We return to the equation that we started with in the beginning of this series, to examine the first determinant of MAP: cardiac output.
MAP = CO x SVR
Cardiac output (CO) is the amount of blood pumped out of the heart per unit of time. This is calculated by multiplying the stroke volume by the heart rate, to give cardiac output as a volume of blood per minute.
CO = SV x HR
The heart rate is set by the sino-atrial node at an intrinsic rate of around 60-100, modulated by the ANS with an increased baseline parasympathetic tone to reduce this to 60-80 bpm. A denervated SAN produces a HR of around 100-120 bpm – something that is seen in heart transplant patients due to loss of vagal nerve input.
Stoke volume is the amount of blood ejected from the ventricle per systolic contraction. This is calculated by end-diastolic volume (EDV) minus end-systolic volume (ESV), and is around 70-80ml.
Assuming a heart rate of 60bpm ejects around 80ml of blood per contraction, this gives a cardiac output of around 4,800ml per minute. So the CO of an average resting adult human is around 5L per minute, and can reach up to around 40L per minute in active elite athletes.
Let’s begin with stroke volume.
Stroke Volume
Stroke volume is affected by 3 important variables;
- Preload
- Myocardial contractility
- Afterload
Preload
Conceptually, we can stack our schema of preload as follows:
- Preload
- Compliance
- Venous return
- MSFP
- Volume
- Tone
- RAP
- MSFP
Preload is the pressure and stretch exerted on the myocardial sarcomeres of the ventricular walls in diastole, when the volume of blood is at its greatest in the ventricles. Frank-Starling dynamics describe the length-tension relationship on the muscle fibres; the greater the stretch, the greater the tension and subsequent inotropy/contraction of the myocardium. There is a sweet spot, however; if overstretched, the reduced actin-myosin crossbridging results in weaker myocyte contractions.
Preload is determined by compliance of, and venous return to, the ventricle.
Compliance
Compliance can become pathologically altered in states such as cardiomyopathies, hypertrophy, heart failure, ischaemia and so on. Increased muscle volume, scarring, ischaemic damage, diastolic failure etc all reduce the compliance of the heart. This means that for every given pressure there is less stretch, meaning less muscular contraction and lower stroke volume.
Since this is less alterable in the immediate term, we will turn our focus onto the most modifiable factor of preload; venous return.
Venous return
In the acute setting, venous return (VR) remains the major determinant of pressure in the ventricle; it is the volume of blood returning to the heart in a given unit of time. VR results from the pressure gradient between the forward flow from the systemic circulation, and the back pressure from the right side of the heart.
Since the cardiovascular system is a closed-loop circuit, venous return must equal cardiac output. Any sustained, even small difference, would rapidly lead to an accumulation or depletion of blood from parts of the circulation; vascular congestion or circulatory collapse. Transient differences between venous return and cardiac output can occur, such as during respiration or positional changes, but these are corrected for by alterations in contractility, heart rate, preload, after load, and other variables. Pulmonary oedema, obstructive shock, reduced pulse pressure or any myriad of clinical signs can betray this uncoupling, with further decompensation eventually leading to cardiac arrest.
The key determinants of VR are mean systemic filling pressure (MSFP) and right atrial pressure (RAP).
VR = MSFP – RAP
Mean systemic filling pressure (MSFP)
This is the driving force for venous return.
Strictly speaking, MSFP is defined as the pressure exerted on the walls of the systemic circulatory system when flow is ceased (ie. no cardiac output). It is a function of the pressure exerted on the vasculature by the ‘stressed volume’ in the circulation, and usually sits between 5-7 mmHg.
Although MSFP is technically a measurement when the heart is stopped, it is still clinically relevant and present in the living patient, as it represents the gradient and driving pressure back to the heart.
“Venous return is not determined by IV fluid infusions, it is determined by a pressure gradient” – Jon-Emile S. Kenny
Venous return will only occur in the context of adequate driving pressure that can flow forwards.
Although we cant directly measure MSFP, it’s determinants are modifiable and clinically important: volume and venous tone.
Volume
Within the variable of volume is the distinction between stressed and unstressed volume. Most of the blood volume (70-80%) in the systemic circulation is ‘unstressed’, and doesn’t in itself exert any wall stress on the systemic circulation. This unstressed volume is the amount of blood required to ‘un-collapse’ a vessel, without exerting any stress whatsoever to the vessel wall; it fills the vascular system without stretching it, with the ‘stressed’ volume above this threshold contributing to the MSFP and driving pressure.
The stressed volume can be increased by either adding more volume, or increasing vasoconstriction. Vasopressors can recruit hundreds of millilitres of unstressed volume into the stressed compartment by vasoconstriction, increasing MSFP and venous return.
Venous tone
This is therefore, is the second component that determines MSFP. Increased venous tone will increase the MSFP, raising the driving pressure toward the heart.
What makes MSFP and MAP different?
MSFP represents the pressure in the entire vascular system if the heart were to stand still, whereas MAP is that pressure only within the arterial system. Because the vast majority of blood resides in the highly compliant, low pressure reservoir of the venous system, MSFP is much lower than MAP.
Right atrial pressure (RAP)
RAP represents the force opposing venous return, pushing back against MSFP. Central venous pressure (CVP), measured in the thoracic vena cava, is also considered a reasonable surrogate of RAP. The RAP/CVP is a low pressure system, normally sitting at around 0-6 mmHg. RAP is influenced by intrathoracic pressure, right atrial compliance and contractility, pericardial compliance, and tricuspid valve function.
Understanding that stressed volume and venous tone dictate venous return can help elucidate why, in a septic patient for example, a collapsed IVC and hyperkinetic LV do not simply mean ‘volume deplete’.
Imagine, you have already administered 3 litres of fluid, but continue to see these sonographic signs of IVC collapse and hyper-dynamic heart function. You may have been increasing volume without addressing the other variable; venous tone. The fluid you continue to pour in sits dormant in a vasoplegic unstressed reservoir, with no effect on venous return. Adding in a vasopressor that increases venous tone will recruit more unstressed volume into stressed volume, increase the MSFP and venous return gradient, and return a more sonographically juicy IVC and fuller LV, with better cardiac output.
Conversely, if RAP increases to match MSFP (approx 7 mmHg), then the pressure gradient enabling venous return is eliminated, and cardiac output falls toward zero. This is why pulmonary embolisms are fundamentally a haemodynamic pathology, as the obstruction that can occur from massive PE causes an acute surge in RV afterload, raising the RAP significantly to the point of blunting venous return, crashing cardiac output and causing cardiac arrest. This is a classic case of obstructive shock.
Afterload
Afterload is the resistance that the heart must overcome in order to eject blood. Phrased differently, it is the load or force that opposes cardiac myocyte contraction.
Factors that influence afterload of the LV include the aortic valve, aortic compliance and pressure, and systemic vascular resistance. Examples that may increase afterload of the LV would include aortic valve disease (stenosis and regurgitation) and systemic hypertension,
Afterload on the RV is determined by the pulmonary valve, lung volumes, and pulmonary vascular resistance (PVR). Anything that raises pulmonary vascular resistance (such as hypoxia, PE, cor pulmonale, COPD) or raises the intrathoracic pressure (such as PPV, valsalva, pneumothorax), would increase RV afterload.
Contractility
Myocardial contractility is the power of contraction of the cardiac myocytes; a higher contractility/inotropy will result in a greater SV for the same given preload/afterload.
As previously covered, increased preload (up to a point) will result in greater contractility of the ventricles via Frank-Starling mechanics. An increased availability of intracellular myocyte calcium ions will also increase contractility. The Bowditch Effect describes the accumulation of intracellular calcium ions during tachycardia, due to reduced time to expel calcium, resulting in greater force of contraction.
↑ HR → ↑ systolic Ca influx → ↑ accumulation of intracellular Ca → ↑ inotropy
Noradrenaline (the primary sympathetic neurotransmitter) and adrenaline (a catecholamine from the adrenal glands) act as beta-1 agonists to increase myocyte contractility. Isoprenaline (β1 agonism), glucagon (↑ c-AMP via glucagon receptors), digoxin (↑ intracellular calcium), dobutamine (β1 and α1 agonism), milrinone are all positively inotropic drugs.
Factors that reduce contractility include metabolic derangement (acidosis, hyper-/hypokalaemia, hypocalcaemia), hypoxia, parasympathetic input, and pathologic states such as sepsis, myocardial infarction, cardiomyopathies, shock, etc.
Heart Rate
Heart rate is the other half of the cardiac output equation.
For any given stroke volume, a higher or lower heart rate will increase or decrease cardiac output (too high may reduce filling time and actually decrease CO, however). It is generally the major modifier of cardiac output, since heart rate can both change rapidly and potentially increase by around 3-fold. Stroke volume, on the other hand, can increase by around 50% maximum (eg from 70ml to 100 or so ml), and is largely a dependant variable that is mostly altered by venous return.
This makes SV no less important than heart rate, however, as it can be negatively impacted by many variables, as explored above.
The heart rate is set by the sinoatrial node, with an intrinsic rate of 60-100bpm, dampened down by a slightly elevated resting vagal tone, via acetylcholine acting on cardiac muscarinic-2 receptors. Sympathetic activation occurs via (nor)adrenaline binding to beta-1 receptors. A denervated heart, without vagal tone, will exhibit an unopposed SAN rate of around 100-120 bpm.
Although higher heart rates can increase CO, as it increases beyond a certain level, diastolic filling time becomes so shortened that stroke volume, and thus CO, may be negatively affected. This is heavily influenced by fitness, age, and structural factors of the heart such as compliance, ventricular size etc.
We have examined stroke volume and heart rate to better understand the determinants of cardiac output.
MAP = CO x SVR
Next, we look at the other half of the MAP equation; the circulation and systemic vascular resistance.