Hello again. I will now present Cardio-Restoratory Interactions, the Heart-Lung Connection. This talk will be based on the physiology of the cardiovascular and respiratory systems and will focus on how changes in mechanical ventilation can adversely or positively affect the cardiovascular system. I'll start with an overview of what I call Cardio-Restoratory Economics. Some basic slides looking at the balance between oxygen supply and oxygen demand. I will acknowledge up front that the first portion of the talk is somewhat dry. It's based on some basic principles, but these are essential to understand the physiologic relationships that will follow. We will then move on to talk about Cardio-Restoratory Interactions from the perspective of the heart. First the right ventricle, then the left ventricle. Then we'll move over to the lungs, largely focused on the pulmonary vasculature. In the second half of the talk, we'll discuss some concepts related to conventional ventilation and then high-frequency ventilation. And lastly, we'll bring this all together with a discussion of some key points related to oxygen delivery. As we discuss Cardio-Restoratory Interactions, a key principle is that oxygen supply and oxygen demand must be balanced. A misbalance, where demand outstrips supply, occurs in those situations in which the patient is in shock and presents with metabolic acidosis, lactic acidosis, and other markers of end organ hypoperfusion. The properties of the heart and the lung intrinsically affect each other. In the healthy condition, the two systems are well-balanced and well-optimized. However, the relationship between the cardiovascular and respiratory systems can greatly vary in disease states and as well as have significant effects on different therapeutic targets, depending on the clinical situation at hand. Next, we'll talk about O2 supply or O2 delivery, abbreviated DO2. DO2 is the product of cardiac output and oxygen content, arterial oxygen content to be more specific, where oxygen content is 1.34 times the hemoglobin times the oxygen saturation plus 0.003 times the dissolved oxygen. If doing a calculation on a board exam, I'd recommend to not waste any time focusing on the dissolved oxygen proportion, since this value is quite small in relation to the oxygen bound to hemoglobin. If we look at the other side of the balance, O2 demand or O2 consumption is the amount of oxygen used for aerobic metabolism. O2 consumption is the product of cardiac output and the arterial venous O2 content difference. In terms of strategies to increase oxygen delivery, I already mentioned that we can increase arterial oxygen content by transfusing the patient, increasing the hemoglobin, and or titrating the mechanical ventilator, including the fraction of inspired oxygen to increase the oxygen saturation and or the dissolved O2 content. In terms of increasing cardiac output, one can approach this through cardiac interventions, including fluid boluses and the initiation or titration of vasoactive agents. Such strategies are beyond the scope of this presentation, as they are cardiac in nature and will be, and I will leave those for the cardiac talks as part of this program. What I'd like to focus on in this session are pulmonary interventions, how one can optimize mechanical ventilation to optimize cardiorespiratory interactions and augment cardiac output. On the other side of the balance, decreasing O2 consumption, if the patient's work of breathing is excessive, one can use ventilatory approaches to normalize, optimize the patient work of breathing. This largely focuses on the elimination or treatment of any patient ventilator dyssynchrony. A patient who is more synchronous with the ventilator is more likely to have an appropriate work of breathing. Of course, pharmacologic sedation and or neuromuscular blockade can be used to reduce a patient's work of breathing. However, the risk-benefit ratio of such an approach must always be considered. Next, one should avoid hyperthermia, as that will lead to unnecessary increases in O2 consumption, and the maintenance of normal thermia can help with the balance between O2 delivery and O2 consumption. In assessing tissue oxygenation, we have basic laboratory assessments, acid-base balance, sending serial blood gases, checking serial serum lactate measurements, and if possible, through the venous access available in a patient, checking mixed venous oxygen saturations can also be helpful. It's worth noting that surrogates for mixed venous oxygen saturation, such as cerebral oximetry, NIRS monitoring, may be helpful. Discussion of that modality and the data that may or may not support such an approach I will leave for other sessions of this program. We also need to assess end-organ function in terms of the kidneys, assessing serial BUN and creatinine measurements, and of course, following urine output over time. It needs to be acknowledged the obvious, that urine output is going to be affected by the use of diuretics. Similarly, assessment of the central nervous system, a patient's mental status, is important, but that is often confounded by the use of sedation. And lastly, following cardiac function, and more specifically, in the pediatric population, right ventricular function can be helpful, and this can be accomplished with serial echocardiograms. A few key points worth mentioning in terms of tissue oxygen delivery. Tissue oxygen delivery is determined not only by arterial oxygen saturation, but also by the hemoglobin, cardiac output, oxygen affinity of hemoglobin, oxygen extraction, and the metabolic demands of the body. One must keep in mind that arterial oxygen saturation alone is not a sensitive index of tissue, of the tissue oxygenation status. And lastly, no, to date, no prospective randomized trial has assessed the relationship between arterios, oxygen saturation, and tissue oxygenation in critically ill patients. This slide shows the relationship between the multiple parameters and physiologic entities that lead to oxygen delivery. So if we work this slide from right to left, optimizing oxygen delivery will require an optimization of cardiac output and oxygen content, and as already mentioned, that it requires an optimization of hemoglobin, O2 binding, and dissolved oxygen. I'm going to focus on the top left portion of this slide now, where cardiac output is the product of stroke volume and heart rate, focusing now on stroke volume that is affected by contractility, again, inotropes, or inotrope usage, which again, I will leave for a different presentation, and in this talk, I'll focus on preload and afterload, and how the use of the mechanical ventilator can affect preload and afterload to both the right and left ventricle, which in turn can augment, or in some cases, adversely affect, stroke volume, which downstream will ultimately affect oxygen delivery in either the positive or negative direction. It's important in any talk about children and cardiovascular interactions to take a moment to discuss the blood pressure response in children. Children have an amazing ability, as we all know, to increase heart rate and increase systemic vascular resistance in the face of hypovolemia. In this schematic shown here, we see on the horizontal axis progressive blood loss, the red vertical line representing 25% loss of blood volume. The vertical axis is percent of baseline, or percent of control. What we see here is the patient experiences progressive blood loss out towards 25%. We see a compensatory increase in both heart rate and systemic vascular resistance, which largely maintains blood pressure stable, with a relatively stable to maybe a slightly decrease in cardiac output. We don't see a significant drop-off in blood pressure and cardiac output until beyond 25% loss of blood volume. Stated very simply, this supports the notion that we hopefully all know that blood pressure or changes in blood pressure tend to be a later finding in pediatric patients, and one of the more sensitive indicators of a change in a patient's overall cardiovascular status is tachycardia, and one should always take unexplained tachycardia seriously in any pediatric patient. With those basic principles behind us, now let's move forward into the heart of the talk, pun intended, as we discuss the right ventricle and the left ventricle. In looking at the heart-lung system in its composite, it's important to note the obvious that the right side of the heart gets its blood from outside the thorax via the SVC and IVC and pumps blood intrathoracic into and then through the lungs. The left side of the heart, the opposite, the left atrium obtains its blood from within the thorax with the left ventricle pumping blood extrathoracic via the aorta. Thus one would expect, in fact we will see, differences in the effects of mechanical ventilation on the preload and afterload of the right and left ventricles. As we are talking physiology and not anatomy, all of the diagrams that I will show will be in schematic format. This first diagram looks at right ventricular filling, where the right ventricle again gets its blood from outside the thorax, pumps it within the thorax, thus positive pressure ventilation, increasing the mean intrathoracic pressure, will likely have an adverse effect as I'll show on the next slide, and systemic venous return as the gradient across which blood must need to pass from the body to the lungs narrows. And within the thorax, changes in positive pressure ventilation are likely to have changes in RV afterload that can be either positive or negative, and we'll see that when we discuss pulmonary vasculature and pulmonary vascular reactivity in the next section of the talk. Here we'll look at systemic venous return, specifically RV preload. The vertical axis is right atrial pressure, the horizontal axis systemic venous return. When systemic venous return is near maximal, right atrial pressures are going to be low. If a patient is spontaneously breathing, such that right atrial pressure remains low, systemic venous return remains near maximal. However, if that patient is converted from spontaneous breathing to positive pressure ventilation, what we see here is an increase in intrathoracic pressure, thus an increase in right atrial pressure, leading to a corresponding decrease in systemic venous return. So what happens in a situation such as this, where you have a patient that has severe RV dysfunction and acute lung injury, where you need higher ventilatory pressures, higher mean intrathoracic pressure to ventilate a patient with severe lung injury, but yet you have a situation of right ventricular dysfunction? If we go back to the prior schematic in the example that I showed, what one needs to do to adequately support this patient often is to increase the PEEP, increase the mean airway pressure, which in turn increases the mean intrathoracic pressure, increases the right atrial pressure, and thus further decreases systemic venous return. So at this point, we're going to look at a situation where we have a patient that has systemic venous return. So at this point, we have a patient who is more hypotensive because of a lack of preload. So standard approach would be to volume augment this patient. But in this physiologic representation, how does volume augmentation help? It shifts the relationship between right atrial pressure and systemic venous return upward and rightward such that for the same right atrial pressure, one sees a higher systemic venous return. Now, of course, looking at the x-ray shown, additional fluid can be a detriment to this patient over time. So it's important to note that the amount of fluid it takes to augment cardiorespiratory interactions tends to be quite small, somewhere between 3 and 5 ml per kilo. This is not a situation in which one needs to bolus 10 to 20 ml per kilo of saline because, again, that is simply going to soak up into the lungs. The other point worth briefly mentioning, again, beyond the scope of this talk, but throughout all these interventions, one could always consider the addition or augmentation of inotropic vasoactive agent support. When preparing for the boards, it is really important in the last weeks or days prior to the boards to look through all the various pressure relationships between intraventricular pressures, intrathoracic pressures, and transmural pressures. It's important to note that alterations in RV compliance is going to affect this relationship because the ventricular diastolic transmembrane pressure is going to be altered. The diastolic transmembrane pressure is going to be altered by the mean intrathoracic pressure. This situation is going to be worsened when the RV is noncompliant. And in a situation of noncompliance, generally a higher intracavatory pressure is going to be required to achieve adequate end diastolic volume. A complex interplay here between volume and pressure. So in summary of this section, what are the effects of positive pressure ventilation on the right ventricle? Increases in intrathoracic pressure tend to decrease cardiac output by decreasing the RV preload and may increase pulmonary vascular resistance. But this is going to depend on lung volume. Of course, an increase in pulmonary vascular resistance will relate to an increase in RV afterload. Instead of working through those complexities here in this discussion of the right ventricle, we'll hold on that until we get to the pulmonary vasculature where this will make more sense. So in general, the best strategy for the failing right ventricle is going to be to limit the mean intrathoracic pressure and to limit the mechanical ventilatory support applied as much as possible, given the gas exchange limits or gas exchange goals that might be needed. OK, now let's move to the left side of the heart. And let's focus on the effects of positive pressure ventilation on LV filling. I show this slide and have this discussion here to be complete in my discussion of cardiorespiratory physiology and also for historical interest. Thoracic pump augmentation states that one can actually push blood from the lungs forward into the left atrium, augmenting left atrial preload, and thus augmenting cardiac output. The reason that I say that this is more of historical importance is that the tidal volume required to be able to get a sufficient augmentation of left atrial preload and an augmentation of cardiac output requires tidal volumes in the 15 to 20 ml per kilo range, obviously volumes much higher than are commonly in use today. So I am not advocating for the thoracic pump augmentation approach simply because the tidal volumes are beyond what's currently acceptable. But again, I just share this for the sake of completeness. Before I move on to a discussion of the effects of positive pressure ventilation on LV afterload, it's worth a brief mention about the concept of ventricular interdependence. In this, on this slide, I'm going to focus first on the insert here, the diagrams. On the left pictorial, what we see here is a normal situation with a normal RV and a normal LV. If that RV becomes hypertensive and we see RV diastolic hypertension, the expansion of that RV volume will compress the left ventricle, leading to a reduction in LV preload and a reduction in the LV output. Situations such as this is most commonly seen when the patient develops or has pulmonary hypertension. If we now look at the effects of positive pressure ventilation on LV afterload, we'll go through a series of schematics as shown on this slide. Let's start on the left panel, the first panel here, which is a situation of quiet breathing. And for the purposes of this example, we'll assume or we'll accept that the mean intrathoracic pressure approaches zero. If we have a normal ventricular interdependence, we'll see that the ventricular interdependence if we have an pressure in the aorta, both the ascending and descending aorta of 100, what pressure does that LV as shown in blue need to generate? Well, it's straightforward in this case, it's 100 minus zero or 100. So the LV is generating the same systolic pressure as seen in the aorta. If we now move to the second insert, which is an example of exaggerated negative intrathoracic pressure stated differently, significant respiratory distress, such that the mean intrathoracic pressure is minus 125. To get that same systemic systolic pressure of 100, the LV again in blue is going to have to generate a pressure of 100 minus a minus 25 or 125 millimeters of mercury. Thus, exaggerated negative pressure, negative intrathoracic pressure, increased work of breathing is an adverse stress on the left ventricle. So if we now take this patient with increased work of breathing and intubate this patient and place this patient on PEEP, such that the mean intrathoracic pressure is now positive 20, what we see to generate the same 100 systemic systolic pressure throughout the aorta is a left ventricle that needs to generate a pressure of only 80 or 100 minus a positive 20. Thus, positive pressure ventilation will decrease LV afterload and make the LV more functional, improve left ventricular output in the face of a positive mean intrathoracic pressure. The last insert shows what occurs with vasodilator therapy. So we now take this fourth insert and go back to the first, which is quiet breathing with a mean intrathoracic pressure of zero, such that now because of peripheral vasodilatation, we have a systemic systolic pressure of 100. That left ventricle only needs to generate a pressure of 80 minus zero or 80. Thus, one can unload the left ventricle in one of two ways. One is through positive pressure breathing and increasing the mean intrathoracic pressure and or two to peripherally vasodilate the patient and thus pharmacologically through the vasculature decrease LV afterload, which would be used in which situation really depends on the specifics of the clinical entities and the pathophysiology at hand as well as clinician preference. So in summary, the effects of positive pressure ventilation on the left ventricle are that increases in intrathoracic pressure, increased cardiac output by decreasing LV afterload. Whether or not this is clinically significant depends on the changes in mean intrathoracic pressure, the patient's underlying cardiorespiratory status, and countless other clinical entities. In some situations, the beneficial effects of increasing mean intrathoracic pressure might be small, and in others, it could be quite significant, especially in the case of baseline poor LV function, whether that be a patient with myocarditis or other cardiomyopathies. The effects of positive pressure ventilation on LV preload can be variable, and they're largely based on the intravascular volume status of the patient and based on the RV effects or ventricular interdependence. Important to review the Frank Starling mechanism prior to the boards. We see here in a normal compliance curve in the black line, volume administration will normally increase stroke volume by increasing preload. However, that relationship is going to change in the situation of decreased ventricular compliance, and the relationships here, one just needs to think about if asked a question with points A, B, C, D, and the question relates to which direction one would move in one clinical entity. You just really need to think about the physiology of whether or not the ventricular compliance is normal or abnormal, and whether the question is related to changes in volume infusion and or changes in contractility. Fortunately, due to time limitations of the talk, it's not possible to go through all of those scenarios in this session. However, during the question and answer session that will follow later in the summer, we'll be able to work through various specific questions and clinical examples. So in summary, positive pressure ventilation will often improve myocardial and oxygen, global oxygen delivery. Decreases in ventricular transmural pressure will decrease myocardial oxygen demand. If one can decrease the transmural pressure, making it more effective or efficient by the ventricle to pump, its intrinsic need for oxygen will be lower. These effects are most profound in those who have baseline left ventricular failure slash severe dysfunction and or those who have exaggerated negative pressure ventilation, such as severe respiratory distress. Also, unloading of the respiratory muscles will help decrease oxygen consumption and thus improve the O2 supply demand balance. Lastly, the use of positive pressure ventilation, including non-invasive ventilation, have been associated with improved outcomes in those with impaired left ventricular systolic function. So an increase in the mean intrathoracic pressure can have varied and sometimes pronounced effects throughout the heart with differences on the right and left side. As general teaching points, increases in the mean intrathoracic pressure will decrease RV preload, increase RV afterload, and decrease LV afterload. These changes may or may not be clinically significant, depending on the patient's baseline cardiorespiratory status, the degree of work of breathing, the underlying right and left ventricular function, and also the degree in which the ventilatory support is changed. The key here is to remember the general physiologic principles and then extrapolate those to the individual clinical situation at hand. So to bring these concepts together in a case, we have a four-year-old male with ARDS secondary to influenza. He's being oscillated with a mean pressure of 25 centimeters of water, an amplitude of 54, frequency of 9 hertz, and 65% oxygen. The blood gas you can see there at 7.30, 58 CO2, 54 PaO2, and a saturation of 86%. The respiratory therapist increases the mean airway pressure up to 32 in an attempt to improve the patient's oxygenation. And in fact, that occurs with an increase in saturation to 94%. In the ensuing few minutes, it is noted by the bedside team that blood pressure has decreased and heart rate has increased. So the deterioration in hemodynamic status after the increase in mean airway pressure is most likely explained by which of the following? An increase in LV afterload, decrease in LV preload, a decrease in RV contractility, a decrease in RV preload, or a decrease in LV contractility. Give you a moment to think, and then we'll go through each of these. So the most likely answer here, the most common answer, is going to be choice four, a decrease in RV preload. To work through these, first, we can eliminate three and five changes in contractility. Yes, in some situations, changes in the mean configuration of the heart, the geometry of the heart, can affect contractility. But those are minor and generally not considered and almost never will be tested in such a situation. So we're left with the other entities. And one could argue that by increasing the mean air intrathoracic pressure, that the LV preload choice two could be affected. And that's very possible. But the only way LV preload in this situation will be adversely affected is through effects on the right side of the heart. And thus, the primary effect is a decrease in RV preload. The increase in mean airway pressure is going to decrease LV afterload and not increase it. So thus, the best answer is choice four. The next case is a previously healthy eight-year-old with acute myocarditis. ECHO shows severely depressed LV function. The patient's intubated and conventionally ventilated, is being managed with mirinone and epinephrine infusions. And after five days, the epinephrine is weaned off as the patient appears to be clinically improving. The ECHO now is consistent with the clinical assessment of improvement, showing moderately depressed LV function, improved from severely depressed. The patient is extubated. And about two hours later, this child develops tachycardia and decreased peripheral perfusion. So the deterioration in this patient's clinical status after extubation is best explained by what? An increase in RV afterload, increase in LV afterload, decrease in LV preload, decrease in RV contractility, or an increase in RV preload. So in this situation, we can again eliminate RV contractility, as I discussed in the prior case. And now we're left with changes in afterload and preload. When you see such an example or such a clinical scenario, extubation with a child who has myocarditis, poor heart function, clinical situation worsens, the most likely effect is going to be an increase in LV afterload. So the correct choice is choice two. Changes in RV afterload might be a factor here. But if so, likely to be secondary. And a lot depends on the patient's lung volume. But I didn't give a lot of information in the stem involving changes in the pulmonary condition or lung expansion. LV preload and RV effects are going to be, again, secondary largely to the LV. And in this case, if anything, RV preload might, in fact, be increased, but is unlikely to be any explanation, the increased loading, for the patient's deterioration in clinical status. So answer here is an increase in LV afterload. OK, and now let's move on to the lungs with a focus on the pulmonary vasculature. So let's start this section with a case. So this is a five-year-old male with ARDS secondary to MSSA. You'll notice that this situation is very similar to the prior case I gave you, where the RT is going to increase the mean airway pressure from 24 to 32 to help improve oxygenation. And again, in this situation, the blood pressure decreases and the heart rate increases. So same situation, but of course, on the next slide, the choices are going to be different. So the deterioration hemodynamic status after the increase in mean airway pressure is most likely going to be explained by which of these changes. Same choices as before, and again, will eliminate contractility both of the right and left ventricle. So if we now focus on an increase in LV afterload, well, that's not the case, because an increase in mean airway pressure is going to decrease LV afterload. So this has to do with either an increase in LV preload or an increase in RV afterload. And the correct answer here is going to be a choice two, an increase in RV afterload, as the increase in mean interthoracic pressure is going to dilate the alveoli and thus compress the capillaries, leading to an increase in pulmonary vascular resistance and increase in RV afterload. So let's focus on the respiratory effects on pulmonary vascular resistance. The mechanisms are varied and due to alterations in blood pH, alveolar oxygen tension, and lung volumes. In terms of lung volume changes, the primary mechanism of these cardiorespiratory interactions is the alveolar transmembrane pressure. We need to consider the alveolar vessels, the capillaries surrounding the alveoli, as well as the extra alveolar vessels, those vessels in the interstitium that are exposed to the interpleural pressures. We have to also consider the fact that these vessels are in series, thus the resistances are additive. And that will make more sense here in the next series of schematics. These next three slides are all aligned similarly, where the vertical axis is pulmonary vascular resistance, the horizontal axis is lung volume, the left side of the slide will represent atelectasis, and the right side of the slide will represent pulmonary overdistension. In this first schematic, we have what is displayed in green are the large pulmonary vessels. When the lung is atelectatic, collapsed, those large vessels become torturous, and the resistance in those large vessels is high. However, as the lung becomes overdistended, these large vessels straighten and the resistance in those vessels fall. If we now superimpose in orange the small vessels, the capillaries surrounding the alveoli, and we start with the insert on the top right of this slide, what we see here is that overdistended alveoli will collapse, compress surrounding capillaries, leading to high resistance. So when a lung is overexpanded, the resistance in the small vessels is high. However, as you move leftward on this slide and have a lung go from overdistension to atelectasis or collapse, and the alveoli collapsed, the resistance in those small vessels falls, and thus the resistance in these small vessels is quite low in the atelectatic lung. Pomevascular constriction related to hypoxia aside. So now, instead of considering the small and large vessels independently, we need to combine them and look at total pomevascular resistance or the summation of the resistances in both the small and large vessels. As shown here in this reddish color, what we see is that pomevascular resistance is high at both lung, when the lungs are collapsed, as well as when the lungs are overdistended. And it's neither here in the middle at an optimal lung volume, which is approximated by managing a patient or ventilating a patient at functional residual capacity. So changes in lung volume can increase pomevascular resistance in the situations of lung collapse as well as lung overdistension. So now let's look at a classic physiologic experiment, publication from nearly 40 years ago in a Journal of Applied Physiology, a series of animals, control in orange, then in red, hypoxic pomevasal constriction as a second bar and the fifth bar on the right is returned to the hypoxic baseline. In the middle, blue and green represent respiratory and metabolic alkalosis. And what we see here is that the reduction in PVR, the improvement in pulmonary artery pressures are related to pH and it does not matter whether the increase in pH is of the respiratory or metabolic component. The key factor here on reducing pomevascular resistance is alkalosis, not necessarily CO2 or bicarb. Now let's go back a decade to the 70s, another article from a Journal of Applied Physiology, looking at the effects of PCO2 on PVR. All of the data on this slide are buffered to a pH of 7.4. The blue dots on the left side of the slide represent a decrease in PaCO2. And I should mention that the vertical axis again is a change in PVR. So what we see here is that a patient is hyperventilated such that the PaCO2 decreases, but yet the pH is buffered to say a 7.4, there is no reduction in pulmonary vascular resistance. So hyperventilation per se, respiratory changes do not lead to a decrease in PVR if pH is buffered such that the decrease in PVR we saw in the prior slide was related to a pH effect, not a CO2 effect. However, on the right side of this slide, what we see is that increases in PaCO2 have a direct and sometimes profound increase in PVR irrelevant of pH, again with all data points buffered to 7.4. So CO2 is a potent pulmonary vasoconstrictor when elevated, but is not a pulmonary vasodilator when reduced. It's important prior to the board examination to go back to the basic diagrams, to look at the west zones and the relationship between ventilation and perfusion. To stay within my time limit, I'm not gonna go through all the variations of zone one, two, and three, something really that it's best visually assessed prior to the exam. And we will also go through these in various test questions and scenarios in the interactive sessions, again, at the end of summer. So in summary, with the pulmonary vasculature, the goal is to optimize lung volume, avoid pulmonary over-distension, avoid atelectasis lung collapse, if possible, avoid hypoxic pulmonary vasoconstriction. And although I didn't discuss it here, inhaled gases, specifically 100% oxygen, nitric oxide, provide the opportunity to modify pulmonary vascular resistance. One of the classic examples of low cardiac output state related to cardiorespiratory interactions is pulmonary hypertension. If we start on the top right of this slide, we see a situation of pulmonary hypertension, leading by definition to increase in RV afterload, which leads to RV failure, low cardiac output state, metabolic acidosis, fueling the constriction of the pulmonary vasculature, worsening the pulmonary hypertension. The RV failure also increases the RV end-diastolic pressure, which through ventricular interdependence can decrease the left ventricular end-diastolic volume, leading again to low cardiac output state. In there, there can be arrhythmias due to ventricular ischemia. The pulmonary hypertension will also lead to a decrease. Through its decrease in pulmonary blood flow will lead to ventilation perfusion mismatching, hypoxia, worse pulmonary hypertension. And not shown on the slide, the hypoxia and potentially the respiratory acidosis will lead to increased ventilatory support, which will further adversely affect ventricular function, especially right ventricular function as previously discussed. So thinking through the various relationships, the best example that brings us all together, again, is pulmonary hypertension. Okay, let's move on to the next portion of the talk on conventional ventilation, looking at lung volumes and patient ventilator synchrony. It's important to note that the dominant effect of positive pressure ventilation is always the mean airway pressure. Any effects due to phasic changes, meaning delta P or minor, must be balanced by the mean airway pressure or the changes in the mean intrathoracic pressure. So the adverse effects of overdistension, I won't review overdistension since we did that in the prior talk, can be pulmonary with significant over expansion, potentially leading to barotrauma, volutrauma, and in the extreme case, air leak, but also can have significant cardiovascular effects with the increases in PVR and increase in RV afterload associated with the decreasing cardiac output as I showed in the prior series of schematics. What I'd like to show here is another older cloud classic experiment here relating tidal volume to pulmonary vascular resistance. As you see in the horizontal axis, tidal volumes of 10 to 20 per kilo, which I am not advocating for, just showing this for the purposes of cardiorespiratory interactions, and the vertical axis pulmonary vascular resistance with the blue line shown with a PEEP of five. And as we see as tidal volume increases and lungs over distend, pulmonary vascular resistance increases. However, if the PEEP is increased from five to 10, now shown in the second insert, what we see is a very dramatic increase in pulmonary vascular resistance. And in fact, pulmonary vascular resistance can increase fivefold by simply increasing PEEP and tidal volume. So mismanaging a ventilator can lead to profound adverse outcomes or adverse effects in elevations in pulmonary vascular resistance. This correlates with decreases in cardiac output shown here again, first in blue with a PEEP of five, and then with a PEEP of 10. One can decrease cardiac output in half, decrease by 50% simply by mismanaging the ventilator. Although high-frequency ventilation is used much less commonly these days, it's worthwhile to go through just a small discussion in terms of the effects of mean airway pressure on cardiorespiratory interactions from this perspective. The physiology at hand is very similar to as we discussed earlier with conventional ventilation. Increases in mean intrathoracic pressure will decrease systemic venous return by increasing through increases in right atrial pressure. Preload augmentation will lead to improvements in systemic venous return and thus right ventricular preload. So cardiac output is generally maintained during high-frequency ventilation. However, in a given patient, cardiac output may decrease if the mean airway pressure is significantly increased, consider volume loading as I just showed, or again, consider inotropic vasoactive support. The bottom line is oxygen delivery. If cardiac output can be maintained, if oxygenation improves, then oxygen delivery will increase. Jet ventilation is not commonly used, but is in some units scattered around the country. I show this slide not to promote jet ventilation, but really again to relate to the effects of ventilation, mean airway pressure, and cardiorespiratory interactions. What we see here, a series of bars. Blue is baseline conventional ventilation. Red is jet, and then that reddish color is return to conventional ventilation. First series of bars, mean airway pressure, second PVR, and third cardiac index. What we note here is by switching from conventional ventilation to jet, which generally functions at a much lower mean airway pressure, we see a reduction in pulmonary vascular resistance and a corresponding increase in cardiac index that's managed in a cardiac catheterization lab. So in the last section of the talk, as we start winding down, we'll bring this all together with a focus on oxygen delivery. I'll start with a classic traditional pressure volume curve, pressure on the horizontal axis, volume on the vertical axis. If we change this from pressure volume to PAO2PEEP, what we see is a very similar pattern here, a trace that looks very much like a pressure volume curve. What we'll see is an increase in mean airway pressure by increasing the PEEP from 10 to 15 to 20 to the point of overdistension. Oxygenation increases. Then as PEEP is weaned and the lungs are allowed to collapse, we see a deterioration in oxygenation, and then a return to baseline, a complete cycle. I should note that these data are obtained in a series of animals to provide real-life clinical simulation. If we now look at cardiac output, similar sequence of events with PEEP going from 10 up to 20 as the lungs are grossly overdistended, what we see is a fall in cardiac output. And then as the lungs collapse and the animals become hypoxic, we actually have an overshoot probably due to release of endogenous epinephrine. And then what should be a return to baseline, the circle isn't exactly closed, theoretically or speculatively due to some myocardial dysfunction as a result of the profound hypoxia experienced. What we see in the insert here is oxygen delivery versus PEEP. And I show this to compare the relationship of this curve to that of the PAO2 PEEP that we previously discussed. And if we focus on the green circles, what we see here is that oxygenation, arterial oxygen content, is maximized at a PEEP of 20 on that top left insert, whereas at the same point here with a PEEP of 20, oxygen delivery is at its lowest point. Why? Because cardiac output is at its lowest point. When looking at oxygen delivery, as we go full circle to the start of this talk, one always needs to consider the relationship between arterial oxygen content and cardiac output. Next question, which of the following shifts the oxygen dissociation curve to? Which of the following shifts the oxygen dissociation curve to the right? A decrease in temperature, an increase in pH, a decrease in PCO2, or quote, chronic hypoxia? Give you a moment to think about this. And then I'll offer the correct answer, B, chronic hypoxia. And we'll go through this in more detail in the next few slides. It's important to note that permissive hypercapnia is not a primary entity. It in and of itself is a subject of another talk. But I do wanna mention, pardon to the prior slide, that respiratory acidosis, permissive hypercapnia, respiratory acidosis, can improve oxygen release in the periphery, resulting in improved tissue oxygenation, although the arterial oxygen saturation may be relatively low. And low pH improves oxygen release to the tissues. So if we now look at the oxygen dissociation curve, the black line in the middle, baseline, shift to the left in blue is a decrease in 2,3-DPG, and a shift to the right in the purple color is an increase in 2,3-DPG. What we see here, that is the curve shifts rightward for the same percent oxygen saturation. We have a higher partial pressure of oxygen at the tissue level. So shifting the curve to the right unloads oxygen to the tissues. And what are those entities that increase or unload oxygen to the tissues shifts the curve to the right, increase in temperature, which we of course don't routinely clinically do, permissive hypercapnia, respiratory acidosis, as previously mentioned, with a decrease in pH and or an increase in PaCO2 and chronic hypoxia. So that's the correct answer to this question. And we can discuss this in more detail as would be helpful in the live sessions. 2,3-DPG concentrations increase in the situation of quote chronic hypoxia. The next question is what is chronic? These are some unpublished data out of Pittsburgh shared with me. And we see that 2,3-DPG concentrations increase after about two to three days of hypoxia. So this unloading of the tissue levels occurs relatively early, upwards of about 72 hours after the initiation of hypoxia. So is more better? Vertical access tissue oxygenation, horizontal access oxygen delivery. And we see the relationship here of a linear increase in oxygen, linear relationship between oxygen delivery and tissue oxygenation until the elbow, which represents the anaerobic threshold, after which further increases in oxygen delivery do not correlate with increases in tissue oxygenation. So if a patient is a leftward of the anaerobic threshold, increasing oxygen delivery will help at the tissue and organ levels. However, super therapeutic or super normal levels of oxygen delivery do not augment tissue oxygenation or end organ oxygen delivery. So the key here in patient management is to function just rightward of the anaerobic threshold. Why not go further just in case it might help? And that is of course, because anything that we do to further augment oxygen delivery to super normal levels may carry adverse effects or other side effects. It's also important to note that all markers of oxygen delivery are global indicators. Regional areas of tissue might be hypoxic. The classic clinical example discussed is the situation of necrotizing enterocolitis, NEC, where a baby may appear to be in a good situation, a good place from global oxygen delivery, but yet develops NEC due to regional areas of hypoxia or ischemia. Unfortunately, regional oxygen delivery is nearly impossible to assess. Beyond the scope of this discussion of cardiorespiratory interactions, we do have to realize that there are numerous respiratory and cardiac diseases that affect the alternate system. For respiratory cyst diseases affecting cardiac function, we have to consider sleep disordered breathing as well as PARs, pediatric ARDS or ARDS in the adult population. And on the other side of the equation, cardiac diseases that affect pulmonary function systolic heart failure, left to right shunting defects, and of course, pulmonary hypertension as previously discussed. So in summary, as clinicians, we always need to consider the balance between oxygen supply and oxygen demand. Increases in the mean intrathoracic pressure may decrease or increase cardiac output depending on ventricular function. And there may be competing pathophysiologic or physiologic entities at place and the changes will trend towards or move towards the primary pathophysiology. In general, the best strategy for the failing right ventricle is to limit intrathoracic pressures, keeping in mind that high intrathoracic pressure may decrease RV preload and may increase pulmonary vascular resistance. The best strategy for the failing left ventricle is gonna be to increase intrathoracic pressure. Keep in mind the effects of intrathoracic pressure on LV preload, which could be increased or decreased depending on effects on the right side of the heart. And in general, increases in mean intrathoracic pressure are gonna decrease LV afterload and help ventricular function. We wanna improve pulmonary vascular resistance or optimize pulmonary vascular resistance by optimizing the patient's lung volume, ventilating the patient as much as possible around FRC, avoiding hypoxia and the associated pulmonary vasoconstriction. We wanna use respiratory mechanics as discussed in the prior presentation to achieve optimal lung volume and to assess the impacts of any manipulations of the ventilator on the cardiovascular system. And lastly, we need to keep in mind that the dominant effect of mechanical ventilation will always be the mean airway pressure to the intrathoracic cavity and its effects on the mean intrathoracic pressure. So with that, I'll conclude this presentation again with my email address if anyone would like to reach out with further questions. And I look forward to discussions with hopefully many of you in the live interactive sessions later this summer at in Chicago, St. Petersburg and Los Angeles. Thank you for your attention. It's been a pleasure to join you albeit virtually and hopefully in two years, we'll be back together in a large ballroom doing this in person. Thank you so much. Have a great day.

Cardio-Restoratory Interactions

Cardiovascular system

Respiratory system

Mechanical ventilation

Oxygen supply

Oxygen demand balance

Cardio-Restoratory Economics

Physiology principles

Oxygen delivery