Fick principle

The Fick principle is commonly applied to cardiac output calculations. It essentially states that blood flow to an organ can be calculated from a marker substance if the following is known:

  1. Amount of marker substance taken up by organ per unit time
  2. Concentration of marker in arterial blood supplying organ
  3. Concentration of marker in venous blood leaving the organ

This can be applied to the measure cardiac output where the marker substance is oxygen.

In other words the amount of a substance taken up by an organ per unit time is equal to the arterial concentration minus the venous concentration, divided by the production or uptake.

CO  =  frac{VO2}{CaO2-CvO2}

Therefore the cardiac output is inversely proportional to the arteriovenous difference of the marker substance.

CO  alpha  frac{1}{a-v}

In reality this method is cumbersome and rarely used as measuring oxygen uptake is difficult in a clinical situation. The Fick determination is a derived version of the Fick principle where a standard oxygen uptake is used based on the assumption that the oxygen consumption is 125ml of O2 per minute perm² of body surface area. The average body surface area for an adult male is 2m², giving a rough oxygen consumption of 250mls per minute.

This method can also be used to estimate renal blood flow, but instead of oxygen a marker such as para-aminohippuric acid or inulin is used.

Control of the circulation

This is essential to ensure adequate blood flow reaches tissues to supply their metabolic demand, an important part of homeostasis. There are multiple control mechanisms which can be grouped into local (intrinsic) or systemic (extrinsic).

  • Circulatory control of the heart and brain are mainly intrinsic to maintain flow independant of systemic circulation
  • Circulation of the skin and gut is largely extrinsically controlled

Resistance vessels
Increasing or decreasing the tone of smooth muscle within arterioles varies the perfusion pressure across a capillary bed. Vascular smooth muscle is primarily innervated by sympathetic fibres that maintain a baseline level of tone.

Capacitance vessels
Increasing or decreasing the tone here varies intravascular volume as veins contain >60% of blood volume. This has no effect on vascular resistance.

Local mechanisms controlling blood flow


This is the most important as it determines the balance of oxygen supply and demand for tissues. Exposure of tissues to hypoxia or injury causes release of factors that cause vasodilatation independant of systemic control. This varies in spectrum from localised erythema to reperfusion syndrome.

  • CO2 and H+ ions: Cause arteriolar vasodilatation. Lactic and pyruvic acid lower pH and have a similar effect.
  • Serotonin: Released from platelets at site of mechanical injury, causes vasoconstriction.
  • Adenosine, ATP, ADP and AMP: Strong vasodilatory effects. Adenosine dilates hepatic arteries in response to decreased portal blood flow.

Mechanical response

Myogenic mechanism: Vascular smooth muscle contracts or relaxes depending on transmural pressure. This means when perfusion pressure varies the flow can remain constant.

Endothelial mechanism: Increases in flow velocity are associated with vasodilalation, probably due to endothelium derived nitric oxide.

Endothelial factors

Prostacyclin and Thromboxane A2: Arachidonic acid derivatives dependent on cyclo-oxygenase. Prostacyclin is a vasodilator that inhibits platelet aggregation by increasing cyclic AMP preventing vesicular release of thromboxane A2 and von Willebrand factor. Thromboxane A2 is a potent vasoconstrictor which promotes platelet aggregation. These two substances are in balance in health, regular aspirin causes prostacyclin effects to predominate.

Nitric oxide (NO): Potent vasodilator. Synthesised from arginine by NO-synthase and inactivated by haemoglobin. The release from the endothelium can be trigged by substances such as bradykinin and acetylcholine.

Systemic control can be humoral or neurological

Systemic humoral control of blood flow


The most powerful agents responsible for humoral control. Adrenaline is released from the adrenal medulla, with primary effects of the heart. Noradrenaline is released from the adrenal medulla and sympathetic post-ganglionic nerve endings and is a powerful vasoconstrictor.


Otherwise known as anti-diuretic hormone (ADH), this is released from the posterior pituitary in response to increased osmolarity sensed by the osmoreceptors in the hypothalamus. It’s primary action is on the kidney collecting ducts to cause retention of free water, but at supranormal doses it causes systemic vasoconstriction and increased blood pressure.

V1 receptors: Vasoconstriction
V2 receptors: Renal effects
V3 receptors: Modulates secretion of ACTH
NB. Vasopressin is a non-selective V receptor agonist, Terlipressin is a selective V2 agonist.

Angiotensin II

Formed from angiotensin I in the lungs by angiotensin converting enzyme (ACE). The central effects are to cause the sensation of thirst and release of aldosterone from the adrenal cortex. It is also a powerful peripheral vasoconstrictor.

Atrial Natriuretic Peptide (ANP)

Released from the atria in response to atrial stretch. It causes natriuresis and subsequent loss of free water, lowering blood pressure. It inhibits vasopressin secretion and there is increasing evidence it causes shedding of the endothelial glycocalyx.


Produced in the central nervous system, gastric mucosa and mast cells. Potent vasodilator, it’s release can be inhibited by H1, H2 and H3 receptor antagonism.

Kinins e.g. Bradykinin

Produced from exocrine glands e.g. pancreas, salivary and sweat glands. Vasodilators. ACE is a kinase, which can explain some side effects of ACE-inhibitors e.g. angioedema, cough.

Systemic neurological control of blood flow

All blood vessels except capillaries and venules have smooth muscles in their walls which are supplied by sympathetic motor fibres. These fibres have a normal firing rate or resting tone than can be increased or decreased. Vascular smooth muscle is supplied by noradrenergic sympathetic fibres which increased activity causes vasoconstriction, whereas skeletal muscle is supplied by cholinergic sympathetic fibres in which increased activity causes vasodilatation.

Vasomotor control centres in the CNS

These are located in areas of the reticular formation in the medulla and pons.
Pressor region: Maintains a tonic output to keep a background level of vasomotor tone. It is capable of increasing the heart rate, vascular tone and myocardial contractility.
Depressor region: Inhibits the pressor region.

Efferent – Project directly to preganglionic neurones in the intermediolateral (IML) grey columns of the spinal cord. Preganglionic fibres pass from the IML to the paravertebral sympathetic chain. Post-ganglionic fibres carry sympathetic outflow to effector sites.

Afferent – Baroreceptors in carotid sinus and chemoreceptors in carotid body feed afferent impulse to CNS via the nerve of Herine, a branch of the glossopharyngeal nerve (cranial nerve IX). Aortic baroreceptors relay impulses via the vagus nerve (X). These synapse in the medulla at the nucleus tractus soliatrius (NTS).



Peripheral: Carotid and Aortic bodies
Respond primarily to a reduction in oxygen tension, also senstivie to increase pCO2 and changes in pH. Main effects are on the respiratory centre, though have some minor effects on the pressor region.

Central: Vasomotor centres respond directly to pCO2 and pH.
This central control predominates over peripheral effects. The central receptors are not sensitive to hypoxia.

The cardiac cycle

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


Coronary anatomy

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.

Coronary arteries

  • 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

Left ventricle:

Systole: [SBP-LVESP] = 120-120 = 0mmHg

Diastole: [DBP-LVEDP] = 70-10 = 60mmHg

In the right ventricle flow occurs throughout the cardiac cycle.

Cardiac myocyte



Troponin I inhibits binding of myosin to actin. Calcium binds to troponin C causing a conformational change, this moves troponin I allowing actin to bind to myosin. Increased stretch of sarcomere increases the affinity of troponin C for calcium, therefore increasing contractility.


Central Venous Pressure

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.

High CVP

  • Increased intrathoracic pressure/PEEP
  • Cardiac failure
  • Vasoconstriction (increased stressed venous volume, more venous return)
  • Cardiac tamponade
  • Tension pneumothorax
  • Volume overload
  • SVC obstruction


  • Hypovolaemia
  • Vasodilation
  • Hypotension

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.


Pacemaker action potential

The pacemaker cells (e.g. in the sinoatrial node) do not maintain a stable resting membrane potential but instead depolarise spotaneously.


Phase 4

Restoration of ionic gradients and resting state
Sodium slowly leaks into the cell, although potassium diffuses out of the cell simultaneously the net effect is a gradual increase in membrane potential. This continues until the threshold potential is reached at about -40mV.

Phase 0
Rapid depolarisation
Mainly due to T-type calcium channels
Slower than rapid sodium channels, therefore gradient less steep than myocyte action potential.

Phase 3
Effectively phase 1 absent and phase 2 very brief, therefore repolarisation is a single phase.
Sodium and calcium pumped out and potassium is pumped in, this requires ATP.

How to alter pacemaker rate

Threshold potential
If the threshold potential becomes less negative, it takes longer to reach and therefore pacemaker rate decreased. E.g. quinidine, procainamide.

If membrane potential becomes more negative then it takes longer to reach the threshold potential during phase 4.
Increased acetylcholine levels increase potassium efflux by altering the permeability of the membrane – this explains how increased vagal tone causes bradycardia.

Cardiac action potential


Phase 0
Initial rapid depolarisation/upstroke
Voltage gated sodium channels open and sodium rushes in down concentration gradient

Phase 1
Early rapid repolarisation
Closure of sodium channels
Continued diffusion of potassium out of the cell

Phase 2
Plateau phase
Voltage gated L-type calcium channels open
Influx of calcium balances efflux of potassium
Absolute refractory period around 150ms

Phase 3
Final rapid repolarisation
L-type calcium channels close
Potassium flows out restoring membrane to resting state
Relative refractory period – overshoots slightly so will require a greater than normal stimulus to depolarise again

Phase 4
Resting membrane potential
Na/K ATPase maintains ionic concentration gradients