Essential features of the microcirculation

This chapter is relevant to Section G4(vi) of the 2017 CICM Primary Syllabus, which expects the exam candidate to "describe the essential features of the micro-circulation". Multiple past paper questions have explored this topic, but have focused on very specific elements, such as pulmonary microcirculation (Question 19 from the second paper of 2016), interstitial fluid recirculation (Question 4 from the second paper of 2017) and fluid exchange across capillary membranes (Question 16 from the second paper of 2018). No question has thus far called for anything like a top-level overview, but the college are certainly capable of those, and one must be prepared for everything. 

There is really no single super-awesome article one could point to, which summarises and explains everything in this topic to a point where the CICM trainee can use it for revision. The best and nearest free full-text offering is probably Guven et al (2020), of which only the last two-thirds are irrelevant. For the truly insane reader, Microcirculation (2008) by Tuma et al is a spectacularly detailed digression, to which entire days of life could be lost. The sheer size and level of detail make it impossible to recommend to anybody, for any reason. The introductory chapter by Paul C. Johnson is probably the only safe part, a short touristy safari through a remote physiological jungle into which the rest of Microcirculation is a total Kurtz-like submersion.

Definition of "microcirculation"

The term is often seen tossed around, but what do people really mean when they say "microcirculation"? Lots of mysterious things seem to happen there. Where does this shadowy area begin and end? Some authors like to give a definition based on the size of the vessels:

"...the terminal vascular network of the systemic circulation consisting of microvessels with diameters <20 µm"

-  Guven et al, 2020

For others, a functional description is more important, as strict size cutoffs might miss vessels which are 21 or 22 µm in diameter but which remain important to the main roles of this circulatory territory.  Moreover, a reasonable person must acknowledge the tendency of these vessels to change their diameter by as much as 50%, which seems to make a mockery of any diameter-based classification.  Thus, one might define the microcirculation functionally,  as:

"...the terminal vascular network where the exchange of substances between the blood and the tissues occurs"

- Lenasi, 2016

That author still went on to give some size boundaries, which were more generous (inclusive of "vessels with a diameter of less than 100 μm, including arterioles, capillaries, and venules"). The main reason for this sustained reliance on size cutoffs actually has some scientific basis behind it. First of all, the rheology of blood flow begins to change at that scale, with a significant decrease in viscosity known as the Fahraeus-Lindquist effect (Pries et al, 1992). Secondly, arterioles of the 200-100 μm size range are responsible for much of the peripheral vascular resistance, which makes them important.

Essential features and characteristics of the microcirculation

There's really just two:

• Massive area: Popel & Johnson (2005) give 70m² as the total capillary surface area in the human, without really giving any experiment as the reference for this claim.  
• Low flow velocity: Arfors et al (1975) measured this directly and found that flow velocity decreased from 30-40 mm/sec in larger arterioles (80 μm) to less than 4 mm/sec in vessels below 20 μm in diameter (for contrast, normal aortic blood flow is expected to be 1500-1750 mm/sec). Interestingly, blood flow even at this peripheral level is still pulsatile, but the pulse pressure width is about 1mmHg. 

Those are the major unique features. Other elements (glycocalyx coating, capacity for regional autoregulation, facilitation of solute movement) are all rather common, as in every endothelial cell in any vessel could probably claim to be able to perform some or most of those basic roles. But the vast size and slow blood flow are specific features which allow the microcirculation to do its job. Which is:

Structure of the microcirculation

If you ever had to list the major structural features of the microcirculation, you would probably organise the list in order of blood flow, and at minimum include the following features:

• Arterioles 
• Precapillary sphincters
• Capillaries
• Endothelial glycocalyx
• Post-capillary venules 
• Post-capillary sphincters

Arterioles have variable size boundary definitions, and most authors mention something in the order of  120-70 μm. Their characteristic feature is the smooth muscle in their walls, which is richly innervated with sympathetic nerve endings. Rhodin et al (1967) has produced some excellent SEM microphotographs, of which one set is reproduced here in the spirit of awe and amazement. The low magnification image (×640) displays the ramification of a 100 μm arteriole into one 90 μm and one 75 μm branch. For most people, those numbers do nothing to impress a sense of scale, but the presence of erythrocytes strewn through the sample helps give the impression that these vessels are mighty rivers. The smaller image (×3000) demonstrates a 5 μm-thick section of the arteriolar wall, dominated by bulging masses of smooth muscle. For peripheral vascular resistance, this is where the magic happens. 

As the arterioles branch and divide, they become smaller and their walls become thinner. The larger arterioles have a beefy layer of overlapping spiral-wound smooth muscle, several cells deep. As the arterioles decrease in diameter down to about 50-30 μm, the smooth muscle in their walls also thins down to a monocellular thickness (about 1-2 μm). This is the defining feature of terminal arterioles. Again, Johannes Rhodin's pictures are of such descriptive and explanatory quality that minimal additional modification was required apart from colour and captioning:

Precapillary sphincters are ring-like arrangements of structures which occur at the branching points of terminal arterioles (i.e. where these vessels give rise to capillaries). These rings of smooth muscle mark a point of transition between terminal arterioles and capillaries. Clever ideas abound regarding what their purpose is (Harris & Longnecker, 1971). For example, it is theorised that their contraction decreases capillary hydrostatic pressure, allowing the reabsorption of oedema fluid to take place. Alternatively, they may play some role in regulating blood flow to tissues in response to changing metabolic requirements. The latter theory appears to be supported by experimental data (Grubb et al, 2020). 

Virtually all textbooks mention these structures, and the CICM trainee needs to respectfully utter their name during the viva exam, but in reality their importance is probably somewhat overhyped. For instance, Sakai et al (2013), after a careful review of the historical literature, has come to the conclusion that they may be unique to specific vascular beds. They are at least present in the mesenteric circulation (which happens to be the most commonly investigated subject for microcirculation research), and in the cerebral circulation where they appear to be important regulatory organs (Grubb et al, 2020). 

Capillaries are the business end of the circulatory system. In fact, maintaining an uninterrupted supply of blood to the capillaries is basically the purpose of the entire circulatory system. They form a dense network, with multiple branching points and reconnections, often no more than 20-30 μm apart. These things are simple 200-500 μm tubes made of a thin layer of endothelial cells, and have no smooth muscles in them. The diameter is often no more than 5 μm, i.e. only large enough to fit a single red cell; the thin wall and narrow bore maximise the transfer of gases and nutrients by minimising the diffusion distance (which is important because a lot of useful molecules are moving around by pure diffusion here). Here's an ancient SEM image, perhaps among the first of its kind, from Kossman & Palade (1961) - a capillary from the skeletal muscle of a rat, splendidly magnified (×71,000) to properly illustrate the impossible thinness of the wall, which is no more than 0.5 to 0.2 μm thick. The massive dark lump dominating the centre is the nucleus of the endothelial cell.

The endothelial glycocalyx is a thin acellular layer which coats the luminal surface of the circulatory system, and which must have been somebody's pet project because it appeared randomly to ambush the exam candidates in Question 18 from the second CICM Fellowship Exam paper of 2014.  Thus, there is a whole chapter dedicated to it somewhere else. In brief:

• The glycocalyx is a thin (500-1000nm) hydrated gel-like layer on the luminal surface of the vascular endothelium
• It is composed of a vast variety of macromolecules, including glycoproteins, polysaccharides, proteoglycans, glycosaminoglycans, plasma proteins, enzymes and enzyme inhibitors, growth factors, cytokines, amino acids, cations and water.
• Glycocalyx degradation may be resposible for much of the organ damaged observed in sepsis.
• Concentration of glycocalyx components shed into the bloodstream correlates with sepsis severity.

Post-capillary sphincters may or may not exist in the systemic circulation. There had been debate about this at various official levels of physiology discourse. Sure, some investigations of mammal lungs seem to find these structures at the junction of the pulmonary capillaries and arterioles, but nobody seems to have been able to demonstrate them in the systemic circulation to a degree which might remove all doubt.  Sure, textbooks mention them in passing, anaesthetists describe them as the therapeutic target of corticosteroids, and people describe their effect on some tangential implication of their central PhD thesis.  On the other hand, respected physiologists often publically refuse to acknowledge their existence ("The evidence...  is very tenuous except in amphibia", trolled E. Neil in a panel discussion from 1974).  There is absolutely no trace of them in the official CICM textbook for the First Part exam, and so one might think that it would probably be dangerous to include them in an exam answer, as there is nothing examiners hate more than difficult-to-grade heterodoxy. On the other hand, the syllabus document itself asks the candidates to describe "control mechanisms present in the pre- and post-capillary sphincters". The trainees need to become comfortable with the idea that some or all of these eminent resources might be wrong.

Post-capillary venules certainly do exist, and are completely real. In fact they are more numerous than arterioles, about 50% wider on average, and as a consequence the blood flow velocity through them can be expected to be about 15% of what is measured in arterioles at the same level of branching (House et al, 1986).  Structurally, these vessels are not hugely different from capillaries, apart from their size- there is minimal smooth muscle and for most of their length they are just flaccid tubes of endothelial cells wrapped in a sock of basement membrane. This probably differs from tissue to tissue, as sympathetic reactivity of these vessels seems to differ from zero (Marshall, 1986, rat skeletal muscle) to full (Bohler, 1977, intestine).

Functions of the microcirculation

If you had to summarise the main aspects of the massive life-sustaining job of the microcirculation, you would probably come up with this list of functions:

• Oxygen transfer
• Regulation of fluid and solute exchange
• Transport of all blood-borne nutrients and hormones
• Regulation of microvascular blood flow
• Capacitance

These should probably get a little more attention.

Oxygen transport in the microcirculation

Oxygen transport seems like a fairly central objective which the circulatory system needs to achieve. Otherwise, why circulate at all? At this stage in an exam answer, one would usually be expected to reproduce some version of Krogh's Cylinder Model of oxygen delivery. August Krogh never called it a cylinder model and did not have any cylinders in his original 1919 paper, so we owe this term to later writers. Without going into too much detail, the model describes a cylinder of perfused tissue which surrounds each capillary, with the cylinder tapering conically in the direction of flow. The boundaries of the cylinder describe an iso-oxic radial distance from the capillary, along the axis of flow. 

Thus, as the oxygen concentration and partial pressure inside the capillary decreases, so the radius of oxygen diffusion shrinks. The oxygenation inside the cylinder is not heroic - most cylinder model diagrams draw the radius boundary at 1mmHg, the Pasteur point. This model is excellent for explaining how oxygen diffusion works in the capillaries, and has significant educational value, but requires a lot of modification to account for various circulatory realities (such as changing demand and supply) and is not particularly accurate in terms of predicting in vivo measurements. 

Regulation of fluid and solute exchange

Control of fluid exchange in the microcirculation can be loosely described by the term "Starling forces".  Whole books have been written about this, and it attracts enough college attention that a whole separate section was dedicated to it.  In short, by adjusting the hydrostatic pressure inside the microcirculation, the arterioles and venules can control the movement of fluid out of the capillaries. The direction of fluid movement is determined by the balance of the "push" from hydrostatic pressure inside the capillary and the "pull" of plasma oncotic (colloid osmotic) pressure back into the capillary, such that when the two are equal, no net fluid movement occurs.  Not all this fluid movement is entirely controlled and regulatory, as it is influenced by many external factors (gravity, etc); otherwise there would be no such thing as oedema.

Solute exchange is slightly different. At a basic level, it can be by three main (very familiar) mechanisms:

• Passive diffusion (gases and small solutes)
• Bulk flow of fluid (i.e. solvent drag, important for middle molecules)
• Facilitated transport (important for the larger molecules).

Small solutes tend to follow the laws of diffusion reasonably closely. The endothelial glycocalyx acts as a size and charge barrier to some of these. Large macromolecules diffuse more slowly, or cheat by undergoing various forms of transcytosis. There is more information about this in Feher et al (2012) and Renkin (1996), but it is not necessary to read either in any great detail.

Regulation of regional microvascular blood flow

As already discussed in the chapter on peripheral vascular resistance, there are multiple control mechanisms which exert control over arteriolar diameter. Some of these are locally active within the microcirculation, and others are systemic neurohormonal effects. Just a brief list from Clifford (2011):

• Intrinsic myogenic regulation (in response to stretch)
• Metabolic regulation (in response to increased tissue demand)
• Flow- or shear-associated regulation (in response to increased local flow)
• Conducted vasomotor responses from neighbouring vascular sites
• Local cooling (which leads to vasoconstriction first, and then to vasodilation again)
• Immunological modulation by inflammatory mediators

Regulation of total peripheral vascular resistance

Owing to the highly skewed relationship of radius and flow rate, the radius of arterioles is a major determinant of systemic peripheral vascular resistance. As arterioles are muscular vessels with the largest cross-section in the arterial circulation, manipulating their radius is a convenient mechanism of control for the resistance of the peripheral circulation. Their dynamic range is relatively large; they  may dilate or constrict their diameter by about 50% in response to various vasoactive stimuli, as demonstrated by this frog mesentery vessel being splashed with noradrenaline:

Systemic reflexes and other factors which exert a systemic influence on the microcirculation include:

• Arterial baroreflex control  (increased BP leads to arteriola vasodilation)
• Peripheral and central chemoreceptors (hypoxia leads to vasoconstriction)
• Pulmonary baroreceptors (hypoxia leads to vasoconstriction)
• Hormones (eg. vasopressin and angiotensin)
• Temperature (hypothermia leads to vasoconstriction)

Pressure drop across the microcirculation

From the abovementioned discussion of flow resistance, one might expect for some sort of pressure drop to occur across the microcirculation. Most of the time, this comes up whenever one mentions Starling forces, as microciculatory blood pressure contributes the hydrostatic force to the Starling relationship. A variety of numbers end up being quoted by the literature (for instance, Pappano & Weir give 32 mmHg at the arteriolar end of capillaries and 15 mmHg at the venous end). Here's some real data from a famous study of  hamster cheek pouch vessels from Davis et al (1986), who measured plausible similar values:

Capacitance

The microcirculation, or more specifically the venules, is the largest part of the circulatory system by volume. Depending on which textbook you read, the veins are home to something between 50% and 85% of the total circulating blood (Jacob et al, 2016), of which about 25% is in the venules. These numbers probably come from Green et al (1963), who basically used anatomical data regarding the size and number of these vessels to estimate their total volume, and so it would be generous to call them "rather crude estimates" (Hainsworth,  1986). It is probably possible to consider this passive act of being the container for blood a "function" of the microcirculation, mainly because there is some evidence that this blood can be retrieved from it to act as preload, at least from some of the vascular beds. 

Immune function

The microcirculation is the site of action of many inflammatory molecules, and is responsible for many of the more constructive phenomena seen during a localised inflammatory response. The migration of leukocytes, for example, would not be possible if it were not for the sudden appearance of adhesion molecules on the surface of the vascular endothelial cells, or for the slowed flow in the now-dilated vessels. It is difficult to decide whether this aspect of microcirculatory function is a completely separate property to be discussed alone, or an extension of its other characteristics (such as the barrier function, or the capacity to regulate blood flow). Klaus Ley's chapter for Microcirculation (2008) argues that the behaviour of the microcirculation in the setting of inflammation is sufficiently interesting and unique that it should be discussed separately. In short:

• Vascular endothelial cells in the microcirculation control the localisation of the inflammatory response
• Endothelial activation is an essential part of the inflammatory response
• Endothelial permeability is necessary for the migration of leukocytes
• Endothelial-mediated vasomotor responses to inflammatory mediators are necessary to allow an increase in blood flow to the area, as well as the decreased velocity of blood flow which allows for leukocyte adhesion
• Expression of adhesins and integrins on the surface of endothelial cells allows leukocytes to attach to the surface of capillaries and small arterioles so that they may migrate into the tissues