Factors which contribute to pulse variation

This chapter is vaguely relevant to Section G4(iv)  of the 2017 CICM Primary Syllabus, which asks the exam candidate to "describe the physiological factors that may contribute to pulse variations in blood pressure". The use of the term "pulse variations" is strange, as it is not usually seen in the English language medical literature. Working from the assumption that every minuscule detail of the Syllabus document has a hidden coded meaning, we can conclude only that all factors which are associated with the variation of the pulse pressure amplitude were included in this term, as that would be the only sane interpretation. Furthermore, even though a reasonable person would probably limit their discussion to the systemic circulation, one must still acknowledge that the pulmonary arteries also have a pulse pressure which is subject to variation. 

Unfortunately, there are no historical CICM SAQs to draw upon. However, "pulse variations" in its various forms has appeared several times in Part One and Part Two past papers. It was discussed as pulsus paradoxus in Question 11 from the second paper of 2015, and in the chapter on cardiac tamponade. It also figured prominently in the chapters on the interpretation of normal and abnormal arterial line waveforms. 

In summary:

The best resource for a quick overview is probably Homan et al (2020). The first few paragraphs of Dart & Kingwell (2001) are also relevant. Safar & Boudier (2005) and van Bortel et al (2001) can give some insight into the physiological mechanisms which explain why flow is pulsatile. 

Pulse pressure

The AHA (or, at least, authors who get published in AHA journals) define pulse pressure as:

"...the difference between the systolic and diastolic pressure, ...a pulsatile component of the blood pressure curve as opposed to the mean arterial pressure (MAP) which is a steady component" 

The normal human standard of systolic and diastolic pressures being about 120 and 80 make the normal pulse pressure about 40 mmHg. Anything less than 25% of the systolic pressure is said to be abnormally narrowed.  The origin of this pressure difference is clearly the cyclical pulsatile nature of blood flow; as the heart ejects blood non-continuously, there are periods of increased flow and there are periods of no flow, which produce a difference in pressure. To summarise the main causes of the pressure difference, one could simply list the main determinants of systolic and diastolic pressure:

• During systole,  the height of the systolic peak of pressure is dependent on
  • Arterial elastance and compliance (a major influence)
  • Stroke volume, insofar as it affects elastance and compliance
  • Total arterial peripheral resistance
• During diastole, the depth of the diastolic blood pressure trough is determined by:
  • Total arterial peripheral resistance (a major influence)
  • Arterial elastance and compliance 
  • The time constant of the peripheral vessels  (and therefore heart rate)

Physiological factors which influence the pulse pressure difference

At a basic level, the pulse pressure is the consequence of a volume being ejected into the arterial circulation, which produces a change in pressure proportional to the arterial compliance. Thus, pulse pressure can be expressed as:

Pp = SV / C

where

• SV is the stroke volume, and
• C is the arterial compliance.

That might seem very simple, but to do justice to the concept by exploring its underlying processes, and to incorporate variations in pulse pressure into the discussion, would require some considerable effort. The stroke volume, in particular, is reliant on virtually every aspect of cardiac and vascular physiology, and has numerous determinants. So numerous in fact that each category of determinant requires a huge long-form essay to describe. In brief summary, the main factors which influence stroke volume include:

• Factors which influence preload
• Factors which influence afterload
• Factors which influence contractility

From an exam answer perspective, listing these determinants would probably be a dangerous path, as it leads the writer to madness. For example, after writing" preload" as a subheading, one would be forced to admit that every variable that affects preload (intrathoracic pressure, pericardial content, ventricular wall compliance, MSFP) contribute to stroke volume and therefore pulse pressure in some way. There would be no end to that list, and it would be an inelegant way of saying that, basically, everything about the interaction of the pump and vessels has some effect on the pulse pressure difference.  So, perhaps, instead, it would be better to start and finish with that statement, or something similar. Unfortunately, that leaves us without a solid physiology-based classification system. 

But, is one really necessary? Taking a pragmatic approach to this subject has merit. In clinical practice, critical care professionals come across pulse pressure variation all the time, and these encounters have easily defined epistemological boundaries. For example, pulse pressure variation occurs with respiratory activity; this can be divided into variation due to respiratory physiology (eg. greatly increased or decreased intrathoracic pressure) or due to cardiovascular physiology (eg. due to low preload or poor cardiac compliance). These concepts overlap with the explanation of pulse pressure variation observed in shock states; one produces an easy segue to the other. The same can be done for changes in pulse pressure during stress or exercise, with changes of posture, due to properties of the vascular tree, or because of the site of measurement. This is the approach taken below. It is only one possible approach, and the contact form at the end of the page waits gladly for any valid alternative.

Pulse variations associated with respiratory activity

The underlying mechanisms for this phenomenon are also discussed in the chapter on the haemodynamic changes associated with a mechanical breath and in the chapter dealing with stroke volume variation as a means of assessing fluid responsiveness. In short, as intrathoracic pressure changes, so do preload and afterload, and this gives rise to a variation in stroke volume, which is, in turn, a major determinant of systolic pressure. Somewhere mid-way through the excellent article by Hoff et al (2019), this is articulated in the best possible way. To paraphrase them needlessly:

• Intrathoracic pressure is one of the determinants of preload, as it contributes to right atrial pressure and therefore to the pressure gradient which drives venous return. 
• In spontaneous breathing:
  • Decreased intrathoracic pressure during inspiration increases the pressure gradient, and thus venous return increases.
  • This increases LV stroke volume after the pulmonary transit time of 2-3 seconds, i.e during expiration.
  • This increase in stroke volume produces a higher systolic blood pressure
  • During expiration, preload decreases; thus stroke volume decreases 2-3 seconds later (during inspiration) and the systolic blood pressure is therefore lower.
• In positive pressure ventilation:
  • The reverse happens:
  • Increased intrathoracic pressure during inspiration decreases the pressure gradient driving venous return, and systolic blood pressure decreases 2-3 seconds later (in expiration)
  • During expiration, venous return is increased, and systolic blood pressure increases (with a delay, and therefore during inspiration).

This can be seen in normal physiological states as well as in pathological conditions where intrathoracic pressure has been somehow interfered with:

• Normal (and exaggerated) physiological pulse pressure variation is observed during deep voluntary breathing and during Valsalva manoeuvres
• An abnormal increase in pulse pressure variation is observed in Kussmaul breathing,  tension pneumothorax, severe asthma and COPD.

It is often said that a normal respiratory pulse pressure variation is said to be less than 12%. That is to say, the difference between the maximum and minimum pulse pressure widths should be less than 12% of the maximum pulse pressure. This is not a "normal" value determined from looking at a normal healthy population, as most "normal" values tend to be. Rather, it is a finding of several studies (Marik et al, 2009) which were looking at pulse pressure variation as an indicator of fluid responsiveness in shock.

Pulse variations associated with shock states

The variation in pulse pressure associated with shock states is a logical extension of the concept discussed above. However, in this case, the cause of the variation is not some excessively raised intrathoracic pressure, but rather an excessive sensitivity of the pressure gradient for venous return to changes in intrathoracic pressure. This can occur in several situations:

• Hypovolemia
  • The decreased mean systemic filling pressure and RA pressure decrease the total magnitude of the pressure gradient which drives venous return
  • This lower pressure gradient is therefore more sensitive to intrathoracic pressure changes, and will be affected by even the pressure changes during a normal respiratory cycle
• Cardiac tamponade
  • Due to increased pericardial pressure, the normal inspiratory increase in RV filling results in an increased leftward bulge of the interventricular septum
  • This decreases the LV stroke volume and exaggerates the normal inspiratory drop in blood pressure, a finding known as pulsus paradoxus

Pulse variations associated with exercise

During and immediately after exercise, the pulse pressure increases. This is mainly due to an increase in systolic blood pressure, although in some individuals a decrease in diastolic blood pressure is also observed.  This widened pulse pressure is quite normal, and in fact a lack of increase in pulse pressure can be viewed as a marker of cardiovascular disease. The mechanisms underlying this phenomenon are:

• Exercise results in an increased sympathetic activity
• This increases cardiac contractility and cardiac output
• At any given preload and afterload, increased contractility will increase the stroke volume and systolic blood pressure
• This results in a widened pulse pressure

Some individuals, particularly the elderly and highly muscular individuals who have undergone strength training, tend to also have a decrease in their diastolic blood pressure with exercise (Bertovic, 1999). There are two main reasons for this.  One is a decrease in peripheral vascular resistance (due to widespread β₂-adrenoceptor activation in their huge pulsating muscle bulk, which leads to vasodilation). Another is the decrease in arterial compliance which occurs as an adaptation to weight training. 

Pulse variations associated with vascular resistance and compliance

Peripheral vascular resistance and proximal arterial compliance has a major role to play in determining the systolic and diastolic pressure, and therefore the pulse pressure. 

• Arterial compliance is a determinant of the systolic blood pressure
  • As arterial compliance decreases (or rather, arterial elastance increases), the systolic pressure increases for any given stroke volume
• Peripheral resistance and arterial compliance both influence diastolic blood pressure
  • As arterial compliance decreases, diastolic pressure drops more rapidly because of the steeper pressure-volume curve

This is probably something that would benefit from a couple of diagrams:

These diagrams are either stolen directly or extrapolated from Elzinga & Westerhof (1973), who observed that increased aortic elastance (decreased compliance) results in a faster drop of diastolic pressure, because the aortic pressure-volume curve in a poorly compliant aorta is so steep. Thus, "pulse variations in blood pressure" will occur over the timeframe of minutes and seconds due to changes in peripheral resistance, and over years due to changes in proximal arterial compliance (eg. due to the gradual process of age-related arterial stiffening). 

Now, that might bring the question: does decreased arterial compliance necessarily accompany increased resistance? The answer is probably no, with a but. 

Consider the aorta and greater vessels of an elderly vasculopath. The vessels centrally will be crusty with ancient atheroma barnacles, and entirely unwilling to distend in response to the systolic ejection, creating a high peak of blood pressure in early systole. Thus, these vessels did not distend very much in systole, and as the aortic valve closes, they do not function as a particularly effective windkessel. The diastolic pressure therefore drops rapidly, as there is no counterpressure from the rebounding aortic wall during diastole. The pulse pressure is widened as the consequence. 

The change in resistance is slightly different.  Resistance increases as smooth muscle of arteries constricts, decreasing the diameter of the vessel (and this is mainly a thing that happens in arterioles). The compliance of a vessel is reliant on the ability of this smooth muscle to dilate in response to pressure, as it is a change in volume per unit pressure. Thus, logically, any stimulus which causes the smooth muscle to constrict will impair its ability to dilate, and thus decrease the arterial compliance. However, separate parts of the circulation are involved in these phenomena. Arterial compliance is very important in the greater vessels, whereas resistance is generated by the small arterioles. Therefore, conceivably, the aforementioned vasculopath could develop sepsis and become severely vasodilated in their peripheral circulation while remaining poorly compliant centrally.

So, that's a way to reason through this answer. However, one might point out that, from the point of view of the left ventricle, there is no distinction between the effects of the distal and the proximal arteries on variables affecting afterload. The ventricle is working against the entire systemic circuit. What, then, is the relationship of arterial resistance and compliance in the total arterial circulation? Fortunately, this question has a handy answer. Here's a graph of arterial compliance and systemic vascular resistance from  Wohlfahrt et al (2015). As you can see, the relationship is hyperbolic. As SVR increases, compliance decreases, and vice versa.

Pulse pressure variation associated with heart rate

As mentioned above, changes in arterial compliance result in a more rapid drop of blood pressure in diastole, because of a steep arterial pressure-volume relationship. This brings diastolic time, and therefore heart rate, into the equation. Observe:

Thus, with a decreased heart rate:

• The diastolic pressure decline occurs over a longer time period, and is therefore deeper
• The diastolic filling is longer, thus ultimately preload is greater, and the stroke volume will be larger (with a corresponding increase in the systolic blood pressure).

Pulse variations associated with site of measurement

Because the pulse pressure is dependent on arterial compliance, the site of measurement becomes very important. Consider putting your pressure probe inside some hypothetical infinitely compliant aneurysmal sack. Of course, the pulse pressure here will be zero, as each time the sack receives more volume it distends without increasing its pressure. The human aorta is not infinitely compliant, but it is certainly the most compliant vessel in the proximal arterial circulation, and so the pulse pressure measured there is usually much lower than peripheral  pulse pressure

Another aspect of this is distal pulse pressure amplification, the phenomenon of constructive interference between reflected waves from the distal circulation and the "forward" pressure waves propagating from the left ventricle. Thus, the most distal vessels, such as the dorsalis pedis artery, should have the greatest pulse pressure because the reflected waves are strongest there.

The consequence of both of these factors is an increase in the systolic pressure and a decrease in diastolic pressure as one moves distally through the circulatory tree. There is no better way to illustrate this than by using an excellent diagram from Gedde's Handbook of Blood Pressure Measurement (1981). 

Pathological causes of widened and narrowed pulse pressure 

Apart from the already mentioned physiological processes, there are all sorts of structural and functional problems which could give rise to changes in pulse pressure. Without going into too much detail, they can be listed in broad groups:

• Narrowed pulse pressure due to reduced stroke volume
  • Cardiogenic shock and heart failure
  • Aortic stenosis
  • Cardiac tamponade
  • High afterload
• Narrowed pulse pressure due to increased arterial compliance
  • High flow arteriovenous fistula
• Widened pulse pressure due to increased stroke volume
  • Sepsis (early, hyperdynamic sepsis)
  • Beri-beri
  • Thyrotoxicosis
  • Anaphylaxis
• Widened pulse pressure due to decreased arterial compliance
  • Age-related changes in healthy adults (Frankin et al, 1997)
  • Atherosclerosis and peripheral vascular disease (increased distal pulse amplification)
  • Aortic aneurysm (a failure of the Windkessel effect, where the flaccid dilated aorta fails to recoil normally in diastole)
• Widened pulse pressure due to structural cardiovascular disease
  • Aortic regurgitation

Do you even need a pulse?

Sure, pulsatile flow is the natural free-range gluten-free way of running your circulatory system, but is it essential for life? For example, here is an arterial line waveform of a patient on VA ECMO, in whom the circulation is sustained by a nonpulsatile rotary pump, and whose left ventricle is producing a barely registered pulse pressure of 6 mmHg. 

It would be disingenuous to pretend that this patient is completely fine, but ECMO patients can remain like this for weeks, and their overall trajectory is often one of improvement. So the question remains: is there anything special about the pulse, apart from its association with life-sustaining forward flow of blood? Is pulsatile flow somehow superior to constant flow, or is flow the objective, irrespective of how it is delivered?

Turns out, our preoccupation with the arterial pulse is probably just a quaint anachronism, arising from a traditionalist reliance on a biological mammalian heart. That thing has significant limitations from an engineering standpoint. The myocardial cells need rest periods, the muscle requires diastole for perfusion, and the device (a duplex diaphragm positive displacement pump) requires alternating periods of filling and emptying to function, making the pulse a mandatory component of "normal" biological circulation. However, it is purely a phenomenon of the proximal circulation. As one moves distally into the arterioles, the pulse pressure is essentially obliterated by the windkessel effect (where elastic energy of the pulse is stored during the high-pressure period and then released during the low-pressure period), producing a "smoothing" of peaks and troughs until they almost disappear. Gore (1974), while measuring the pressure in cat capillaries, noted that the pulse pressure width there was somewhere around 1-3 mmHg. 

In short, the tissues (the main consumer base for blood flow) couldn't possibly care less whether the flow is pulsatile or not. Russel et al (2009) and Saito et al (2002) were able to confirm this by means of cruel experiments which were essentially endurance marathons for VAD devices fitted into healthy experimental animals (or humans) and adjusted to a flow rate at which pulsatile flow was absent. The winner was a Terumo DuraHeart LVAD, attached to a sheep who had spent 340 days running around with no pulse. "All animals remained in good condition until sacrifice", rejoiced the authors;  "there were no histologic differences between the organs of pulsatile and nonpulsatile animals." The study by Russel et al was particularly interesting, as their population consisted of chronically ill heart failure patients with vulnerable organs. All remained with satisfactory organ function over the six month follow-up period, as they waited for their transplant.

However, nonpulsatile flow may have some downsides for the vessels themselves. For example, Amir et al (2006) found that flow-mediated vasodilation basically disappeared from the brachial arteries of continuous-flow VAD patients (see their diagram below). 

To remind the reader, flow-mediated vasodilation is one of the peripheral autoregulatory mechanisms which ensures that larger proximal  vessels dilate in response to higher flow demand in smaller distal vessels they are feeding. The authors theorised that, with continuous flow, the normal release and activity of nitric oxide may be impaired.  Not only this, but large proximal vessels may also undergo some undesirable remodelling in the absence of pulsatile flow. Ambradekar et al (2015) compared aortic wall samples from VAD patients and found substantial increases in smooth muscle and collagen content, corresponding to an increase in stiffness. It is possible that these vascular changes contribute to some of the vasoplegia which is seen in 20-40% of patients following LVAD explantation (de Waal et al, 2018).

Moreover, pulsatile flow is a prognostic indicator. As one of the readers had put it, "La esperanza lo necesita". One looks for a pulse pressure in a patient on VA ECMO as a positive sign, suggesting that some recovery is possible. Park et al (2013) found that an initial pulse pressure of >30 mmHg was associated with a much better prognosis among patients receiving emergency ECLS, as it probably represented relative preservation of contractile reserve. Conversely, a  pulse pressure under 10 mmHg suggests that the patient is not ready to wean from ECMO (Mihalj et al, 2020). Lastly, as a purely practical point, having poor pulse pressure means the possibility of LV distension and intracardiac stasis, with the potential for further LV damage and intracardiac thrombosis. Often, a vent cannula would need to be inserted to solve these problems.