What am I losing

This is the discussion of the loss of 1 litre of whole blood; that is to say, about 300ml of cells and 700ml of plasma fluid, as well as all the dissolved electrolytes and proteins.

So together with 1 litre of blood, you lose about 40 grams of albumin, 140mmol of sodium, 100mmol of chloride, 4mmol of potassium, and so on and so forth. This volume of haemorrhage was chosen deliberately, partly because it is not a “mild” blood loss (to lose 20% of your circulating volume is a rather substantial problem), but mainly because it makes all the calculations very easy.

The response to haemorrhage seems to take 3 stages, which are indistinct and with significant overlap:

  1. Hypovolemia and cardiovascular compensation
  2. Transcapillary fluid redistribution and isovolemic anaemia
  3. Renal fluid/electrolyte conservation and haemopoiesis

images/loss of 1 litre of blood - stage 1

Stage 1: hypovolemia and cardiovascular compensation

The immediate changes relate to the loss of circulating volume.  The removed fluid is whole blood; what remains behind is also whole blood; provided the haemorrhage occurred rapidly, there has been no time for the composition of the intravascular fluid to change, and if one were to take a sample of the intravascular blood, one would not detect any changes. The hematocrit and the concentration of electrolytes will not be altered at this early stage, as the compartments have not yet had a chance to equilibrate.

Osmoreceptor response

The osmolality of the remaining fluid (that’s 2800ml of plasma fluid left behind, or 4000ml of whole blood) has not yet changed. Osmoreceptors are ignorant of the volume reduction. However, vasopressin release is triggered anyway, by baroreceptors sensing a loss of blood pressure.

Baroreceptor response

Given that the loss of volume is substantial (around 20%) the baroreceptors will sense a drop in arterial and venous pressure. The result is an increase in sympathetic tone, which constricts both the venous capacitance vessels and the cutaneous and splanchnic arterial beds, concentrating the blood volume in the central and cerebral circulation. The heart rate increases and cardiac output is maintained in spite of decreased preload.

Weirdly, this sensible response is only the first phase of a triphasic response to blood loss. Let us elaborate.

Cardiovascular response to haemorrhage

The topic of cardiovascular response to haemorrhage is sufficiently interesting that an entire chapter has been dedicated to discussing it in the cardiovascular section. Here, the following bref summary will suffice:

  • Autonomic effects
    • Arterial hypotension causes baroreflex activation.
    • Decreased cardiac output causes chemoreceptor activation.
    • Both reflexes result in autonomic phenomena:
      • Decreased vagal stimulus; thus increased heart rate
      • Sympathetic activation, which has multiple effects:
        • Increased peripheral vascular resistanc
        • Redistribution of blood flow away from the cutaneous and splanchnic circulation
        • Stimulation of systemic catecholamine release from adrenal glands, which produces an increased systemic effect in addition to the peripheral sympathetic nervous system effecs
        • Stimulation of vasopressin release via the projections from the nucleus of the solitary tract to the hypothalamus
        • Stimulation of renin release by sympathetic stimulation of the juxtaglomerular cells, and due to lower renal perfusion
  • Neurohormonal effects
    • Renin secretion causes:
      • Vasoconstriction (by angiotensin)
      • Increased sodium retention (by aldosterone)
    • Vasopressin release causes:
      • Vasoconstriction (by V1 receptors)
      • Increased water retention (by V2 receptors)
    • Venous hypotension decreases atrial natriuretic peptide secretion,
      which causes:
      • Decreased renal blood flow
      • Decreased urinary water and sodium excretion
    • The net effect is decreased urine output and increased retention of sodium and water

Now, let us return to examining the fluid shifts which occur in response to the loss of blood.

Transcapillary refill restores intravascular volume

The restoration of blood volume occurs by transcapillary refill. This is the term given to the net movement of fluid and of protein (mainly albumin) from the interstitial compartment into the intravascular compartment. It is well described by Drucker et al in this article, the complete form of which is not available for free anywhere.

The Starling equation, which describes the net movement of fluid in the capillaries, describes transcapillary refill.

starling forces pre hemorrhage

Essentially, the sympathetic response to haemorrhage results in a decrease in the diameter of the arterioles, and therefore a decrease in the pressure at the capillaries. 

Oncotic pressure remains the same as it was before the haemorrhage (remember, the fluid composition of the intravascular compartment is unchanged). However, it is no longer balanced by high capillary hydrostatic pressure. The result is a movement of free water out of the interstitial space and into the intravascular space.

This dilutes the capillary fluid, and the process comes to a rest when the capillary fluid is so diluted that the hydrostatic attraction into the capillary is balanced by the osmotic (oncotic) attraction out of the capillary.

starling forces post hemorrhage

The next stage of these fluid shifts is the movement of interstitial albumin into the intravascular compartment. This movement is probably unrelated to the Starling forces, because by all rights the albumin should stay put. It may be mediated by a protein concentration gradient, and appears to be related to the volume of the interstitial compartment, and the pressure in it. In any case, it seems that interstitial albumin replenishes the intravascular albumin deficit. Not only that, but haemorrhage stimulates albumin synthesis by the liver (for this very reason).

How much of my blood volume can be restored by transcapillary refill?

The vast majority. A study performed on hemorrhaging dogs has revealed that the rate of transcapillary refill does not seem to be related to arterial pressure, cardiac output or systemic resistance. Rather, it is a function of the severity of the haemorrhage. At the terminal stages of shock in the aforementioned dogs, transcapillary refill fluid accounted for more than 75% of plasma volume.  The refill rate was sufficiently high to sustain a plasma volume roughly 2/3rds of the initial plasma volume, irrespective of the rate of bleeding.

graph of transcapillary refill

How rapidly can transcapillary refill restore the blood volume?

Another study from 2010 repeats this dog experiment with a few methodological differences. Their article is accessible for free, and there are graphs which demonstrate roughly how much refill one can expect  in uncontrolled haemorrhage, and how fast.

After bleeding for 30 minutes, there was around 20ml/kg of transcapillary fluid in the circulation (which is generally held to be 70ml/kg) – another words, after half an hour of bleeding the blood volume is already diluted and contains about 30% interstitial fluid.

These numbers are consistent with the gospel of St. Brandis; the chapter on rapid blood loss reports that up to 1000ml of fluid per hour is restored to the intravascular compartment in this fashion.

This has implications for the man with the syringe. Yes its true that immediately after the loss of a large volume of blood one will not record a difference in haemoglobin concentration.  However, at half an hour post haemorrhage, you can already see a haemoglobin drop. The loss of blood pressure associated with volume loss also activates the renin-angiotensin-aldosterone system, the net effect of which is the conservation of sodium and water.

Stage 2: isovolemic anaemia after 30 minutes

isovolemic anaemia post haemorrhage

Thus. transcapillary refill has all but replenished our intravascular compartment. The repletion is incomplete- not all of the volume compensation was required, as venous tone and sympathetic tone have also increased, and these other compensatory measures will ultimately increase the capillary hydrostatic pressure to a point where transcapillary fluid migration can no longer occur.

The fluid which has migrated out of the interstitial space is in composition essentially the same as the fluid in the intravascular space. Electrolyte concentration at this stage is not meaningfully altered in this simple model. In a real person, there may be changes to the concentration of bicarbonate as the acid-base balance is disturbed by rising lactate in the poorly perfused tissues; additionally the increase in ADH will result in the retention of free water, and therefore some dilution of the electrolytes will occur.

Stage 3: replenishment of lost volume and blood components

replenishment of volume post haemorrhage

The interstitial fluid deficit is replaced over the period of some hours. The activation of the renin-angiotensin-aldosterone system results in sodium retention, and sodium is distributed into extracellular fluid. There may be some shift of water out of the intracellular compartment, but because the concentration of extracellular sodium does not change very much with haemorrhage, there is little osmotic incentive for water to move out of cells.

The  haemopoietic response to haemorrhage is nearly immediate, and the bone marrow makes attempts to replenish the lost erythrocytes by ramping up production and by releasing immature reticulocyte forms into the circulation. The replacement of erythrocyte numbers can take as long as 20 days.


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