ICU Primary Exam

Vivian Imbriotis

These are my primary exam notes. They have not been vetted and are not useful.

Pharmacology

One compartment model One compartment model A one compartment model has an input, an elimination, and a volume. The drug is introduced and is diluted by the volume of distribution. It is then first-order eliminated. Ke, Clearance, volume of distribution, half life Ke relates amount of drug in the compartment to rate of elimination:$$\frac{dX}{dt} = k_e \cdot X$$The half life is $$t_{1/2} = \frac{\ln 2}{k_e}$$Clearance relates concentration in the compartment to rate of excretion:$$\frac{dX}{dt} = Cl \cdot C_X$$They are related by the volume of distribution (a larger volume of distribution dilutes the drug, so for the same clearance, $k_e$ is lower):$$k_e = \frac{Cl}{V_d}$$After a bolus,$$X = \text{Dose} \cdot e^{-k_et}$$and$$C = \frac{\text{Dose}}{V_d} \cdot e^{-k_et}$$After initiation of an infusion at rate $k_0$, we have:$$C = \frac{k_0}{Cl} \cdot (1 - e^{-k_et})$$ Effect site concerntration The effect site is a theoretical compartment with vanishingly small volume where the drug target resides (e.g the brain, the neuromuscular junction). We can't measure the effect site, but we can measure the effect of the drug (e.g. BIS, train-of-hour, spectral edge) and use experiments to model it. Its transfer to and from the central compartment is characterized by two transfer constants $K_{1e}$ and $K_{e0}$, which are related by the intercompartmental clearance $Cl_1e = K_{1e} \cdot V_1 = K_{e1} \cdot V_e$
Multicompartment model Multicompartment model These are the dark domain of Charles Minto. Nothing can save you from them. Bi-exponential solution This is the closed from solution to the 2-compartment model.$$X = dose \times \left(A e^{-\alpha t} + B e^{-\beta t} \right)$$What are A and B, alpha and beta? Horrible combinations of the various ks in the model. Distribution phase:Rapid loss of solute from central compartment into peripheral compartmentElimination phase:Slow elimination of solute from central compartmentFalling central concentration drives redistribution from peripheral compartment Context-sensitive half time "Time taken for a drug to fall to half it's initial plasma level after stopping an infusion."Depends on:Duration of infusion (longer $\to$ more accumulation in peripheral compartments)VdSS (higher $\to$ less drug in unbound plasma to be cleared)Elimination rate constant VdSS Volume of distribution at steady state. Equal to the sum of all the volumes of all the compartments!
Absorption, first pass, and bioavailability Absorption, first pass, and bioavailability Absorption is the process of a drug moving from its site of administration to the plasma. Absorption occurs prior to first pass metabolism. Oral absorption has two steps:The dissolution of the tablet in chymeThe movement of the drug across the GIT membrane. Most drugs are absorbed by simple or facilitated diffusion, and are therefore governed by Fick's law:$$\frac{dX}{dt} = \text{D} \cdot \Delta C \propto \frac{\text{SA}\cdot\text{solubility}}{\text{Thickness}\sqrt{MW}}$$First pass metabolism has two components:Enterocyte metabolism of drug (e.g. of midazolam)Hepatic metabolism of drugNeglecting the first component, for a drug that only undergoes hepatic metabolism, the bioavailability is expressed as $1 - HER$$$\underbrace{\text{Drug in tablet} \to \text{drug in chyme} \to}_{\text{Absorption}} \underbrace{\text{drug in portal plasma} \to \text{drug in systemic plasma}}_{\text{First pass metabolism}}$$ Drug factors influencing oral absorption Step 1: Tablet dissolutionTablet disintegration: Stability of tablet determines rate of drug dispersionParticle size: Smaller particles increase rate of drug elution into chymeStep 2: Movement across membraneMode of transport: Passive diffusion, vs facilitated diffusion (gabapentin), vs active absorption (levodopa), vs active excretion by pumps (digoxin).Concentration gradient: higher doses result in higher flux.Molecular mass: lower molecular mass = faster absorptionLipophilicity and pKa: More lipophilic substances are absorbed more readily. Weak acids are ionized when pH is above their pKa i.e. they are UNionized and absorbed in an ACIDIC environment (the stomach). Weak bases are unionized and absorbed in the basic environment of the small bowel. Patient factors influencing oral absorption Gastric motility: decreased motility decreases absorption of all drugs (even those well-absorbed in the stomach) because the small intestine has such a large surface area, and theIntestinal motility: If very high transit diarrhoea, the transit time in the small bowel will be insufficientSplanchnic perfusion: to maintain concentration gradientAvailable surface area: lost in crohn's, coeliac disease, necrosis of villi in shockIntestinal content: food and other drugs that interact with the drug of interestEnterohepatic recirculation: Increases AUC of the drug through reabsorption.Gut microbiota: Metabolism will inactivate the drugMetabolism in intestinal wall: Contributes to first-pass (e.g. of midazolam by CYP) Factors influencing non-oral absorption IM and subcut: depends on regional blood flowSublingual: Small surface area. Bypasses portal circulation = no first pass.Rectal: Small surface area. Distal rectal circulation bypasses portal circulation = partial first pass.Inhaled: Depends on particle size. Particles < 5 micron diameter will reach bronchioles for local effect (e.g. salbutamol). Particles < 1 micron diameter will reach alveoli $\to$ rapid systemic absorption due to large surface area, high blood flow, no first pass. Transdermal: Surface area, skin thickness, drug lipophilicity (and therefore pKa and skin pH), molecular weight. Absorption in critical illness Delayed gastric emptying = decreased drug absorption (paracetamol)Gastric pH is higher = decreased drug absorption (clopidogrel)Increased GIT permeability = increased drug absorption (electrolyte replacement)Decreased mesenteric perfusion = decreased drug absorption (paracetamol)Increased preabsorptive interactions = decreased drug absorption (NG feeds and phenytoin)Decreased active efflux = increased drug absorption (digoxin)Decreased skin/muscle perfusion tissue = decreased absorption from subcutaneous or intramuscular injections (heparin) Antibiotic use = less bacterial metabolism = increased absorption (digoxin) Absorption in shock Anaphylactic shock: increased IM / subcut / transdermal absorption due to systemic vasodilation.Decreased inhalational absorption due to bronchospasm. Decreased GI absorption due to decreased GIT blood flow, delayed gastric emptying, intestinal wall oedema. All other forms of shock: Decreased IM / subcut / transdermal absorbtion due to decreased perfusion. Decreased inhalational absorption due to consolidation ($\downarrow$ SA), low CO ($\downarrow$ perfusion $\to$ $\downarrow \ \Delta C$), and alveolar oedema ($\uparrow$ membrane thickness).Decreased GI absorption due to decreased GIT blood flow, delayed gastric emptying, intestinal wall oedema.
Drug metabolism, elimination, excretion Drug metabolism, elimination, excretion Drug metabolism is a chemical modification of a drug to another (active or inactive) chemical. Drug elimination is the removal of drug from the plasma (by distribution or excretion). Drug excretion is the removal of drug from the body.$$\text{Rate of excretion} = C_{\text{Plasma}} \sum_{\text{organs}} Cl_{organ}$$and$$Cl_H = \frac{Q_H F_{ub} Cl_{int}}{Q_H + F_{ub} Cl_{int}}$$$$Cl_R = F_{ub} \cdot \text{GFR} + Cl_{\text{secreted}} - Cl_{\text{reabsorbed}}$$ Hepatic metabolism Occur in hepatocyte endoplasmic reticuluum. All usually increase water solubility. Metabolites may be inactive, active, or more active than the parent molecule. Prodrugs are inactive substances with active metabolites. Phase 1 reactions: Oxydation, reduction, or hydrolysis. Phase 2 reactions: conjugation with another, polar, molecule (e.g. sulfyl, glucuronyl, acetyl, methyl group). Hepatic clearance and hepatic extration ratio $$Cl_H = Q_H \cdot HER$$The HER is the proportion of drug that is cleared from hepatic blood by the liver:$$HER = \frac{C_{in} - C_{out}}{C_{in}} = 1 - \frac{C_{out}}{C_{in}}$$Note that 1 - HER gives the bio-availability. What determines the HER? From a mass balance:$$\text{Mass into liver} = \text{mass in hepatic vein}+\text{mass metabolized}$$$$C_{in} \cdot Q = C_{out} \cdot (Q + CL_{int})$$$$C_{out} = \frac{C_{in} \cdot Q}{Q + CL_{int}}$$And then from the definition of HER we have$$HER = 1 - \frac{C_{in} \cdot Q}{C_{in}(Q + CL_{int})}$$$$HER = 1 - \frac{Q}{Q + CL_{int}}$$And a funky algebra move gets us$$HER = \frac{CL_{int}}{Q + CL_{int}}$$But we're usually dealing with protein bound drugs, so we have to account for the fraction unbound:$$HER = \frac{F_u CL_{int}}{Q + F_u CL_{int}}$$$$Cl_H = \frac{Q F_u CL_{int}}{Q + F_u CL_{int}}$$When intrinsic clearance is very low, such that it is much smaller than Q,$$Cl_H = \frac{Q F_u CL_{int}}{Q}$$$$Cl_H = F_u CL_{int}$$then clearance does not depend on hepatic blood flow, only intrinsic clearance and fraction unboundWhen the intrinsic clearance is very high, such that it is much larger than Q,$$Cl_H \approx \frac{Q F_u CL_{int}}{F_u CL_{int}}$$$$Cl_H \approx Q$$then clearance is close to hepatic blood flow, and the fraction unbound and intrinsic clearance do not matter.High intrinsic clearance drugs: GTN, lidocaine, ketamine, propofol, morphineLow intrinsic clearance drugs: warfarin, diazepam, rocuronium Important hepatic enzymes in drug metabolism CYP3A4: metabolizes 50% of drugs. Midazolam $\to$ inactive, tacrolimus $\to$ inactive. Induced by azoles and macrolides. CYP2D6: Metabolizes codeine $\to$ morphine, oxycodone $\to$ oxymorphone (potent), metoprolol and flecainide $\to$ inactive. High inter-individual variability (10% poor metabolizers) CYP2C9: Propofol $\to$ inactive, warfarin $\to$ inactive, phenytoin $\to$ inactive. Inducers: carbemazepine, phenytoin, St John's Wort. Inhibitors: Amiodarone, metronidazole, fluconazole, bactrim. Renal clearance $$Cl_R = F_{ub} \cdot \text{GFR} + Cl_{\text{secreted}} - Cl_{\text{reabsorbed}}$$At steady state, we have a constant renal excretion and a constant plasma concentration, so:$$\text{Renal mass excretion} = Cl_{\text{renal}} \cdot C_{\text{plasma}} = C_{\text{urine}} \cdot V_{\text{urine}}$$or$$Cl_{\text{renal}} = \frac{C_u \cdot V_u}{C_p}$$Factors influencing filtrationDrugProtein bindingSize (<30kDa not filtered)PatientRenal blood flowRenal diseaseAgeFactors influencing secretionMultiple drugs compete for the same transporters, which can become saturated:Weak acid transporters (furosemide, beta-lactams)Weak base transporters (trimethoprim, creatinine)p-glycoprotein tranporters (digoxin, verapamil)Factors influencing reabsorptionClinically relevant drugs are not actively reabsorbed, so this is via Fick's lawLow urine flow rate and high dose $\to$ high concerntration gradientUrine pH, pKa, and whether drug is acid or base contribute to ion trapping.
Receptor theory Receptor theory A receptor is a protein that undergoes a conformation change in response to ligand binding. Drugs bind to receptors to produce a physiological effect.The proportion of receptors bound by drug is usually monotonic with drug effect. Competition of multiple ligands for one receptor explains agonist, antagonist, and partial agonist behavior of drugs. Law of mass action $$K_{on}[D][R] = K_{off}[DR]$$$$K_{\text{dissociation}} = \frac{K_{off}}{K_{on}} = \frac{[D][R]}{[DR]}$$When $[D] = K_d$, then...$$[D] = \frac{[D][R]}{[DR]}$$$$[DR] = [R]$$...half of receptors are in the bound state. In general, $$\text{prop. receptors occupied} = \frac{[D]}{[D] + K_d}$$(don't revise the derivation...)$$\text{prop. receptors occupied} = \frac{[DR]}{[DR] + [R]}$$$$= \frac{[D][R]}{K_d([DR] + [R])}$$$$= \frac{[D][R]}{K_d(\frac{[D][R]}{K_d} + [R])}$$$$= \frac{[D][R]}{[D][R] + K_d[R])}$$$$= \frac{[D]}{[D] + K_d}$$ Affinity and the association and dissociation constants Affinity is the tendency of dissimilar chemical compounds to form compounds. $k_{on}$ is the association rate constant. $k_{off}$ is the dissociation rate constant.The dissociation constant is $K_d = \frac{k_{off}}{k_{on}}$. When the effect site concentration equals $K_d$, half of receptors are occupied (so a high $K_d$ implies low affinity and vice versa).The association constant is $K_a = K_d^{-1}$. A high $K_a$ implies high affinity.
Mechanisms of drug effect Mechanisms of drug effect Drugs can exert an effect on the body by four mechanisms:Acting physically or chemically on the body gasses or fluidsActing by agonizing, antagonizing, partially agonizing, or modulating receptors (ion channels, GPCRs, nuclear receptors)Inhibiting enzymesBinding to a foreign substance Drugs acting physiochemically Osmotic: mannitolDensity: helioxAcid-base: sodium bicarbonateRedox: methylene blue, nitrates (in cyanide poisoning)Chelation: Vitamin B12 (cyanide chelation) Drugs acting via ion channels Blockade: lignocaineAllosteric modulation: Benzodiazepines bind to and increase flux throug GABAa receptors Drugs acting via GPCRs GPCRs that increase adenylate cyclase: beta-1 agonistsGPCRs that increase IP3 and DAG: alpha-1 receptor agonists Drugs acting via DNA transcription Cystosol receptors: glucocorticoidsNuclear receptors: thyroid hormone Drugs acting via enzyme inhibition Intracellular: milrinoneExtracellular: neostigmine Drugs that act by binding a foreign substance Binding other drugs: sugammadexBinding toxins: sodium thiosulfate
Dose-response relationships Dose-response relationships For almost all drugs, there is a monotonic relationship between dose and effect. This can be demonstrated with dose-response curves, either for a graded or quantal response (old terms for continuous or binary outcomes). Quantal curves demonstrate the potency, efficacy, LD50, TD50, and ED50 of the drug. Dose-response curves are modified by the presence of an antagonist. Graded response curve This is the curve of a continuous measure of drug effect against dose in an individual subject. Quantal response curve This is the curve of a binary measure of drug affect against dose in a population. Intrinsic activity, potency, and efficacy The potency of a drug is the dose or concentration required to achieve some effect (usually 50% of the drug's maximally effect, the $ED_{50}$ or $EC_{50}$. The efficacy of a drug is the maximal effect achievable by that drug $E_{max}$. The intrinsic activity is the maximum efficacy of a drug as a fraction of the maximum efficacy of a full agonist. Agonists An agonist is a drug that binds to a receptor, induces a conformational change, and thereby a physiological response.Agonists can bind to the binding site of endogenous ligands ('orthosteric') or to other binding sites ('allosteric').Full agonists will produce the maximal response the target system can acheive. It has an intrinsic activity of one. E.g. oxycodone. Partial agonists have a lower efficacy than full agonists, and an intrinsic activity between zero and one. In the presence of a full agonist they will act as an antagonist. E.g. buprenorphine Inverse agonists have a negative efficacy, they decrease the activity of the receptor below its basal function. E.g. naloxone. Antagonists Antagonists have an intrinstic activity of zero, but a nonzero affinity. A competitive antagonist binds to the same site as the agonist. A sufficient concerntration of agonist can displace it. It reduces the potency of the agonist but not the efficacy. A noncompetative antagonist binds to some other site, rendering the receptor useless to the agonist. They reduce both the potency and efficacy of the agonist. LD50, ED50, TD50, therapeutic window and index Consider a quantal dose-response curve. The ED50 is the dose at which 50% of subjects achieve the binary therapeutic effect.The TD50 is the dose at which 50% of subjects achieve the binary toxic adverse effect (note the issues here: DAEs may not be dose-related and may take a long time to emerge e.g. carcinogenesis). The LD50 is the dose at which 50% of subjects die. $$\text{therapeutic index} = \frac{TD_{50}}{ED_{50}}$$
Adverse drug reactions Adverse drug reactions An adverse drug reaction is a reaction whereThe reaction is directly related to the drugThe drug was being used correctly and appropriatelyThe reaction is harmfulType A: Augmented dose-related adverse effects (hypotension from antihypertensives)Type B: Bizarre dose-independant adverse effects (anaphylaxis)Type C: Chronic Dose- and Time-related (HPA axis suppression)Type D: Delayed Time- related effects (tardive dyskinesia)Type E: End-of-use withdrawal effectsType F: Failure of therapy (antibiotic resistance, ECMO adsorbtion, plasmapheresis removal).
Drug-drug interactions Drug-drug interactions Drug-drug interactions can be pharmacokinetic or pharmacodynamic.Pharmacokinetic interactions involve absorption, distribution, metabolism and elimination.Pharmacodynamic interactions can produce synergism or antagonism.Pharmacodynamic interactions involve Binding to the same siteBinding to different sites on the same receptorBinding to different receptors, but affecting the same messenger systemAffecting different messenger systems, but the same physiological process Pharmacokinetic drug interactions Absorption interactionsInsoluble complexes: bisphosphinates and calciumInhibition of efflux pumps: verapamil inhibits p-glycoprotein, increases digoxin absorption. Distribution interactionsCompetition for protein bindings sites: phenytoin and valproateMetabolism interactionsCompetition for enzyme: warfarin and phenytoin both metabolized by CYP2C9Induction or inhibition of enzyme: carbemazepine increases CYP2C9, removing warfarinExcretion interactionsCompetition for transporters: metformin and trimethoprim at the OCTIon trapping: acetezolimide ion traps salicylates in urine Pharmacodynamic drug interactions Binding to the same site: Antagonism between opioids and naloxoneBinding to different sites on the same receptor: synergism between benzodiazepines and alcohol on the GABAa receptorBinding to different receptors, but affecting the same messenger system: e.g. high-dose insulin increases intracellular calcium in beta-blocker overdoseAffecting different messenger systems, but the same physiological process: e.g. administration of noradrenaline in dihydropyradine overdose.

Cells

Membrane voltage Membrane voltage The resting membrane potential is maintained by three mechanisms:First, by selective permiability to potassium and chloride, which have Nerst potentials of -90 and -80. respectively.Second, by the 3Na/2K ATPase pump, which exports charge and maintains the potassium gradient. Third, by the Gibbs-Donnan effect, where impermiate intracellular anions generate a charge difference. The Nernst potential If there is a membrane, permeable only to one ion, then the voltage across the membrane is given by the Nernst potential for that ion.$$\Delta V = \frac{RT}{zF}\ln\frac{[Ion]_{\text{out}}}{[Ion]_{\text{in}}}$$where R is the gas constant, T is the absolute temperature, z is the ion valence, and F is the Faraday constant. $\frac{RT}{F} = 26.7\text{mV}$. This gives a good way to understand the opening of an ion channel - it "drags the membrane voltage towards the Nernst potential for that ion". The Goldman-Hodgekin-Katz equation This is an extension of the Nerst equations to account for multiple ions:$$\Delta V = \frac{RT}{F} \ln \frac{\sum_{\text{Cations C}} P_C[C]_{out} + \sum_{\text{Anions A}} P_A[A]_{in}}{\sum_{\text{Cations C}} P_C[C]_{in} + \sum_{\text{Anions A}} P_A[A]_{out}}$$When the permeability of all but one ion is set to zero, this reduces to the Nerst equation. The Gibbs-Donnan effect This occurs when there is an impermiable ion on one side of a semipermiable membrane. Consider the case of anionic protein inside a cell, with a membrane permiable to chloride.The chloride diffuses down its concerntration gradientThis creates a negative charge in the inside of the cellThis drags some cations, against their concerntration gradient, into the cellThe overall effect is to create a negative intracellular charge and an increase in intracellular osmolalityThe osmolality change is counteracted by sodium export from the Na/K pump in vivoThis effect also amplifies the oncotic pressure exerted by plasma proteins, with exert a Gibbs-Donnan influence by dragging extra cations into the plasma (in excess of what would be expected from their charge).
Transport across membranes Transport across membranes Simple diffusion: the molecule passes either through a channel or simply through the lipid bylayer. This is goverened by Fick's law for solutes:$$Flux = \frac{K \cdot \Delta C \cdot SA}{\text{Thickness}}$$Facilitated diffusion: the molecule binds to a protein, they move together through the lipid bilayer. Governed by Fick's law until saturated (e.g. aquaporins).Primary active transport: The substance is moved, hydrolyzing ATP (e.g. the Na/K pump)Secondary active transport: Substance one (usually sodium) is actively transported, then substance two is either symported or antiported with it. E.g. SGLT2 symporters, Na/Ca antiporters.Exocytosis: Vesicle containing a substance to be secreted fuses with the cell membrane when activated by calcium, depositing the substance outside the cell.Endocytosis: The cell membrane invaginates around the substance, absorbing the substance into the cell. A vesicle (or vacuole) may or may not be created. Endocytosis may be subdivided into phagocytosis and pinocytosis (big and small vesicles).
Organelles Organelles Organelles previously interrogated in the exam include: The mitochondria 2 membranes which create three spaces:The cytoplasmThe intermembrane spaceThe inner mitochondiral matrixThe mitochondria is the site of aerobic metabolism. The citric acid cycle crackles along in the inner matrix, producing electron donators that reduce the cytochrome enzymes in the inner membrane proteins, which pumps hydrogen ions into the intermembrane space to power ATP synthase. The inner matrix is also the site of beta-oxydation and haem synthesis. The cell membrane Structure:5nm thick membraneLipids (50%):Phospholipid Bilayer, polar phosphate group and nonpolar fatty acid tail; Choelsterol, provides rigidityProteins (50%)Surface proteinsReceptors → Δ cell fn when bound by ligandsEnzymes → Catalyse reactionsCell adhesion molecules → anchor cells to neighbours or basal laminaeIntegral Proteins → provide stabilityTransmembrane ProteinsIon Channels/Carriers → passive transportPumps → active transport; maintain homeostasisFunction:Barrier functionSelective permeability (e.g. to glucose)Signal transduction The nucleus StructureInner and outer nuclear membrane with nuclear poresNucleoplasm consisting of hetero- and euchromatinNucleolus, site of manufacture of ribosomes and RNAFunctionConcentrates and maintains DNARegulates gene expression Other organelles Endoplasmic reticuluum: 3d mesh of membranous sheets. RER bears ribosomes and is site of most protein transcription. SEM is site of phospholipid and steroid manufacture.Golgi apparatus: Stacked cysternae which gives off vesicles. Post-transcriotion modification of proteins. Prepares proteins for exocytosis.Cytoskeleton: Provides structure, contributes to motility.

Respiratory

Non-ventilatory functions of the lungs Non-ventilatory functions of the lungs They do other things too! A summary of non-ventilatory lung functions A FIRM TITS is the unfortunate acronym.Acid-base: controling PaCO2Filtration: of gas and bloodInfection control: by secreting IgA and the mucociliary escalatorReservoir: of blood (500mL), O2 ($2.2L \cdot 0.21\text{FiO2} \approx 500mL$Metabolism: ACE acts on ATI and bradykinin, $\alpha 1\text{-antitrypsin}$ acts on neutrophil elastaseThermoregulation (and humidification, water retention): by the warming of turbulent gas during inspirationInhaled route (for drugs)Talking / phonationSurfactant production Heating and humidification Isothermic saturation boundary: point where gas hits body temperature and 100% relative humidity. Usually at secondary bronchi.During inspiration, cool, dry gas flows past warm musosa. Fluid evaporates from the mucosa into the dry gas. At the same time, heat is transferred by convection from musosa to gas, cooling the mucosa.During expiration, warm, humid air flows past the cooled mucosa. Gas condenses on the cooler mucosal surface, and heat is transferred from gas back to mucosa. The warmer the environment, the less the gas can be cooled as it is exhaled, and the more fluid is lost.This process relies on turbulent flow, which is promoted by the nasal turbinates.
Control of breathing Control of breathing Physiological factors that affect breathing include PaCO2 (most potently), PaO2, pH, temperature and fever, fear, pain, anxiety, and stimulation of pulmonary nerve fibres (chemical irritation, pulmonary oedema). Sensors for control of breathing Aortic Arch chemorecetors. Respond to low oxygen content, high PaCO2, low arterial pH, high temperature. Via vagus nerve.Carotid body chemoreceptors. Respond to low PaO2, high PaCO2, high temperature. Via glossopharyngeal nerve. Central chemoreceptors in medulla. Respond to local (CSF) pH. As the BBB is impermeable to most acids, but permeable to CO2, and has minimal protein buffering, this is a very sensitive barometer of PaCO2. Via medullary interneurons.J fibers and other pulmonary sensory nerves. Respond to chemical and physical irritants, especially pulmonary oedema. Via vagus nerveCerebral cortex and thalamus, responds to fever, anxiety, pain, fear, and voluntary control. Via white matter tracts. Controllers for control of breathing Respiratory control center in medulla, composed of a collection of neuron groups:Dorsal respiratory group: upper motor neuron to contralateral inspiratory musclesVentral respiratory group: upper motor neurons to contralateral expiratory musclesNucleus Ambiguus: Airway dilator muscles via viagus nerve $\to$ larynx, pharynxPre-Botzinger Complex: central pattern generatorPontine respiratory group: integrates cortical and thalamic inputs$$\require{AMScd}$$ $$\begin{CD} @. @. {Cortex} @. @. \\ @. @. @VVV @. @.\\ {Thalamus} @>>> {Pontine Resp group} @. @. \\ @. @VVV @. \\ {CNX} @>>> {Pre-Botzinger Complex (CPG)} @. @. \\ @. @VVV @. \\ {DRG} @<<< {Interneurons} @>>> {VRG} \\ @VVV @VVV @VVV \\ {Inspiratory mm} @. {N Ambiguus} @. {Expiratory mm} \\ @. @VVV @. \\ @. @. {Airway dilators} @. @.$$ Effectors for control of breathing Muscles of inspirationPhrenic nerves $\to$ diaphragm $\to$ increased vertical + lateral + AP dimensions of chest $\to$ responsible for 75% of ventilation during TV breathingSpinal nerves $\to$ external intercostals $\to$ increased lateral and AP dimensions of chestCervical plexus $\to$ scalenes, SCM, pectoralis major $\to$ elevention of shoulder girdle, first 2 ribs, sternumMuscles of expirationThoracoabdominal nerves $\to$ rectus, obliques, transversus $\to$ increased IAP $\to$ increased intrathoracic pressureSpinal nerves $\to$ internal intercostals $\to$ decreased AP and lateral dimension of chest CO2 and O2 response curves CO2 response curve in linear, $MV \propto P_aCO_2$O2 response curve is flat for PaO2 > 80, then sharply rises at a PO2 of 60
Mechanics of breathing Mechanics of breathing Inspiratory musclesDiaphragm: contracts, flattens, increases vertical dimension of chestExternal intercostals: bucket handle action, increase AP and lateral dimensions of chestAccessories (SCM, scalenes): pump handle action, increase vertical dimension of chestExpiratory musclesAbdominal muscles increase IAP -> increase ITPInternal intercostals: decrease AP and lateral dimensions of chestPleuraFilled with incompressable fluid. -5cmH2O at rest. With inspiration, overcome the elastic recoil of lung.AlveolusExpands during inspiration. Alveolar pressure falls below atmospheric pressure, Flow from upper airways to alveolus. Inflates until pressure equalizes, then flow ceases.
Oxygen and CO2 cascade Oxygen and CO2 cascade These describe the series of concentration gradients that drive the diffusion of oxygen from the atmosphere into the mitochondria, and the diffusion of CO2 from the mitochondria to the atmosphere. Oxygen Cascade Atmosphere. Here the total pressure is 760mmHg at sea level, and $760 \cdot FiO_2 = 760 \cdot 0.21 = 160\text{mmHg}$Isothermic saturation boundary. Here the gas is heated to 37% and 100% relative humidity; here 47mmHg of H2O dilutes atmospheric gas, leaving $(760-47) \cdot 0.21 = 713 \cdot 0.21 = 150\text{mmHg}$Alveolus. Here the gas is diluted by CO2 diffusing out of the blood. Via the alveolar gas equation:$$P_AO_2 = (760 - P_AH_2O) \cdot FiO_2 - \frac{P_aCO_2}{RQ}$$$$P_AO_2 = 150 - P_aCO_2 \cdot 1.25$$$$P_AO_2 = 150 - 50 = 100$$Arterial blood. Here the oxygen tension is diluted by venous admixture (from thebesian and bronchial veins). The difference between this and the PAO2 is the A-a gradient (normal is 7 in youth, 14 in age), so PaO2 = 92Tissue. Tension drop due to diffusion distance, PO2 10-30mmHgMitochondria. Tension drop due to diffusion distance, PO2 1-10mmHg CO2 cascade Mitochondria. Highly variable depending on tissue metabolic rate. PCO2 20-100mmHgTissue. Tiny drop in tension due to diffusion distance. Capillary blood. Highly variable depending on metabolic activity of tissue. Mixed venous blood. $P\bar{v}CO_2$ is 6mmHg higher than PaCO2, or about 46mmHg. Alveolar capillary blood. Here oxygen charges in, flicking the haemoglobin into R state and displacing bound CO2 - the "reverse Haldane" effect. This spikes the PCO2 to... say, 50mmHg [citation needed]. Alveolar gas. Identical to alveolar capillary blood due to high diffusivity of CO2Atmosphere. PCO2 of 0.3mmHg.
Respiratory compliance Respiratory compliance For an elastic container, the compliance is the change in volume brought about by a unit change in pressure:$$C = \frac{\Delta V}{\Delta P}$$It is the reciprocal of elastance, which is the pressure exerted by the vessel against a given filling volume:$$\text{Elastance}=\frac{\Delta P}{\Delta V}$$ Dynamic compliance Dynamic compliance is the apparent compliance that is measured in the presence of gas flow, i.e. during breathing. $$C = \frac{\Delta V}{\Delta P}$$$$C_{dyn} = \frac{TV}{PIP - PEEP}$$This is affected by all the determinants of static compliance, but also by airway resistance and respiratory rate ('frequency dependence'). The latter is becauseIncreasing respiratory rate increases the pressure required to overcome a fixed resistance, and increases gas velocity, which favours turbulent flow and increases resistanceThe respiratory units with lower compliance fill first due to shorter time constants. As inspiratory time shortens, the proportion of volume going to these units increases. Static and specific compliance Static compliance is compliance measured in the absence of gas flow. The compliance of the respiratory system is composed of the compliance of the chest wall and the compliance of the lung.In this case, elastances add, not compliances. This is because the change in volume is constant across all the components, and the pressures are additive (consider stuffing one balloon inside another balloon and then inflating both balloons together. The total elastance is naturally the sum of the two balloon's elastances, since both are recoiling against the same volume). Therefore$$\text{Elastance}_{Total} = \text{Elastance}_{Lung} + \text{Elastance}_{wall}$$$$\frac{1}{C_{Total}} = \frac{1}{C_{Lung}} + \frac{1}{C_{wall}}$$$C_{Lung}$ and $C_{wall}$ are both about 200ml/cmH20, so $C_{total}=200\mathrm{ml\ cmH2O^{-1}}$Specific compliance is compliance over FRC. Usual value is $0.05 \mathrm{cmH2O^{-1}}$. 1cmH20 should drive five percent of FRC. For an adult with a 2L FRC, 1cmH2O should drive a $\Delta V$ of 100mL (so a pressure support of 5cmH2O should drive a 500mL tidal volume). Factors increasing $C_{Lung}$Volume close to FRCUpright positionAgeEmphysemaFactors decreasing $C_{Lung}$Decreased effective volume: lobectomy, atelectasis, pneumoniaInterstitial changes: interstitial fibrosis, pulmonary oedema, increased pulmonary blood volumeExtremes of volume (derecruitment, overdistension)Loss of surfactant (ARDS)Factors increasing $C_{Wall}$Open chest ($C_{Wall} \to \infty$) and it's cousins (flail segments, rib fractures)Ehler-DanlosCachexiaFactors decreasing $C_{Wall}$Bones: kyphoscoliosis, pectum exscavatumMuscles: tentany, seizureSkin: circumferential burnsAdipose: obesityExternal compression: supine or lateral positoin, abdominal compartment syndrome Hysteresis For any given pressure, the lung volume is higher during expiration than during inspiration. This is due to:Surface tension forces which need to be overcome to inflate alveoli ($\mu \propto \frac{Pr}{T} \to P \propto \frac{1}{r}$. Surfactant behaves differently during inspiration and expiration (with surfactant concerntrated at the air-fluid interface during expiration)Re-recruitment of collapsed alveoli during inspirationStress relaxation of elastic polymers (loss of energy at end-inspiration)
Respiratory resistance Respiratory resistance Gas flows from areas of higher to lower pressure. The opposition to this flow is resistance.In laminar conditions, $\dot{V} \propto \Delta P$, so resistance is well defined (as the constant of proportionality). This is sometimes called "ohm's law for a pipe" by analogy with the linear electrical resistance seen in circuits.In turbulent conditions, $\dot{V} \propto \sqrt{\Delta P}$ and resistance is not well-defined. Turbulance and resistance Turbulence significantly increases opposition to flow. In turbulent conditions, $\dot{V} \propto \sqrt{\Delta P}$Reynold's Number is the ratio of a fluid's inertia and viscosity. Turbulence occurs when this quantity is >2000. In a pipe of fixed diameter,$$Re = \frac{\rho V D}{\mu}$$where $\rho$ is density, V is fluid velocity, D is pipe diameter, and $\mu$ is viscosity. Confusingly, decreasing diameter would appear to decrease the Reynold's number. But, for a fixed gas flow Q, we have$$Q = V \cdot \pi \left( \frac{D}{2} \right)^2$$$$Q = V \cdot \pi \frac{D^2}{4}$$$$V = \frac{4Q}{\pi D^2}$$and therefore$$Re = \frac{\rho 4Q D}{\mu \pi D^2}$$$$Re = \frac{\rho 4Q}{\mu \pi D}$$So, if gas flow (minute ventilation) is held constant, then a smaller diameter increases turbulence. Resistance in laminar flow In laminar conditions, $\dot{V} \propto \Delta P$, or $\dot{V} = \frac{\Delta P}{R}$Resistance to laminar flow is given by the Hagen-Poiseuille equation.$$R = \frac{8 l \mu}{\pi r ^ 4}$$Where l is the pipe length, $\mu$ is the viscosity, and r is the pipe radius. Factors affecting resistance in the lungs Lung volume decreases resistance by expanding the airways through radial tension from the elastic tissues.Airway radius is the most important, and is affected by:Bronchiolar muscle thickness (hypertrophied in asthma)Bronchiolar muscle tone ($\uparrow$ $H_1$, $M_3$, bronchospasm; $\downarrow$ $\beta_2$ Mucus and secretionsAirway oedemaCompression or obstruction (extrinsic, gas trapping, forced expiration, ETT kinked).Airway length is increased by circuit components e.g. increased by ETT, decreased by tracheostomyGas velocity ($\therefore$ turbulence) is increased by a short inspiratory time or high respiratory rate.Gas density ($\therefore$ turbulence) can be reduced by heliox.Resistance is much higher in infants.
Work of breathing Work of breathing Work of breathing is the energy expended by the muscles to take one breath.$$\Delta E = \int P dV$$Each breath consists of elastic work, inspiratory resistive work, and expiatory resistive work. Elastic work is done on inspiration against the elastic tissues (lung, chest wall, surface tension). It is stored as elastic potential energy, which is released during expiration (65% of work)Inspiratory resistive work is the remainder of work during inspiration, which is lost as heat. It is done against tissue resistance and airflow resistance. It is increased at high respiratory rates or with high resistance. Usually, expiratory resistive work is less than the stored elastic potential energy, so there is no net work during expiration. With active expiration where the intraplueral pressure falls below resting pressure, there is additional resistive work. Minimizing Elastic WOBMaximize compliance by keeping lung close to FRC and recruiting with PEEPGive surfactant if needed to minimize surface tension.Minimizing resistive WOBIncrease airway radius (bronchodilators)Ensure laminar flow (decrease flow rate, decrease RR, consider heliox)Avoid active expirationFor a given minute ventilation, WOB is minimized by a given respiratory rate. Higher respiratory rates (with lower tidal volumes) decrease elastic work but increase resistive work.
Pulmonary vascular resistance Pulmonary vascular resistance Pulmonary vascular resistance is the hydraulic resistance of the pulmonary vessels (veins, capillaries, arteries).$$\Delta P = \text{PVR} \cdot Q$$This flow is laminar, so the resistance is given by the Hagen-Poiseuille equation:$$R = \frac{8 \mu l}{\pi r^4}$$Where l is the tube length, r is the pipe (total cross-sectional) radius, and $\mu$ is the fluid viscosity. It is influenced by six factors. PVR and pulmonary arterial pressures Confusingly, PVR is not independent of pressure. Resistance falls roughly with $\frac{1}{\Delta P}$, due toRecruitment: Collapsed cappillaries are reexpaned by higher pulmonary arterial pressures $\to$ added in parallelDistension: Elastic capillaries are stretched by higher pulmonary arterial pressures $\to$ increased vessel radiusTherefore, the relationship between PAP and pulmonary blood flow is roughly parabolic:$$Q \propto {\Delta P}^2 \text{ (roughly)}$$ PVR and Lung volume PVR is minimal at FRC.At volumes greater than FRC, the expanded alveoli compress the small pulmonary capillaries, increasing PVR. At volumes less than FRC, the larger pulmonary arterial vessels, which are thin-walled and stented open by radial tension from the elastic lung parenchyma, collapse due to loss of this radial tension. PVR and hypoxic pulmonary vascoconstriction Mechanism:Low O2 sensed by pulmonary endothelial cells. Exact mechanism unknown (possibly direct effect on O2-sensitive K channels)Suppression of normal eNOS activityDecreased NO release $\to$ diffuses into smooth muscle cellsDecreased cGMP Decreased protein kinase G $\to$ smooth muscle relaxation(note that sildenafil blocks this pathway by preventing cGMP breakdown by PDE5)And:Endothelin-1 released from pulmonary endothelial cellsBinds to endothelin-A receptors on smooth muscleCalcium influxPotent vascoconstriction(note that bosentan blocks this pathway by antagonizing endothelin receptor)In normal physiology, HPV improves v/q matching by directing blood away from areas of low ventilation. In global pulmonary hypoxia, however, increases PVR substantially. Biphasic process: rapid, then slow, with very gradual return to normal after withdrawal of hypoxic stimulus. PVR and hormonal/endocrine factors Just a laundry list of things that ALL increase PVR...HistamineCatecholaminesthromboxane A2PaCO2 (mildly)Acidaemia Drugs that affect PVR Pulmonary vasodilatorsMilrinone (PDE3i)†Levosimendin (calcium sensitizer that also opens endothelial $K_{ATP}$ receptors) (note NOT dobutamine!)**Vasopressin**CCBs, ACEIs, PDE5is e.g. sildenafil, endothelin antagonists e.g. bosentanNitric oxide / nitroglycerin†Prostacyclin††inhaled agentPulmonary vasoconstrictors (basically all non-vasopressin systemic vasocostrictors...)CatecholaminesMethylene blue PVR and blood viscosity Because of Poiseuille:Paraproteinaemia (MM, WM)PolycythaemiaRaging leukaemiaThrombocytosis
Regional variation in ventilation and perfusion Regional variation in ventilation and perfusion Both ventilation and perfusion are heterogenous, with both being higher in dependent regions of the lung and central (rather than peripheral) lung units. The degree of mismatch between the regional variation contributes to V/Q scatter, which can decrease PaO2 by contributing to the venous admixture. The V/Q ratio in the bases is ~0.6The V/Q ratio in the apices is ~3 The regional distribution of ventilation In an upright position, bases compressed more than apices by weight of lung and by pleural pressure gradient, therefore bases have higher compliance (on a more favourable part of the compliance/volume curve). This means bases are ventilated more than apices.In all positions, central lung units are ventilated more than peripheral lung units. The right lung is ventilated more than the left (because of the heart). The regional distribution of perfusion Perfusion is heterogenous largely due to West Zones.West zone 1: In hypotension or high $P_A$ (e.g. dynamic hyperinflation, high PEEP). $P_A > P_a > P_v$, such that $P_A$ abolishes flow. Flow is either absent or phasic (with the respiratory cycle).West Zone 2: $P_a > P_A > P_v$ such that $P_A$ forms a starling resistor and $\text{Pulmonary blood flow} = \frac{P_a - P_A}{PVR}West zone 3: \(P_a > P_v > P_A$ so normal flow occurs and $\text{Pulmonary blood flow} = \frac{P_a - P_v}{PVR}West zone 4: High interstitial pressure from dependant tissue oedema causes a rise in the interstitial pressure such that \(P_a > P_I > P_v$ and the interstitial pressure forms a starling resistor, \(\text{Pulmonary blood flow} = \frac{P_a - P_I}{PVR}The net effect is that the bases are perfused much more than the apices, especially when alveolar pressure is high or PASP is low. Central units and perfused more than peripheral units. V/Q matching including effect of position V/Q is optimal at 1V/Q 0.6 at the apex (over-ventilated; West Zone 2) and 3 at the bases (over-perfused; West zone 4), because perfusion increases more dramatically moving from cranial to caudal. V/Q matching is best in the prone position, because this eliminates the pleural pressure gradient (there is no appreciable anterior-posterior gradient). Pleural pressure gradient Pleural pressure is -10cmH2O at apex, -2cmH2O at bases, because of weight of lung, mediastinum, and pressure from abdominal contents. Affected by position: when supine the effect is halved, when prone it is minimal. In the lateral position the dependant lung's pleural space is less negative (increasing ventilation in a spontaneously breathing patient, potentially decreasing ventilation of the dependant lung in a ventilated patient due to a fall in FRC putting the dependant lung on a flat part of the compliance/volume curve). 
Diffusion of respiratory gasses Diffusion of respiratory gasses Fick's law of diffusion$$\frac{dV}{dt} = k \cdot \frac{\Delta P \cdot SA \cdot \text{solubility}}{\text{thickness} \cdot \sqrt{MW}}$$ Diffusion- vs perfusion-limited transfer If a gas is perfusion-limited, then $t_{\text{equilibrium}} < t_{\text{transit}}$ and increases in perfusion will result in increased rate of transfer. (Normally oxygen is perfusion limited, where $t_{transit} \approx 4t_{equilibrium}$.If a gas is diffusion-limited, then $t_{\text{equilibrium}} > t_{\text{transit}}$, i.e. there is still a persisting gradient at the end of the capillary. Increases in perfusion will not increase the rate of transfer. CO is an example, because $P_aCO \approx 0$ always, due to its aggressive binding to Hb. Diffusing capacity $$\frac{dV}{dt} = \frac{\Delta P \cdot SA \cdot \text{solubility}}{\text{thickness} \cdot \sqrt{MW}}$$or$$\dot{V} = \text{DL} \cdot \Delta P$$In words, diffusing capacity of the lung = "volume of gas that will diffuse over the membrane per minute per mmHg"CO is used to measure this because $P_aCO_2$ is always almost zero due to its Hb affinity. Therefore$$\frac{V_\text{CO exhaled} - V_\text{CO inhaled}}{\text{time}} = \text{DLCO} \cdot (P_ACO - P_aCO)$$$$\frac{V_\text{CO exhaled} - V_\text{CO inhaled}}{\text{time}} = \text{DLCO} \cdot P_ACO$$Measured thusly:Exhale to RVInhale mix of oxygen, helium, and CO to TLCAllow time for equilibriumExhale, discarding dead space gasMeasure $P_{exhaled}He$ and $P_{exhaled}CO$Compute the TLC from $P_{exhaled}He$Compute the uptake of CO from the difference in CO partial pressure and then the DLCOFactors affecting diffusing capacity are:Gas factors: molecular weight, solubility, temperatureSurface area factors: age ($\downarrow$), lung volume ($\uparrow$) and therefore position, lung disease, obesity, pregancy. Shunt and dead space both decrease effective SA; V/Q scatter decreases efficiency.Membrane thickness factors: pulmonary oedema, interstitial lung diseaseErythocyte uptake factors: [Hb], cardiac output (in low output states Hb can become more saturated with CO)Sources of error: alveolar haemorrhage, endogenous CO from smoking or haemolysis, high FiO2 (competes)Significant increase with exercise!
Respiratory anatomy Respiratory anatomy . Nasal cavity anatomy RelationsInferior: roof of mouthsuperior: cribriform plateposterior: nasopharynxanterior: external nose, nareslateral: orbit, maxillary sinusmedial: septumFeaturesVestibular area (skin, at nares), olfactory area (at roof), respiratory area (ciliated columnar)Contains hairs which filter large particlesChonchae: promote turbulant flow to faciliate heating and humidification of inspired gas, and reclaimiation of expired gasFunction  Humidification and warming of inspired air  Reclamation of expired moisture and heat  Olfaction and sense information about air temperature  Speech (nasalisation)  Sneezing (protective reflex) Oral cavity anatomy RelationsSuperior: hard and soft palateinferior: tonguelateral: cheeksanterior: lipsposterior: oropharynxFeaturesTongue sensory:     Anterior 2/3: lingual nerve & chorda tympani    Posterior 1/3: Glossopharyngeal nerveTongue taste: Anterior 2/3: facial Posterior 1/3: GlossopharyngealTongue motor: Hypoglossal, nerve, except for the palatoglossus muscle (supplied by cranial part of the vagus)Function Respiration (alternative airway, low resistance at high MV) Mastication Saliva (digestive and immunological roles) Speech Sensory roles, including taste Pharynx anatomy Pharyngeal dilator reflexNegative upper airway pressure $\to$ mucosal stretch receptors $\to$ hypoglossal nucleus $\to$ genioglossus and other dilator musclesGenioglossus pulls base of tongue anterior (hypoglossal N) and maintains upper airway patency Larynx anatomy Relations  Superior: hyoid  Anterior: skin, thryoid Inferior: becomes trachea at c6  Posterior: laryngeal inletLaryngeal inlet    Faces backwards and upwards    Bounded anteriorly by the upper edge of the epiglottis,    Bounded laterally and postriorly by the aryepiglottic folds    Bounded posteriorly by the interarytenoid fissure  Divided by the vocal folds into upper and lower halfFeaturesSupply: superior and inferior thyroid arteriesInnervation: all muscles by the recurrent laryngeal nerve except cricothyroid (external laryngeal nerve)Function  Respiration (conductive airway)  Swallowing  Phonation  Cough reflex Trachea anatomy Relations: Superior: larynx at c6 Inferior: carina at t5Features Innervations by vagus and recurrent laryneal nerves Posterior wall formed by trachealis muscle (constricts during coughing $\to$ increased gas velocity)Function  Airway  Cough  Mucus clearance: mucociliary escalator function  Restoring the position of the larynx during swallowing Alveolar structure Diaphragm anatomy Diaphragm is dome-shaped fibromuscular structure. Separates thoracic and abdominal cavities. Primary muscle of inspirationOrigin: L1-L3 posteriorly, costal cartileges 6-12 anterolaterallyInsertion: central aponeurotic tendon continuous with inferior pericardium + liver capsuleOpenings:Caval hiatus @ T8: contains IVCOesophaeal hiatus @ T10 contains oesophagus, vagal trunksAortic hiatus @ T12 contains aorta, azygous veinSupply: aorta $\to$ superior and inferior phrenic arteriesInnervation: Motor and senosry by paired phrenic nn (C3-5)Function:Diaphragm contracts $\to$ flattens and descendsRibs pushed outwardsAP, lateral, and vertical dimensions of chest increased, abdomen compressed$\uparrow$intrabdominal pressure, $downarrow$intrathoracic pressureInhalation occursOesophageal hiatus constricts $\to$ prevents reflux
Neonatal respiratory physiology Neonatal respiratory physiology Neonates have difficult upper airways that are prone to collapse, as well as less favorable respiratory mechanics, altered O2 transport, and immature control of breathing. The neonatal upper airway More difficult to intubate:  Small mandible  Large tongue  Larger tonsils and adenoids  Superior laryngeal position Large, floppy epiglottis Anatomical subglottic narrowing  Soft, narrow, short trachea Neonatal respiratory physiology MechanicsResistance: higher (smaller airways)Compliance: lower lung compliance (less surfactant), higher chest wall compliance (not ossified)Higher WOB, minimal WOB at respiratory rate 40VolumesSpecific FRC is unchangedClosing capacity is increased (less radial tension on airways)Anatomical dead space is increased (big heads, small chests)Gas transportIncreased shunt due to ductus arteriosusLeft-shifted HbODC due to HbFHigher [Hb] to compensateControl of breathingDecreased response to hypoxia and hypercapnoeaPeriodic apnoeas
The pulmonary circulation The pulmonary circulation The pulmonary circulation carries deoxygenated blood from the heart to the lungs, and oxygenated blood from the lungs to the left ventricle. Physiologically, is a high-flow, low-pressure system that accepts 100% of the cardiac output in adults. Histologically, the vessels are thin-walled, with decreased musculature compared to the systemic circulation.Tracing the path of a blood cell, it travels from the right ventricle, through the pulmonary trunk, pulmonary arteries (elastic, muscular, non-muscular), to the pulmonary capillaries, where it recevives some blessed oxygen. Then to the pulmonary vein, the right atrium, LV, and aorta. The bronchial circulation arises from the left and right bronchial arteries (from aorta), which supply the bronchi. 2/3 of the bronchial veins then drain into the pulmonary veins, forming a shunt.
Volumes and capacities Volumes and capacities The lung consists of several volumes. Capacities are sums of these volumes.Residual volume = 15ml/kgExpiratory reserve volume = 15ml/kgTidal volume = 7ml/kgInspiratory reserve volume = 45ml/kgTherefore total lung capacity = RV + ERV + TV + IRV = 82ml/kgVital capacity = ERV + TV + IRV = 67ml/kgFRC = RV + ERV = 30ml/kgSpirometry can measure ERV, TV, and IRV.To measure RV (and TLC / FRC), we can measure FRC then use spirometry to calculate everything else. Methods of measuring FRC $N_2$ wash-out methodSubject breathes 100% FIO2Exhaled nitrogen concentration over time is collected, and integrated to find total exhaled $N_2$ volumeDividing by 0.79 (initial $N_2\_ concentration) gives TLVDrawbacks: Some \(N_2$ is washed out from blood and tissues (~250mL), only measures ventilated lung volume, leaks will befoul measurementHelium wash-in methodInhale gas bolus of known concentration and volumeHold breath and wait to equilibrate throughout lung volimeExhale gas$$C_1 V_{\text{bolus}} = C_2 (\text{FRC} + V_{\text{bolus}})$$Drawbacks: Helium will dissolve into tissues, only measures ventilated lungBody PlethysmographySubject confined in a closed box; airway pressure + box pressure measuredExhales against closed airway $ \to \ \downarrow V_{\text{Chest}} \ \uparrow V_{box} \ \to \uparrow P_{\text{mouth}} \ \downarrow P_{\text{box}} $Measures whole intrathoracic gas volumeDrawbacks: Expensive, immobile equiptment$$PV = nRT = \text{constant}$$$$P1_{mouth} = P1_{box} = P_{\text{barometric}}$$$$P1 V_{box} = P2_{box} (V_{box} + \Delta V)$$$$\Delta V = V_{box} \frac{P1 - P2_{box}}{P2_{box}}$$$$P1 FRC = P2_{mouth} (FRC - \Delta V)$$$$\Delta V = FRC \frac{P1 - P2_{mouth}}{P2_{mouth}}$$$$FRC \frac{P1 - P2_{mouth}}{P2_{mouth}} = V_{box} \frac{P1 - P2_{box}}{P2_{box}} $$$$FRC = V_{box} \frac{P1 - P2_{box}}{P1 - P2_{mouth}} \frac{P2_{mouth}}{P2_{box}} $$$$FRC = V_{box} \frac{\Delta P_{box}}{\Delta P_{mouth}} \frac{P2_{mouth}}{P2_{box}} $$Because the pressure swings are small compared to barometric pressure, $\frac{P2_{mouth}}{P2_{box}} \approx 1$ and$$FRC = V_{box} \frac{\Delta P_{box}}{\Delta P_{mouth}}$$ Closing capacity The maximal lung volume at which airway closure occurs.Equals RV + closing volume. Effect of increased closing capacityImpairs denitrogenation (collapsed airways when FRC < CC are not preoxygenated)Causes atelectasisCauses age-related decrease in sats by creating shuntAggrevates lung injuryIncreased by:Higher gas flow rateHigher expiratory effortSmall airways diseaseIncreased pulmonary blood volumeDecreased surfactantAge (at 44, supine FRC = CC; at 66, erect FRC = CC)Measured by nitrogen washoutSubject exhales to RV (apical alveoli open, dependant alveoli collapsedInhales 100% FiO2 (apical alveoli filled with mixed gas, dependant filled with pure O2)Exhalation has four stages - dead space is pure O2, then N2 rises with mixed alveolar/dead space gas, plateaus with alveolar gas, then sharply rises again as dependant alveoli collapse and more nitrogenated apical alveoli continue to exhale Determinants of FRC FRC occurs at balance of outwards chest wall recoil and inwards lung recoil, i.e. point of no potential energy. Therefore it is altered by...Factors affecting lung recoilElastic tissue of lung (\uparrow\) in fibrosis, $\downarrow$ in emphysema; age $\to$ FRC increases with ageSurface tension forces (\uparrow\) in infantile ARDSFactors affecting chest wall recoilSkin; FRC $\downarrow$ with circumferential burns Fat; FRC $\downarrow$ with obesityBones; FRC $\uparrow$ with chest fractures, open chest, Ehlers-DanlosExternal compression; FRC $\downarrow$ with $\uparrow$IAP, bindings
Carriage of gasses in the blood Carriage of gasses in the blood The dioxygen molecule looked back at the artery and saw only one set of footprints. "Oh haemoglobin," she cried, "during my time of need, why did you let me circulate alone?""My child," said the haemoglobin, Carriage of oxygen in blood Oxygent content is given by $$C_aO_2 \text{ (in ml/L)} = (1.34 \cdot \overbrace{ceHb}^{\text{[Hb] excl. COHb/metHb}} \cdot SaO2) + 0.03 \cdot P_aO_2$$Obeys Henry's law - dissolved concentration $\propto$ partial pressureCarried as: 99% bound to Hb, remainder dissolved. Poorly water soluble, coefficient 0.003, so content drastically reduced in anaemia.Tension (mmHg): 95 (arterial), 40 (venous)Content (mL/L): 200 (arterial), 150 (venous), $\Delta$ -50Hb dissociation: Sigmoid due to cooperative binding. Each Hb has 4 haem binding sitesDeoxyHb is in T-state, with low O2 affinityWhen an O2 binds to haem, it tugs on the attached histidine residue $\to$ progressive conformational change to R state $\to\ \uparrow$O2 affinityThe p50 is the PaO2 at which sO2 is 50%.Curve is left shifted (increased affinity, poor offloading) by: metHb (left shifts remaining functional Hb), COHb, FHb, $\uparrow$pH, $\downarrow$PaCO2, $\downarrow$2,3DPG, $\downarrow$temperatureand right shifted (decreased affinity, good offloading) by: sulfHb,  $\downarrow$pH, $\uparrow$PaCO2, $\uparrow$2,3DPG, $\uparrow$temperatureThe right-shift induced by rising PaCO2 is called the Bohr effect.These features of Hb facilitate binding of oxygen in the pulmonary capillary (low PCO2, high pH) and offloading in the periphery, especially in hypoxic conditions (high PCO2, low pH). Carriage of CO2 in blood Obeys Henry's law - dissolved concentration $\propto$ partial pressureCarried as: Bicarbonate (80%), dissolved gas (10%), carbamino compounds (10%).Tension (mmHg): 40 (arterial), 45 (venous)Content (mL/L): 480 (arterial), 520 (venous), $\Delta$ +40Hb dissociation: Linear (no cooperative binding). Binds mostly to Hb, also a little to albumin and globulin, as carbamino groups. Transport as HCO3 is also facilitated by Hb via the Hamburger effect:CO2 diffuses into erythrocyte $\xrightarrow{\text{carbonic anhydrase}}HCO_3^- + H^+$Proton buffered by HbBicarbonate antiported with ChlorideRelationship with PaO2 - "The Haldane effect": OxyHb has lower affinity for CO2 than DeoxyHb, so as PaO2 rises, CO2 is displaced. Facilitates binding of CO2 in venous blood and offloading of CO2 in the pulmonary capillary.
Compostion and function of surfactant Compostion and function of surfactant Surfactant is a substances produced by T2 pneumocytes in the lungIt is composed of 90% phospholipids (80% DPPC)8% proteins2% carbohydratesFast turnover, $T_{1/2} \approx$12 hoursSurface tension forcesIn alvoli there is a air-fluid interface. Water molecules attract each other, which tends to collapse the alveolus. The collapsing pressure is given by the young-laplace equation for a sphere: $$\Delta P = \frac{2 T}{r}$$Small alveoli would tend to collapse due to pressure diffrerence with large alveoli, and low intraalveolar pressure draws in fluid $\to$ pulmonary oedemaEffect of surfactantDPPC is amphipathic (hydrophilic glycerol lead, hydrophobic fatty acid tail). Sits at air-fluid interface $\to$ steric hindrance $\to\ \ \downarrow$tension.$\downarrow$Alveolar radius $\to\ \ \uparrow$[surfactant] $\to$ larger effect, stabilizing small alveoli.ThereforePrevents collapse $\to$ better V\Q matchingImproves compliance by decreasing recoil from STPrevents transudation of fluid into alveoliHysteresisDuring inspiration, surfactant moves slowly from fluid phase $\to$ interface; during expiration already at interface. This produces hysteresis (for any given pressure, lung volume is higher during expiration than inspiration).

Cardiovascular

Cardiac Functional Anatomy Cardiac Functional Anatomy The heart, the heart, the heart, the heart is a muscle!Contained in the pericardiumSuperiorly becomes the great vesselsRight border from lower margin rib 3 -> lower margin rib 6 at right sternal edgeInferior border from rib 6 to apexApex located 1cm lateral to left midclavicular lineOriented at ~60 degrees to the left; apex descends during inspiration, and is pushed upwards in pregnancy Chamber and valve anatomy Atrial and ventricles separated by fibrous skeleton of heart (dense irregular connective tissue). They are only electrically connected by the conducting system. Right atrium:Forms right aspect of heartIVC, SVC, and coronary sinus drain hereOne auricleLeft atrium:Forms posterobasal aspect of heart4x pulmonary veins drain hereOne auricleThese are separated by the interatrial septum which bears the fossa ovalisRight ventricle:Concave in shapeContains moderator band (trabeculum containing the RBB)Smooth-walled outflow tract "infundibulum"Left ventricle:Conical in shape3x thicker than the RVBoth contain trabeculae (thick outcroppings of myocardium), the largest of which are called papillary muscles and attach to the AV valves with chordae tendinae, preventing regurgitation.Ventricles separated by the interventricular septumMembranous portion superiorly (thinnest part)Thicker muscular portion basallyThis causes ventricular interdependence (when one ventricle is distended, the septum bulges into the other ventricle and decreases ventricular compliance)Tricuspid valve:Deep to the sternum in the midlineAnterior, posterior and septal cuspsFibrous ringMitral valve:Deep to the sternum in the midline, just superior and left of the tricuspid valveAnterior and posterior cuspsFibrous ringPulmonic valve:At the lower border of the 3rd rib at the left sternal edge. Anterior, right, and left cuspsFibrous ringAortic valve:At the lower border of the third rib, inferior and to the right of the pulmonic valveLeft, right, and noncoronary cuspsNo fibrous ring; 3 triangular fibrous archesCardiac plexusT1-T4 sympatheticsVagus Coronary anatomy Left coronaryArises from aorta just distal to the left coronary cusp of aortic valvequickly bifurcates into anterior interventricular (LAD) and left circumflexLCx gives off obtuse marginalsLAD gives off diagonals and forms anastomosis with PDA at the apexRight coronaryArises from the aorta, just distal to right coronary cuspSupplies the SA node in 60%Travels down the right margin of the heart then circles posteriorlySupplies the AV node in 90%Forms the posterior interventricular artery in 85% of people (right-dominance; the remaining 15% are split between arising from the LCx, LAD, or a combination of vessels) Excitatory elements AV node: small group of cells in the superior right atriumPrimary pacemaker; regular depolarizations regulated by the $I_K$ funny currentIntrinsic rate: 60-100bpmRegulated by parasympathetics from the cardiac plexus (except post-transplant) and serum catecholaminesInternodal tracts: barely-modified myocardiocytes that aid atrial conductionAV node: modified myocardial cells at the basoseptal part of the right atriumCentral part of AV node slows conduction to allow for AV synchrony; accomplishes this due to lack of fast sodium channelsProlonged refractory period, limiting AV conduction to ~220 beats per minute; this is also under autonomic control by hyper-polarization of cellsAutomaticity, with an intrinsic rate ~40bpm (these 'junctional' rhythms result in cannon a-waves)Bundle of His -> right bundle branch and left bundle branch (which becomes left anterior and posterior fascicle) -> Purkinje fibers are all heavily modified myocytes, insulated by fibrous tissue.
The coronary circulation The coronary circulation The left and right coronary arteries provide the entire blood supply of the myocardium. Blood flow through these vessels is determined by the interplay of ventricular and aortic pressures (and therefore by heart rate), by local control which matches flow to myocardial work, and by autonomic control. Functional coronary anatomy Left coronary arteryArises from aorta just distal to the left coronary cusp of aortic valvequickly bifurcates into anterior interventricular (LAD) and left circumflexLCx gives off obtuse marginalsLAD gives off diagonals and forms anastomosis with PDA at the apexRight coronary arteryArises from the aorta, just distal to right coronary cuspSupplies the SA node in 60%Travels down the right margin of the heart then circles posteriorlySupplies the AV node in 90%Forms the posterior interventricular artery in 85% of people (right-dominance; the remaining 15% are split between arising from the LCx, LAD, or a combination of vessels)Venous drainage is via the great cardiac vein, which begins paired with the LAD and wraps around the course of the LCx until it becomes the coronary sinus, where it drains into the RV. There are also thebesian veins that drain directly into both atria, contributing to anatomical shunt. Aortic and ventricular pressures affect coronary flow $$Q = \frac{\Delta P}{R}$$The major backpressure to coronary perfusion comes from the compressive forces within the myocardium during systole. To put it another way:$$Q = \frac{P_{\text{Aorta}} - P_{\text{Ventricle}}}{R}$$This effectively means that the left ventricle is best perfused during diastole, and in early systole there the flow is abolished or reversed. The right ventricle is supplied during both systole and diastole, because the RV pressures are so much lower (and never overcome the aortic pressure). Myocardial work affects coronary flow Increased myocardial work increases blood flow to maintain the oxygen supply/demand ratio by coronary vasodilation, reducing the resistance to flow. This is achieved by four mechanisms.Direct action of $K_{\text{ATP}}$ channelsThese channels are the same that are on pancreatic beta cells. They open in response to low intracellular ATP, causing an outwards potassium leak from myocardiocytes (decreasing myocardial work), and hyperpolarization of vascular (coronary) smooth muscle $\to$ decreased Ca influx $\to$ vasodilation. Nitric OxideLocal hypoxia causes upregulation of eNOS (probably also by $K_ATP$ channels) $\to$ NO release and diffusion into SM cells $\to$ upregulation of guanylate cyclase $\to$ increase cGMP $\to$ vasodilationSensing byproducts of metabolism (Adenosine, pH, lactate, potassium)All cause smooth muscle dilation Humoral factors affect flow Myogenic mechanism: Increased intraluminal pressure directly causes smooth muscle vasodilationAlpha-1 agonism: PLC -> IP3 + DAG -> increase intracellular calcium -> vasoconstrictionBeta-2 agonsism: adenylate cyclase -> cAMP -> PKA -> posphorylation (inactivation) of MLCKOverall effect of endogenous catecholamines: Coronary vasoconstriction (alpha > beta); catecholamines also increase LV systolic pressure and heart rate, which can impair flow; but they also increase myocardial work which can overcome all those things and increase flow. M2-agonism: Coronary arteries have M2 (rather than M3) receptors, which cause vasodilation by a guanylate cyclase -> cGMP pathway
Electrical properties of the heart Electrical properties of the heart Don't go breaking my heart (into cardiomyocytes) The fast sodium channel These are integral to myocardial function. 1 alpha subunit, 2 beta subunits, 2 activation (M) gates, one inactivation (H) gate.One can pretend that the gates are named for the shape the channel makes, see? (Actually they are just algebraic terms in the hodgekin-huxely model). In resting state, the M gates are closed, sodium cannot flow, and the gate looks like an M.As membrane voltage hits the threshold of -50, the M gates open in a sliding helix action, and sodium can flow into the cell, dragging the cell towards the sodium Nernst potential (+70mV). This is the open state.After one to two ms, the H gate closes. This is the inactivated state. It lasts around 140ms, before the M gates once again close; repolarization then opens the H gate, returning the cell to the resting state. These states correspond to the refractory periods of the cell:The absolute refractory period is phase 0, 1, and 2, and part of phase 3. In this phase, the sodium channels are all either open (and the cell is maximally depolarized) or in inactivated state. During the relative refractory period at the end of phase 3, some of the sodium channels are resting, but some are still inactivated, so any stimulus will produce a subnormal action potential. The effective refractory period is the absolute refractory period plus part of the relative refractory period where any depolarization will be too small to spread to adjacent myocardium. The fast cardiomyocyte potential These have a fast upstroke, which facilitates a very fast conduction velocity of 50cm/s (the heart is about 12cm long, so that's about 240ms, or a wide QRS.) Purkinje fibres are faster, about 200cm/s.Phase 4: Resting potential. -90mV. Maintained byNa/K ATPase pump exporting charge and maintaining K+ gradientIk1 inwards-rectifying channel, which drags the membrane potential towards the K+ Nernst potentialThe Gibbs-Donnan effect generated by impermiate intracellular proteinsPhase 0: Fast depolarization:Positive charge leaks into the cytosol via gap junctions at intercalated disks until the threshhold of -65mV is reached. Fast sodium channels open, and sodium floods in, spiking the Vm to +30mVPhase 1: Early repolarizationOutwards flux of potassium via the voltage-gated Ito channelsRestores the Vm to 0mVPhase 2: PlateauPotassium efflux continuesL-type calcium channels openCalcium influx = potassium efflux, no change in VmLasts about 120msPhase 3: RepolarizationL-type potassium channels are inactivated by rising intracellular calciumIkr, Ik1 channels openVm drifts back to....Stage 4: Resting potential (-90mV). The slow cardiomyocyte potential and automaticity These have a slow conduction speed, about 5cm/s. But! They show initiative AKA automaticity.Phase 4: Resting potential, -60mV. There is a slow inward Na+ current through $I_f$ channels, resulting in a gradual increase in membrane potential until it hits a threshold of -40mV, then...Phase 0: A slow, slow upstroke owing to the absence (or blockade of) fast sodium channels, mediated by special T-type calcium channels causing calcium influx, until the usual L-type calcium channels can take over.Phase 1: N/APhase 2: N/APhase 3: Slow repolarization by Ikr and Ik1 channelsCardiomyocytes with automaticity potential exhibit overdrive suppression.Frequent depolarizations (e.g. due to SA nodal impulses) increase intracellular sodiumThis increases sodium export via the Na/K ATPase, which hyperpolarizes the cell (because 3Na/2K ATPase exports charge)The If current is constant, so it takes a longer time for these cells to reach their threshold potential. Once the overdrive stimulus is removed, the resting potential is allowed to drift up until the cell becomes a pacemaker Excitation-contraction coupling During phase two of the cardiac action potential, calcium enters the cell. This sets off a chain of events:The action potential propagates along the membrane and down the t-tubules, letting calcium all up into the cell via L-type calcium channelsThe calcium then binds to the calcium-gated ryanodine calcium channel (yep) on the sarcoplasmic retuculuum surfaceMasses of calcium burst forth. This is the final common pathway for all excitation-contraction coupling in all muscle cellsCalcium binds to troponin C, which moves tropomyosin out of the way of the actin binding siteWhile the actin binding site is exposed, myosin does its thang:At rest, myosin is bound to an actin binding site with head flexedMyosin binds an ATP, dissociating from actinMyosin hydrolyzes the ATP, unflexing its head (its higher energy state)Myosin binds to the new actin binding siteMyosin ejects the phosphate and flexes its head, sliding the actin fiber towards the H zoneMyosin ejects the ADP. This shit continues ad nauseam until the calcium gets removed. Processes of calcium removal from cardiomyocytes Mechanism 1: SERCA (Sarcoendoplasmic reticulum calcium ATPase)Active transport of Ca2+ into the sarcoplasmic reticulum. Normally these have the breaks on in the form of an inhibitory protein called phospholamban (thank you ma'am). Protein kinase A, which gets activated by B1 agonism, phospophorytes and cleaves off phospholamban, which improves lusitropy. These consume heaps of ATP, about half of the muscle's ATP usage!Mechanism 2: BufferingTo negatively charged proteins like paralbuminMechanism 3: Na/Ca ATPase Exports the calcium extracellularly
Determinants of cardiac output Determinants of cardiac output $$CO = \frac{MAP - CVP}{TPR} = SV \cdot HR$$Stroke volume is affected by preload (sarcomere length at end-diastole) and afterload (the valvular-arterial impedance); the residual effects on stroke volume after controlling for those two factors is termed inotropy. Inotropy (Contractility) and its determinants Inotropy describes the stroke volume with a given preload and afterload. Three indicies are used to approximate the inotropy. The maximal rate of pressure increase, $\frac{dP}{dT}$ in the LV, which occurs during isovolaemic contraction (although this is still partly preload dependant!)The ejection fraction is a nasty, dirty approximation (because it is preload and afterload dependant!)The left ventricular end systolic pressure volume linear relationship. This is the line of end-systolic (pressure,volume) points produced by sequential pressure-volume loops with different preloads (the $\frac{d\text{LVESV}}{d\text{LVESP}}$ if you will)$\uparrow[Ca^{2+}]_{intracellular} \to \ \uparrow \text{Toponin-}Ca^{2+} \text{ binding} \to \ \uparrow \text{Active myosin units} $ (This is how in-vivo way inotropy is modulated and how all intotropes except levosimendan work).Intracellular calcium is modulated by extracellular calcium concerntration, and calcium conductance during phase 2 of the myocardial action potential.$\beta_1$ agonism increases adenylate cyclase $\to$ increases cAMP $\to$ increases PKA. PKA then phosphorylates two important targets: the L-type calcium channel of the sarcolemma and the SERCA transporter of the sarcoplasmic reticulum. The first increases calcium conductance into the cell during phase 2, and the second increases calcium export rate during phases 3 and 4. Things that increase inotropyThe Anrep effect - $\uparrow$afterload increases intropy (on top of the Frank-Starling response) probably due to aldosterone $\stackrel{probably}{\to}$ increased expression of L-type calcium channelsThe Bowditch effect - $\uparrow$heart rate increases intotropy because there's not enough time for calcium efflux to finishCatecholamines (endogenous or exogenous) directly stimulate $\beta_1$ receptors. Ephedrine displaces catecholamines from sympathetic vesicles, which then stimulate $\beta_1$ receptors. PDE3 inhibitors (milrinone) prevent the breakdown of cAMP. Exogenous calcium increases extracellular calcium concentration. Thyroid hormone increases $\beta_1$ receptor expression. Digoxin competes with extracellular potassium for Na/K ATPase $\to$ increased intracellular Na $\to$ increased Na/Ca antiport via Na/Ca exchanger $\to$ increased intracellular calciumInsulin by increasing intracellular calcium by an unclear mechanismLevosimendan by stabilizing troponin C in the open state (the only calcium-independant inotrope)Things that decrease intotropyNonfunctional (e.g. Infarcted) myocardium, or the disorganized myocardium associated with cardiomyopathies, infiltration of myocardium by sarcoidosis, amyloidosis (typically transthyretin amyloid)Hypoxia (hypoxaemic, anaemic, ischaemic, histotoxic): decreased ATP availabilityMyocardial stunning (a transient decrease in inotropy following ischaemia that does not result in myocardial death)Hypothermia - the myosin ATPase is temperature dependantAcidosis - hydrogen competes with calcium for binding on troponin and the ryanodine receptor The Frank-Starling mechanism; preload and its determinants Preload is the sarcomere length at end-diastole, which is approximated by left ventricular end diastolic volume.From the definition of compliance, we have immediately$$LVEDV = C_{\text{LV wall}} \cdot LVEDP$$Determinants of LVEDPIntrathoracic pressure (decreases RV preload, increases RV afterload, decreases LV preload, decreases LV afterload)Atrial contribution (about 20% of LVEDV). Lost in AF, relatively higher in tachycardia or diastolic dysfunction.Passive filling by the gradient between MSFP and CVP (increased by increased venous tone, increased blood volume, and diastolic time)Afterload (an increased end-SYSTOLIC volume will result in an increased end-DIASTOLIC volume on the next stroke)Determinants of LV compliancePericardial compliance (decreased by tamponade and constrictive pericarditis; increased by pericardotomy)Wall thicknessWall fibrosisLusitropy (active relaxation, inhalenced by catecholamines)Frank-starling mechanismThe Frank-starling mechanism causes increased stroke volume as sarcomeres length increases. This is probably becauseStretch decreases the diameter of the myocyte (which has constant volume)Titin acts as a mechanoceptor These two things bring actin and myosin closer togetherThis increases the sensitivity of myofibrils for calciumThis also increases the number of myofilament cross-bridges that can interactThe relationship is concave-down (it plateaus out). With reduced contractility, the curve can begin to decrease beyond a maximum stroke volume.This matches the LV output to the RV output and adapts to sudden changes in preload. Afterload and its determinants The afterload of the heart is the hydraulic input impedance of the aortic valve and vascular tree. If we think of this in Pouseillean terms:$$Q = \frac{\Delta P}{I}$$$$I = \frac{\Delta P}{Q}$$$$I = \frac{LVSP}{Q}$$$$I = \frac{\text{Aortic Systolic Pressure} + \text{Mean LVOT gradient}}{\text{Stroke volume}}$$And like everything else in cardiology, we should normalize it to body surface area...$$\text{Valvuloarterial Impedance} = \frac{\text{Aortic Systolic Pressure} + \text{Mean LVOT gradient}}{\text{Stroke volume index}}$$Basically, if the afterload is high, we need a higher LV systolic pressure to force out the same amount of fluid.Alternatively, we can think of afterload as the wall tension in the ventricle: the radial force exerted by a unit volume of myocardial tissue given by the Young-Laplace equation for a spherical shell:$$\rho = \frac{P \cdot r}{2w}$$$$\rho = \frac{\text{LVSP} \cdot \text{LV radius}}{2 \cdot {\text{LV wall thickness}}}$$Therefore the things that increase afterload are:Increased total peripheral resistance to flow (principally vessel radius and blood viscosity)Decreased aortic and peripheral compliance (which results in increased hydraulic reactance)Aortic stenosis and LVOT outlet obstructionIncreased chamber sizeAfterload is decreased by:Increasing wall thickness Venous return and the Guyton model The Venous return is the flow of blood from the systemic veins to the heart. It equals cardiac output. $$VR = CO$$$$VR = \frac{MSFP - CVP}{\text{Systemic Venous Resistance}}$$The mean systemic filling pressure (the pressure in the capillaries, or equivalently the pressure throughout the circulation during cardiac arrest). This is determined by:The venous compliance ($\downarrow$ by venoconstriction e.g. catecholamines $\to \ \alpha_1$ agonism)The total blood volumeThe Guyton model involves two functions. The independent variable is the CVP. Then we consider the cardiac output and venous return as functions of the CVP.The cardiac output CO(CVP): This has the usual Frank-Starling shape.The venous return: this is constant (and maximal) below a CVP of 0cmH2O due to venous collapse, then falls with increasing CVP, because $VR = \frac{MSFP - CVP}{\text{Systemic Venous Resistance}}$Of course, $CO = \text{Venous return}$ - so the point where these two curves cross is the steady state operating point.Three things can therefore affect the cardiac output in this model.$\uparrow\text{Stressed volume}\to\uparrow\text{MSFP}\to\ \ \uparrow\text{CO and }\uparrow\text{CVP}$$\uparrow\text{Inotropy}\to\ \ \uparrow\text{CO and }\downarrow\text{CVP}$$\uparrow\text{TPR}\to\uparrow\text{Arterial:Venous blood volumes}\to\ \ \downarrow\text{CO and }\downarrow\text{CVP}$ Pressure-Volume loop analysis Pressure-volume loops illustrate some important features:The stroke volumeThe isovolaemic contraction and relaxationThe end-diastolic pressure volume relationship (ventricular elastance)The end-SYSTOLIC pressure volume relationship (contractility)The effective arterial elastance, which is the LVESP over the stroke volume (the slope of the red line; the afterload)
The cardiac cycle, CVP, arterial waveforms The cardiac cycle, CVP, arterial waveforms Blood comes in, blood goes out. You can't explain that.Systole: the period of ventricular contraction and blood ejection (from initiation of QRS to t-wave, and from closure of the AV valves to closure of the A and P valves)Diastole: the remainder of the cardiac cycle, during which the ventricle relaxes and fills with blood (i.e. the period where the AV valves are open).Why read any further when you can just have a Wiggers diagram? Wiggers diagram Phases of the cardiac cycle Systole:Isovolaemic ventricular contraction (The period between closure of the mitral valve and opening of the aortic valve). This occurs immediately following the R wave.Early (fast) ejection phase (The period of active myocardial contraction)Late (slow) ejection phase (Ventricular contraction continues due to inertia imparted to the ventricular wall and contents). This begins at the beginning of the t-wave.Diastole:Isovolaemic relaxation (The period between closure of the aortic valve and opening of the mitral valve). This corresponds with the end of the t-wave.Early (elastic) diastole (rapid ventricular filling)Diastasis (slower ventricular filling)Atrial systole. This occurs at the p-wave (RA) or right after (LA).Timing differences between the left and right heart:The right atrium contracts before the left (because of the SA node's location just inferior to the SVC in the RA)The RV isovolaemic contraction is shorter (because the PADP is so low), so the pulmonic valve opens before the aortic valveRight isovolaemic contraction is also shorter The CVP waveform, normal and abnormal A wave: Right atrial contraction. C wave: The right ventricle contracts. The tricuspid valve cusps balloon into the RAX descent: The ventricle contracts, making the floor of the atrium drop, increasing RA volumeV wave: distension of the RA from filling during late ventricular systoleY descent: the triscupid valve opens, blood rushes into the empty RVAF: no A waves.Triscuspid regurgitation: Increased pressure during all of ventricular systole. Therefore fused CV waves with loss of the X descent.AV dissociation: Cannon a-waves (atrial contraction against a closed tricuspid valve. Occurs in junctional rhythms, CHB, ventricular pacing, ventricular ectopics, and VT.Constrictive pericarditis: This sets the maximum volume of the heart to some low valve. That means that the end systolic volume will be very low, and the ventricles will be hungry hungry hungry for some blood, resulting in very steep X and Y descents:Tamponade: obliteration of the y-descent (because drainage into the RV is so impaired) and a markedly elevated CVP. The normal radial and aortic pressure waveforms Key differencesLower pulse pressure and higher MAP in the aorta due to windkessel (hydraulic accumulator) effectLater systolic peak in the radial artery due to pressure wave travelling through the arteries at 100 m/sHigher systolic peak due to distal pulse amplificationSteeper upstroke due to lack of compliance in the radial arteryHigh frequency components smoothed by dampingDiacrotic notch from reflected wave from the arterioles
The peripheral circulation The peripheral circulation The peripheral circulation is composed of large, elastic blood vessels that exhibit a windkessel (hydraulic accumulator) effect, which reduces cardiac work by smoothing out the pressure-time curve; of smaller resistance arterioles that regulate the total peripheral resistance and thereby arterial blood pressure; of capillaries that deliver and reabsorb fluid and solute; and of venous vessels that regulate the stressed volume.The peripheral circulation has to maintain high local flow to critical tissues, and maintain sufficient total peripheral resistance to regulate the systemic blood pressure. The regulation of the peripheral circulation is under dual control: in nonessential tissues (peripheries, splachnic) autonomic control predominates, in essential tissues (heart, brain), local control (AKA autoregulation) predominates. The physiology of smooth muscle in blood vessels The ratio $Ca^{2+}\text{-Calmodulin-MLCK} : \text{MLCP}$ determines force of contractionSmooth muscle lacks troponin.Instead, contraction is initiated when the light chain of myosin is phosphorylated. Intracellular calcium binds with calmodulin and then to myosin light chain kinase. This $Ca^{2+}\text{-Calmodulin-MLCK}$ complex phosphorylates myosin light chain.Myosin light chain phosophotase dephosphorylates myosin light chain.Because both enzymes are acting, the total force of contraction is determined by the ratio of their activities.$\alpha_1$: IP3 (from phospholipase C, e.g. from alpha-1 receptors) liberates intracellular calcium from the sarcoplasmic reticulum, which increases $Ca^{2+}\text{-Calmodulin-MLCK}$ $\to$ constriction.$\beta_2$ or prostatcyclin receptor: cAMP, via PKA, increases MLCP $\to$ relaxation.NO: cGMP, via PKG, increases MLCP $\to$ relaxation.More positive membrane voltage increases calcium influx and decreases calcium efflux by modulating L-type Ca channels and Na/Ca exchanger. Membrane voltage is controlled by $K^+$ channels which, when open, hyperpolarize the cell. Increased shear stress is translated to the glycocalyx, and from there to the endothelium, which release prostatcyclin and NO. Movement of solutes across capillary membranes Diffusion is, as always, governed by Fick's law:$$D \propto \frac{\text{SA}\cdot \text{Solubility} \cdot \Delta C}{\text{Thickness}\cdot\sqrt{\text{Molar mass}}}$$But lipid-insoluble molecules have to diffuse through endothelial pores. Molecules >60kD simply can't fit. The rate of delivery of highly permiable substances (H2O, urea, glucose) is delivery: they are flow limited. The rate of diffusion of larger stuff is diffusion limited. Diffusion limitation can occur in oedema when the capillary-cell distance is embiggened by fluid. Large molecules have to use pinocytosis to get across the endothelium. Movement of fluid across capillary membranes Flux of fluid through the capillary membrane is proportional to the pressure difference over the membrane, and also to other things:$$Q_fluid \propto K_t \Delta P$$where $\K_t$ is the filtration constant for a given tissue. $$\Delta P = [(P_{Hc} - P_{Hi}) - \sigma (P_{\pi c} - P_{\pi i})]$$$$P_H = \begin{cases} 32 \text{ arterial systemic capillary} \\ 15 \text{ venous systemic capillary} \\ 10 \text{ pulmonary capillary} 0 \text{ interstitium} \end{cases}$$$$P_{\pi} = iCRT \approx 25\text{mmHg}$$Note that the oncotic pressure of albumin is augmented by the Gibbs-Donnan effect (chloride is pulled into the capillary by a concentration difference, and then sodium by the negative charge on both albumin and chloride).Effect of a fall in cardiac outputThe arterial blood pressure falls. Through myogenic and adrenergic mechanisms, precapillary arterioles constrict. The CVP falls because the MSFP falls. All of this drops the $P_{Hc}$, causing absorbtion to dominate filtration. This causes fluid to shift from the interstitium to the vascular space, expanding plasma volume and increasing preload, restoring cardiac output. As a consequence, the haemoglobin concentration is diluted. Effect of dehydrationThe plasma proteins get concerntrated. $P_{\pi c}$ rises. Fluid moves from interstitium to vascular space, restoring normal osmolality. Cardiovascular function of lymphatics These are thin-walled, blind-ended vessels that resemble veins histologically. They allow diffusion of interstitial fluid and - importantly - protein. They are the only way albumin can get back into the vascular space (it can't move up its concentration gradient). One whole circulating volume, and half of circulating protein, is returned as lymph every 24 hours. Autoregulation of vascular resistance Flow is maintained at a constant level over a wide range of blood pressures, because increases in driving pressure cause arteriolar vasospasm, and falls in driving pressure cause arteriolar vasodilation, by four mechanisms.Myogenic mechanismIncreased intraluminal pressure causes increased depolarization and intracellular calcium flux in vascular smooth muscle (independant of endothelium). $$\uparrow Ca^{2+}-\text{-Calmodulin-MLCK activity} \to \text{dilation} \to \text{normalization of flow}$$Flow-mediated endothelial responseHigher shear stress from higher flow rates is tranduced by glycocalyx to endothelium, which releases NO and prostacyclin. $$NO \to cGMP \to PKG \to \uparrow MLCP$$ $$\text{Prostacyclin receptor} \to cAMP \to PKA \to \uparrow MLCP$$It also causes upstream vasodilation in response to arteriolar vasodilation (because distal resistance falls and flow increases). Metabolic control$$\downarrow DO_2:VO_2 \to \uparrow \uparrow P_aCO_2 / [K^+] / [\text{Lactate}^-] /\text{Adenosine}$$Unclear which of these substances produces vasodilation, or how. Conducted responsesVascular smooth muscles have gap junctions. Intracellular calcium (and therefore vasodilation / constriction) propagates along vessels. Autonomic control of peripheral circulation Only a small part of the vascular tree (mostly splanchnic vessels) are innervated by parasympathetic nerves. The sympathetic nervous system is doing all the heavy lifting. SensorsBaroreceptors: Carotid sinus (more sensitive) and aortic arch (less sensitive)ControllerPressor region (dorsal-lateral medulla)Depressor region (dorsal-medial medulla)EffectorsDescending fibres $\to$ T1-L2 lateral horns $\to$ sympathetic chain $to$ resistance vessels $\to$ noradrenaline release.This causes $\alpha_1 \text{ agonism} \to IP_3 + DAG \to \ \uparrow [Ca^{2+}]_{\text{intracellular}} \to \text{constriction}$
Blood pressure and the cardiac reflexes Blood pressure and the cardiac reflexes Systolic blood pressure is the maximal arterial blood pressure. It is relevant to bleeding / clot disruption, and aneurysm wall stress.Diastolic pressure is the minimum arterial blood pressure. It is relevant to coronary perfusion (especially LV).Pulse pressure is their difference; it is proportional to stroke volume.Mean arterial pressure is the area under the curve divided by the cardiac cycle time. It most closely predicts microvascular flow / organ perfusion. The total peripheral resistance is the resistance of the peripheral vasculature to a constant laminar flow, $\frac{8 l \mu}{\pi r^4}$. Determinants of peripheral blood pressure parameters Determinants of MAPBecause of Ohm's law for a pipe,$$\text{MAP} - \text{CVP} = \text{TPR} \cdot \text{CO}$$Therefore the MAP is determined by preload, afterload, contractility, vessel length, vessel diameter, and blood viscosity. Determinants of systolic blood pressureBecause $C = \frac{\Delta V}{\Delta P}$, stroke volume and arterial compliance determine the systolic blood pressureReflected pressure waves from impedance mismatch at the arteriole level also increase the systolic pressure. Determinants of diastolic pressureDetermined by total peripheral resistance, time constants of arterial vessels, and heart rate. Pulse pressure variation Pulse pressure is given by$$PP = SBP - DBP = \frac{\text{Stroke volume}}{\text{Arterial compliance}}$$So the pulse pressure is proportional to stroke volume.Widened in high-output states (Aortic regurg, AV fistulae, distributive shock) and bradycardia with compensatory high SV.Narrowed in low output states (AS, high afterload, cardiogenic shock, tachycardia). Pulse pressure variation is a measure of stroke volume variation.$$PPV = \frac{PP_{\text{max}} - PP_{\text{min}}}{PP_{\text{mean}}} = \frac{\Delta PP}{\overline{PP}}$$Recall that $VR = \frac{\text{MSFP} - \text{CVP}}{\text{TVR}}$With inspiration, CVP falls as intrathoracic pressure falls, increasing VR and RV preload. The pulmonary vasculature expands, decreasing LV preload. During normal inspiration, there is some (<10%) PPV. This effect is exaggerated in:Tamponade or constrictive pericarditis: The increase in RV filling causes leftward septal movement, decreasing LV filling (ventricular interdependance)Hypovolaemia: A low MSFP means VR is more affected by variation in CVPAcute asthma: Very low inspiratory pressures and high expiratory pressures Cardiac reflexes Baroreceptor reflexSensors: pressure (carotid sinus and aortic arch)Afferent: vagus and glossopharyngeal nervesProcessor: nucleus of the solitary tract and nucleus ambiguusEfferent: vagus nerve and sympathetic chainEffect: increased HR, TPR, and contractility in response to a fall in BPBainbridge reflexSensors: mechanoreceptors in RAAfferent: vagus Processor: nucleus of the solitary tract and the caudal ventral medullaEfferent: vagus nerve and sympathetic chainEffect: increased RA pressure produces an increased heart rateBezold-Jarisch reflexSensors: C fibres (noxious mechanical or chemical stimulus)Afferent: vagusProcessor: nucleus of the solitary tractEfferent: vagus nerve and sympathetic chainEffect: hypotension and bradycardia in response to myocardial ischaemiaChemoreceptor reflexAfferent: carotid / aortic chemoreceptors (low PaO2 and/or high PaCO2)Processor: nucleus of the solitary tract and nucleus ambiguusEfferent: vagus nerve and sympathetic chainEffect: tachycardia and hypertension in response to hypoxiaCushing reflexAfferent: Raised ICP - mechanosensors in the rostral medulla?Processor: rostral ventrolateral medullaEfferent: sympathetic fibres to the heart and peripheral smooth muscleEffect: hypertension (to maintain CPP) and baroreflex-mediated bradycardiaDiving reflexAfferent: trigeminal nerve (cold temperature; pressure of immersion)Processor: sensory nucleus of CN V; nucleus of the solitary tractEfferent: vagus nerve and sympathetic chainEffect: vagal bradycardia, systemic vasoconstriction, cerebral vasodilationOculocardiac reflexAfferent: trigeminal nerve (pressure to the globe of the eye) Processor: sensory nucleus of CN V; nucleus of the solitary tractEfferent: vagus nerve and sympathetic chainEffect: vagal bradycardia, systemic vasoconstriction, cerebral vasodilationVasovagal reflexAfferent: emotional distress, hypovolaemiaProcessor: unknownEfferent: vagus nerve and sympathetic chainEffect: bradycardia, systemic vasodilation, hypotensionRespiratory sinus arrhythmiaAfferent: central respiratory pacemakerProcessor: nucleus ambiguusEfferent: vagus nerve, via the cardiac ganglionEffect: cyclical increase of heart rate during inspiration
Special peripheral circulations Special peripheral circulations These are peripheral circulations that have distinct physiology. The contribution of cardiac output to each circulation is approximately HAVING SEX BRINGS MANY KIDS LATER:Heart 5%Skin 10%Brain 15%Muscle 20%Kidney 25%Liver 30% Cutaneous circulation 10% COGoal of maintaining temperature homeostasis2 types of vesselArteriolesBasal tone presentAV AnastomosesNo basal toneWhen dilated → act as low resistance pathway to increase skin blood flowConstricts when coldCountercurrent mechanism exists between the arteries and veins which allows direct heat exchange (Vein returning cool blood, Arteries delivering warm blood)Intrinsic regulationCapillaries have a myogenic mechanism (not so for anastomoses)Locally medited vasodilation when warm, vasoconstriction when coolProlonged cold causes cell damage, releases vasoactive mediators and causes vasodilation, "reactive hyperaemia"Extrinsic regulationSNS when cold -> NA -> vasoconstriction of both vessel typesSNS when warm -> ACh (exclusive to skin!) -> vasodilation and sweatingHypothalamus -> blushing, blanching in response to emotion (embarrassment, arousal, fear). Cerebral circulation 15% CO$$\text{Cerebral blood flow} = 50\text{ml}\text{min}^{-1}100\text{g}^{-1} = 700\text{mL}\text{min}^{-1} = 15\% CO$$$$\text{Cerebral blood flow} = \frac{CPP}{\text{Cerebral vascular resistance}} = \frac{MAP - \text{min}(CVP, ICP)}{CVR}$$Myogenic mechanism maintains cerebral blood flow at around 50ml/min for a MAP of 60 to a MAP of 160.Neurovascular coupling: increased neuronal activity is sensed by one pole of astrocytes, which release potassium onto cerebral vessels from their other pole. The potassium ramps up the Na/K ATPase pump on the smooth muscle, causing hyperpolarization and vasodilation. CO2 and low plasma pH cause cerebral vasodilation via endothelial cells producing eNOS $\to$ NO releaseOxygen: A fall in PaO2 or a rise in oxygen requirements will cause adenosine formation -> vasodilation; also induce eNOS $\to$ NOTemperature: Fever increases cerebral blood flowViscosity: increases CVR, decreasing CBF. Splanchnic circulation From the Coeliac, SMA, and IMA. Arterioles and venules in the villi form a countercurrent exchange, facilitating rapid absorption. This also allows for shunting of O2 from the arteriole to the venule at the bases of the villi. This is exaggerated at low flow rates -> necrosis of villi. Local:Weak myogenic mechanismWeak adenosine-mediated autoregulation in response to hypoxiaExtrinsic:Gastrin, CCK, and absorbed glucose all vasodilate in response to food ingestion$\alpha_1$ receptors abound; potent vasoconstriction of both arterioles and capacitance vessels in response to catecholamines Hepatic circulation 30% COInflow: 75% portal vein, 25% hepatic artery (but the artery delivers 75% of the DO2).These combine to form sinuoids.Large pressure drop over the resistance arterioles such that the pressure in the sinusioid is only ~10mmHg. Changes in venous pressure are transmitted directly to the sinusoids.Local regulation:Portal vein resistance is not under local regulation; portal vein flow is largely determined by splanchnic arterial flow.Hepatic arterioles have a myogenic mechanism, and exhibit the hepatic arterial buffer response, i.e. they increase flow inversely with portal flow changes. Normally the portal vein washes away adenosine. If portal flow falls, adenosine accumulates, vasodilating the artery until equilibrium. Extrinsic regulation:Portal vein resistance is deceased by VIP following a mealThe portal system vasoconstricts in response to catecholamines, increasing stressed volume.The arterial system also constricts with catecholamines.Other factorsRaised CVP results in impaired venous drainageExercise, stress, and shock all reduce both arterial and portal blood flow. Structure of the foetal circulation Umbilical artery, from the internal iliacs, carry deoxygenated blood to the placenta. Umbilical vein returns oxygenated and nutrient-containing bloodHalf goes through the liver (for nutrition), half to the IVC via the ductus venosus.Ductus venosus, lower extremity, and post-hepatic blood then all join in the IVC.Mostly ductus venosus blood travels in a jet to the foramen ovale, into the LA and thence the LV.The remaining IVC blood mixes with the coronary sinus and SVC blood in the RA and is ejected into the pulmonary artery. Only 10% goes to the lungs (which are heavily vasoconstricted because of HPV). This 10% ultimately joins the foramen ovale blood in the LV. The remainder travels to the arch of the aorta via the ductus arteriosus. The LV blood supples only the head, upper limbs, and left coronary artery. The RV (by way of the ductus arteriosus) supplies the rest of the body, and pumps twice as much blood as the LV. Changes in circulatory system with birth During birth:Stretch of the umbilical vessels triggers vasoconstriction.Once flow through the umbilical vein ceases, the ductus venosus also closes.From asphyxia during birth:Respiratory center triggered and neonate inhales, filling the lungs with airPulmonary vascular resistance falls precipitouslyFlow to the LA increases, flow to the RA (previously from umbilical vein) decreasesThis snaps the foramen ovale valve closedOver the next 2 days:Ductus arteriosus closes in response to high oxygen tensionThis is caused by FALLING levels of PGE2Ibuprofen promotes closure, while PGE1 keeps the thing open
Applied cardiovascular physiology Applied cardiovascular physiology These should be approached by describing the initial effects on preload, afterload, and contractility, then the relevant cardiac and vasomotor reflexes, then the long-term adjustment that occurs Cardiovascular response to change in posture With moving from supine to standing - Initially,RV preload falls due to gravity (70% of venous blood is redistributed to lower limbs, decreasing stress volume and MSFP)Cerebral perfusion pressure fallsThen,Decreased pressure at the aortic arch + carotid sinus (due to lower CO and also being located above the hydrostatic indifference point)Sensed by baroreceptors $\to$ vagus and glossopharyngeal $\to$ vasomotor + cardiac centers of rostral medulla $\to$ increased heart rate and vasoconstrictionCerebral blood vessels vasodilateUltimately,Cerebral blood flow is stableHeart rate is higher, blood pressure is higherCardiac output is slightly lower Cardiovascular response to a fluid bolus Immediately:$\uparrow$ Blood volume $\to \ \uparrow$MSFP $\to \ \uparrow$Preload $\ \xrightarrow{\text{Frank-Starling}} \ \uparrow$Cardiac output $\to \uparrow$MAPOver seconds to minutes:$\uparrow$Atrial stretch $\xrightarrow{\text{Bainbridge reflex}} \ \uparrow$ heart rate (transiently)$\uparrow$MAP $\xrightarrow{\text{Baroreceptor reflex}} \ \uparrow \text{Vagal tone} \ \downarrow \text{SNS} \ \to \downarrow{HR} \downarrow{\text{contractility}} \downarrow{TPR}$Due to this BP remains stableOver minutes to hours:$\uparrow$Capillary hydrostatic pressure $\to $ net movement of solute out of vascular space until ~$\frac{3}{4}$ infused volume is interstitial$\uparrow$Atrial stretch $\to \ \downarrow$ANP $\to \ \uparrow Na+H_2O$ renal excretion$\uparrow$Renal perfusion $\to \ \downarrow$ Renin $\to \ \downarrow$ ATII / Aldosterone $\to \ \downarrow Na+H_2O$ renal excretion Cardiovascular response to exercise Prior to exercise,CNS anticipates effortVagus nerve $\to$ increased HRSNS $\to$ adrenaline release $to$ increased splanchnic and skin resistance ($\alpha_1$), decreased SkM resistance ($\beta_2$), increased contractilityDuring exercise,Working muscles release CO2, lactate, and potassiumEndothelium releases NO, prostacyclinResults in regional vasodilation TPR falls $\to$ MAP falls $\to$ baroreceptor reflex $\to$ tachycardia and vasoconstrictionUltimately,CO increases massively (~30L/min) due to decreased afterload + increased contractility + tachycardiaMAP, CVP, and PCWP all risePulse pressure increases, diastolic BP fallsTPR decreases Cardiovascular response to aging MyocardiumConcentric hypertrophy; LVOT narrowingValvular sclerosisIncreased systolic functionDecreased diastolic function due to increased afterloadDecreased cardiac outputIncreased reliance on atrial kickAtrial dilation and increased propensity for AF; increased ANPVasculatureDecreased vascular compliance $\to$ increased afterload, widened pulse pressure, hypertensionDilation of aorta and large arteriesEndothelial dysfunction $\to$ impaired autoregulation, procoagulant stateAutonomic nervous systemBlunting of baroreceptor responseDecreased sympathetic innervation of myocardiumConduction system Decreased maximum heart rateSA node atrophyLoss of conductive tissue Cardiovascular changes in obesity Total body oxygen demand increased due to increased lean body mass (adipose itself low O2 requirement)Leptin synthesized by adipose $\to$ RAAS activation $\to$ fluid retention$\uparrow$ Blood volume $\to \ \uparrow$ MSFP $\to \ \uparrow$Cardiac output, atrial pressuresIncreased parrellel capillaries usually decrease TPR, but leptin-induced RAAS causes vasospasm, increases TPR, and OSA causes chronic $\uparrow$SNS, increases TPR $\to$ LV afterload typically increasedPVR increased (LV diastolic failure and OSA$\to$ chronic hypoxic pulmonary vascoconstriction)Ultimately increased preload and afterload for both ventricles leads to remodellingConcentric hypertrophyChamber dilationDiastolic dysfunction

Renal, body fluids, electrolytes

Renal structure and function Renal structure and function The kidneys are paired retroperitoneal structures, organized into a cortex (containing glomeruli, the cortical labyrinth, and medullary rays), the outer medulla (with an outer and an inner stripe), and an inner medulla which forms the renal papillae. Structure of the nephron Glomerulus sits inside Bowman’s capsule. It consists of capillary loops with an afferent and efferent arteriole. Between the capillary loops are mesangial cells, which phagocytose material trapped in the filtration barrier, and contractile to close off glomerular loops.Filtration barrier has 3 layers1.      Fenestrated capillary endothelium of glomerulus (blocks RBCs and plts)2.      Basement membrane (NOT a lipid bilayer; a glycoprotein gel)3.      Interdigitated podocyte foot processes, linked by slit diaphragms (modified tight junctions)Bowman’s capsule gives off a tubule, which has a proximal part, then Henle’s loop (descending thin, ascending thin in long loops, ascending thick segments), the DCT, and then tubules merge in the collecting-duct system.The JG apparatus is where the thick ascending limb (the ‘macula densa’) passes between the afferent and efferent arterioles. 3 cell types1.      Granular cells in the afferent arteriole, secrete RENIN2.      Mesangial cells3.      Macula densa cells (detect osmolality and flow rate of filtrate) Functions of the kidney Maintaining homeostatic concentrations of important ions (Na, K, Mg, SO4, PO4, etc) and organic solutes (urea, uric acid, glucose)Maintaining serum osmolalityRegulating ECF volume and blood pressureExcreting foreign substances (drugs, toxins)Performing gluconeogenesisRegulating haematopoesis and maintaining HCTHydroxylation of 25-OHcholecalciferol
Renal blood flow and GFR Renal blood flow and GFR $$RBF = \frac{MAP - \text{Renal venous pressure}}{R_{\text{afferent}} + R_{\text{efferent}}}$$$$RPF = RBF \cdot (1 - \text{haematocrit})$$$$GFR = RPF \cdot \text{filtration fraction}$$The kidneys receive 25% of the cardiac output, RBF = 1.25L/minOf this, 0.55 is plasma, RPF = 700mL/minOf that plasma, the filtration fraction is typically 20%, so GFR = 130mL/min Determinants of renal blood flow 20% of cardiac output = 1.1L/minIf HCT is 0.45, then RPF is 0.6L/min, and about 20% (filtration fraction) is filtered (GFR = 0.12L/min)90% of the unfiltered blood then flows through glomeruli -> peritubular capillaries (cortex) -> renal veins10% flows from glomeruli -> vasa recta (medulla) -> renal veinsLocal regulation is by:1.      Myogenic autoregulation: myogenic reflex minimizes changes in GFR that occur with changes in BP by maintaining almost-constant RBF for MAP 80-180. Stretch of arteriole $\to$ reflex constriction.2.      Tubuloglomerular feedback: Increased flow and decreased filtrate osmolality is sensed by macula densa cells $\to$ mesangial cell constriction and afferent arteriolar constriction which increases renal resistanceSystemic regulation is by The sympathetic nervous system. Catecholamines constrict efferent > afferent arterioles, reducing RBF and GFRAngiotensin II, which constricts efferent >> afferent arterioles, reducing RBF but maintaining GFROther determinants are:MAP outside of the autoregulatory rangeRenal venous pressure (e.g. in renal venous thrombosis)Viscosity e.g. in polycythaemia Determinants of GFR 20% of cardiac output = 1.1L/minIf HCT is 0.45, then RPF is 0.6L/min, and about 20% (filtration fraction) is filtered (GFR = 120mL/min)$$\text{GFR} = \text{hydraulic permeability} \cdot SA \cdot \text{net filtration pressure}$$$$\text{GFR} = K_f (P_{\text{plasma}} - \pi_{\text{plasma}} - P_{\text{filtrate}})$$The $P_{\text{plasma}}$ is decreased by afferent arteriolar constriction, and increased by efferent arteriolar constriction.$\pi_{\text{plasma}}$ is increased by low RBF and decreased by hypoalbuminaemia. Surface area is decreased by mesangial cell constriction or loss of glomeruli in renal disease.Regulation is therefore by1.      Myogenic autoregulation: myogenic reflex minimizes changes in GFR that occur with changes in BP by maintaining almost-constant RBF for MAP 80-180. 2.      Tubuloglomerular feedback: Increased flow and decreased filtrate osmolality is sensed by macula densa cells $\to$ mesangial cell constriction $\downarrow SA$ and afferent arteriolar constriction $\downarrow P_{\text(plasma)}$ 3.      Circulating catecholeamines and angiotensin II (constrict efferent > afferent arteriole, which decreases GFR but LESS THAN they decrease renal blood flow)4.       Increased systemic blood pressure outside of autoregulatory range (“pressure diuresis”)
Countercurrent mechanisms and ADH Countercurrent mechanisms and ADH A countercurrent system is a system in which the inflow runs parallel to, counter to, and in close proximity to the outflow for some distance.Countercurrent multiplication allows the "single effect" of the ion pumps in the ascending loop of Henle to be magnified by concerntrating the filtrate and interstitium of the inner medulla. Countercurrent exchange prevents vasa recta blood flow from disrupting the medullary osmotic gradient.Urea recycling allows the concentrated urea in the distal collecting duct to diffuse into the medullary interstitium, further concentrating it. Countercurrent multiplication The single effectThe ascending loop is actively excretes solutes (secondary active transport by NKCC2)This increases the osmolality in the interstitium. (e.g. 300 $\to$ 400mOsm)The descending LOH is water-permiable, solute-impermiable; water flows out by osmosis to equilibrate with the interstitium.The descending fluid is now more concerntrated than the ascending fluid. Multiplication of the single effect by counter current flowThe concerntrated descending fluid is delivered to the deep part of ascending LOH (400mOsm). The medulla remains concerntrated (400mOsm)This allows more solute to be pumped out (the inner medulla is now 500mOsm)More water moves out of the descending loop, concentrating it furtherAnd so on in a positive feedback loop...Osmolality valuesCortex: 300mOsmOuter medulla: 800mOsmInner medulla: 1200mOsmProximal tubule: 300mOsmDescending limb: 800mOsmHairpin turn: 1200mOsmAscending thin limb: 800mOsmEnd of ascending thick limb: 100mOsm Countercurrent exchange Descending and ascending vasa recta are highly permiable vessels. The flow is low, ~10% of renal blood flow. Water leaves descending vasa recta, concerntrating plasma and reducing flow rate as it penetrates deeper into the medulla. It diffuses to nearby ascending vasa recta and is carried back to the cortex.Solutes diffuse out of ascending vasa recta, carrying concerntrated fluid from the inner medulla, and move into descending vasa recta.This prevents washout of the medullary osmotic gradient. Urea recycling Proximal collecting system is permeable to water (via ADH-sensitive aquaporins), not to urea. Urea becomes very concentrated (~500mmol/L)The inner medullary collecting duct is highly permiable to urea. About half the urea load diffuses into the inner medulla, contributing to the medullary osmotic gradient. Half is excreted. Urea diffuses from the medulla to the ascending limb of LOH, and is then re-delivered to the cortical collecting duct. Effect of ADH on countercurrent multiplication Increased ADHV2 receptors in collecting duct cells agonisedIncreased aquaporin expression throughout the collecting duct.Increased urea transporter expression in the inner medullary collecting ducts.Urine becomes very concerntrated in the collecting systemMost urea is then reabsorbed in the distal collecting ductVery high inner medullary osmolality results $\to$ increased reabsorption in LOH. V1 receptors in the vasa recta are agonized, decreasing medullary blood flow.
Consequences of chronic renal failure Consequences of chronic renal failure NEUROUraemic polyneuropathy / myopathyRESPVolume overload pulmonary oedemaCVSVolume overload hypertensionAtherosclerosisUraemic pericarditisRENALOliguria / anuriaCalcium disturbancesHyperPO4HyperkalaemiaHypotonic hyponatraemia (water-wasting, salt-wasting)Urea increases (decreased glomerular clearance)Mixed HAGMA and NAGMA (loss of both Cl- excretion and excretion of anions like PO4 and SO4)GITDecreased GI motilityGI bleedingMay be protein-restrictedHAEMEPO-deficiency anaemiaUraemic platelet dysfunctionTPO-deficiency thrombocytopaeniaIMMUNOLOGYIncreased risk of infectionsPHARMACOLOGYDecreased clearance of renally excreted drugsDecreased protein binding if protein-wasting $\to$ hypoalbuminaemia
Osmosis and starling forces Osmosis and starling forces Osmosis is the movement of solvent through a semipermeable membrane from a less concentrated solution to a more concentrated one.The pressure generated by osmosis is described by the van 't Hoff equation:$$\Pi V = nRT$$Where n is the number of particles, V is the volume, R is the ideal gas constant, T is the absolute temperature. This is because solute particles in dilute solution behave like an ideal gas. Colloid osmotic pressure is the osmotic pressure generated by plasma proteins, which retains water in the vascular space. Because the capillary is partly permeable to albumin, the capillary oncotic pressure is given by $$\sigma [\pi_{capillary} - \pi_{ISF}]$$where $\sigma$ is the reflection coefficient (1 for a perfect semipermeable membrane, 0 for a membrane permeable to solutes). $\sigma$ is $\approx 1$ in glomeruli and $\approx 0$ in liver sinusoids.Movement of water across a semipermiable membrane, such as a capillary wall, is regulated by the balance of osmotic and hydrostatic pressures, i.e. the "net filtration pressure". $$NFP = (P_{capillary} - P_{ISF}) - \sigma (\pi_{capillary} - \pi_{ISF})$$ and $$Q_{H_2O} = k \cdot \text{surface area} \cdot NFP$$ where k is the permeability coefficient.
The body fluid The body fluid The body contains around 0.6L/kg of water (~40L for an adult). It is a lower proportion of body weight in woman (~0.5L/kg) obesity, and the elderly.The relative sizes of the compartments are determined prinicpally 2/3 (27L) is intracellular fluid, which is high in potassium, magnesium, and anionic protein.K 150mM, PO4 100mM, Na only 10mM, no calcium, ample proteinOsmolality 290Size regulated by the movement of free water1/3 (13L) is extracellular fluidNa 140, Cl 100HCO3 25, K 3-5, Ca 1.1, Mg 0.5Osmolality 290 determined by sodium, chloride, glucose, ureaProtein variableSize regulated by total body sodiumExtracellular fluid is divided into:10% (1L) transcellular fluid, which is fluid in epithelial lined cavities (urine, CSF, aqueous humor). It's composition is organ-specific and regulated by active transport20% plasma volume (note $40 \cdot \frac{1}{3} \cdot \frac{1}{5} = 2.\overline{6} \approx 0.5 \cdot 5$ i.e $(1-\text{HCT}) \cdot \text{circulating volume}$The remaining 70% is interstitial fluid, the fluid between cells. Composition similar to plasma, but low protein content. Returns to circulation via lymphatics.
Renal handling of water and solute Renal handling of water and solute If you try to upset my homeostasis, urine big trouble.Renal handling of water should be answered with sensor/controller/effector.Renal handling of Na or K should be answered by breaking the nephron down into segments.Renal handling of glucose should describe glucose, then describe its handling in the PCT, then describe the consequences of glucosuria. Renal handling of water ECF volume is largely regulated by sodium balance, so H2O balance typically $\approx$ serum osmolality.ECF osmolality tightly maintained ~280mOsmH2O balance regulated by ADH, polypeptide hormoneSynthesized in hypothalamusStored in posterior pituitary until released$T_{\frac{1}{2}}=20$mins; degraded by vasopressinase in liver + kidneySensorsOsmoreceptors in vascular organ of lamina terminalis in hypothalamus; exposed to ECF. These cells have copious aquaporins and stretch-activated Na channels $\to$ depolarize when water moves into cells $\to$ sense changes in ECF osmolality.Central vein stretch receptors and carotid body/aortic arch baroreceptors $\to$ hypothalamus when $\downarrow$preload or $\downarrow$MAP. Decreased renal perfusion $\to$ renin $\to$ ATII $\to$ hypothalamus (2) and (3) are more potent stimulus $\to$ water retention $\to$ $\uparrow$ECF volume $\downarrow$tonicity in shocked statesControllerHypothalamus integrates signalsSignals posterior pituitary to release ADHEffector; ADH $\to$Brain: increased thirstRenal vasculature (V1 receptor): constrict efferent arterioles $\to$ decreased pressure and flow in peritubular vessels $\to$ pressure gradient favors water reabsorption; reduced medullary concentration gradient washoutCortical collecting duct (V2 receptor) - aquaporin vesicles translocated to surface $\to$ increased water permeability; also increases urea permeability in distal collecting duct $\to$ magnified H2O reabsorption by countercurrent mechanism Renal handling of sodium Na is main ECF cation and determines ECF volume.$140\text{mM} \cdot 0.130\text{L/min} \cdot 60\text{min/hr} \cdot 24\text{hr/day} = 26,000\text{mmol/day}$ but only ~140mmol excreted (so 99.5% reabsorbed). Regulation mainly by SNS, RAAS and ANPFreely filtered. Catecholamines or ATII $\to \ \downarrow GFR \to \downarrow$Na filtered $\to$ Na retention. PCT - 65% reabsorbedApical symport with AAs and glucose (e.g. via SGLT1). Responsible for tubuloglomerular balance ($\uparrow GFR \to \uparrow \text{tubular Glucose/AA mass} \to \uparrow Na\text{ reabsoption}$)Apical antiport with $H^+$. CO2 diffuses into cell $\xrightarrow{\text{carbonic anhydrase}} HCO_3^-+H^+$, then bicarb symported 3:1 with sodium basolaterally.Both are secondary active powered by basolateral Na/K ATPase which is upregulated by ATII. Descending LOH impermeable to NaAscending LOH - 10% absorbed (90% cumulative)Apical symport w/ 2Cl + K via NKCC2; K cycled back to tubule. Secondary active powered by basolateral Na/K ATPase; $\propto$ medullary concentration gradient, $\therefore$ determined by ADH. More Cl anion reabsorbed then cation, which generates...Positive transtubular voltage $\to$ paracellular Na reabsorptionDCT - 6% absorbed (96% cumulative)Symport w/ chloride with via NCC channel (thiazide-sensitive channel); secondary active with basolateral Na/K ATPase. Collecting duct - variable absorptionExchange with potassium. Na apically absorbed by ENAC $\to$ K excreted by ROMK. Maintained by basolateral Na/K ATPase. Upregulated by aldosterone. Renal handling of potassium K is main ICF cation. $[K]_{ECF}$ important for resting membrane potential $\to$ tightly regulated.Normal $[K]_{ECF} \in [3.5-5]$Regulation of excretion is by aldosterone; $\downarrow [K]_{ECF} \to$Aldosterone release from adrenal cortex.Freely filtered.PCT - 60% reabsorbedEntirely paracellular via solvent dragDescending LOH is impermiable to KAscending LOH - 20% reabsorbed (80% cumulative)Apical symport with Na + 2Cl via NKCC2; secondary active with basolateral Na/K ATPase, which also creates positive transtubular voltage $\to$ paracellular K reabsorptionDCT / Collecting ducts - secreted or reabsorbedPrinciple cells: secretion in exchange with sodium. Na apically absorbed by ENAC $\to$ K excreted by ROMK. Maintained by basolateral Na/K ATPase. Upregulated by aldosterone. Increased by $\uparrow$ sodium delivery or flow rate to distal nephron. Inhibited by low pH. $\alpha$-intercalated cells: Apical active antiport of K (in) and H (out) by K/H ATPase Renal handling of glucose Glucose, an essential monosaccharide, is freely filtered$$Glu_{\text{filtered}} = GFR \cdot BGL = 0.135 \cdot 5 \approx 0.7\text{mmol/min}$$ (note BGL analysers actually display the plasma glucose concentration)Normally kidney reabsorbs 100% of filtered load $\to$ no glucose in urineAll reabsorption is in PCT, by symport with sodium, secondary active powered by basolateral Na/K ATPase. Glucose then exits basolaterally by GLUT1/2.SGLT2 is high-capacity, low affinity (reabsorbs first 90% of glucose)SGLT1 is low-capacity, high affinity (mops up remaining 10%)SGLT has a maximal reabsorption rate. When filtered glucose load >Tmax of 2mmol/minute (typically BGL > 16mM), additional glucose is lost to urine. Renal consequences of glycosuria Water loss by osmotic diuresisWasting of glucose $\xrightarrow{may}$ ketogenesisLoss of K due to increased flow rate in distal tubulePredisposition to UTI
Physical mechanisms of haemodialysis Physical mechanisms of haemodialysis DialysisBlood and dialysate flow in countercurrent, separated by a solute-permeable membrane.Small molecules are cleared by diffusion. $$\text{Solute flux} = k \Delta C \frac{SA \cdot \text{solubility}}{\text{membrane thickness} \cdot \sqrt{MW}}$$Therefore, flux is increased byHigher concentration gradient (most important, $\uparrow$ by $\uparrow$blood and dialysate flow, and by countercurrent arrangement $\to$ maintains gradient along tube)Higher surface area and porositySmaller particle sizeDiafiltrationBlood in the circuit is placed under pressure. Water is ultrafiltered from blood$\to$dialysate; small and middle molecules follow by convection / solvent drag. $$H_2O\text{ flux} = Q_{UF} = SA \cdot K_{UF} \cdot (TMP - \Delta P_{\pi})$$ where $TMP = \text{Transmembrane pressure} = \frac{1}{2}(P_{filter} + P_{return}) - P_{effluent}$. Then, $$\text{Solute flux} = S \cdot Q_{UF} [\text{solute}]_{plasma}$$ where S is the sieving coefficient for the (solute,membrane) pair. NB that convection rate is largely independent of solute size. Factors affecting both modalitiesAdsorption of protein to membrane $\to$ worse performanceProtein bound fraction of solute cannot be dialysedDistribution; only drug in central compartment can be dialysedGibbs-Donnan; impermeable anionic protein resists dialysis of cations Composition of dialysate Sterile water5000mL bagsElectrolytesPhysiological levels of sodium and magnesium; isotonic + isoosmolarVariable potassium, from absent to physiologicalVariable calcium, from absent to supraphysiologicalBuffers increase the SID to alkalinize the body fluidsBicarbonate,Lactate, orCitrate
Lymph Lymph Lymph is fluid in lymphatic vessels which originates in interstital spaces.ContentDerived from ISF so similar compisitionMostly waterElectrolytes in same composition as ISFSmall amount of proteins, including clotting factorsHepatic lymph has higher protein (sinusoids very permeable)Lymphocytes and antigen-presenting cellsFollowing meal, chylomicrons = chyleCirculationBlind-ended lymphatic capillaries with permiable BM (everywhere except CNS, bone, cartilage)$\to$ lymphatic vessels with one-way valves$\to$ travel through lymph nodes$\to$ converge into the right lymphatic duct (20%) and cysterna chyli which becomes thoracic duct (80%)These drain into the right and left subclavian respectivelyDrainage is enabled by breathing and muscle pumpsFunctionFluid return: Starling forces at capillary result in 2ml/min of fluid escaping into interstitium, this is returned at same rate by lymph. If capillary leak > lymph drainage $\to$ oedema.Protein return: protein which escapes vessels (typically sinusoids) is returned to circulationLymph nodes filter and phagocytose bacteria. Lymphocytes proliferate in response to antigen presentation.Dietary fats + fat-soluble vitamins transported to circulation as chyle
Role, distribution and regulation of ions Role, distribution and regulation of ions Sadly, the college does not care to ask about chloride, the best ion. These questions are best answered by defining the role of the ion, describing it's absorption, distribution, and elimination, and then describing the mechanisms by which the plasma level is regulated. Role, distribution and regulation of sodium Sodiumis the major cation of the ECF (~140mmol)Determines ECF volumeDetermines resting membrane potential and excitabilityAbsorption is unregulated symport with nutrients from the GIT, 0.5g/day requirementDistribution45% in bone matrix50% in ECF at ~140mM5% in ICF at ~10mMEliminationMatches intake~10% in sweat~10% in stoolRemainder in urineFreely filtered; 65% absorbed in PCT by secondary active symport with glucose, AAs, and bicarbonate, 20% in LoH by the NKCC2 transport and paracellularly by a positive transtubular voltage, 6% in DCT by NCC2, variable in collecting duct by the ENAC/ROMK system.RegulationGlomerulotubular balance (~65% filtered Na load reabsorbed regardless of GFR)Low tubular flow / [Na] at JGA $\to$ renin $\to$ ATII $\to$ increases Na/K ATPase activity across nephron $\to$ more reabsoption in PCT and LoHAldosterone upregulates ENAC and ROMKANP increases GFR, inhibits ENAC Role, distribution and regulation of potassium Potassiumis the major ICF cation; controls ICF tonicity / volumedetermines resting membrane potential and membrane excitabilityextracellular messenger (e.g. for nociceptors)Absorption is unregulated paracellular ~90% bioavailableDistribution90% ICF ~150mM8% bone2% ECF ~3.5-5 mM$[K^+]_{ECF}$ tightly regulated. $\uparrow[K] \to$ less negative RMP $\to$ overexcitability $\to$ VTThe ICF:ECF ratio is increased byHigh Na/K ATPase activity ($\beta-2$ agonists, insulin, Increased K/H exchanger activity (alkalosis)And decreased byLow intracellular ATP (opens $K_{ATP}$ channels)Opening of nicotinic channels (e.g. suxamethonium in SCI)Elimination10mmol/day in sweat, 10mmol/day in faeces, remainder in urine. Of this:60% in PCT by solvent drag20% in LoH by NKCC2 and positive transtubular voltagevariable in the distal nephron by ENAC/ROMK system (principal cells) and hydrogen antiport ($\alpha$-intercalated cells). RegulationAldosterone release directly stimulated by low serum K $\to$ upregulates ROMK, ENAC, and basolateral Na/K ATPase in distal nephron $\to$ more excretionROMK excretion also increased by $\uparrow$ sodium delivery or flow rate to distal nephron, low Mg. Inhibited by low pH. Role, distribution and regulation of magnesium Magnesiumdivalent cationmainly intracellularubiquitous enzyme cofactor (e.g. adenylate cyclase)L-type calcium channel blocker $\to$ vasodilator, antiarrhythmicNMDA channel blocker ("coincidence detector")ROMK channel blockerAbsorption is paracellular and unregulated, driven by electrochemical gradient and solvent drag, bioavailability ~30%.DistributionBone hydroxyapatite ~60%ICF ~40%, 20mM, tightly regulatedECF <1%, 0.5mM, of which 40% is protein bound, 10% is complexed with phosphate/citrate (same as calcium)EliminationFreely filtered at glomerulus15% reaborbed by solute drag in PCT60% reaborbed by the positive transtubular voltage at the loop of Henle~15% reabsorbed at the DCT; this is regulated by plasma Mg levelsAfter a bolus, the half life is ~4 hours.RegulationMg GIT absorption increased + DCT reabsorption increased in hypomagnesaemiaLow $[Mg]_{plasma} \ \to \ \uparrow$PTH, liberating Mg from bone matrix Role, distribution and regulation of calcium CalciumIs a divalent cationis a structure component of bone matrixis a coagulation cofactoris an intracellular signalling molecule, responsible for excitation-contraction coupling in muscles neurotransmitter release in neurons hormone release in glandsraises the threshold potential, stabilizing excitable membranesAbsorption is tightly regulated, ~10-50% bioavailabilityDistribution99% in bone hydroxyapatite1% ECF, 2.1-2.6mM, of which 40% is protein bound, 10% is complexed with phosphate/citrate, so free plasma calcium is 1.05-1.3mM~none in ICF (<0.1mM)EliminationUnbound calcium filteredReabsorbed by solvent drag in PCT and by positive transtubular voltage in LoHReabsorption in distal nephron is regulated by...RegulationCholesterol $\xrightarrow{light}$ vit D3 $\xrightarrow{liver}$ 1-OH-vitD $\xrightarrow{kidney \ \uparrow \text{by low Ca}}$ 1,25-OHvitD $\to$ increased calcium GIT absorption, DCT reabsorptionLow [Ca] $\to$ PTH release from parathyroid $\to$ iincreased osteoclast activity, decreased osteoblast activity $\therefore$ net bone reabsorption, $\uparrow$ 1,25-OHvitD, direct and indirect $\uparrow$ increased calcium GIT absorption, DCT reabsorptionHigh [Ca] $\to$ calcitonin release from thyroid $\to$ decreased 1,25-OHvitD, decreased osteoclast activity Role, distribution and regulation of phosphate Phosphateis the major intracellular anionacts as second messenger (e.g. IP3)has a metabolic role (as G6P and ATP)forms bone hydroxyapatiteis an important buffer system in ICF and urineForms 2,3DPG $\to$ right-shifts ODCAbsorptionActive and passive from GIT. Increased by 1,25-OHvitD. ~65% bioavailableDistribution~85% in bone hydroxyapatite ~15% in ICF<1% in ECFEliminationElimintated in stool and urineRenally, freely filtered, then reabsorption is regulatedRegulationHigh serum phosphate or 1,25-OHvitD stimulates FGF23 release from osteocytes $\to$ decreased PO4 reabsorption, decreased vitD hydroxylation.Renal elimination increased by acidosis (by titration to H2PO4- in urine), PTHReabsorption increased by vitamin D, calcitriol, thyroxineLiberation from bone matrix increased by PTH
IV fluid therapy IV fluid therapy Intravenous fluids can be given to expand ECF volume, expand or contract ICF volume, meet daily nutritive requirements, or manipulate the osmolality, pH, and ionic concentrations of the body. Osmolality of an IV fluid is the concentration of all solutes presen. Tonicity is the concentration of "effective osmoles" which cannot cross membranes $\to$ exert an osmotic pressure. Urea and (in the presence of appropriate insulin) glucose are both ineffective. Recall that 2/3 of total body water is ICF, leaving 1/3 as ECF; of this, roughly one quarter is IVF (therefore one-twelfth of the TBW). When a fluid changes both the initial volume and osmolality of a compartment, the final effect can be found byFinding the sum of all the volumes of all compartments (including the added fluid)Writing the number of osmoles in each compartment, including the added osmolesSumming of all the osmoles of all compartments and calculating the new whole-body osmolalityUsing the osmoles and osmolality to calculate the volume of each compartment Pharmacology of normal saline 1L of sterile water containing 9g of NaCl154mM Na, 154mM Cl $\to$ 308mOsm/LDistributes throughout ECF (1/4 stays in IVF)Low SID acidifies the body fluidsCan cause mild hyponatraemia or volume toxicity Pharmacology of 5% glucose 50g of glucose in 1L of sterile water278mOsm/LHypoosmolar but hypotonic (in presence of insulin, glucose in an ineffective osmole, and rapidly enters cells $\xrightarrow{\text{citric acid cycle}}$ H2O and CO2$\therefore$ effectively a free water infusionContains 850kJ/LDistributes through total body water (1/12 remains in IVF, about 83mL)Causes hypotonic hyponatraemia $\xrightarrow{potentially}$ cerebral oedema Pharmacology of 5% albumin 25g of albumin in 500mL of sterile water, with added sodium chloride. 50g/L= 0.15*50 = 7.5mM albumin140mM Na, 128mM Cl290mOsm Sodium distributes through ECFAlbumin is initially confined to IVF, before distributing through the ECF with a distributional half-life of 17 hoursAlbumin retains sodium and chloride in the IVF by Gibbs-Donnan effectThe colloid oncotic pressure is increased, which shifts fluid from the ISF to the IVFElimination half-life of albumin is 20 days (by reticuloendothelial system) Pharmacology of compound sodium lactate 1L of sterile water containing a mix of salt and buffer:Na 131mM Cl 111mM (gap of 20!)K 5.4mM Ca 2mM Lactate 29mMOsmolality 260mOsm/kg, therefore slighly hypoosmolar and hypotonicDistributes throughout ECF (1/4 stays in IVF)Normally, lactate $\xrightarrow{\text{citric acid cycle}}$ H2O and water, leaving a wide SID that alkalinizes the body fluidsCa binds to the citrate in blood products and to some drugs e.g. ceftriaxone $\to$ not compatibleCan cause hypercalcaemia or hyperkalaemiaIn liver failure, lactate is not cleared and can produced a lactic HAGMA Pharmacology of 20% mannitol 100mL of sterile water containing 20g of mannitol, an inert sugar alcohol1200mM of mannitol $\to$ 1200mOsm/kgConfined to ECF and does not cross BBBCauses an initial hypertonic hyponatraemia, with rapid dehydration of the ICFThen, as it is freely filtered and not reabsorbed, it causes an osmotic diuresis with a subsequent hypernatraemia and ECF volume contractionIt can be monitored using the osmolar gap Pharmacology of 3% saline 1L of sterile water containing 30g of sodium chlorideNa 513mM, Cl 513mM1026mOsm/LConfined to ECF; produces intracellular dehydration and hypertonic hypernatraemiaCan be monitored with serum sodium Pharmacology of 8.4% bicarbonate 100mL of sterile water containing 8.4g of sodium bicarbonateNa 1000mM, HCO3 1000mM $\to$ 2000mOsmAdding sodium without chloride widens the SID, alkalinizing the ECFThe added bicarbonate equilibrates with CO2, producing transient hypercapnoea. In low-ventilation states, this CO2 can diffuse across the membrane and produce a transient intracellular acidosis until steady state is reachedHyperosmolar $\to$ results in hyperosmolar hypernatraemia, shifts fluid from ICF to ECF and results in ADH release Pharmacology of plasma-lyte 1L of sterile water containing a mix of salt and bufferNa 140mM, Cl 98mMK 5.0, no calciumMg 1.5mMAcetate 27mM, gluconate 23mMOsmolality 290mOsm/LDistributes throughout ECF (1/4 stays in IVF)Normally, acetate and gluconate $\xrightarrow{\text{citric acid cycle}}$ H2O and water, leaving a wide SID that alkalinizes the body fluidsCan cause hyperkalaemia or hypermagnesaemia

Acid-Base

Stewart approach Stewart approach The physiochemical approach to acid base is derived from fundamental chemical principles (laws of mass action, water dissociation, conservation of mass and electroneutrality). pH depends on CO2 and bicarbonate according to the Henderson Hasselbalch equation:$$pH = 6.1 + \ln \frac{[HCO3-]}{0.03 x PaCO2}$$The PaCO2 is directly set by the alveolar ventilation.But [HCO3-] is not under physiological control; it depends on the strong ion difference and total quantity of weak acids. This is because electroneutrality must be maintained (i.e. total bicarb cannot exceed the SID) and because bicarb is in competition with other weak acids for potential anion space.$$\require{AMScd}$$$$\begin{CD} @. \substack{\text{Dead} \\ \text{space}} @. @. @. \\ @. @VVV @. @. @. \\ \substack{\text{Minute} \\ \text{volume}} @>>> \substack{\text{alveolar} \\ \text{ventilation}} @>>> {\mathbf{PaCO_2}} @<<< \substack{\text{Metabolic} \\ \text{rate}} @. \\ @. @. @VVV @. @. \\ @. @. {pH} @. @. \\ @. @. @AAA @. @. \\ \substack{PO_4^- \\ \text{(renal clearance)}} @>>> {\mathbf{A_{TOT}}} @>>> {HCO_3^-} @<<< {\mathbf{SID}} @<<< \substack{\text{Other strong} \\ \text{anions}} \\ @. @AAA @. @AAA @. \\ @. \substack{\text{Albumin} \\ \text{ }} @. @. \substack{\text{Na/Cl} \\ \text{balance}} \end{CD}$$SID is under renal control, because the kidneys canReabsorb sodium, without chloride, by bicarbonate symport in the proximal convoluted tubulePerform ammoniogenesis, then excrete ammonia with chloride$A_{TOT}$ is 75% albumin, ~10% phosphate. Liver failure $\to$ hypoalbuminaemia $\to$ alkalosisRenal failure $\to\ \ \uparrow PO4^- \ \to) acidosisStrong ion gap = \(SID_{apparent} - SID_{effective}$, where$$SID_{apparent} = [Na^+] + [K^+] + 2[Ca^{2+}] + 2[Mg^{2+}] - [Cl^-] - [Lactate^-]$$$$SID_{effective} = [PO4-] + 0.25 \cdot Albumin$$Analogous to anion gap but incorporates lactate and albumin, therefore only altered by the presence of ketones, pyroglutamate, salicylates, toxic alcohols etc.
Renal handling of an acid load Renal handling of an acid load Acid is constantly generated by metabolism. Volatile acids (i.e. carbonic acid) can be exhaled, but fixed acids, while they can be buffered or respiratory compensation can occur, must be excreted by the kidney. 3 mechanisms allow the kidneys to acidify urine (alkalinise the body), all 3 upregulated by acidosis:Ammoniagenesis - quantitatively most importantAmmonia symthesized from glutamine in PCT, immediately binds $H^+$. Renal systhesis can $\uparrow$ up to 10x in acidosis.NH4 secreted in PCT, then reabsorbed in ascending limb of Loop of Henle via NKCC2 (masquerading as potassium)Concentrated ammonium in medulla then excreted in medullary collecting duct, along with equimolar amount of chloride $\to$ widens SID $\to$ alkalinizationReabsorption of filtered bicarbonate80% in PCT$H^+$ apically secreted via antiport with Na; this is secondary active transport powered by basolateral Na/K ATPase$H^+$ + HCO3 in tubule $\xrightarrow{\text{apical carbonic anhydrase}}$CO2 + H2O $\to$ CO2 diffuses back into cellIn cell, CO2 $\xrightarrow{\text{carbonic anhydrase}}$ HCO3 + $H^+$New HCO3 is symported basolaterally with sodiumProcess continues until tubular HCO3 is exhaustedDoes little to help with an acid load; it does not generate new bicarbonate and under normal circumstances 100% of filtered bicarbonate is already reabsorbedExcretion of titratable acidsPhosphate, creatinine, and other organic weak bases are buffer molecules. Phosphate most important (pKa 6.8)In PCT, $H^+$ apically secreted via antiport with Na (secondary active with basolateral Na/K ATPase)In DCT, $H^+$ apically secreted via active antiport with K in $alpha$-intercalated cells. This $H^+$ is buffered by phosphate et al and the buffers are excreted as conjugate acids. Limited by amount of buffer present.
Buffers Buffers A buffer is a solution with a weak acid and conjufate base in equilibrium. It resists changes in pH due to addition of other acids or bases.Buffering allows for large changes in acid/base load with near-constant [H+].Buffer systems can be Closed (total quantity [A-] + [AH] is constant), orOpen (one/both of [A-] or [AH] can be excreted or generated $\to$ shifts equilibrium by mass action $\to$ physiological control of pH)Buffering capacity is maximized when buffer concentration is high, the buffer is open, and the pH is near the buffer's pKa:$$pH = pKa + \log \frac{[A-]}{[AH]}$$All buffer systems share the same pool of hydrogen, so they are in equilibrium with one another (the "isohydric principle").Bicarbonate: the major buffer of the ECF $CO_2 + H_2O \rightleftharpoons H_2CO_3 \rightleftharpoons HCO_3^- + H^+$pKa 6.1High concentrationBoth ends open (CO2 $\propto \ V_A$ and kidneys can generate/secrete bicarbonate $\to$ most important buffer system)Allows for rapid control of pHHaemoglobin: the secondary buffer of the ECFOxyHb pKa 6.6, DeoxyHb pKa 8.2 ($\pm$0.8 from physiological 7.4)Very high concentrationTherefore high buffering capacityHydrogen ions bind to imidazole residuesIncreased propensity for DeoxyHb to bind hydrogen gives rise to the Haldane effect ($\uparrow$H+ binding $\to$ equilibrium shifted to right, $\downarrow$PaCO2 $\uparrow$[HCO3-] $\to$ Hamburger effect, HCO3- antiported out of cell, chloride in.Intracellular proteinspKa 6.8Very high concentrationH+ binds to imidazole residuesMost important buffer of ICFPhosphate: buffer of urine and ICF $H_2PO_4^- \rightleftharpoons HPO_4^- + H^+$pKa 6.8, low extracellular quantitiesMostly important as intracellular buffer and buffer of urineTechnically open, but slow. In chronic acidosis, active release of HPO4 from bone $\to$ H2PO4 in renal tubule poorly absorbed $\to$ lost in urine.

Neurology

Neuromuscular blockers Neuromuscular blockers Nondepolarizing NMBs mechanism: Competitively antagonize the nicotinic receptorOnce >95% of sites are occupied, this prevents ACh binding $\to$ prevents depolarizationDepolarizing NMBs (suxamethonium is the only one in use) mechanism:Continiously agonising the nicotinic receptor, keeping the channel openThis maintains a depolarized endplateThis initially results in a normal depolarization as the fast sodium channels move into the open stateThese sodium channels then become inactivated as the H gate closesFor the fast sodium channels ringing the endplate, the lack of repolarization prevents opening of the H gateFurther depolarization is not conductedThis is called "accommodation block" Aminosteroids and sugammadex RocuroniumAminosteroid NDNMBDose: 0.9mg/kgOnset in 60 secondsLasts ~30 minutes but highly variableIntermediate incidence of anaphylaxisHepatically metabolized and excreted in bilePrecipitates with thiopentoneVecuroniumAminosteroid NDNMBDose: 0.1mg/kgOnset in 3 minutesLasts ~30 minutes, less variable than rocLow incidence of anaphylaxisHepatically metabolized and excreted in bileSugammadexBinds to aminosteroid NMBs (i.e. roc and vec)The complex is then excreted renallyReversal of paralysis within 3 minutesHalf-life 2 hoursDose 2mg/kg Benzylisoquinolines CisatracuriumBenzylisoquinoline (cis-enantiomer of atracurium)4 minute onset45 minute duration0.15mg/kg doseOrgan-independent metabolism (Hoffman elimination)Lowest incidence of anaphylaxisReliable pharmacokinetics $\to$ NMB of choice for infusions Suxamethonium Near-immediate onset (one arm-heart-muscle circulation time)~5 minute duration1mg/kg IV4mg/kg IMDegraded by plasma pseudocholinesteraseMechanism of actionContiniously agonising the nicotinic receptor, keeping the channel openThis maintains a depolarized endplateThis initially results in a normal depolarization as the fast sodium channels move into the open stateThese sodium channels then become inactivated as the H gate closesFor the fast sodium channels ringing the endplate, the lack of repolarization prevents opening of the H gateFurther depolarization is not conductedThis is called "accommodation block"With repeated doses, the muscles will fail to depolarize even with electrical stimulus (phase II block), mechanism unknown"Scoline apnoea" (serum cholinesterase deficiency)Congenital or acquiredResults in prolonged paralysis, up to hoursAcquired causesLiver disease (the liver makes the stuff), malnutrition, malignancy (no substrate)Pseudocholinesterase inhibitors (neostigmine, organophosphates, MOAIs)Cocaine (competes with sux for pseudocholinesterase)Nicotinic receptor proliferationSux can result in hyperkalaemic arrest due to exaggerated potassium efflux from supranormal whole body depolarizationSpinal cord injury, extended immobility (and therefore critical illness), stroke, muscular dystrophy, burns all due to negative feedback (muscles starved for ACh upregulate their nicotinic receptors)AnaphylaxisHighest rate of any NBMMalignant hyperthermiaMost common triggerUnregulated calcium influx from the sarcoplasmic reticuluum via an abnormal ryanodine receptorMassive ATP hydrolysis by myosin ATPaseIncreased metabolic rateIncreased VCO2 and internal temperatureLactate production and acidosisRhabdomyolysis and then renal failure
Production, function, and composition of CSF Production, function, and composition of CSF Modified ultrafiltrate of plasma in the ventricles of brain and the subarachnoid spaceTotal 150mL (25mL ventricles, 25mL spinal cord, 100mL subarachoid space).Secretion from coroid plexus - 25ml/hrUltrafiltrate of plasma formed in coroidal interstitiumCoroid plexus cells have tight junctions that prevent passive ion flow into CSFCoroid plexus cells use Na/K ATPase to primary actively transport sodium into CSFBicarbonate and chloride follow by secondary active transport with sodiumWater follows transcellularly by osmosisSecretion is constant, not CPP dependent, but falls when CPP<55Composition vs plasmaNa similarK much lower - preserves excitabilityProtein almost absent - therefore Cl and HCO3 higherGlucose $\frac{2}{3}$ plasmapH similar to blood to facilitate central chemoreceptor functionFunctionBarrier function ("blood-CSF barrier")Chemical stability and waste removal (flowing CSF prevents accumulation of waste products in CNS)Buoyancy - reduce net weight of brain to 50gMechanical cushion functionHydraulic pressure buffering - $\uparrow$ICP $\to$ CSF moves into spinal canal ReabsorptionAt arachnoid granulationsRate $\propto P_{\text{CSF}} - P_{\text{venous}} \approx P_{\text{CSF}} - 7$
Determinants of intracranial pressure Determinants of intracranial pressure ICP is pressure in the intracranial space. It is normally 0-10mmHg.Kelly-Monroe doctrine: the skull is fixed in volume and contents are minimally compressible fluids. Normally containsBrain (1500mL)CSF (150mL)Blood (150mL)Increase in any of these volumes must be matched by equal decrease in another, or ICP will rapidly increase, unless skull disrupted (open fracture, decompressive craniotomy).Brain volume$\uparrow$ in oedema, space-occupying lesion$\downarrow$ with age (atrophy)CSF volumeHigh ICP drives reabsorption $\to$ homeostasis$\uparrow$ with efflux failure (SAH, obstructive hydrocephalus)$\downarrow$ with drainage or decreased production (low ICP, diuretics, carbonic anhydrase inhibitors)Blood volume$\uparrow$ with cerebral vasodilation (hypoxia, hypercapnia, fever, high cerebral metabolic rate incl. seizure)$\downarrow$ with cerebral vasoconstriction$\Delta$MAP outside autoregulatory range (or with failure of autoregulation)Venous outflow obstruction (head down, ETT ties, c-spine collar, SVC syndrome, sinus venous thrombosis)
Physiology of pain Physiology of pain Pain is an unpleasant sensory and emotional experience, associated with or resembling that associated with actual or potential tissue damage.Nociceptive pain is created byPeripheral nociceptors respond to physical and chemical stimuli $\to$ depolarize 1° nociceptorSynaptic transmission in dorsal horn, modulated by gating and descending inhibition2° nociceptor decussates and travels in contralateral spinothalamic tractTransmission to the thalamus $\to$ sensory and affective features Nociception and peripheral sensitization Nociceptors are unmyelinated free nerve endings which respond to a range of noxious stimuli. Mechanosensitive (pressure) $\to$Type I A$\delta$Thermosensitive ($\Delta$Temp) $\to$Type II A$\delta$Polymodal (pressure, $\Delta$Temp, chemical*) $\to$C-fiber*$\downarrow$pH, intracellular contents (ATP), inflammatory mediators (prostaglandins/leukotrienes)APs travel via axon to the primary nociceptive soma in the dorsal root ganglion, then to the dorsal hornA$\delta$: myelinated, thick, fastC-fiber: unmyelinated, thin, slowIn absense of stimulus, electrically silentMaximal firing rate ~100, firing rate $\propto$ stimulus intensityPeripheral sensitizationIn response to activation, release substance P $\to$ local inflammationLocal inflammation $\to$ Substance P, serotonin, leukotrienes, cytokines$\to$ decreased activation thresholdLesion $\to$ ectopic discharges $\to$ neuropathic pain Spinal pain pathways In dorsal horn, 3 mechanisms for synaptic transmission of pain stimulus1° Nociceptive afferent $\to$ glumtate $\to$ AMPAr $\to$ fast depolarization1° Nociceptive afferent $\to$ substance P $\to$ NK1r $\to$ second messages, slow depolarizationRepeated depolarization + further glutamate $\to$ NMDAr $\to$ second messenges $\to$ potentiation ($\to$ wind-up, central sensitization)Gating of pain in dorsal horn$$\require{AMScd}$$$$\begin{CD} {\text{1° nociceptor}} @>{inhibits}>> {\text{Interneuron}} @<{excites}<< {A\delta\text{ touch fiber}} \\ @. @V{inhibits}VV @. \\ @. \text{2° nociceptor} @. \end{CD}$$Interneuron system facilitates withdrawal reflexAlso descending modulation (noradrenergic, sertonergic, GABA) from medulla.2° nociceptors then decussate and travel in contralateral spinothalamic tract. CNS processing of pain + descending control ThalamusLateral $\to$ sensatory-discriminatory component $\to$ parietal cortexMedial $\to$ affective-behavioral component $\to$ frontal cortex + cingulate gyrusMedulla: Physiological component (tachycardia, HTN)Periaqueductal grey: Descending pain inhibition
Cranial nerve reflex arcs Cranial nerve reflex arcs A reflex arc is an involuntary reaction to a stimulus mediated by an afferent nerve, a central integrator, and an efferent nerve. The relevant reflexes are: The pupillary light reflex Retina $\to$ optic nerve (ipselateral retinal info) $\to$ optic tract (contralateral field info) $\to$ ipselateral pretectal nucleus $\to$ bilateral Edinger-Westfall nuclei $\to$ bilateral CNIII $\to$ ciliary ganglion $\to$ bilateral pupillary constriction Corneal blink reflex Light touch receptors in cornea $\to$ CN V1 $\to$ spinal trigeminal nucleus (light touch information of ipselateral face) $\to$ facial motor nucleus $\to$ CN VII $\to$ orbicularis oculi $\to$ blink Oculomotor reflex $\Delta$ head angular momentum $\to$ $\Delta$Flow in semicircular canals $\to$ CN IIX $\to$ vestibular nucleus $\to$ ipselateral and contralateral medial longitudenal fasciculus $\to$ oculomotor, trochlear, and abducens nuclei $\to$ extraoocular muscles to keep gaze fixed as head moves Gag reflex Light touch receptors in pharynx $\to$ CN IX $\to$ spinal nucleus of V (ipselateral facial light touch) $\to$ Nucleus ambiguus $\to$ CN X $\to$ soft palate elevation, pharyngeal constriction
The blood-brain barrier The blood-brain barrier The blood-brain barrier is an interface that seperates the brain from the blood. It impedes the influx of almost all but non-essential molecules from blood $\to$ brain. StructureEndothelium: no fenestrae, numerous tight junctions between each other, many mitochondriaBasement membraneFoot processes of astrocytes: ensheath vessels, contain enzymes e.g. MAOBarrier functionEndothelial cell tight junctions $\to$ minimize paracellular diffusion of hydrophilic substancesEnzymes in astrocytes and endothelium degrade substances or alter them to be water-soluble $\to$ cannot cross endotheliumTransport functionMetabolic substrate, vitamins, electrolytes and antibodies are transported in controlled mannerPassive diffusion $\to$ must be very small and/or very lipid-soluble e.g. O2, CO2, waterFacilitated diffusion e.g. glucose via GLUT1 channelsActive transport e.g. of calciumPinocytosis e.g. of antibodiesAreas with no blood-brain barrierThe circumventricular organs. Either sensors that sample plasma or excretors of a hormoneVOLT $\to$ osmoceptorPineal gland $\to$ secretes melatoninPosterior pituitary $\to$ secretes ADHChemoreceptor trigger zone $\to$ chemoreceptor that integrates vomiting signalsDrug features that facilitate movement across BBBSmall MW, highly lipophilicHigh $\Delta$C $\to$ low protein binding, low Vd, low potency ($\therefore$large dose), cerebral metabolism of drug)Substrate for active transport (e.g. lithium masquarades as sodium, valproate as lactate)
Classification of nerve fibers Classification of nerve fibers $$ \begin{array}{|l|r|r|r|r|} \text{Nerve type} & \text{Function} & \text{Diameter } (\mu m) & \text{Velocity } (m/s) & \text{Myelinated?} \\ \hline A \alpha & \text{Skeletal motor} & 10-20 & ~90 & Y \\ \hline A \beta & \text{Touch, pressure} & 5-10 & ~90 & Y \\ \hline A \gamma & \text{Muscle spindle} & 3-6 & ~90 & Y \\ \hline A \delta & \text{Pain, temperature} & 2-5 & ~90 & Y \\ \hline B & \text{Visceral afferent, autonomic} & 1-3 & ~90 & Y \\ \hline C & \text{Pain} & 0.5-1 & ~90 & N \\ \hline \end{array} $$
Major somatosenosory pathways Major somatosenosory pathways These pathways involve transduction of a signal from the peripheries, which causes a primary sensory neuron (a pseudounipolar neuron with cell body in the dorsal root ganglion) to fire. Signals ascend via the spinal cord and ultimately converge on the thalamus for processing and distribution to the cortex. Light touch, vibration, and conscious proprioception sensory pathway Mechanoreceptors $\to$ primarily $A\beta$ fibers $\to$ pseudounipolar cell body in DRG $\to$ ascends in ipselateral dorsal column of spinal cord (without synapsing in the dorsal horn) $\xrightarrow{synapse}$ nucleus cuneatus + gracilis $\xrightarrow{\text{great sensory decussation}}$ contralateral medial lemniscus $\to$ thalamus $\to$ parietal cortex Pain and temperature sensory pathway Polymodal nociceptors $\to$ C-fibers. Mechanosensitive and thermosensitive $\to \ A\delta$ fibersBoth have cell bodies in DRG. Synapse onto interneuron in dorsal horn of spinal cord $\xrightarrow{synapse}$ secondary nociceptor $\xrightarrow{\text{immediate decussation}}$ \to contralateral spinothalamic tract of spinal cord (lateral STT carries pain/temperature, anterior carries course touch); continues laterally up through brainstem $\xrightarrow{synapse}$ thalamus.Thalamus signals frontal cortex and cinguate gyrus (affective component) and parietal cortex (discriminatory component). Unconscious proprioception sensory pathway Muscle spindles + joint position receptors $\to$ A$\gamma$ fibers $\to$ Cell bodies in DRG $\xrightarrow{synapse}$ secondary sensory neurons.These form two tractsThe dorsal spinocerebellar tract ascends to the ipselateral cerebellum via the inferior cerebellar peduncleThe anterior spinocerebellar tract decussates immediately, travels up to the brainstem, then decussates again and enters the ipselateral cerebellum via the superior cerebellar peduncle.
The autonomic nervous system The autonomic nervous system The ANS is a collection of peripheral nervous system efferents that are responsible for involunatary organ and tissue actions to maintain homeostasis.It consists of sympathetic and parasympathetic parts.In both, fibers exit the CNS, synapse at a ganglion, and then innervate target structures:Preganglionic fibers are myelinated B fibersPostganglionic fibers are unymelinated C fibersThe preganglionic neurotransmitter is ACh $\to$ nicotinic receptors on postganglionic neuron The sympathetic nervous system The sympathetic nervous system prepares the body for stress and intense muscle activityOrigin: Cell bodies in lateral horn of thoracic spinal cord from T1 to L2Pathway: short preganglionic B fibers $\to$ white rami $\xrightarrow{synapse \ ACh \to N_2}$ sympathetic chain ganglia $\to$ travel up or down levels in sympathetic chain $\to$ long postganglionic C fibers $\to$ grey rami $\to$ visceral or spinal nerves $\to$ release NorAd (or ACh for sweat glands) on target organ. Adrenal medulla = modified postganglionic neurons that release adrenaline directly into plasmaAnatomy:Sympathetic chain ganglia is paired structure that runs parallel to spinal column from base of skull $\to$ coccyx; subdivided into:Cervical $\to$ head, neckThoracic $\to$ aortic, cardiac, pulmonary, renal plexiLumbar $\to$ coeliac plexusPelvic $\to$ pelvic plexusEffects on...Heart $\to$ $\beta_1 \ \to $ positive inotropy, chronotropy, lusitropy, dromotropyLung $\to \ \beta_2 \ \to$ bronchodilationArterioles $\to$ $\alpha_1 + \beta_2 \ \to $ net vasoconstriction $\to \uparrow$TPRVeins $\to$ $\alpha_1 + \beta_2 \ \to $ net vasoconstriction$\to \uparrow$MSFPGIT $\to \ \beta_2 \ \to \ \downarrow$motility Liver $\to \ \beta_2 \ \to \ \uparrow$glycogenolysis + gluconeogenesis + lipolysis $\to$ lactate formationKidney $\to \ \beta_1 \to \ $ renin releaseBladder $\to$ detrusor relaxation ($\beta_2$), sphincter contraction ($\alpha_1$)Eye $\to \ \alpha_1 \ \to$ mydriasis The parasympathetic nervous system The parasympathetic nervous system prepares the body for digestion and recovery. Origins:Edinger-Westphal nucleus $\to$ CNIII $\to$ eyeSuperior salivary nucleus $\to$ CNVII $to$ parotid glandInferior salivary nucleus $\to$ CN IX $\to$ submandibular glandDorsal nucleus of X (most important, ~75% of outflow) $\to$ CN X $\to$ thoracic and abdominal organsSacral parasympathetic nucleus $\to$ sacral nerves $\to$ pelvic/sex organsPathway: long preganglionic B fibers $\xrightarrow{synapse \ ACh \to N_2}$ plexus near or in target organ $\to$ short postganglionic C fibers $\to$ release ACh onto target organAnatomy: L+R vagus nerve formed in medulla from 4 nuclein ambiguus $\to$ motorn of solitary tract $\to$ visceral afferentspinal n of V $\to$ somatic afferentDorsal n of X $\to$ parasympathetics$\to$ exits skull via jugular foramen $\to$ travels in carotid sheath $\to$ gives off pharyngeal, superior largyneal, recurrent largyneal branches $\to$ enters thorax $\to$ gives off cardiac and pulmonary branche$\to$ oesophageal hiatus $\to$ becomes anterior and posterior trunks $\to$ hepatic, gastric, coeliac branchesEffects on...Heart $\to \ M_2 \ \to $ negative chronotropy, dromotropyLung $\to \ M_2 \ \to$ bronchoconstriction,Arterioles $\to \ M_3 \ \to$ vasodilationVeins $\to \ M_3 \ \to$ vasodilationGIT $\to \ M_3 \ \to$ increase motilityLiver $\to \ M_3 \ \to$ glycogenesisKidney $\to \ M_3 \ \to$ no parasympathetic innervation!Bladder $\to \ M_3 \ \to$ detrusor contractionEye $\to \ M_3 \ \to$ myosis, lactimationSalivary glands $\to \ M_3 \ \to$ salivation

Gastrointestinal, nutrition, metabolism

Gastrointestinal blood supply Gastrointestinal blood supply Arterial supply:Coeliac trunkLeft gastricSplenicCommon hepaticSuperior mesenteric artery:Inferior pancreaticoduodenalintestinal branchesright and middle colic arteriesInferior mesenteric:left colicsigmoidsuperior rectalCoeliac trunk supplies: Abdominal oesophagusStomachSpleenLiverSuperior half of pancreas + duodenumSMA supplies:Inferior half of pancreas + duodenumAll of jejunum and ileumColon to splenic flexureIMA supplies:Colon from splenic flexure Venous drainage (portal):Superior + inferior mesenteric vein, join to becomePortal vein, drains via liver toIVCOther venous drainage:Oesophagus drained by azygous Lower rectum and anus by middle rectal artery $\to$ IVC
GI secretions GI secretions The GI tract secretes 9L/day of fluid = 1.5+2+2.5+3. Saliva - water, calcium and phosphate (for teeth), amylase, lipase, IgA - 1.5LGastric acid - pH 2, pepsin - 2LPancreatic juice - many enzymes, pH 8, Cl 30, HCO3 130 - 2.5LSmall bowel - bicarb-rich mucus - 3L Composition of gastric secretions CellsGoblet $\to$ mucusChief $\to$ pepsinogen $\to$ pepsinParietal $\to$ HClEnterochromaffin $\to$ histamineG-cells $\to$ gastricD-cells $\to$ somatostatinComposition95% waterHCl - pH ~2.5HCO3- rich mucus forms unstirred layerEnzymes (pepsin, lipase, intrinsic factor)Electrolytes (low Na, high K, high Cl) Control of gastric acid secretion Cephalic phase (increased secretion)Central control $\to$ vagus $\to$ M3 receptor on parietal cellCentral control $\to$ vagus $\to$ M3 receptor on enterochromaffin cell $\to$ histamine $\to$ H2 receptor on parietal cellGastric phase (increased secretion)Mechanical stretch, peptides, alcohol $\to$ gastrin from G-cells Gastrin $\to$ CCKB receptor on parietal cellGastrin $\to$ CCKB receptor on enterochromaffin cell $\to$ H2 receptor on parietal cellIntestinal phase (decreased secretion)CCK and VIP from duodenumNegative feedbackSomatostatin from D-cell (if pH < 1.5)Prostaglandin E2 promotes bicarb + mucus release Mechanism of gastric acid secretion In the parietal cell, basolaterally:CO2 diffuses into the cellCarbonic anhydrase converts it to H+ and HCO3-The HCO3- is antiported with Cl-Apically,The H+ is primary active antiported with K+The K+ diffuses back out of the cell via passive channels to be recycledThe Cl- is passively excretedOverall,The gastric pH is reduced to ~2The body becomes more alkalotic Exocrine functions of pancreas 90% of pancreas is exocrine; 2.5L is secreted per dayComposed of acini $\to$ intercalated ducts $\to$ main pancreatic ductAcini secrete enzymes and fluid, intercalated ducts alkalinize it.Enzymes include typsin, pancreatic lipase, RNAase, amylase, and exopeptidases.Stimulated byVagal stimulus (cephalic phase) 20%CCK (intestinal phase) 80%Inhibited bySomatostatinCatecholaminesOverall,The intestinal pH is reducedThis activates pancreatic enzymes (trypsin, pancreatic lipase)The body becomes more acidotic
Absorption of nutrients Absorption of nutrients CHOs: Salivary and pancreatic amylase lyse polysaccharides into disaccarides $\to$ brush border lyses to monosacchardies $\to$ glucose absorbed by SGLT1Lipids: Bile acids emulsify triglyceride into micelles $\to$ Pancreatic lipase lyses triglyceride into glycerol + 3 FFAs $\to$ diffuse into enterocytes $\to$ lymph as chylomicrons.Proteins: Acid denatures protein $\to$ endopeptidases (pepsin and trypsin) lyse internal bonds $\to$ exopeptidases lyse external bonds $\to$ oligopeptides absorbed by faciliated diffusion by PEPT1 and others.Sodium is actively absorbed (mostly by symport with nutrients), and water with it by osmosis. Potassium is absorbed by passive, unregulated paracellular diffusion.Fat-soluable vitamins (ADEK) absorbed by passive diffusionWater-soluable vitamins (BC) are absorbed by active transport (either with Na+ or H+)
GI motility GI motility Peristalsis is rhythmic smooth muscle activity that propels luminal contents distally. It consists of Proximal circular SM contraction, with distal circular SM relaxationDistal longitudinal SM contraction, with proximal longitudinal SM relaxation.Migratory motor complexes (regions of $\uparrow$ peristalsis) spread from stomach to terminal ilium during fasting and are interrupted by eating. The myenteric reflex StimulusIrritant moleculesRadial stretch of gut lumenSensorIntrinsic primary afferent neurons (stretch and chemoreceptors)ControllerInterneurons in the myenteric plexusEfferentInhibitory (NO) and excitatory (ACh) motor neuronsEffectorCircular and longidudenal smooth muscle Determinants of intestinal peristaltic activity Mechanical features of contentStretch (myenteric reflex) $\uparrow$Chemical features of chymeAcidic pH $\uparrow$Hyperosmolar $\uparrow$Lipids $\downarrow$ (so there's time to absorb them)Serum electrolyte disturbances $\downarrow$ peristalsisHypoK, hypoCa, hypoMgCalcium channel blockersExcitatory hormonesACh (+ nicotine, neostigmine)Motilin (+ erythromycin)SerotoninInhibitory hormones:NOVIPCatecholamines Mechanics of gastric emptying ProcessThe fundus and body relax to store food bolusThe antrum tonically contracts to create a 5mmHg pressure gradient with the duodenumThe antrum then produces peristaltic waves, pulverizing larger particles against the closed pylorus + pusing small particles throughSolidsReceptive relaxation of fundus and body (stores food)Lag phase of ~1 hour as antrum grinds foodLinear emptying phase as particles becomes small enough, with half-time of ~1 hourOverall takes 3-4 hours for stomach to emptyLiquids$\uparrow \Delta V\ \ \to \ \uparrow \Delta P$ Therefore exponential emptying with $t_{\frac{1}{2}} = 30\text{mins}$ Determinants of rate of gastric emptying Fed or fasted?MMCs in fasted state sweep stomach of secretonsAbolished in fed statePositionLeft lateral or supine $\downarrow$Mechanical features of contentSolids slower than liquids (lag phase $\to$ linear emptying vs exponential emptying)For liquids, $\uparrow V \ \to \ \uparrow$ rate of emptying due to stretchFor solids, stomach stretching depresses peristalsisChemical features of content (mostly opposite of the intestinal effects!)Acidic pH $\downarrow$Hypertonicity $\downarrow$Lipids $\downarrow$ (same as intestine)Excitatory hormonesMotilinGhrelinAChCirculating catecholaminesInhibatory hormonesCCK and secretinNOVIPGlucagon, GLP1 Factors preventing GORD PositionUpright posture (gravity)Right lateral (pylorus dependent)Anatomical featuresHis angle forms a mucosal flap (one-way valve)SphinctersLOS; smooth muscle, around lower oesophagus. Tonically contracted. Diaphragmatic crura; skeletal muscle, sides of the oesophageal hiatusLOS tone > gastric pressure (usually 20mmHg)Determinants of LOS toneNeruogenic (vagal inhibition $\to$ NO $\to$ relaxation)Myogenic (tonic contraction)Hormones that increase rate of gastric emptying also increase sphincter tone (to maintain difference)GastrinMotilinAnd vice versaSecretinGlucagonCCKVIP
Hepatic physiology Hepatic physiology The liver has 5 main functions:SynthesisStorageMetabolismImmunological functionBile (both nutritional and excretory) Functions of the liver Synthesis90% of plasma proteins (albumin, factors, compliment)Regulatory proteins (thrombopoetin, angiotensinogen, herceptin)Nutrients (gluconeogenesis, ketones, non-essential amino acids)StorageEnergy (glycogen and lipid droplets)Fat soluble vitamins (ADEK + B12)Minerals (ferritin, copper)Blood (25% of total blood volume)MetabolismGlucose $\leftrightarrow$ GlycogenTriglycerides $\leftrightarrow$ FFAs $\to$ ketonesAmino acids $\to$ ammonia + $\alpha$-keto acidLactate $\to$ glucoseAmmonia $\to$ ureaPhase 1 + phase 2 metabolism of xenobioticsImmunologicalSynthesis of compliment$\uparrow$herceptin $\to\ \ \downarrow$ferroportin to deny iron to bacteriaKuffner cells (liver macrophages) phagocytose opsonised pathogensIgA and IgG in bileExcretion (via bile)Bile acids (95% enterohepatically cycled)Cholesterol (1g/day)Conjugated bilirubinDrugs (ceftriaxone, apixaban, digoxin)Heavy metals (lead, arsenic) Composition, formation, function of bile Composition95% water, 5% solutesOrganic solutes: bile salts (40mM), cholesterol (4mM), conjugated bilirubin (2mM), lipids, de minimus protein. Bile salts formed from neutralization of bile acids; primary = made by hepatocytes, secondary = made by intestinal bacteriaInorganic solutes: similar ionic profile to plasmaFormation of bile95% of bile salts reabsorbed in terminal ileumRecirculate to hepatocytes and actively transported into bileH2O follows by osmosis ("bile-salt dependent")Other substances (conjugated xenobiotics, bilirubin) are also actively excreted, with H2O following by osmosis ("bile-salt independent")Bile ducts $\to$ water addedGall bladder $\to$ ions + H2O reclaimed, concentrating bileFunctions of bileEmulsify lipids: $\uparrow$SA $\to \ \uparrow$lipid absorption + $\uparrow$absorption of fat-soluble vitaminsExcrete xenobiotics, cholesterol, bilirubinImmune functions (IgA and IgG)Growth factors for enterocytes Physiological effects of liver failure Synthesis failureHypoalbuminaemiaThrombocytopenia and macrocytic anaemiaCoagulopathyStorage failureHypoglycaemiaMetabolism failureAccumulation of lactateAccumulation of ammonia (hepatic encephalopathy)Accumulation of drugs normally hepatically conjugatedAccumulation of unconjugated bilirubinImmunologicalLoss of compliment $\to$ susceptibility to sepsisExcretion (via bile)Accumulation of conjugated bilirubinAccumulation of drugs normally excreted in bile Ammonia metabolism and excretion SourcesProtein deamination: amino acid $\to\ \ \alpha$keto acid + ammoniaPurine metabolism in skeletal muscleRenal ammoniagenesis from glutamateDistribution98% ionized and largely ion trappedMetabolismExclusively in liverAmmonia + CO2 $\to$ ureaEliminationUrea mostly excreted renally~15% enterohepatically cycled (metabolized by flora back to ammonia and returned by first-pass to the liver; lactulose diverts bacterial metabolism)
Hepatic functional anatomy Hepatic functional anatomy Liver tissueThe histological unit of the liver is the lobule (a central vein, surrounded by a hexagon of tissue). The functional unit it the acinus, a rhombus formed by two portal triads (arteriole, portal venule, bile duct) and two central veins.There are three zones formed by falling tissue oxygen tensionHighest PO2. High metabolic rate. Synthesizes proteins, secretes glucose.Intermediate PO2 and function.Low PO2. Injured first in shock. $\uparrow$[CYP450], site of drug metabolism. Absorbs and utilizes glucose. The hepatic sinusoidOrigin: union of portal venule and hepatic arterioleTermination: joins central veinFenestrated epithelium with absent basement membrane. Kuffner cells (resident macrophages) and Pitt cells (resident NK cells) sit on the endothelium, in the vessel. Kuffner cells phagocytose anything opsinized (yummy yummy).Beneath the endothelium is the thin space of Disse, which contains Ito cells (contractile cells that modulate sinusodal capacitance and store fat-soluable vitamins).Beneath that is hepatocytes.

Haematology

Coagulation Coagulation Don't have a thrombo, baybee. The process of coagulation InitiationVessel injury exposes bare collagen and tissue factor.FVII $\stackrel{\text{Tissue factor}}{\to}$ FVIIaFX $\stackrel{\text{FVIIa}}{\to}$ FXaMeanwhile, platelets undergoAdhesion to the denuded collagen via vWFAggregation by binding to each other via GPIIb/IIIa-fibrinogen complexActivation, which releasesSerotonin $\to$ vasoconstrictionThromboxane and ADP $\to$ activate more plateletsLots of FVVasoconstriction + platelet plug formation produces primary haemostasis$$FV \xrightarrow{\text{FXa (slow)}} FV_a$$$$\text{Prothrombin} \xrightarrow{\text{FXa+FVa+activated plt membrane+iCa}} \text{Thrombin}$$AmplificationThrombin...Activates more plateletsActivates FV (from platelet granules)Activates FXI, which activates FIXCleaves vWF off factor VIII and activates it; FIX+FVIII activates more FXFXa + FVa + plt membrane + iCa $\to$ more thrombin $\to$ positive feedbackPropagation$$\text{Fibrinogen} \xrightarrow{\text{Thrombin}} {\text{Fibrin}}$$$$\text{FXIII} \xrightarrow{\text{Thrombin}} {XIIIa} \to \text{Crosslinks fibrin strands}$$Negative feedbackProtein C $\xrightarrow{\text{thrombin}}$ Protein Ca (with protein S) $\to$ inactivates thrombin, indirectly initiates thrombolysisAntithrombin III: circulating serine protease that inactivates thrombin, FXa, FIXa, FXIa. Potentiated by heparin. Intact endothelium express anticoagulants that prevent clot propogation out of area of injuryTissue factor pathway inhibitor (TFPI) $\to$ inhibits TF-VIIa complexThrombomodulin $\to \ \uparrow$activation of protein C by thrombin Natural thombolysis ProcessPlasminogen binds to thrombin at lysine residues (N.B. TXA resembles lysine and diverts plasminogen)tPA (produced by endothelial cells) binds to plasminogen-thrombin complextPA converts plasminogen to plasmin, which cleaves fibrin into degradation productsThese products...Bind to GPIIb/IIIa on platelets without crosslinking $\to$ impaired aggregationCompete with fibrinogen for thrombin binding $\to$ anticoagulationFactors decreasing tPA activityPlasminogen Activator Inhibitor 1 (PAI1): produced by liver, direct tPA inhibitor$\alpha$-2 antiplasmin: binds plasminFactors increasing tPA activityProtein C cleaves PAI1 and promotes lysis

Endocrinology

Regulation of calcium Regulation of calcium Calcium in the human body is 99% hydroxyapatite in bone. The remaining 1% is a readily exchangeable pool in equilibrium with the ECF, comprising45% free calcium ("ionized calcium, iCa"), ~1.15mM - biologically active35% bound to albumin10% bound to globulin10% complexed with anionsTwo hormones regulate iCa, PTH (from parathyroid, released with $\downarrow iCa \to$ decreased binding to CSR)Calcitonin (from thyroid, released when $\uparrow iCa$They do so by modulatingAbsorption and excretion, partly by the vitamin D systemThe bone reabsorption/formation balanceHypocalcaemia $\to\ \ \uparrow$ Ca absorption, $\downarrow$ Ca excretion, $\uparrow$ PO4 excretion, net bone formation, and vice versa for hypercalcaemia. Mechanistically,$$\require{AMScd}$$$$\begin{CD} @. {\uparrow \uparrow \substack{\text{Renal PO4} \\ \text{excretion}}} @. @. @. @. @. \\ @. @AAA @. @. \\ \text{Parathyroid} @>>> {\uparrow PTH} @>>> {\downarrow \downarrow \substack{\text{Renal Ca} \\ \text{excretion}}} @. @. \\ @A{stimulates}AA @VVV @AAA @. \\ \mathbf{\downarrow iCa} @. {\uparrow \substack{\text{25OH-D} \\ \text{hydroxylation}}} @>>> {1,25OH\text{-vitD}} @>>> {\uparrow \substack{\text{GI Ca} \\ \text{reabsorption}}} \\ @V{inhibits}VV @AAA @VVV @. \\ \text{Thyroid} @>>> {\downarrow \text{Calcitriol}} @. {\downarrow \substack{\text{Renal PO4} \\ \text{excretion}}} @. @. \end{CD}$$ and,$$\begin{CD} \text{Parathyroid} @>>> {\uparrow PTH} @>{inhibits}>> \text{Osteoblasts} @. @. \\ @A{stimulates}AA @V{stimulates}VV @VVV @. \\ \mathbf{\downarrow iCa} @. \text{Osteoclasts} @>>> {\substack{\text{Net bone} \\ \text{reabsorption}}} @>>> {\uparrow PO4^-} \\ @V{inhibits}VV @A{disinhibits}AA @VVV @. \\ \text{Thyroid} @>>> {\downarrow \text{Calcitriol}} @. {\uparrow iCa} @. @. \end{CD}$$
Control of blood glucose Control of blood glucose BGL is tightly regulated. Fasting BGL ~ 5mM, post prandial BSL ~ 10mM.Glucose flux consists ofAbsorption of carbohydratesConsumption by glycolysisStorage and release from glycogen storesGluconeogenesis (80% liver, 20% kidney)Insulin and glucagon release regulates blood glucose.The primary effector is the liver, which functions as a glucostat.Response to hyperglycaemiaInsulin released $\uparrow BSL \to \uparrow ATP \to K_{ATP}$ blockade, glucagon suppressedLiver: increased glycolysis, glycogenesis; decreased gluconeogenesis, free fatty acid oxidation (ketone production)GLUT-4 bearing tissues (muscle, adipose): increased glycolysis, glycogenolysisResponse to hypoglycaemiaInsulin suppressed, glucagon released, catecholamines releasedLiver: increased glycogenolysis, gluconeogenesis, FFA oxidation (ketone production); decreased glycolysis, glycogenesis Physiology of insulin Insulin is a polypeptide anabolic hormone produced in the $\beta$ cells of the pancreatic islets. C-peptide is produced as a byproduct of its production. It is stored in intracellular vesicles.Insulin releaseGlucose is principal stimulus. Beta cell ATP acts as a measure of serum glucose concentration$$\uparrow BGL \xrightarrow{GLUT-2} \text{Glucose}_{\beta \text{ cell}} \xrightarrow{glucokinase} \text{G6P} \to \text{pyruvate} + 2ATP \to \text{citric acid cycle} \to \uparrow[ATP]_{\beta \text{ cell}} $$The $K_{ATP}$ channel is blocked in the presence of ATP, and causes membrane voltage to rise until...$$\uparrow[ATP]_{\beta \text{ cell}} \to K_{ATP} \text{ blockade} \to \text{depolarization}$$Calcium binds to calmodulin which effects exocytosis of insulin-filled vesicles$$\uparrow[Ca]_{\beta \text{ cell}} \to \text{exocytosis}$$Other substrates that raise $\uparrow[ATP]_{\beta \text{ cell}}$ also cause insulin release (amino acids, keto acids, fatty acids).Insulin release is potentiated byPost-prandial hormones (GLP1, CCK, Ach)Glucagonand inhibited by$\alpha_2$ agonists (i.e. catecholamines)CortisolFastingExerciseSomatostatinInsulin effectsBinds to insulin receptor; receptor-ligand complex endocytosed and destroyed. Activates PI3k second messenger pathway.In GLUT-4 bearing tissues (adipose, skeletal muscle)Translocate GLUT-4 vesicles to surface $\to$ glucose absorption $\to\ \ \downarrow$ BGLIncrease lipoprotein lipase + free fatty acid transporters on adipose tissues $\to$ absorbtion of triglyceride and free fatty acidsIn the liver$\uparrow$ Glucokinase - increased glycogenesis $\downarrow$ G-6-phosphatase - decreased gluconeogenesis$\downarrow$ free fatty acid oxidation $\to \ \downarrow$ketone productionIn the heart$\uparrow [Ca^{2+}]_{intracellular} \to \uparrow \text{inotropy} \ (\beta_1 \text{ independent})$In all cellsIntracellular shift of potassium and phosphate Physiology of glucagon Insulin is a polypeptide catabolic hormone produced in the $\alpha$ cells of the pancreatic islets. The mechanics of glucagon release are unclear.InhibitiorsInsulinHyperglycaemia, partly by means of increased insulin secretionPost-prandial hormones (e.g. GLP-1)Stimulation of glucagon secretion:Hypoglycaemia (direct stimulus and loss of insulin-mediated inhibition)Amino acidsFastingExercise$\alpha_2$ agonists (i.e. catecholamines)Effects:Increased gluconeogenesisIncreased glycogenolysisIncreased free fatty acid oxidation $\to \ \uparrow)ketone productionDecreased hepatic glycogenesis\(\uparrow [Ca^{2+}]_{cardiomyocyte} \to \uparrow \text{inotropy} \ (\beta_1 \text{ independent})$
Thyroid hormones Thyroid hormones $\require{AMScd}$ $$\begin{CD} {\downarrow T_{3/4}} @>{stimulates}>> \text{Hypothalamus} @<{stimulates}<< {Cold}\\ @. @V{TRH}V{stimulates}V @.\\ {\uparrow T_{3/4}} @>{inhibits}>> \text{Pituitary} @<{inhibits}<< \substack{\text{Cortisol} \\ \text{dopamine}}\\ @. @V{TSH}V{stimulates}V @.\\ {\text{Iodide}} @>{ion \ trapping}>> \text{Thyroid} @>>> T_4\\ @. @VVV @VVV\\ @. T_3 @<<< \substack{\text{Peripheral} \\ \text{deiodinases}}\\ @. @. @VVV\\ @. @. \substack{rT_3 \\ \text{(inactive)}}\\ \end{CD}$$Synthesis and release of thyroid hormoneIodide taken up into follicular cells of thyroid by secondary active transport with sodium ('iodine trapping")Iodide converted to iodine $ 2I^- + 2H_2O_2 +2H^+ \xrightarrow{Thyroid \ peroxidase} I_2 + 2H_2O$Iodine then binds thyroglobilin to produce T3 and T4Hormone excreted into follicular colloidColloid uptaken by pinocytosis $\to$ proteolysis $\to$ T3 and T4 release basolaterallyAll increased by $\uparrow TSH \to \ \uparrow cAMP$Carriage: Circulates bounds to thyroxine binding globulin, transthyretin, and albumin, >99% protein bound (T4 more than T3). Metabolism and elimination: Deiodinated in peripheries. T4 half life = 7 days, T3 half life = 7 hours.Effects of thyroid hormone:Bind to thyroid receptors, which are mostly nuclear receptors that modulate gene expressionIncrease BMR by non-specifically increasing cellular enzyme activityDecrease efficiency of electron transport chain $\to$ increased non-activity thermogenesisIncreased glycolosis and gluconeogenesisIncreased expression of adrenergic receptors $\to\ \uparrow$sensitivity to catecholamines $\to$ positive inotropy and chronotropyVasodilationIncrease FFA mobilization from adipose tissue

Measurement and equipment

Pulse oximetry and cooximetry Pulse oximetry and cooximetry A pulse oximeter measures arterial oxygen saturation. It relies onThe different absorption spectra of OxyHb and DeoxyHbThe pulsatile absorption signal generated by change in optical lengthThe Beer-Lambert law, optical absorbance by a solute is proportional to the length of the light ray, the concentration of the solute, and the extinction coefficient for the solute and wavelength, $A = \Delta L \epsilon_{\text{solute}}C_{\text{solute}}$The device measures the ratio of the pulsatile absorbances (each normalized by the nonpulsatile part to account for different LED intensities):$$R = \frac{AC_{660} / DC_{660}}{AC_{940} / DC_{940}}$$And, by applying Beer-Lambert twice, we can see$$R = \frac{\Delta L}{\Delta L} \frac{(\epsilon_{\text{oxy}} C_{\text{oxy}} + \epsilon_{\text{deoxy}} C_{\text{deoxy}})_{660}}{(\epsilon_{\text{oxy}} C_{\text{oxy}} + \epsilon_{\text{deoxy}} C_{\text{deoxy}})_{940}}$$$$R = \frac{(\epsilon_{\text{oxy}} C_{\text{oxy}} + \epsilon_{\text{deoxy}} C_{\text{deoxy}})_{660}}{(\epsilon_{\text{oxy}} C_{\text{oxy}} + \epsilon_{\text{deoxy}} C_{\text{deoxy}})_{940}}$$If we then assume that there is only OxyHb and DeoxyHb i.e. $F_{oxy} + F_{deoxy} = 1$ then$$R = \frac{(\epsilon_{oxy} F_{oxy} [Hb] + \epsilon_{deoxy} (1-F_{oxy}) [Hb])_{660}}{(\epsilon_{oxy} F_{oxy} [Hb] + \epsilon_{deoxy} (1-F_{oxy}) [Hb])_{940}}$$$$R = \frac{(\epsilon_{oxy} F_{oxy} + \epsilon_{deoxy} (1-F_{oxy}))_{660}}{(\epsilon_{oxy} F_{oxy} + \epsilon_{deoxy} (1-F_{oxy}))_{940}}$$We could then solve for $F_{oxy}$ directly; unfortunately, there is a lot of error (due to differential scattering of the different wavelengths, such that $\Delta L_{660} \neq \Delta L_{940}$In practice, R is regressed against SpO2 of healthy subjects breathing gas of varying hypoxic FiO2. R of 1 $\approx$ SO2 of 85%. Values below 70% are extrapolated.Issues due to R's calibrationDark skin tone $\to$ overestimates sO2Anaemia $\to$ low signal:noise ratioSats < 70% $\to$ never calibratedIssues due to abnormal Hb speciesCOHb has a 660nm and 940nm absorbance close to OxyHb, and also left-shifts the ODC $\to$ overestimates the sO2MetHb readily absorbs both wavelengths; $R \to 1,\ sO_2 \to 85\%$Issues due to pulsatilityShock/tourniquet/malposition $\to$ poor waveform $\to$ artifact included in pulsatile component $\to \ R \approx 1 \to sO2 \approx 85\%$Movement $\to$ tissue/venous blood included in AC component $\to$ underestimated sO2Venous pulsations e.g. severe TR $\to$ venous blood in AC component $\to$ underestimated sO2 Co-oximetry Cooximeters analyse a blood sample extracorporally and expose it to >4 (usually 128) wavelengths of light. The total absorbance spectrum is the sum of the absorbance spectra of each species, multiplied by each concentration:$$A(f) = \sum_{i \in \text{Hb species}} \epsilon^f_i \cdot [i]$$We can therefore compute the concentration of oxyHb, deoxyHb, COHb, metHb, and sulfHb, and derived quantities:$$[Hb] = \sum_{i \in \text{Hb species}} [i]$$$$sO2 = \frac{[oxyHb]}{[Hb]}$$Cooximetry is not confused by abnormal haemoglobin species, abnormal pulsatility patterns, or a moving patient, and can measure total Hb; but it requires venepuncture (or arterial puncture to get saO2), is not continuous, and does not incidentally measure the heart rate.
Resonance and damping in arterial lines Resonance and damping in arterial lines The arterial line is a driven harmonic oscillator. The driving function is the arterial blood pressure. The response is the strain signal recorded by the Wheatstone Bridge resistor. $$m\ddot{x} = \overbrace{F(t)}^{\text{driving function}}-\overbrace{\gamma\dot{x}}^{\text{damping}}−\overbrace{(2 \pi f_n)^2x}^{\text{oscillation}}$$DefinitionsThe damping coefficient $\gamma$ is the rapidity with which oscillations cease.The natural frequency $f_n$ is the frequency of oscillations after an impulse if there was no damping. $$f_n \propto \text{Tube radius} \cdot \sqrt{\frac{1}{\text{Compliance} \cdot \text{Tube length} \cdot \text{Fluid density}}}$$The resonant frequency is the frequency of oscillations after an impulse. It is decreased by damping. If the driving function (blood pressure signal) or a large term in its fourier series is near the resonant frequency, resonance will occur (i.e. increased oscillation). Critical damping occurs at the lowest $\gamma$ such that the system does not overshoot, called $\gamma_{crit}$The damping ratio $\zeta$ is $\frac{\gamma}{\gamma_{crit}}$.Causes and effects of resonanceResonant frequency increased by short, fat tube with noncompliant walls and minimal dampingIf any large amplitude harmonics in the fourier series of the blood pressure waveform near resonant frequency, they will be amplified $\to$ inaccurate waveform, widened pulse pressureFirst 10 harmonics contain most amplitude so resonant frequency must be 10 times the heart rate $\to$ 25hz. Typical natural frequency 200hz.Causes and effects of dampingCaused by bubbles/clots in line, vasospasm, 3 way taps, narrow/long/compliant tubingFast flush test $\to$ $\zeta$ is the amplitude ratio of 2 consecutive waves, resonant frequency is the frequency of these wavesOptimal damping occurs when $\zeta \approx 0.6-0.7$. Below this, pulse pressure is widenedAbove this, pulse pressure narrowedThe importance of damping depends on $f_n$. $\uparrow f_n \to$ signal less affected by resonance $\to$ broader range of acceptable $\zeta$.
Cardiac output monitoring Cardiac output monitoring By the Fick methodOxygen uptake equals the arterio-venous oxygen difference times flow rate$$CO \cdot (CaO_2 - CvO_2) = \dot{V_{O_2}}$$VO2 can be directly measured by knowing the minute volume, the partial pressure of O2 in mixed expired gas, and the FiO2: $$\dot{V_{O_2}} = MV \cdot (P_aO_2 - P_{\bar{E}}O_2)$$The CaO2 and CvO2 can be computed with knowledge of the ceHb, and the arterial and mixed venous PO2 and saturations, because $$C_{O_2} = 1.34 \cdot ceHb \cdot sO_2 + 0.03 \cdot P_{O_2}$$ with $C_{O_2}$ measured in ml/LLimitationsPulmonary O2 consumption (increase VO2 $\to$ overestimate CO)Intracardiac shunt (reduces the a-v difference $\to$ overestimate)Assumes steady-stateBy the indirect Fick methodAs the Fick method, but some terms are estimated from a nomogram $\to$ more errorBy indicator dilution (including thermodilution)The Stewart Hamilton equation reports that, for a concentration measured distal to an infusion of indicator, $$CO = \frac{\text{indicator dose}}{\int_0^{\inf} C(t) dt}$$If a thermal indicator i.e. cold saline is used, then this becomes $$CO = k\frac{(T_{blood} - T_{saline}) \cdot V_{\text{saline}}}{\int_0^{\infty} \Delta T(t) dt}$$ where k depends on the injectate.Limitations of dye dilutionDye accumulates and recirculates, which limits how often CO measurements can be takenAssumes uniform mixing of blood and unidirectional flowSpot measurement $\to$ inaccurate with erratic respirationLimitations of thermodilutionHeat sinks (e.g. pleural effusions) may interfereIntracardiac shunt $\to$ overestimates cardiac output (in essence a left-to-right shunt effectively reduces the thermal dose)Rapid infusion of IV fluids will interfere (effectively increases the thermal dose)By pulsed wave dopplerPulsed wave doppler is placed over the LV outflow tract in A5C or A3C. The velocity signal is integrated over one systole to give a velocity-time integral (VTI), the displacement that a line blood has accumulated during that systole. The LVOT radius is measured in PLAX. Then,$$CO = HR * VTI * \pi r^2$$ LimitationsOperator dependent; doppler beam must be aligned with LVOT; small errors in LVOTd are magnified when it is squaredAssumes each stroke volume is equal $\to$ inaccurate in AF or erratic respirationNot continuousBy pulse contour analysisThe area under an arterial pressure waveform is integrated. Since pressure is proportional to flow, this integral is proportional to the stroke volume. $$SV \propto \int_0^{\text{end of systole}}P_{\text{arterial}}(t) dt$$The coefficient of proportionality can be determined by using an intermittant method (typically thermodilution), then pulse contour analysis can be used for continuous monitoring.
Capnography Capnography Principles of capnography:By the Beer-Lambert law:$$\text{Absorbance} = \Delta L \cdot \epsilon^{\text{wavelength}}_{gas} \cdot P_{gas}$$IR light is shone through 2 chambers - the sample chamber and reference chamber (contains no CO2, for calibration); the absorbance is used to calculate the CO2 partial pressure.Sample can be side-streamsample taken from thin tube connected to ventilator circuitincreases delay to ~3 secondssampler can be placed e.g. beneath a hudson mask...or main-streamsample taken directly from circuitadds dead spaceA capnograph waveform has 4 phases:Phase 1: Inspiration and the first part of expiration, where anatomical dead space gas is expired. No CO2.Phase 2: mixed dead space gas and alveolar gas Phase 3: pure alveolar gas. Phase 0: inspiration washes out CO2 from monitorSources of error:Blockage by secretions / condensationAmbient IR lightN2O absorbanceCollision broadening from high FiO2 or FiN2OLimitationsFalse positive CO2 from gastrict gas post BVM ventilationIncreased dead space will widen PaCO2-EtCO2 gapVentilation and perfusion info obtained from trace:Height (EtCO2): composed ofPaCO2 (\uparrow\) with $\downarrow V_A$ or $\uparrow$ CO2 generation e.g. malignant hyperthermia. PaCO2 - EtCO2 gap which $\propto$ dead space or high V/Q lung units. Usually <5mmHg. Gap widened with $\uparrow$ anatomical/instrumental dead space, PE, fall in cardiac output. Frequency = respiratory rateRhythm = presence of abormal breathing patterns, e.g. dyssynchrony or Cheyne-StokesBaseline = Presence of rebreathing (closed ventilator circuit $\to$ exhausted lime, open ventilator circuit $\to\ \ V_D > V_T$) ShapeDecreased phase II slope, increased phase II slope, "shark fin" appearance $\to$ prolonged mixing of alveolar and dead space gas $\to$ time constant heterogeneity (e.g. obstructive lung disease)Curate clefts $\to$ dyssynchronyIrregular waveform $\to$ intermittent blockage by secretions, leakage
Principles of medical ultrasound Principles of medical ultrasound Sound = longitudenal compression/refraction wave that travels in matter. Sound waves can beReflected: at area of acoustic mismatch (boundary between two different speeds of sound). Amplitude of reflected wave $\uparrow$ with $\uparrow$ mismatch and $\uparrow$ angle of incidence (AoI). Refracted: at area of acoustic mistmatch when AoI$\neq$0Scattered: by small acoustic interfacesAttenuated: Exponential decease in amplitude by absorption, scattering, and reflection.Imaging principlesPiezoelectric crystals will $\Delta \text{shape} \leftrightharpoons \Delta \text{current}$, and therefore applying AC current generates a sound wave, and absorbing sound waves generates AC current $to$ form ultrasound transducers.Transducer generates wavepacket $\to$ listens for reflected wavepacket.Fourier analysis decomposes reflected packet into contributory waves $\to$ allows reconstruction of acoustic density in a 1D line.2D array of crystals $\to$ 2D image.Higher wavepacket frequency $\to$ better axial resolution, worse penetration (more attenuated)Image depth $\propto \frac{1}{\text{temporal resolution}}$ because more time taken to acquire each frame Doppler principlesReflection off a moving object in same direction as wavepacket changes frequency of wavepacket $$\vec{V} = \frac{c \cdot (f_{\text{reflected}} - f_{\text{transmitted}})}{2 f_{\text{transmitted}} \cos{\theta}}$$ where $\theta$ is the angle between the object velocity and the wave.Lower wavepacket frequencies $\to$ less aliasingBeam parallel with motion $\to$ accurate $\vec{v}$ estimateDisplayed atop 2D image $\to$ colour dopplerContinuous-wave doppler - samples higher frequencies, but includes all velocities in the beam directionPulsed-wave doppler - smaller frequency band, selective for only motion in a small gate

Sadly, anatomy

Anatomy of vessels for line insertion Anatomy of vessels for line insertion "I hate anatomy...surely there's a specialty for me when I can save people's lives with only drugs, physics, chemistry, and physiology!"Maybe there is, but it ain't this one. Now get t'work. Anatomy relevant to a radial art line The radial arteryOrigin: Division of brachial artery into radial and ulnarCourse: Deep to brachioradialus, then beneath anatomical snuffbox into dorsal handTermination: Anastamosis with ulnar artery $\to$ deep palmar arch of handSuppliesLateral forearm musclesradial nervecarpal bonesthumblateral $\frac{1}{2}$ 1st digitRelationships at the wrist:Medial: Flexor carpi radialis $\to$ palmaris longus $\to$ median nerveLateral: Brachioradialis tendon Anatomy relevant to an IJ CVC The IJVOrigin: inf. petrosal + sigmoid sinuses $\to$ jugular bulb $\to$ IVJCourse: skull $\xrightarrow{\text{jugular foramen}}$ carotid sheath, deep to SCM $\to$ joins subclavian to form brachiocephalic behind clavicleRight > LeftRelations@C2 carotid anterior@C3 carotid anteromedial@C4 carotid medialAlso medial: CN IX X XI XIIPosterior: cervical sympatheticsSuperficial: skin, fat, SCM, clavicleInferior: pleuraLateral to pulsatile carotid in Sedillot's triangleInferior: claviclemedial: SCM; sternal headlateral: SCM; clavicular headTributaries ("Medical schools let fun people in")Middle thyroidSuperior thyroidLingualFacialPharygnealInferior petrosal + sigmoid sinuses Anatomy relevant to a subclavian CVC The subclavian veinOrigin: continuation of axillary vein at lateral edge of 1st ribCourse: Moves medially, over 1st rib and behind medial 3rd of clavicleAnterior to subclavian artery, seperated by anterior scaleneJoins IJV behind medial edge of clavicle $\to$ becomes brachiocephalic veinRelations:Lateral: inferior trunk of brachial plexus, axillary veinMedial: trachea, vagal trunks, bracheocephalic vein, R lymphatic duct (right) / thoracic duct (left)Posterior: Anterior scalene, subclavian arteryAnterior: medial 3rd clavicleInferior: pleura, first ribSuperior: skin, fatSurface anatomy: Anatomy relevant to a femoral CVC or art line The femoral veinOrigin: popliteal veinBecomes common femoral after union with deep femoralBecomes external iliac at inguinal ligamentThe femoral arteryOrigin: External iliac artery at inguinal ligamentTerminates when becomes popliteal artery at adductor hiatus The femoral triangle Borders:Superior: inguinal ligament runs between ASIS and pubic tubercleLateral: medial edge of sartoriusMedial: lateral edge of adductor longusFloor: iliopsoas fasciaCeiling: Skin, fat, fascia lata Contents lateral $\to$ medial at base of triangle (NAVEL)Femoral nerveFemoral arteryFemoral veinInguinal canal ('empty space')LympaticsAt apex of triangle, femoral vein deep to artery Landmarks:Femoral artery felt at mid-inguinal point (between ASIS and pubic symphysis), vein ~1cm medial Anatomy relevant to a PICC Preference for PICC insertion basilic > cephalic > deep brachial veinBasilic: large, straight, has a shallow angle where it rejoins the brachials to form axillary veinCephalic: sharp angle at deltopectoral groove where it rejoins axillary v, often with a valve. Deep brachial: run with median nerve and brachial artery, risk of damage to both. Much deeper. Anatomy relevant to a dorsalis pedis art line Origin: Anterior tibial arteryCourse: Crosses ankle joint $\to$ plantar surface of foot just lateral to extensor hallucis longus, medial to extensor digitorum longus.Termination: Division into 1st metatarsal a and deep plantar arteryRelations: Runs with deep peroneal nerve $\to$ can be damaged
Anatomy relevant to airway procedures and ICCs Anatomy relevant to airway procedures and ICCs Unfortunately I have a poor lung-term memory. Anatomy relevant to tracheostomy Tracheostomy - percutaneous insertion of tube into trachea to facilitate ventilation. Ideally inserted between 2nd and 3rd tracheal rings.The tracheaFibroelastic tube, 10-15cmOrigin: from larynx at c6 / cricoid cartilageAnteriorly has 16-20 c-shaped cartilagenous ringsPosteriorly has trachealis muscleTerminates at carina at T4/5; divides into 2 main bronchiRelations of trachea in the neckAnterior: Skin $\to$ fat $\to$ superficial fascia $\to$ deep fascia. Thyroid isthmus overlies rings 2-4; superior thyroid arteries, superior, middle, and inferior thyroid veins, anterior jugular vein.Anterolateral: Sternohyoid and sternothyroid musclesImmediately lateral: recurrent laryngeal nerve (innervates all muscles of larynx except cricothyroid m), superior laryngeal nerve, thyroid lobesPosterolateral: Carotid sheath (IJV, carotid a, CN X)Posterior: Oesophagus, vertebral bodies Anatomy relevant to an intercostal catheter ICC - percutaneous insertion of tube into pleural space to drain air or fluidInserted eitherAnteriorly, in 2nd ICS in mid clavicular line (rare), orIn the triangle of safety:Neurovascular bundle runs on inferior edge of rib in groove (intercostal a., v., n.); so ICC must be inserted just atop rib.Layers encounteredSkinSubcutis/fatFasciaExternal $\to$ internal $\to$ innermost intercostal mmFasciaParietal pleuraPleural spaceRelations: For a left ICCDeep: lung, pericardium, heartInferior: Diaphragm, spleen, splenic flexure For a right ICCDeep: lungInferior: Diaphragm, liver, hepatic flexure For an anterior ICCDeep: Lung, heartSuperior: subclavian vesselsMedial: internal mammary artery
Anatomy relevant to lumbar puncture Anatomy relevant to lumbar puncture In lumbar puncture, a needle in inserted posteriorly in the midline into the intrathecal space to remove or sample CSF. Surface anatomy5 thoracic vertebraeT1/2: termination of spinal cord $\to$ becomes cauda equinaT4: in line with line joining L + R ASIST4/5: site of needle insertionNeedle passes through:SkinSubcutis $\to$ fatSupraspinous ligament $\to$ interspinous ligament $\to$ ligamentum flavumepidural fatdura and arachnoid materepidural space with CSF and cauda equinaSagittalTransverse