We give fluid and vasopressors every day, and we usually describe what they do with a small set of familiar phrases. Fluid increases preload. Noradrenaline increases venous return. Venoconstriction mobilises stressed volume. Vasopressors increase arterial pressure by vasoconstriction.
These statements are not necessarily wrong. The problem is that they are shorthand. They describe what we observe, but they do not tell us what has physically changed inside the circulation.
The same intervention can produce very different haemodynamic effects in different patients. A fluid bolus may increase stroke volume and cardiac output, or produce little additional flow while raising venous pressure and worsening congestion. A vasopressor can raise arterial pressure while cardiac output rises, barely changes or falls. Changes in flow, vascular tone and blood distribution can all contribute to the observed response.
Fluid and vasopressors can therefore produce similar bedside changes while acting on the circulation in fundamentally different ways.
So rather than starting with labels such as preload, afterload or venous return, it is more useful to ask a simpler question.
What has actually changed?
To answer that, we first need to think about something that is usually left implicit: where the blood is.
Vascular pressure-volume behaviour
A vascular pressure-volume relationship describes how much blood a vascular compartment contains at different transmural pressures. Some physiologists use the term capacitance to mean this but I will use pressure-volume behaviour here because capacitance is often used much less precisely. See here for more on this.
It is related to compliance, but it is not the same thing. Compliance is:
C = ΔV / ΔP
where C is compliance, V is volume and P is pressure.
It tells us how much the vessel’s volume changes when its pressure changes. In other words, compliance describes how easily the vessel expands as pressure rises. The full pressure-volume relationship tells us something broader: how much blood the vessel contains at different pressures. That depends on its size, intrinsic stiffness, smooth-muscle tone, the pressure around it and how full it already is.
Two vascular compartments can therefore have similar local compliance yet contain very different volumes at the same pressure. Conversely, a change in vascular tone can alter the amount of blood a vessel contains at a given pressure without being captured adequately by the simple statement that “compliance has fallen”.
This is particularly important in veins. Venous smooth muscle can change the size of the vessel without necessarily changing its compliance very much. So the important question is not simply whether the vein has become more or less compliant, but how its pressure-volume behaviour has changed.
With increased venous tone, less blood can reside in the venous circulation at the same pressure. Looked at the other way around, the same amount of venous blood would generate a higher pressure. The venous pressure-volume relationship has changed.
This gives us a useful distinction between blood volume and vascular pressure-volume behaviour. Blood volume tells us how much blood exists. The pressure-volume behaviour of the vascular compartments helps determine where that blood can reside.
Those two can change separately. We can add blood without changing vascular tone. We can change vascular tone without adding or removing a drop of blood. Either manoeuvre can alter central filling, but by a different physical mechanism.
This also helps explain why the usual image of venoconstriction “pushing blood back to the heart” is incomplete. When venous tone rises, total blood volume has not changed. At the previous pressure, the venous system would now contain less blood. The circulation therefore settles into a new state of volume distribution, pressure and flow.
The redistribution is transient. Once the new vascular configuration has been established, the veins do not continuously squeeze blood forwards. Venoconstriction changes the container; it does not turn the veins into an auxiliary pump.
The obvious next question is where the displaced blood goes.
If blood leaves the veins, where does it go?
Some of it is initially presented more centrally, but it does not follow that it simply accumulates in the heart. That would treat the heart as another passive compliant reservoir. It is not. The heart is a throughput organ, and its output changes when its volume changes.
If more blood reaches the heart and cardiac reserve remains available, end-diastolic ventricular volume rises slightly. This recruits the Frank-Starling matching mechanism: increased fibre length and length-dependent activation increase stroke volume, allowing cardiac throughput to match the greater systemic delivery. A relatively small increase in chamber volume can therefore support a much larger increase in the amount of blood passing through the heart each minute.
The heart is, in that sense, dynamically matched to the blood presented to it. If inflow transiently exceeds outflow, chamber volume rises slightly. The resulting increase in end-diastolic volume recruits a greater stroke volume, which reduces the mismatch between inflow and outflow. Over successive beats a new steady state develops in which mean inflow and mean outflow again match.
The heart does not therefore need to retain all the additional volume presented to it. With adequate reserve, most of the redistributed blood can pass through the cardiac chambers and be transferred to the arterial side of the circulation.
In the simplest model of isolated venoconstriction with preserved cardiac acceptance and otherwise unchanged arterial properties, the new steady state can contain less blood on the venous side, only a small additional volume within the heart, and more blood on the arterial side. Stroke volume and cardiac output rise. Because the arterial circulation is much less compliant than the venous circulation, even a relatively small increase in arterial blood content can accompany a substantial increase in arterial pressure.
That does not mean that arterial pressure rises first and then “drives” the greater cardiac output. The new arterial pressure, arterial volume and flow are coupled features of the new resolved state. Venous redistribution changes cardiac chamber volume, Frank-Starling recruitment changes stroke volume, and the arterial and resistive properties of the circulation determine how the resulting volume and flow are expressed.
More blood is indeed presented to the heart, but a functioning heart does not simply store it. It transfers it onwards. The increase in cardiac chamber volume may be small while the change in throughput is substantial.
That is what happens when the cardiopulmonary system can accept the additional delivery. When it cannot, the picture changes completely.
Delivery has to meet acceptance
The heart and pulmonary circulation have a finite ability to convert additional systemic delivery into additional flow. I use the term cardiopulmonary acceptance to describe that ability.
Acceptance is not a single property. It depends on ventricular filling characteristics, cardiac reserve, systolic capacity, RV and LV loading conditions, the pulmonary circulation, pericardial constraint, ventricular interaction, intrathoracic pressure, valve or pathway obstruction, rhythm and heart rate. All of these can limit the ability of additional systemic delivery to become additional throughput.
If acceptance reserve is good, more systemic delivery produces only a modest change in chamber volume and filling pressure while stroke volume and cardiac output rise. In practical terms, more delivery becomes predominantly more flow.
If acceptance is poor, the same increase in delivery produces little additional throughput. Blood accumulates upstream instead. Right atrial pressure and CVP rise, systemic venous pressure rises, and congestion worsens. More delivery now becomes predominantly more pressure.
The same change in venous tone can therefore produce very different haemodynamic responses in different patients. The systemic intervention may be identical, but the state of the cardiopulmonary circulation is not.
A vasodilated patient with preserved ventricular reserve may respond to venoconstriction with only a small increase in cardiac chamber volume, a substantial increase in stroke volume and little change in right atrial pressure. In a patient with severe ventricular dysfunction, the same increase in systemic delivery may produce little extra throughput. RAP and venous pressure rise, and congestion worsens.
In both cases venous tone has changed the systemic vascular state. What differs is what the circulation can do with the additional delivery.
This is also why right atrial pressure is better thought of as an operating point than a target. It reflects where systemic delivery meets cardiopulmonary acceptance. If delivery rises and flow increases easily, RAP may barely move. If delivery rises but flow cannot, RAP climbs.
Fluid changes something different
A fluid bolus can produce many of the same bedside observations, but its primary physical action is different. It adds volume to the circulation.
There is now more intravascular volume that has to be distributed somewhere within the circulation.
With venoconstriction, total blood volume remains unchanged while venous pressure-volume behaviour changes. With fluid, total blood volume rises.
The distinction can be stated simply:
Fluid changes the contents. Venous tone changes the container.
Both interventions can increase central filling. Both can increase cardiac output. Both can increase arterial pressure. Both can also increase CVP and worsen congestion. Similar haemodynamic phenotypes do not imply similar mechanisms.
What happens to the added fluid again depends on cardiopulmonary acceptance. If acceptance reserve exists, the additional volume increases end-diastolic chamber volume, recruits Frank-Starling and increases cardiac output. If acceptance is limited, relatively little additional flow appears and more of the added volume expresses itself as increased filling pressure and venous congestion.
A fluid bolus therefore has no predetermined haemodynamic destination. It does not simply “go to the heart”, and fluid responsiveness does not tell us that the patient was necessarily short of blood.
A patient with low blood volume may certainly respond to fluid. But a patient with normal blood volume and marked vasodilation may also respond. In that case, the problem is not necessarily too little blood, but where the existing blood resides within the circulation.
This gives a useful way of contrasting hypovolaemia and vasodilation. Hypovolaemia reduces the contents. Vasodilation changes the container so that more blood can reside on the venous side at a given pressure. Both can reduce the systemic delivery presented to the heart.
The reverse also explains why venoconstriction is useful during blood loss. It cannot replace lost blood, but it can shift the venous pressure-volume relationship so that the remaining blood is redistributed. A fall in total volume can therefore be partly compensated by a change in where that volume resides.
This is more physically satisfying than saying that sympathetic activation simply “mobilises venous blood”. It changes the pressure-volume behaviour of the vascular system, and the volume redistributes accordingly.
Stressed volume, elastic state and Pms
Traditional descriptions of venous physiology often divide blood into “stressed” and “unstressed” volume. That language remains useful as a reduced-order model. The problem comes when we start treating those terms as literal anatomical pools.
There is not one bucket of unstressed blood sitting beside another bucket of stressed blood, with venoconstriction transferring volume from one to the other. There is one continuous vascular system containing blood within vessels that have particular geometries, wall properties, external pressures and smooth-muscle states.
Change those properties and the pressure-volume relationship changes. Blood redistributes. The systemic elastic state changes.
So when we say that venoconstriction converts unstressed into stressed volume, the more physical translation is that venoconstriction shifts vascular pressure-volume behaviour and redistributes the existing blood volume.
This also helps place mean systemic filling pressure, Pms, in the right part of the causal hierarchy.
Pms is not the mechanism. It is not an energy source driving flow through a venous resistance. It is a reduced-order descriptor of the systemic vascular elastic state. At no-flow equilibrium, the pressure that remains in the systemic circulation depends on how much blood is present and on the pressure-volume behaviour of the systemic vessels.
The hierarchy is better thought of as:
blood volume + vascular pressure-volume behaviour → systemic elastic state → Pms
Pms can therefore tell us something about the state of systemic delivery, but it does not tell us what cardiac output must be. Flow only emerges when that delivery state interacts with the acceptance of the cardiopulmonary circulation.
That distinction becomes particularly important when we think about vasopressors.
Noradrenaline does more than constrict veins
Noradrenaline changes several cardiovascular properties at once.
On the venous side, increased smooth-muscle tone changes venous geometry and shifts the venous pressure-volume relationship. At the same pressure, the veins now contain less blood, so existing volume is redistributed and systemic delivery increases.
On the arterial side, increased tone raises arterial resistance and changes arterial pressure-volume behaviour. This contributes directly to the rise in arterial pressure and changes the conditions against which the ventricle ejects.
The heart is affected as well. Increased arterial tone can increase ventricular afterload, while beta-1 stimulation may increase contractile performance. A higher arterial pressure may improve coronary perfusion, particularly when baseline pressure is low, and reflex changes in heart rate and autonomic tone may modify the response further.
These effects can pull cardiac output in different directions. Venous redistribution can increase systemic delivery and recruit Frank-Starling. Increased arterial load can limit ejection. Direct cardiac effects may support contractile performance.
In a vasodilated patient with preserved ventricular reserve, increased venous tone increases systemic delivery. Cardiac chamber volume rises only slightly, Frank-Starling recruitment increases stroke volume, and flow increases as blood is transferred to the arterial side. This increase in flow is a major contributor to the rise in arterial pressure. More blood also resides in the arterial circulation, while the increase in arterial tone contributes further to the pressure response.
In a patient with severe ventricular dysfunction, the same increase in systemic delivery may produce little extra throughput. RAP and venous pressure rise, and congestion worsens. Increased arterial load may further limit ejection, so arterial pressure can rise while stroke volume and cardiac output change little or even fall.
The sequence
noradrenaline → venoconstriction → venous return ↑
therefore captures only part of what the drug does.
At steady state, venous return and cardiac output are necessarily the same flow. If cardiac output rises, venous return has risen too. The problem is treating venous return as an independent causal intermediate rather than the same resolved flow viewed from the venous side.
Noradrenaline changes venous tone and pressure-volume behaviour, arterial tone and resistance, ventricular loading and cardiac performance at the same time. The resulting changes in pressure, flow and volume distribution depend on the state of the circulation before the drug is given.
What should we ask instead?
The language of preload and venous return is not useless, but it often jumps too quickly from intervention to outcome.
A better approach is to ask what physical property we have actually changed.
If we give fluid, we have increased total intravascular volume.
If we increase venous tone, we have shifted the venous pressure-volume relationship and redistributed existing blood.
If we give noradrenaline, we have changed several vascular and cardiac properties simultaneously.
The next question is whether systemic delivery was limiting flow in the first place. If it was, increasing delivery may recruit more cardiac throughput. If it was not, the intervention may achieve little.
Then we have to ask whether the cardiopulmonary circulation can accept the additional delivery. Frank-Starling recruitment allows a small increase in chamber volume to match greater delivery with greater stroke volume and throughput; it does not require a sustained rise in filling pressure. Once cardiopulmonary acceptance is constrained, further delivery increasingly produces pressure rather than flow.
This is also why fluid responsiveness should never be equated with hypovolaemia. A positive response only tells us that, under the conditions of the test, increasing systemic delivery increased cardiac throughput. It does not tell us whether the original problem was low blood volume, altered vascular tone and volume distribution, or simply a circulation operating on a recruitable part of its filling-output relationship.
Likewise, venous congestion is not synonymous with excess total body volume. Congestion can arise because there is too much volume, because vascular pressure-volume behaviour has changed, because cardiopulmonary acceptance is poor, or because several of these coexist. At the haemodynamic level, excessive venous pressure tells us that the prevailing systemic delivery state cannot be processed without a pressure penalty.
The physiology can therefore be reduced to three statements.
Fluid changes how much blood there is.
Venous tone changes venous pressure-volume behaviour and therefore redistributes blood.
Cardiopulmonary acceptance determines whether greater delivery becomes predominantly greater flow or greater pressure.
The intervention changes the constraints.
The circulation resolves the result.