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7: Pulmonary Hypertension in Critical Illness: the ...
7: Pulmonary Hypertension in Critical Illness: the "Right" Management (Lee Goeddel, MD)
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Hello, I'm here to talk to you about one of my favorite topics, and that's managing pulmonary hypertension in critical illness, or the right management. Let's start with a patient, we have a 32-year-old female with severe pulmonary arterial hypertension, post-op day zero, status post an open cholecystectomy coming to your ICU. Here's her echo. What you see here is a parasternal short axis view, the right ventricle on top in cross section, the intraventricular septum in the middle, and the left ventricle below. You see here a very large right ventricle. This talk, just like any others on pulmonary hypertension, will also be a talk on right ventricular function. What we really want to know is how is this patient's pulmonary arterial hypertension affecting her right ventricle before coming to the ICU, during surgery in this case, but ultimately how the right ventricle and the pulmonary arterial hypertension are affecting each other during her critical care. I like to propose a mental model of a hexagon of topics to simultaneously manage when addressing pulmonary hypertension and right ventricular dysfunction. These are the six topics, preload optimization, reducing RV afterload, treating causes of RV failure, supporting RV contractility, and maintaining perfusion pressure. Ultimately, if necessary, considering mechanical circulatory support. How about epidemiology? So pulmonary arterial hypertension does result in worse ICU outcomes. A couple of recent studies demonstrated that there was increased perioperative morbidity and mortality in patients with pulmonary arterial hypertension, an odds ratio of 1.4 for the outcome of major adverse cardiac and cerebrovascular events, and a four times increase in death. In all ICU patients, in one particular study in chest, patients admitted with pulmonary arterial hypertension to the ICU had high in-hospital six-month and 12-month mortality from right ventricular failure particularly. Before we move to diagnosis and treatment of pulmonary arterial hypertension as well as right ventricular dysfunction or even failure, there are some key anatomic and physiologic topics to discuss. So first, anatomy and pulmonary hypertension. The history of nomenclature for pulmonary arterial hypertension used to revolve around the capillaries where the lesion resulting in pulmonary arterial hypertension if before the capillaries referred to pre-capillary hypertension or if after the capillary bed was post-capillary hypertension. In a second, I'm going to show how that was updated to a more useful nomenclature related to the different pathophysiology of pulmonary arterial hypertension. Pulmonary vascular resistance is a really important physiologic term to understand. It truly refers to the intraluminal diameter of the pulmonary arteries. As you see here anatomically, the arteries in the pulmonary system are made up of adventitia, media, and intima. And over time, you have proliferation and smooth muscle hypertrophy of those layers. Even with this proliferation, it is possible to reverse disease at that point. However, it can progress to irreversible disease where you have. Further increased proliferation, the existence of plexiform lesions that lead to lower flow states and in situ thrombosis and also ultimately narrowing of those pulmonary vascular beds resulting in elevated pressures. The classification of causes of pulmonary hypertension previously was based on the anatomic location of the primary lesion that was driving this proliferation process in the pulmonary vascular bed. However, that was updated by WJ classification in 2008 where class 1 pulmonary hypertension is considered to be a primary pulmonary arterial vessel problem, usually idiopathic in nature, resulting in that vascular proliferation I showed on the previous slide. Class 2 is typically considered a left heart or valve problem where you have decreased cardiac output, increased left atrial and pulmonary capillary pressures that then result in increased pulmonary arterial pressures and end-stage proliferation of the vascular beds. Class 3 is an inherent lung or parenchyma problem that then ultimately results in that vascular proliferation. Class 4 is thromboembolic disease where clot is deposited throughout the pulmonary arterial beds and leading to significant in situ thrombosis and plexiform lesions and large increases in pulmonary systolic pressures. Class 5 is other which often includes many other systemic diseases, immune diseases, rheumatologic diseases that can lead to increases in pulmonary systolic pressure. Now let's focus on the heart. So the right ventricle, as I mentioned before, is critical in any discussion about pulmonary arterial hypertension. Focusing on right ventricular anatomy and mechanics in particular, the right ventricle is thin-walled, only about 3 mm on average. It sits over the curved septum. The free wall contracts by an inner movement without rotation like the left ventricle, much more like a bellows. The myocardium has sequential contraction and is a very low afterload chamber. Low pressure, low afterload. Second physiologic concept, ventricular interdependence. I show here a picture of Abraham Lincoln from his 1958 Senate campaign that he ultimately lost to Douglass for the state of Illinois where he spoke about a house divided against itself cannot stand. I come from Maryland and so we have a tremendous amount of history around us. So I thought that this was a perfect analogy for the heart as well. We can't think about the right ventricle in isolation from the left ventricle. And we have this physiologic concept of ventricular interdependence. Now there are multiple aspects of this physiologic concept that go from easy to understand and a bit more complex. Let's start easy. Ultimately, ventricular interdependence basically states that the function of each ventricle is dependent upon the other. So really this is not a house we can divide because without each other the ventricles cannot stand. What does that mean? In a little bit more detail, right ventricular cardiac output is necessary to provide the preload to the left ventricle. So typically, whatever the cardiac output is in the right ventricle, that equates to whatever the left ventricular output is. With a failing right ventricle, the preload for the left ventricle will plummet and the left ventricle function will dramatically decrease. Second aspect of ventricular interdependence, however, has to do with conduction. So, dyssynchrony can occur in the setting of one of the ventricles failing that will result in the timing of ejection being dyssynchronous between the two ventricles. We'll discuss that more later on in the talk. But that ultimately leads to that first problem as well, where you will have decreased output from one ventricle resulting in decreased output from the next ventricle. Thirdly, in a closed pericardium state, when the RV starts to fail, pressure will increase within that right ventricle and it will push the septum over into the left ventricle and then affect preloading of the left ventricle, thus resulting in failure of both ventricles. In talking about the concept of ventricular interdependence, here are a few examples of ventricular dyssynchrony in one ventricle that leads into dysfunction of the other. So a dilated RV that results in delayed RV emptying will delay LV preloading and ultimate LV output. When you have a non-homogenous regional contraction of the RV that can relate in what I just mentioned, delayed RV emptying. RV systole that is also extending into LV diastole will have the same effect. And then with delayed RV filling due to dyssynchrony, the RV will start to fill inappropriately and exacerbate the issue. And then, as mentioned before, with ventricular interdependence, here is a figure to show that third state that I mentioned, that as you have RV pressures increasing and enlarging of the cavity, flattening of the septum, it pushes into the LV and can worsen LV preload and ultimate LV output. That's borne out by some of the physiologic work that's been done. Let's discuss right ventricular function under increased pressure and really compare how the right ventricle tolerates increased pressure, pulmonary arterial hypertension, and how the left ventricle tolerates increases in pressure. So here, if you see on the left, you see how stroke work on the y-axis changes with atrial pressure with preload on the x-axis. Typical Starling curve response, you see that stroke work for both the left ventricle and the right ventricle increased. Certainly the left ventricle increases more here. On the right, we have mean vessel pressure or afterload on the x-axis and stroke work on the y-axis. Note that LV is able to tolerate increases in afterload up to a point and then stroke work really does decrease due to afterload, but it's able to maintain a relatively large amount of percent of control value within 90% of stroke work. The right ventricle, however, does not tolerate increases in afterload or pressure. Here from an increase of 15 to 20, it's tolerated reasonably, but really beyond that, there's a precipitous decline in right ventricular function. RV dysfunction can quickly deescalate into RV failure. This slide shows how RV dysfunction quickly escalates into other issues that propagate the problem. So when the RV is overloaded due to pressure, it increases RV wall tension and then subsequent oxygen demand. The RV is also very sensitive and has many aspects of the conduction system close. So when it dilates and contractility drops, arrhythmia is also quick to start. So you can very quickly get into a spiraling process that is self-propagating, resulting in worse contractility and then worse output, then LV drop in preload, decrease in cardiac output, hypotension, and shock. And this, as mentioned, can happen on the acute or on the chronic timeline. What you see in a chronic timeline is decreased in an individual's functional capacity. This can certainly be seen on the acute timeline as well, where you'll then also see increases in right atrial and central venous pressure, then in particular, congestion of the splanchnic organs and renal, hepatic, and intestinal dysfunction. What are some of the acute intrinsic cardiac causes of right ventricular dysfunction? Acute myocardial disease can cause this. Acute infarction, myocarditis, arrhythmias, valvulopathies. Acute extrinsic causes. Vasculopathy can really stress the right ventricle. Acute respiratory distress syndrome, sepsis, acute chest syndrome in the setting of sickle cell anemia, or vascular or extrinsic obstruction with acute PE, pericardial disease, and tamponade. Speaking a little bit more about pulmonary vascular resistance in ARDS, this is driven by known hypoxic pulmonary vasoconstriction that occurs in this state. But then also, it's been well documented that there's non-hypoxic pulmonary vasoconstriction due to the release of thromboxane, leukotrienes, endothelians, and there's also macro and micro thrombi that have been appreciated in the setting of ARDS that worsen right heart function and acute pulmonary hypertension. Acute on chronic RV failure can occur due to COPD exacerbation, acute on chronic embolic disease, or idiopathic pulmonary fibrosis with an inter-occurring infection. So let's go back to physiology. There's another concept that is important to understand called the ANREP effect. I showed you a couple slides ago how the right ventricle does struggle to respond to increases in afterload and has decreased stroke work. Both the left ventricle and the right ventricle demonstrate the ANREP effect, which is shown here by pressure volume loops. So here at baseline in loop A, you see here that the ejection fraction is around 68% and stroke work is about 1980. In loop B, when large increases in afterload occur, immediately you have a severe narrowing of the flow volume loop. The ejection fraction drops to 35% and the stroke work increases to 2110. What each ventricle does to respond to this is, over the course of seconds to minutes, you have an increase in heart rate, but also increase in calcium release within the myocardium. This, in healthy hearts, recruits a more vigorous contraction from the myocardium and within seconds to minutes takes you from loop B to loop A. Notice that the ejection fraction returns to normal around 67%, but the stroke work is 3108. This is the ANREP effect and really important because it demonstrates how much more work the heart is doing in this afterload state. Any underlying pathology that had led to an oxygen demand supply mismatch in either the right or left ventricle could be exacerbated by this increased stroke work state. The ANREP effect that we just spoke about is homeometric functional adaptation. There is another type of adaptation called the heterometric or dimensional adaptation and this is referred to as the Starling Law. Starling Law essentially, as you might recall, provides for increased and appropriate stretch of atom myosin such that the dimensional adaptation of those two fibers within the myocardium will result in increased contractility. This doesn't relate to increased anaphylode, but increased preload. The last important physiologic concept to discuss before we dive back into our patient and discuss diagnosis and management is RV ischemia and its role in pulmonary hypertension. This is different in chronic and acute. First, chronic. People that develop increased pulmonary arterial hypertension, they increase their PVR. That results in RV hypertrophy and dilation. An increase in RV wall tension, as I introduced earlier in that diagram, decreases perfusion to the right ventricle. This is a critical point at which the RV will thicken to try to compensate and remodel for this problem. But at this point, if pressures continue to increase over time, the right ventricle will ultimately start to experience ischemia. When ischemia occurs, output will decrease and then deterioration can be quite rapid, where increased RV overload occurs on top of that and then can result in heart failure and death and chronic RV dysfunction. People that have chronic RV dysfunction are really at risk for acute on chronic dysfunction. An acute on chronic increases in pulmonary arterial hypertension that can result in acute right heart failure. People that don't have chronic pulmonary arterial hypertension, also due to different acute events in the ICU, can be subject to increases in pulmonary arterial hypertension and experience acute right heart failure. So multiple different patient populations that are important to consider. But in both acute and chronic pulmonary hypertension, it's important to consider coronary perfusion pressure to the right heart, which is typically diastolic blood pressure minus CVP. Now, how this changes depending on these different states is that the right ventricle is used to perfusion in both diastole and systole. As you can see in this chronic patient who is developing increased pressures over time, the right ventricle may learn to equilibrate to only being perfused during diastole. Because if the pressures in the right ventricle exceed diastolic pressures, it's only going to be perfused during systole. Someone who experiences new and high acute levels of pulmonary hypertension may not tolerate that change of perfusion only during systole. This is a seminal study published in Circulation in 1981 that forms a lot of the basis for what we'll talk about later on in the critical care management of pulmonary hypertension. Essentially showed that if you band the pulmonary artery and increase pulmonary pressures, it will result, no question, in heart failure. But there is some protection that you can provide by giving phenylephrine. As seen here in the aortic pressure, this is a surrogate of cardiac output from this study in 1981. Even in this setting, when you increase RV pressure, you can recover output and you can recover RV function by increasing perfusion pressure. So back to our patient. We know that she has severe pulmonary hypertension due to idiopathic disease. We know that she has right ventricular dysfunction at baseline. What we are going to be considering throughout her care is does she just have her normal amount of ventricular dysfunction? Or is she exhibiting elements of right ventricular failure? Clinical findings are critical to diagnosing RV failure. Venous congestion is really important to recognize. Increased JVD or the hepatic jugular reflex. Peripheral edema worsening. Paradoxical pulse seen with breathing. Progressive tricuspid regurgitation. But ultimately, low cardiac output from RV failure can not only show hypertension and shock, but renal dysfunction, hepatic dysfunction, coagulation dysfunction. Biomarkers may be useful to see trends in them. Elevated proBNP for someone who on admission is higher than you'd expect. Elevated troponin. Lactate. Renal and hepatic function. There are novel factors that are currently being studied to try to directly assess the right ventricle. There are chest radiographic findings that you may see in chronic disease. Dilated interlobar arteries. A prominent PA and certainly the size of the heart. Dilated RV. The chest CTA may be revealing with a pulmonary artery greater than 29 millimeters. And typically, if you see that the pulmonary artery is greater than the aorta, it should make you concerned about increased pulmonary artery pressure and right heart dysfunction or failure. The echocardiogram is very useful to look at both function and structure of the right ventricle. First, size. So RV dilatation is assessed by the dimension at the level of the tricuspid amulus. Consider the basal measurement of the RV in a four-chamber apical view. Dynamic IVC assessment can be very useful to assess right ventricular function. And you would expect a plethoric or widely dilated IVC in the setting of RV failure, consistent with venous congestion. Ventricular interdependence is often recognized on echo. You see here the right ventricle, very large, flattened interventricular septum and small left ventricle. Tricuspid regurgitant velocity can also be very useful over time to follow pulmonary artery systolic pressures as well as right heart dysfunction. The tricuspid regurgitant velocity is typically taken and then used with the modified Bernoulli equation to assess the pressure gradient. Using assessments of the right atrial pressure combined with this number to estimate what pulmonary artery systolic pressure is via this equation. Tricuspid annular plane systolic excursion, or TAPSI, is a typical measurement of right ventricular function. With 1.6 being the low limit of normal and measured with M mode in the apical four-chamber view focused on the right heart. Right ventricular wall thickness is an important measurement. Greater than five millimeters measured in the subcostal view is considered consistent with RV hypertrophy and is reflective of remodeling over time due to pulmonary arterial hypertension. Pericardial fusions are also critically important to evaluate because they can exacerbate right ventricular dysfunction. So back to our patient. I showed you this video earlier. Echocardiography can be really useful to see how the right ventricle functions over time. So it's very important in someone you're worried about, as you learn this skill, to document what the exam looks like on arrival, if you have access to the exam prior to coming to the ICU, and then to see how things change over time, depending on the patient's status. So let's break for a question. So we talked about calculating the right ventricular systolic pressure, or the RVSP, of our patient. Here is her waveform. What is it? Now we'll transition into talking about the principles of management of pulmonary arterial hypertension and right ventricular dysfunction in this patient and others in the critical care unit. And I'll remind you of this hexagon of right heart function that I introduced to you earlier in the talk, focusing on these different strategies, optimizing preload, reducing RV afterload, treating the causes of RV failure, supporting RV contractility, and maintaining perfusion pressure. To avoid, but if necessary, utilize mechanical circulatory support. So first, how do we identify and manage underlying causes of RV failure? Critically thinking about myocardial ischemia and reducing challenges to oxygen supply and demand to the heart is critical. Protecting against pulmonary embolism, appropriate DVT prophylaxis, and thinking about pulmonary embolism early in these patients, considering CTA if necessary, and starting heparin when indicated. Arrhythmias, hypoxemia, generally managing them with supplemental oxygen when needed, avoiding intubation if possible, and avoiding hypercarbia. Mechanical ventilation bears a little bit more discussion on its impact on pulmonary arterial hypertension. And you see here at FRC, this is the lowest area of pulmonary vascular resistance. But unfortunately, with positive pressure ventilation, that increases pulmonary vascular resistance. If necessary, if needing to be mechanically ventilated, it can't be avoided. But it does have additional detriment to this patient population. We aim to avoid positive pressure ventilation if possible because it does, it uncouples the RV and the pulmonary circulation in that way and drives up pulmonary vascular resistance. But in these patients, I just also told you that hypoxia and hypercarbia are also dramatically bad to worsen pulmonary vascular resistance. So it's sometimes inevitable. So in those patients, you do have to mechanically ventilate. What are some strategies you might consider? You might consider limiting PEEP to avoid atelectasis and restore FRC. But you don't want to use no PEEP at all. You want to find the most optimal FRC. And that can be difficult to do. You want to avoid hyperinflation, as that'll exacerbate the increases in pulmonary vascular resistance from positive pressure. In severe ARDS, you just have to recognize that maybe these aren't attainable. You might have to see, because hypoxia, if you limit PEEP, might not be tolerated. And hypercarbia, which is necessary from limiting tidal volume for protective lung ventilation, is necessary. You might then consider extracorporeal support earlier for this population. Moving on, preload and volume optimization is critically important in these patients. You don't want to give too much volume and cause RV overload, RV volume overload. But you don't want to be under-resuscitated and not maximize the utility you can get from the Starling mechanism of adaptation and increased cardiac output. So this is often like threading a needle. And ECHO can help guide assessment of the RV size when fluid resuscitation is considered. And small fluid challenges are often a good way, when appropriate, to guide resuscitation and not larger amounts. When volume overload is suspected, this is one of the most operational aspects that we can treat and actually make a difference on these patients. So diuretics or earlier chemofiltration, earlier CVHD, may be useful in this population. We don't have a study that shows that yet. But tightly managing volume in this at-risk population may consider that. Next, RV contractility support. Inotropic therapy can be really critical. Some options are dibutamine or epinephrine. Dibutamine can unfortunately cause hypotension from peripheral vasoviolation. It can also be chronotropic and cause arrhythmia. Milrinone typically has less chronotropic effects, although it can have some. And it may also cause systemic hypotension. These may be tolerated with the addition of a vasopressor at the same time. Next, what about epinephrine? So epinephrine also can provide inotropic support. But perhaps the mainstay of our management is to maintain perfusion pressure. So let's move back to our patient. So our hemodynamic goals have been adequately met. And she's doing well. We've managed her volume appropriately. Now we're on post-op day two. Which of the following medication combinations are we most likely to restart today? So for those patients with severe pulmonary hypertension that fail single therapy, class 1 guidelines are to add Bosentin. So she's probably on that as well. You probably wouldn't start them together. But you'd consider starting them staggered. But you'd want to get her back on her own therapy. It was noted in the BREATHE-5 trial that a combination of PDE5 and endothelial antagonist in these patients improved systemic saturation and six-minute walk testing. In this same patient, what other considerations do you have when thinking about restarting her home PDE5 inhibitor and endothelial antagonist? Moving on to RV after-live reduction. So how do we do that? We can do that intravenously with epiprostanol prostanoids or sildenafil even. There's other intravenous delivery agents. If the patient is struggling and still needs critical care and we need something that is not going to last quite as long, we choose an inhaler that's not going to last quite as long. If the patient is not going to last quite as long, we choose an inhaled pulmonary vasodilator, like nitric oxide or epiprostanol. As we just discussed, we might be transitioning her back to her home medications and her oral PDE5 inhibitor or endothelial antagonist. A little bit more about sildenafil PDE5 inhibitor. It's approved for the use of pulmonary arterial hypertension, and it's additive to epiprostanol, for those on that. We don't have a great experience in critical care, even though we've had this drug for a while, as these patients are hard to standardize. There appear to be adverse effects with dyspepsia and dysphagia. And here are its pharmacokinetics. So if you were to start it and experience hypertension, you're committed to it to about three, four hours. Bosentin is approved for group 1 PAH, and also limited experience and critically ill. It has a risk of hepatotoxicity and birth defects, and its half-life is about five hours. So also something to consider if you have further concerns about a patient in ICU. Inhaled nitric oxide is usually dosed up to about 20 parts per million, and it causes direct vasodilation via the nitric oxide pathways in cyclic GMP. Inhaled epiprostanol stimulates adenocyclase to create cyclic AMP, and to result in pulmonary vasodilation. It reduces PA pressures without hypertension, but it can have antiplatelet effects. So how do nitric oxide and epiprostanol compare? We have a couple of observational studies that compare the two. Here is one that I report that essentially showed that they have fairly similar effects on decrease in pulmonary pressures, but overall really no change in clinical outcomes. It's important to think about how these may or may not be useful, both intravenous epiprostanol or inhaled agents in the setting of pulmonary embolism, which is a particular increase in pulmonary artery systolic pressure. And unfortunately, they really weren't able to reduce that major mechanical cause of increase in pulmonary pressure. So the last aspect of management of right heart function via that mental model I described was mechanical support. We'll talk about that in other lectures as well, but that might mean a temporary centromag or a temporary impella to allow this heart to recover, if we believe that's possible. ECMO, maybe for the same reason. Or mechanical support as a bridge to transplant. So in summary, acute pulmonary hypertension frequently accompanies critical illness and may complicate underlying chronic pulmonary hypertension. Pulmonary arterial hypertension can lead to and drive RV failure, hypotension, and shock. ECMO is really useful for the assessment and management of these patients. And it's essential to diagnose and treat these patients expeditiously to prevent decompensation and to manage multiple things at the same time. This hexagon of right heart function. Thank you so much for your time.
Video Summary
The video discusses the management of pulmonary hypertension in critical illness, focusing on right ventricular function. The speaker presents a mental model of six topics to address when managing pulmonary hypertension: preload optimization, reducing RV afterload, treating causes of RV failure, supporting RV contractility, maintaining perfusion pressure, and considering mechanical circulatory support if necessary. The speaker emphasizes the importance of ventricular interdependence and discusses the physiology of the right ventricle under increased pressure. They also cover the classification of pulmonary hypertension causes and the anatomy and mechanics of the right ventricle. The video emphasizes the need to identify and manage underlying causes of RV failure, optimize preload and volume, support RV contractility, and reduce RV afterload. The use of inotropic therapy, pulmonary vasodilators, and mechanical support is also discussed. The speaker concludes by highlighting the importance of early diagnosis and treatment to prevent decompensation in patients with pulmonary hypertension.
Keywords
pulmonary hypertension
critical illness
right ventricular function
preload optimization
RV afterload
RV failure
RV contractility
mechanical circulatory support
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