring. For example: (CI is lower in plasma water and higher in ISF due to the Gibbs-Donnan effect. Sodium and chloride are the ions present in the highest concentrations in plasme and ISF and we can for our purposes consider only these two ions. ‘What is important is the overall net change in ion concentrations and not just the change in [Ne"]. The net change is approximated by the difference between the rise in [Na‘] and the fall in [CI]. This difference is an increase of 0.4 mOsm in plasma. The net increase in the plasma osmolality due to the Gibbs-Donnan effect is 0.4 mOsnv/l so the apparent protein concentration is 1.3 mOsmoles/l (ie 0.9 + 0.4), The 0.4 mOsmi/l increase in overall ion concentration can contribute to oncotic pressure because these ions are effectively held within the capillary (even though they are not bound to the proteins) In summary: the ner increase is only 0.4 mOsnv/I because the fallin total anion concentration offsets most of the rise in [Ne"] What is the sodium chloride concentration in plasma? Zero. Sodium chloride is fully dissociated into Na" and Clr in aqueous solutions. There is no undissociated NaC present. In chemical terms, sodium chloride is astrong electrolyte meaning that it dissociates completely into its component ions. How much sodium is in the body? Whar is its distribution? Toual body sodium is about 60 mmols/kg, This is abo male. ,000 to 4.200 mmols in an adult Distribution is: Extracellular fluid Intracellular fuié Exchangeable Na” is 70% of total sodium, It ean be measured using ‘The non-exchangeable sodium is mostly in bone crystalFluid & Electrolyte Physiology 15 Potassium What is the total amount of potassium in the body? How is this distributed in the body? ‘The total amount of potassium is about 40 to 45 mmols/kg The distribution is Intracellular fluid: 902% (with (K*] = 150 mmol/l) + Extracellular uid: 2% (with (K-] =3.5 to 5 mmol Bone a% The distribution is often quoted as 98% intracellular and 2% extracellular. This is incorrect but is useful clinically. The potassium in bone is fairly stable and is not readily able to be mobilised, So excluding the bone K* and considering the physiologically mobile pool of K- (the exchangeable pool) only it is indeed approximately correct to say that about 98% of this is intracellular (because °,, x 100 = 97.8%). K* is the major intracellular cation. How is the total body potassium measured? The naturally occurring potassium isotope “K makes up 0.017% ofall the potassium in the body. The amount of this isotope can be measured in a whole body scanner and the total body potassium calculated. This is larger than the exchangeable pool of potassium because the potassium in bone is included. The exchangeable potassium can be measured by injecting another radioactive potassium isotope (“*K). Exchangeable potassium is about 40 mmols/kg and this is about 90 to 92 ppercent of the total potassium in the body. What are the functions of potassium in the body? ‘The major functions or roles of potassium in the body are + major component of intracellular tonicity + involved in sodium pump (Ne--K* ATPase) in all cell membranes + membrane potentials (esting membrane potential, action potential) + regulation of some intracellular processes (eg protein & glycogen synthesis) + neuromuscular excitability What are the ECG changes associated with acute hyperkalaemia? Hypetkalaemia causes a decrease in RMP. The consequences of this are + hyperexcitabilty (initially). + reduced conduction velocity ‘The hyperexcitability decreases if the hyperkalaemia is severe because of inactivation of N: channels, ECG changes can be variable but a typical progression of changes as [K-] increases would be: ‘+ Initially: increased T wave height * Shortening of the Q-T interval + Prolonged P-R interval + Pewave flattening ogressive widening of the QRS complex + Finally: sine wave appearance, VF or asystole How would you treat a patient with acute hyperkalaemia? Serious arrhythmias can occur with acute hyperkalaemia. The potential cardiac effects are16 Chapter + the major life-threatening clinical consequences of hyperkalaemia. The severity is related to the absolute Jevel of (K") and also importantly to the rate of rise of [K"]. The management depends on the severity of the ECG changes. A working classification of severity is: Severe: (K"]> 8 mmols/l or marked ECG changes (immediate treatment required) Moderate: (K-] 6 10 8 mmols/l without marked ECG changes. Mild: [K-] 5 to 6 mmols/ (treatment not usually required) Treatment options are: Intravenous caleium This is used for severe hyperkalaemia. The plasms level isnot altered but increased [C3] ‘stabilises’ the myocardial membrane (je decreased excitability) and acutely decreases the risk of serious arrhythmias. This does not alter plasma [K-] but is a temporising measure to allow tzeatment. Glucose and Insulin This is used to acutely decrease the plasma [K"] in severe hyperkalaemia and in moderate hyperkalaemia (particularly if significant ECG changes are present orth level is continuing to rise). Onset is fairly rapidly but is of short duration. The potassium moves intracellularly. Sodium Bicarbonate This also will acutely decrease plasma [K*] by moving K° intracellularly and restoring the transmembrane potassium gradient. This is fairly rapid in onset but duration of the effect is shor. Resonium ‘This is an ion exchange resin which is administered orally or rectally. The resin exchanges 1 mmol ef K for 1 mmol of Ne” for every gram of resin. The exchange occurs in the colon so ‘oral administration may be very slow in onset, Administration as an enema will have a more rapid effect because of delivery directly to the site of exchange. There will be a net loss of K" from the body and a net gain of Ne Dialysis ‘This is the preferred option in severe chronic renal feilure and in acute renal failure. The presence of hyperkalaemia is a major indication ro urgently initiate dialysis in acute renal failure Treatment and Correction of the Cause Clearly the preferred long-term option but not always possible or the rate of correction may bbe to0 slow in severe hyperkalaemia, How much glucose and insulin would you use in treating an adult with significant hyperkalaemia? Regimes vary but 25 grams of IV dextrose (50 mls of 30%) together with 10 U of subcutaneous insulin should be effective. This should decrease (K"] by 1 102 mmols/1 within 30 mins and the effect can persist for 2 to 3 hours. The dase can also be repeated. This treatment redistributes the K~ intracellularly and does not cause any net excretion of K- from the body.Fluid & Blecroiyte Physiology 7 Functions of Magnesium What is the reference range for serum [Mg7]? From 0.7 to 1.0 mmols!l (or alternatively: 1.4 to 2.0 mEq/L.) Only 1% of magnesium is in the ECF: this is a total amount of only 10 mmols (out of the total body content of 1,000 mmols). What are the functions of magnesium in the body? ‘The major roles are as a coféctor in metabolism and actions on nerves and muscles, Ie is major intraceliolar cation Iniracellular catalyst or cofactor Magnesium is responsible for catalysing or activating over 300 separate enzymes within the body. Magnesium dependent enzymes include all enzymes catalysing phosphate transfer, and all enzymes requiring thiamine pyrophosphate as a co-factor. Magnesium is required for the sodium pump, oxidative phosphorylation, and all reactions involving ATP - so it is ‘important fora cells without exception. Effects on nerves and muscles ‘These actions are frequently contrasted to those of calcium, Magnesium fons reduce nerve and muscle membrane excitability in a similar way to caleium ion but less powerfully. However, calcium and magnesium ions are antagonistic to each other in their actions on transmitter release at cholinergic and adrenergic junctions, and on excitation contraction coupling in skeletal and cardiac muscle, Both transmitter release and excitation contraction coupling are inhibited by magnesium. The clinical effect of elevated levels of magnesium is to cause & potentiation of both succinyleholine and non-depolarising relaxant blockade. Actions on smooth muscle are similar to those in skeletal and cardiac muscle. The effect of therapeutic administration of magnesium is vasodilatation. Conversely, magnesium deficiency can cause coronary vasospasm and precipitate angina ‘Magnesium has other important roles in the nervous system, for example itis the physiological blocker of the NMDA receptor What are the effects of hypermagnesaemia at various plasma [Mg] levels? The patient usually remains asymptomatic until magnesium levels are above 4 mmol/l Early symptoms are nonspecific and include nausea, vomiting, and drowsiness. Significant symptoms occurring at high levels of magnesium involve the neuromuscular and cardiovascular systems, Neuromuscular transmission becomes progressively impaired with decreasing deep tendon reflexes and eventually respiratory paralysis. Minor ECG changes ccan progress to complete heart block and eventually asystole. When used therapeutically ‘monitoring for loss of the deep tendon reflexes can be used as a clinically relevant sign of significant toxicity which preceeds cerdiorespiratory collapse. Mg] (mmol) Effect 07-10 Reference Range 2035 ‘Therapeutic range in Toxaemia (anticonvulsant) 40 ‘Symptoms occur 2.5-5.0 ECG changes (increased PQ, wide QRS) 5.0 Loss of patellar reflex 6.0-8.0 Respiratory paralysis 15 Complete hear: block 120 Asystole Nore: The numbers will be ewice as high ifmEg/l are the units used as is common in US texts. For example: 3 mmol = 10 mEgh. |8 chapter t Gibbs-Donnan Relationship What is the Gibbs-Donnan equilibrium? Ifa semipermeable membrane separates two solutions and one solution contains @ non-diffusible anion or cation, then the distribution of all the other diffusible cations and anions across the membrane is altered. The Gibbs-Donnan effect states the situation at equilibrium, Consider a simple example: two solutions of Na” and Cr (solutions A and B) which are sep2- rated by a semipermeable membrane. Let one solution also contain a nos-diffusible anion (protein). The membrane is permeable to Na” and Cl: and these ions are free to distribute passsively across the membrane. At equilibrium, the products of [Ne"] and [CI] on each side of the membrane are equal. That is, for solutions A and B: [Nava x [CHA = [Na‘sx [CIs This holds for any pair (cation & anion) of univalent ions. ‘The Gibbs-Donnan factor for univalent cations is 0.95. For example [Na'} in ISF is 0.95 x. {Na‘]in plasma water. The Gibbs-Donnan factor for anions is 1.05 Does this ‘equilibrium’ represent a stable state? ‘No. It is based on the ions distributing across the membrane until the electrical and chemical gradients are balanced. But ths is not stable unless the volumes of the 2 solutions are fixed because atthe ‘equilibrium’ state, there is an unequal particle concentration on the 2 sides of the membrane. So there is an osmotic gradient which has not been considered. This osmotic gradient leads 10 water movement across the membrane, which upsets the Gibbs-Donnan, equilibrium again, There is no stable stare. (See also ‘Control of Intracellular Volume’ on p7) What about divalent ions like Ca and Mgu? ‘The situation for Ca~ and Me™ is more complicated because these ions are significantly protein bound so only the concentration of the frce ion should be used. ‘The Gibbs-Donnan factor for divalent cations is 0.90 (ie 0.95 x 0.95) & for divalent anions is 110, Is the Gibbs-Donnan effect important in the body? Extremely important, in particular for: + Stability ofcell volume + Plasma oneotic pressure Ik is vitally important in maintenance of cell volume. The Donnan effect due 10 the non-diffusible intracellular proteins and organic phosphates is balanced by the Donnan effect of the effectively non-diffusible Na” in the ISF. This dynamic balance is responsible for the stability of ceil volume, ‘The equilibrium also causes elterations in the distribution of other ions across the capillary membrane, This results in a small net increase in ions present in the plasma. This is very important because it causes & significant increase in the effective velue of the plasma oncotic pressure in the blood. also makes small contribution to the value The Gibbs-Donnan e' f the resting ‘membrane potentialFlue & Eleovoite Physiology 18 Lymph Tell me about lymph. How does interstitial fluid enter the terminal lymphatics? Lymph is the name given to interstitial luid which enters the lymphatic vessels. Lymphatic capillaries are present in nearly all tissues. Exceptions include cartilage. bone marrow and ‘the central nervous system. ‘The lymph capillaries are blind-ending and possess flap valves between adjacent lymphatic endothelial cells. These fimetional valves permit entry of ISF but prevent its return to the interstitium. Nearly all lymph passes through lymph nodes before return to the venous circulation. Lymph returns to the circulation via the thoracic duct (Which drains into the circulation at the junction of the left subclavian and internal jugular veins) and the right lymphatic duct, What makes lymph flow? Intrinsic (muscular Walls and valves) and extrinsic (external pressure) factors promote lymph flow. Larger lymph vessels have smooth muscle in their walls and contraction causes some of the flow. Valves in the lymph vessels ensure forward (unidirectional) flow occurs. Lymph flows also because of external pressures which act to compress the Iymph vessels, ‘The flap valves between the endothelial cells of the Iymphatic capillaries prevent return of iymph to the interstitium. The major sources of the external pressure are muscular contractions and pulsations in neighbouring arterial vessels. Lymph vessels usually travel ‘with the arteries and veins and this is a convenient arrangement to promote lymph flow What are the functions of the lymphatic system? ‘The functions are + Return of protein (and excess fluid) tothe circulation from the interstitial uid * Role in ansport of fat from the stall intestine. + Immunological roles = filtration and removal of bacteria by macrophages in the lymph glands (reticuloendothelil system) - role of lymphatics in lymphocyte circulation throughout blood & lymph + role of lymphocytes in the lymph nodes being activated to proliferate by contact with antigens in the lymph The removal of protein keeps the interstitial uid protein concentration ow (about 20 g/l) and this maintains the oncotic pressure gradient across the capillary membrane. edema ‘will occur if ISF oncotic pressure is not kept low. The sinusoids of the lymph nodes are lined by macrophages of the reticulocndothelial system. These phagocytose any bacteria or cellular éebri present in the lymph, The Iymph nodes also coniain lymphocytes which can proliferate on exposure to specific antigens. Whar isthe protein concentration of lymph? This is typically low when compared with plasma but is the same as the [SF from which it was erived. For much of the body the concentration is about 20 g/l but hepatic lymph can have @ protein concentration of about 60 g/. Liver contributes about 50% of the total body lymph at rest because the hepatic sinusoids are extremely permeable and protein easily leaves the circulation (ie the reflection coefficient is low),20 Chapter The large amount of liver lymph causes the thoracic duct lymph to have a protein concentration of about 50 gf The proportion of fibrinogen present in ISF and lymph in most tissues is much Jower than in plasma. This is because fibrinogen is a large molecule (MW about 340,000) and it is more difficult for fibrinogen (as compared to albumin) to cross the capillary membrane. Are there any differences in composition between ISF & lymph? No as lymph is simply ISF which has entered the lymphatic channels. However, thoracic duct lymph has a higher protein concentration then the ISF in most of the body. This is due to the large contribution of protein-rich hepatic lymph to thoracic duct Iympb. Where does the ‘thoracic duct’ drain? The thoracic duct drains into the circulation at the junction of the left subclevian vein and the internal jugular vein How much lymph is produced per day? Atrest, about 2 mls/min (120 mls/h) of lymph is produced. Ths is almost 3 lites per day. Total lymph flow increases quite markedly with exercise so the actual amount of lymph produced per day is quite variable. Net filtration at the arterial end of capillaries is about 20 mis/min of which 18 mls/min returns to the circulation at the venous end of the capillaries leaving a net production of 2 mis/min of lymph. Ten percent of all the fluid filtered in the capillaries rerur circulation. as lymph What percent of the body's lymph returns to the circulation via the thoracic duet? About $3%. The 120 mls/br total Iymph flow at rest includes 100 mis/hr of thoracic duct lymph When is lymph ‘milky’? This occurs when lymph conteins 2 igh fat content asin after 2 meal ph draining from the bowel What is the role of the lymphatics in fat absorption? ‘The majority (90%) of the fat absorbed from the gut is extruded from the bowel epithelial cells into the ISF and passes into the central lacteal vessels inthe villi, The fat is in the form of special globules which are termed chylomicrons, These are responsible for the milky appearance of bowel lymph and can cause @ milky appearance (lipaemia) in plasma after 2 fatty meal as well. Note that the iymph and the chylomicrons pass into the circulation via the thoracic duct and do not pass through the liver in the portal blood, Will lymph clot if eollected into a test tube? Yes, This is what is observed to happen. Lymph contains all ofthe coagulation factors but the level of the high molecular weight fibrinogen is low. Platelets are not present in lymphFuid & Electoiyte Physiology 2 Sweat What is the normal skin blood flow? Normal skia blood flow is about 300 misimin What factors control skin blood flow? Skin requires blood flow for two reasons: ‘+ Metabolism: supply nutrients and remove wastes + Temperature Regulation Nusritive skin blood flow is low. The main factor causing an increased skin blood flow is the need for heat loss. Skin blood flow can increase about 10 times to 3,000 mis/min under conditions of heat stress. Heat loss is increased because of: + increased sweating and increased evaporative heat loss (main factor) *+ increased loss of heat from the warm skin by radiation, conduction and convection Heat loss by evaporation isa particularly effective form of heat loss because the evaporation of each gram of water causes loss of 0.58 keals. What is ‘insensible water loss"? Insensible water loss consists of * water that passes through the skin (‘transepidermal diffusion’) and is lost by evaporation from the skin surface + evaporative water loss from the respiratory tract during ventilation The loss is called ‘insensible’ because we are not aware of it occurring The key points are: + there is loss of pure water without any associated solute loss + the loss cannot be prevented * minimal insensible loss is about 800 mls per day (400 mis from the skin and 400 mls from the respiratory tract.) * the associated heat loss is quite significant: evaporation of 800 mis results in loss of 464 keals which is about 25% of basal heat production, How does insensible loss differ from sweating? The main differences are: + Insensible loss is solute.frve and only water (and heat) is lost. Sweat always contains solutes so sweating always causes loss of electrolytes. + Insensible water loss from skin involves water which has diffused trough the skin. ‘Sweat is produced in specialised skin appendages called sweat glands. What is sweating and what is its role? ‘Sweat is the secretion from sweat glands in the skin, The major role of sweating is 10 increase heat loss in situations of heat stress. The losses that occur with sweating are loss of: + water + electrolytes (especially Na) + heat Can you tell me about the fluid loss that occurs with sweating? From the fluid perspective, only the sweating from the eccrine sweat glands in important, These glands are distributed over 99% of the skin surface. They have a sympathetic cholinergic (muscarinic) innervation. Sweating is controlled by a centre in the hypothalamus.22 Chapter This has input from thermosensitive neurones in the hypothalamus which sense core temperature, There is also modifying input from temperature receptors in the skin. ‘The fluid loss from sweating can be very large in extreme environments (ie hot and dry). ‘Maximum sweat lass is 1,500 to 2,000 mis in an hour and up to about 12,000 mls per day! Losses at high levels can continue only if there is adequate oral fluid replacement Electrolytes (Na’) also need to be replaced. Can you tell me about the solute loss that occurs? The [Ne"] of sweat varies from 30 10 65 mmols/i depending on the degree of ecclimatisation of the subject. The (Ne"] is also decreased by aldosterone, Daily Na" loss in sweat can vary from 5 to 350 mmoisiday. What is ‘acclimatisation’ of the sweating mechanism? “Acclimatisation’ refers to the adaptive changes that occur over a period of time in the sweat ‘mechanism when a person moves from living in a cold climate to a hot climate. The major changes are + the maximum rate of sweating increases markedly + the [Ne"] in the sweat decreases markedly .aximum heat loss is increased and the associated ‘These changes are beneficial because solute loss decreases. How effective is sweating in causing heat loss? ‘Sweating is a very effective way to lose heat from the body. Every litre of sweat evaporated from the skin results in @ loss of $80 kcals. The important point here is that the evaporation ‘must oecur from the skin for heat loss to occur. If sweat is wiped away or absorbed in a towel, there is only water (and electrolyte) loss and no heat loss. ‘The ambient temperature and humidity a and thus heat loss, High humidity marke mportant in determining the rate of evaporation creases the rate of evaporation Say you were called to assess a febrile patient and when you arrived the patient was hot and sweaty. What is the significance of this? When a patient is ill and the body temperature is still rising to an increased hypothalamic set point, the skin is dry and typically shivering is present. When the set point is decreesed again, the patient tops shivering and starts sweating. This causes heat loss and a fall in body temperature cance of e hot end sweaty patient is thatthe temperature to fall, Amtipyretics are not necessary. You can confidently predict that the fever will subside (Ge the fever has “broken”)Fluid & Electrolyte Physiology 2 Infusion of 1000mls of 3N Saline What are the effects of an infusion of 1,000 mls of 3N Saline? ‘This solution is very hypertonic with an osmolality (about 900 mOsnvkg) three times that of plasma. The fluid shifis and osmolar changes that occur can be predicted, The Nz” content of the fluid limits the distribution of the infused fluid to the ECF. Water crosses cel] membranes easily and distributes passively in response to osmolar gradients. The infused fluid is hypertonic so additional water will be drawn out of cells until the tonicity is the same on both sides of the membrane Consider a 70 kg subject with 2 TBW of 42 litres (ICF 23 litres: ECF 19 litres) with en ‘osmolality of 290 mOsnvkg. (& assuming that | litre of water weighs I kg) Before che infusion Total body solute content ECF solute conten ICE solute content 2 x 290 = 12,180 mOsm, After the infusion: oral body water Total body solute content = 12,180 ~ 900 = 13,080 mOsm, ECF solute content = 5,510 ~ 900 = 6,410 mOsm ICF solute content = 6,670 mOsm (je unchanged) Therefore Osmolality = 13,080 /43= 304 mOsm/kg ECF volume = 6,410 / 304» 21.1 litres, ICE volume = 6.670 / 304 = 21.9 litres. ‘The increase in ECF volume is 2.1 litres with about a quarter of this (say 500 mis) insravascularly. Plasma osmolality has increased by 4.8% and this is well above the threshold (1 to 2%) of the hypothalamic osmoreceptors. The blood volume has increased by about 10%, The volume receptors respond to changes above about 7 to 10%. ‘The increase in osmolality will be sensed by the osmoreceptors in the hypothalamus and this will be a potent stimulus to the secretion of ADH to retain water in the kidneys. Thirst will also be increased, The increase in blood volume is at about the lower level of sensitivity of the volume receptors. The effect via the volume receptors will be to inhibit ADH secretion 19 allow water excretion, In general, volume stimuli tend to be less sensitive but more potent than osmotic stimuli ‘There will also be effects on Na“ excretion. The volume expansion will stimulate secretion of atrial natriuretic factor (ANF). Secretion of aldosterone will be inhibited because of a decreased renin and angiotensin LI production, ANF also inhibits renin secretion, ‘The final outcome of all these changes is natriuresis and excretion of the excess water. The increased osmolality by tending to cause an increased ADH will inhibit the rate of excretion of the excess water, ‘The decrease in ICF volume may have effects on the brain with confusion and obtundation due to cerebral cellular dehydration and hypertonicity. These effects on cerebral function will probably be the predominant clinical effects. The function of other organs or tissues is unlikely to be significantly affected ‘The increase in ISF volume is not sufficient to cause oedema or interfere with gas transfer or nutrient and waste transfers between cells and capillaries