A summary of three different action potential graphs: Cardiac myocyte, pacemaker myocyte and mixed nerve cell.
Aortic pressure-volume loop
This diagram summaries the mechanical performance of the heart.
The cardiac cycle starts at the end diastolic point (EDP) when the mitral valve closes.
Isovolumetric contraction then occurs causing a vertical ascending segment, ending at the opening of aortic valve marking the beginning of systole. Ejection ends at the end systolic point (ESP) when the aortic valve closes.
Isovolumetric relaxation ends when the mitral valve opens allowing ventricular filling to begin again.
The area of this loop is called the stroke work.
Aortic vs Ventricular pressure
Sinoatrial node: At the junction of the SVC and right atrium on the posterolateral surface.
Atrioventricular node: Lies in atrial septum above coronary sinus.
Left coronary artery arises from the posterior aortic sinus, and the right coronary artery arises from the anterior aortic sinus. The sinuses of valsalva (also known as the aortic sinuses) are shaped to encourage equal bilateral flow.
- Right Coronary Artery (RCA): Supplies the RA, RV, and interatrial septum. It usually supplies both the SA and AV nodes.
- Posterior Descending Artery (PD): Supplies the inferior portion of the LV and the posterior septum. The PD arises from the RCA in 70% of cases and the CFX in the remaining 20%.
- Left Main Coronary Artery (LCA): Gives rise to the LAD and CFX.
- Left Anterior Descending artery (LAD): Supplies the LV, RV, and interventricular septum. Arises from LCA. May also be called the anterior interventricular artery.
- Circumflex artery (CFX): Supplies the LA and LV. Arises from the LCA and anastamoses with the RCA.
Schematic of coronary arteries
The right coronary artery supplies to SA node in 60% of people, and it supplies the AV node in 90% of people.
Dominance refers to which side supplies the posterior interventricular artery (also called the posterior descending artery). 70% of people are right side dominant, 20% co-dominant and 10% left side dominant.
Coronary perfusion pressure
CPP = aortic pressure – intraventricular pressure
Systole: [SBP-LVESP] = 120-120 = 0mmHg
Diastole: [DBP-LVEDP] = 70-10 = 60mmHg
In the right ventricle flow occurs throughout the cardiac cycle.
A must read article on the subject of CVP is this systematic review by Paul Marik. Essentially static CVP readings are useless for predicting fluid responsiveness, you may as well flip a coin.
Central venous pressure is measured using a central venous catheter commonly placed in the subclavian or internal jugular veins, using fluid filled tubing and a strain gauge which converts pressure change into a change of resistance. Using a wheatstone bridge this can be used to calculate change in pressure.
Historically it has been used to guide fluid resuscitation, however this is falling out of favour.
CVP is used as a measure of right atrial pressure as there are no valves inbetween the large central valves and the right atrium.
- Increased intrathoracic pressure/PEEP
- Cardiac failure
- Vasoconstriction (increased stressed venous volume, more venous return)
- Cardiac tamponade
- Tension pneumothorax
- Volume overload
- SVC obstruction
The CVP trace
a wave – right atrial contraction
c wave – isovolumetric contraction of right ventricle causing tricuspid valve to bulge upwards into right atrium
x descent – contraction of right ventricle elongates the right atrium causing a pressure drop
v wave – right atrial filling
y descent – tricuspid valve opens, passive right ventricular filling
Large (“cannon”) a waves – atriventricular dissociation, the atrium contracts against a closed tricuspid valve causing pressure to be transmitted backwards into central veins.
Absent a waves – atrial fibrillation, no organised atrial contraction to cause an a wave.
Large v waves – tricuspid regurgitation.
Volume of distribution of drugs is increased by 5 litres at term. This affects predominantly water soluble (polar) molecules.
A fall in albumin concentration affects the binding of acidic drugs. Basic drugs predominantly bind to alpha-1-glycoprotein which falls to lesser extent and are therefore less affected. Most anaesthetic drugs are basic so are not affected, however fentanyl can bind to albumin so may have an exaggerated effect at term.
Plasma cholinesterase levels fall by 25% during pregnancy, though an increased volume of distribution balances this so the duration of action of drugs like suxamethonium is not really affected in vivo.
Drug distribution to the foetus
The placental membrane seperates foetal and maternal blood. This is phospholipid in nature, fused to form a single membrane. It is much less selective than the blood brain barrier, even molecules with only moderate lipid solubility can cross relatively easily.
Placental blood flow and free drug concentration in foetus affect the rate of transfer as governed by the Fick principle:
The rate of transfer of a gas through a sheet of tissue is proportional to the tissue area and the difference in gas partial pressures between the two sides, and inversely proportional to tissue thickness.
Where is the diffusion constant (Graham’s law), stating that diffusion is proportional to solubility but inversely proportional to the square root of the molecular weight (or density).
The foetus has a lower pH than the mother due to increased pCO2 and immature kidneys not able to excrete organic acids as well as mature kidneys. These acids instead diffuse out via the placenta which is slower.
Basic drugs: [BH+] ⇐⇒[B] + [H+]
Foetal pH is lower, therefore more negative than the drugs pKa. Therefore more drug is ionised in the foetus and unable to diffuse back across the placenta.
e.g. Local anaesthetic toxicity, pethidine (metabolised to norpethidine by foetus which can be trapped).
Drugs at the time of birth
A newborn will commonly have anaesthetic drugs in it’s circulation.
Thiopentone crosses the placenta rapidly, peak umbilical artery levels occur within three minutes of maternal injection.
Non-depolarising muscle relaxants are large polar molecules that do not cross the placenta. However if the mother has suxamethonium apnoea, maternal levels will remain high and some transfer will occur – this is particularly a problem if the foetus has inherited the same enzyme deficiency.
Propofol is not licensed for use in late pregnancy, which is historically why thiopentone is used.
The foetal circulation is unique in the sense that less than 10% of cardiac output passes through the lungs. This is suited to life in utero because the foetus does not breathe, instead gets all it’s gas exchange via the placenta, however after birth this situation has to rapidly change to ensure survivial outside the womb.
Blood leaves the placenta via the umbilical vein with an oxygen saturation of around 80%. The ductus venosus shunts half of the blood across the liver directly into the inferior vena cava. The mixed venous blood oxygen saturation is around 65%. Two thirds of blood is shunted directly into the left atrium via the foramen ovale.
There is intense hypoxic pulmonary vasoconstriction, therefore the majority of the blood in the pulmonary artery flows through the ductus arteriosus into the aorta. Less than 10% of the cardiac output passes through the pulmonary circulation.
The umbilical arteries arise from the internal iliac arteries and pass to the placenta.
With the first breath a negative intrathoracic pressure of around -50cmH20 is generated, expanding the FRC and encouraging blood flow through the lungs. Ventilation of the alveoli reduces hypoxic pulmonary vasoconstriction and therefore reduces pulmonary vascular resistance. This reduces the amount of blood flowing across the ductus arteriosus and when the umbilical cord is clamped this raises the systemic vascular resistance and can reverse the flow of blood through the ductus.
Exposure to oxygenated blood and a drop in prostaglandin E2 causes closure of the ductus arteriosus in less than 24 hours.
Oxygen saturation at different points
Umbilical vein: 80%
IVC pre-ductus venosus: 25%
Mixed IVC: 65%
Aorta pre-ductus arteriosus: 60%
Descending aorta: 50%
Contain two alpha and two gamma chains, the gamma chains do not bind to 2,3-diphosphoglycerate shifting the oxyhaemoglobin dissociation curve to the left. The P50 of foetal haemoglobin is 2.5kPa, compared to adult haemoglobin which is 3.5kPa. The Hb concentration is around 160g/l at birth.
A baby starts to synthesis haemoglobin A (adult haemoglobin: two alpha, two beta chains) a few weeks before birth and by the age of 2 years haemoglobin F is no longer present.
Coumarin derivative used widely for prophylaxis of systemic thromboembolism in patients with AF, prosthetic heart valves and in the treatment of DVT/PE.
Warfarin inhibits the synthesis of vitamin K dependant clotting factors (II, VII, IX and X).
Clotting factor precursors are produced in the liver and are activated by the gamma carboxylation of their glutamic acid residues. This process is linked to the oxidation of reduced vitamin K. Warfarin inhibits to action of vitamin K epoxide reductase, preventing the return of vitamin K to it’s reduced active state.
Warfarin doesn’t effect circulating factors that are already active so onset can take 72 hours. It can also inhibit the effect of protein C and protein S first, creating a prothrombotic state initially. In some patients this period of time will need to be covered with LMWH or unfractionated heparin.
Teratogenicity – in particular during organogenesis in the first trimester, however in the third trimester warfarin can cross the placenta and cause foetal haemorrhage in particular intraventricular haemorrhage.
Drug interactions – metabolised by hepatic cytochrome P450 system, therefore any enzyme inhibitors or inducers will effect circulating levels of warfarin.
Vitamin K can take time to work as it will not be effective until new clotting factors are activated. Also in high doses (e.g. 10mg) it can prevent anticoagulation for a number of days.
More rapid reversal can be achieved with FFP or clotting factor concentrates e.g. Octaplex.
Completed absorbed from the gut and 95% protein bound. Hepatic metabolism and renal excretion.
Prothrombin time (PT) is a measure of extrinsic system (factor VII) activity, as well as common factors like factor X. This is converted into the INR which standardises the result for laboratory variations in PT measurement across the world.
An anionic mucopolysaccharide organic acid containing many sulphate residues.
Used as a continuous intravenous infusion to treat DVT, PE and in critical arterial occlusion. May have a role in DIC.
Heparin potentiates antithrombin III, increasing the rate of formation of the the antithrombin-thrombin complex by 1000 fold. Factors XIIa, XIa and IXa also inhibited as dose increases.
Haemorrhage is the most common due to a relative overdose.
Heparin Induced Thrombocytopaenia (HIT)
Non-immune mediated (type 1): Onset around four days post heparin, mild and self-limiting – recovers when heparin stopped. Unusual to have severe complications from this.
Immune mediated (type 2): Onset around four to fourteen days after administration. Much more severe than type 1, incidence around 1-5% with unfractionated heparin but less than 1% with low molecular weight heparins. Heparin and platelet complexes bound by IgG causing aggregation and occlusive symptoms. 50% of patients will get serious thrombotic events e.g. pulmonary embolus.
A good review of heparin induced thrombocytopaenia is available on Life in the Fast Lane.
Ineffective orally therefore given SC or IV.
Low lipid solubility – doesn’t cross placenta or blood brain barrier.
Negatively charged and highly protein bound.
Hepatic metabolism by heparinases – desulphated and excreted in the urine.
A basic protein originally isolated from salmon sperm, though now synthesised through recombinant biotechnology.
Given intravenously to reverse effects of unfractionated heparin.
It is a positively charged molecule that forms an inactive complex with heparin that is cleared by the reticuloendothelial system.
1mg of protamine will reverse 100 units of heparin.
Hypotension, dyspnoea and flushing (mediated by histamine release)
Anaphylaxis in particular in individuals with fish allergy
Low molecular weight heparin (LMWH)
e.g. Dalteparin, enoxaparin
6-8kDa, formed from depolymerisation of heparin. More effective at inhibiting factor Xa and less effective at potentiating antithrombin-thrombin complex formation.
Can be given as a single daily dose with less need for monitoring. Less risk of HIT (<1%).
APTT (activated partial thromboplastin time) measures activity of intrinsic pathway factors (XII, XI, IX, VIII).
LMWH inhibit Xa and therefore will not effect APTT, need to measure activated factor X levels.
Cyclo-oxygenase 1 inhibitor
Used to reduce the risk of unstable angina progressing to MI and reduces mortality following acute MI. Reduces risk of stroke for patients suffering from TIAs. May potentially reduce cardiovascular risk when taking daily in a low dose, though the benefits vs risks of this remain controversial.
Mechanism: Irreversibly inibits cyclo-oxygenase isoenzyme 1 within the platelet, reduced the production of thromboxane A2. This reduces platelet activation and aggregation.
Platelet phosphodiesterase inhibitor
May reduce stroke risk when combined with aspirin.
Mechanism: Inhibits phosphodiesterase in the platelet which normally breaks down cyclic AMP. This counteracts the effects of calcium on the glycoprotein IIb/IIIa receptor by limiting vesicular release of thromboxane A2 and other activating substances. This potentiates the effects of prostacyclin which works in a similar way by increasing the concentration of cyclic AMP.
Inhibition of ADP binding
Used to reduce risk of stent thrombosis following coronary artery intervention. It also reduces stroke risk in peripheral vascular disease.
Mechanism: Irreversibly prevents ADP from binding to it’s platelet receptor, therefore preventing glycoprotein IIb/IIIa receptor from transforming into it’s active form.
Tirofiban and Abciximab
Glycoprotein IIb/IIIa antagonists
Used concurrently with heparin around the time of acute coronary events.
Mechanism: Antagonises the glycoprotein IIb/IIIa receptor, limiting platelet activation and aggregation. It doesn’t effect the final common pathway or coagulation cascade.