Good morning everyone, welcome to CHEST and Hawaii. My name is Saini Kumar, welcome to our session on Oncological Critical Care. I'm joined by Dr. Stephen Pistorius and Dr. Padma Sudhirakela. So I'm going to start with my presentation on pleuropericardial emergencies in the oncological patient. I work at Kilburn Clinic, Akron Journal, and Mercy Hospital. I have no disclosures. These are my objectives of the talk. Because it's majorly focused on emergencies, so the major part will be discussing about pericardial effusion and tamponade and malignant pleural effusion. So pericardial involvement and malignancy. Pericardial cancer is the second leading cause of death in the United States, and in this year it is expected to have around 1.9 million new cases, and each day around 1,670 people die from malignancy. Now malignant involvement of pericardium has been identified in 5 to 20% of patients with metastatic neoplasms, and malignancy is a common cause of large symptomatic pericardial effusion, and in some cases it's the initial presentation. The mean survival is actually very poor, you know, around four to six months from the diagnosis in patients, either they have newly onset diagnosed malignancy or they have previous diagnosis of cancer. And if you have a positive pericardial fluid cytology, it's an independent poor prognostic factor. So cardiac tamponade, it's basically a pericardial syndrome that is characterized by impairment of diastolic filling of the ventricle that causes reduction in the cardiac output. So when your pericardial effusion becomes so bigger in the size, it accumulates so rapidly that it causes some effect on the hemodynamic properties of the heart, and so it leads to, you know, reduction in the cardiac output, then, you know, when you categorize the cardiac tamponade. So 20% of cases of cardiac tamponade are of malignant etiology, and by far the lung cancer is the most important cause of this oncological emergencies that is followed by breast esophageal, melanoma, lymphoma, and leukemia. So it's going to take a lot of, you know, a lot of work to see, you know, like a lot of your detective skills to diagnose tamponade because patient may not be that much hemodynamically unstable, but if you have findings on echocardiogram that you can diagnose early cardiac tamponade. So just, you know, touch base on pathophysiology. So whenever you have a fusion around your heart, you know, it increases the pericardial pressure. That increase in pericardial pressure causes decrease in the transmural filling of the coronary vessels, and that leads to decrease in your right ventricle to left ventricular perfusion, and from that, you have decrease in the chamber filling and that leads to decrease in cardiac output. And this is the same mechanism, you know, when we read about ventricular interdependence. So whenever you have, like, as you know, when we inspire, we have, you know, there's an increase in the preload toward the right side of the heart, and there's a circumferential effusion around the heart, and your right side cannot accommodate that volume. So you're going to shift your septum towards the left side of the heart, and that's going to decrease your cardiac output. Now, in order to compensate, you know, our heart goes into this compensatory mode where you have, you know, like the heart rate goes up high, you have increased ejection fraction, you know, constriction, and if someone have a chronically tolerated effusion, you have activation of the endangered ends in the aldosterone system, and you have sodium and water retention. Now, if you have, if you don't compensate well, you go into decompensated cardiac temper mode, and then, you know, if you don't act immediately, you're going to go into electromechanical dissociation, pericardial leading to death. Now, as we know that, you know, with relation to pericardial strain and stress, there's a limit. If you fill up your pericardial space way too quickly, you're going to go into cardiac temper mode. But if you're slowly accumulating effusion, you know, it can troll it up without having to open up cardiac temper mode. Clinical presentation. So it's very interesting, you know, in 1935, actually, Dr. Beck, also belonging from Cleveland, Ohio, you know, he mentioned in this article in JAMA that, you know, William Osler was not able to categorize the symptoms of cardiac temper mode. Then he was thinking in the same way that we think about Cushing's stride. So he was trying to correlate, like, the patients who have these lesions around, on their autopsy around the, like, pericardium, they have this presentation that this, and now we know as a Beck's stride. Now, you know, Beck's stride comprising of elevated JVD, hypertension, muffled or diminished heart sounds. If you look at, you know, another article published in 2007 JAMA, their sensitivity is not that good, you know, and around, if someone have cardiac temper mode, 76% have elevated JVD, hypertension, only a quarter of patients, and diminished heart sounds, only a quarter of patients. The most common presenting symptom is dyspnea. And pulses paradoxes, you see on an 82% of patients. What about sensitivity of EKG and chest X-ray? You know, EKG, actually not too much sensitive, you know, around, sensitivity is around 40%, where you see, like, low voltage EKG. What about chest X-ray? Sensitivity of chest X-ray depends upon how much fluid you have in your pericardial cavity for you to see the enlarged cardiac cell heart. So if you have more than 300 of pericardial fluid, you can appreciate on the chest X-ray, but if you have a rapidly accumulating effusion with a volume of 100, 150, you may not be able to even see it on the chest X-ray. So we know echocardiography is a gold standard tool, and also to diagnose cardiac tamponade. So echocardiographic finding for tamponade, you know, for pericardial, first thing you should have a pericardial effusion, and then you can categorize the size of effusion by, you know, by calculating how much the diameter is. So if it's large, it should be more than two centimeter. If it's, you know, moderate, one to two centimeter. So if you look at, like, you know, this echocardiogram showing with a red dot, you know, this is indicative of a complex effusion because you can see the septation over there. And in the second video you see over here, you know, this is a malignant pericardial effusion because you can see the mass around the, on this peristal long axis around the RV cavity. So you know, sometimes just looking at the effusion just gives an idea that it is, you know, what it's going to be because if the presentation, if it looks more complex in nature, it's likely going to be exudative, and if you see something physically a mass or something, it's likely going to be a malignant in nature. The second finding that we see on the echocardiogram, this is one of the sensitive signs that we see is a systolic right atrial collapse. It's not very specific, but if your right atrium is more collapsed during the cardiac cycle, the specificity increases. As we see on this apical four chamber, you know, there's a collapse of the right atrium over here. And also look at this effusion. This is a very complex effusion, this anechoic with a septation presence around the LV cavity. Diastolic RV collapse, you know, this is also one of the most sensitive and somewhat specific signs that we see, you know, on this. Here you can see physically there's a collapse of the RV cavity. And another simple way to categorize, if you see there's a collapse or not, just to drop your M mode on the peristal long axis, and then you can see if there's a RV collapse. When your mitral valve opens, there is a, you know, the start of diastole, there's a bulge in the RV cavity over here, you can see, you know, that is indicative of RV diastole collapse. What about IVC plexor? It's one of the sensitive signs, but the specificity, you know, it's not very specific. It just adds up if someone have IVC plexor with a large pericardial effusion, it's likely going to be a tympanoid. Now this physiological finding of this paraphysic variation, the mitral inflow and the tricapsid flow, very, very sensitive and also have decent specificity on echocardiogram. So on the mitral inflow, when you drop your continuous wave Doppler, and you have more than 25% changes on inspiration, you have your drop in your E inflow, mitral inflow, that is kind of surrogate for pulses paradoxes. And on the tricapsid on expiration, if you have more than 40% variation, that is also indicative sensitive and specific for tympanoid. So you know, you have a patient who has these echocardiographic finding in their presentation and you know, with a tympanoid, and you want to get a drain, you know, there are different ways to get a drain, either by fluoroscopic, by echocardiographic, CT guided, or a surgical window. So depending upon the practice nowadays, you know, echocardiography is more safer, but if someone have a large mass with a complicated pericardium looking on the echocardiography, then the pericardial window is preferred. I'm just going to go through a few cases. You know, it's a 67-year-old gentleman, present history of allergic rhinitis, present with a sudden dyspnea. This was a chest X-ray. As you can see, the patient has a bilateral pulmonary effusion and enlarged cardiac cell heart. So the CT scan, you know, on the soft tissue window, you can see there's a large pericardial effusion, a decent right-sided pericardial effusion, and the lung window, you can see there's a lung mass on the left side. This was the, you know, only presentation was sudden dyspnea. Hemodynamic profile was not, that significant patient was hemodynamic stable, but this was echocardiogram. Now, you don't need to drop any M-mode, you don't need to. If you see there's clearly a bulge in the RV with this large pericardial effusion, you know, it needs to be drained. So this patient underwent pericardial synthesis, have a 900 mL of hemorrhagic pericardial fluid drain, and around two and a half liters in three days at a drain place that was taken out. Now, interestingly, the cytology showed it was positive for pulmonary adenocarcinoma, and the immunohistochemical analysis showed that there's a 60% PD-1 expression. So this kind of also guides you that you don't need to go through a bronchoscopic way to diagnose a cancer, because if you see this, and if someone have a malignancy with effusion, you get it drained, and if you have this expression, so you can start an immune checkpoint inhibitor on this patient, because this is likely the lung cancer causing the malignant pericardial effusion. It's a 20-year-old with a history of asthma, present with progressive dyspnea for seven days. This is a chest x-ray and EKG. So if you look at the chest x-ray, you know, patient has bilateral pulmonary effusion, enlarged cardiac, still hard. And if you closely look at the EKG, patient does have some degree of electrical alternates. If you look at the QRS, they kind of vary from beat to beat. So pre-pericardiocentesis, this was echocardiogram. You know, large, swinging heart. You don't need any of the hemodynamic profile. This is a cardiac tympanoid. You know, even though patient has a stable hemodynamic, this needs to be drained, right? So patient underwent pericardiocentesis, and after that, patient will have pulmonary edema and went into shock. This was echocardiogram post day three. Now here you can see the patient has actually acute RV failure. Now why would someone who had presented with pericardial tympanoid, and after that went into acute pulmonary edema and went into biventricular failure? So this patient was started on, you know, inotropic and diuretics, and then have some recovery of biventricular function. So, you know, one of the things that you see in the patient who have chronic malignant diffusion are someone who have a history of pulmonary hypertension. Because you may not be, you know, you may not see like dilated RV, but when you drain it, you see those hemodynamic manifestation. So these patients develop pericardial decompression syndrome. So once, you know, you see a lot of malignant diffusions being drained, and you know, they look okay, but the next day they go into pulmonary edema, respiratory distress gets intubated. So pericardial decompression syndrome, you know, there's no exact mechanism known, but there are three theories that has been hypothesized, you know, in this article published in American College of Cardiology. There's this hypothesis that there's a hemodynamic hypothesis where, you know, you have decreased in your cardiac output and go into acute pulmonary edema. Second hypothesis is a ischemic hypothesis that you're decreasing the RV to LV perfusion. And the third one is that you take the sympathetic drive away, and you develop like sympathetic overdrive hypothesis, and then you develop acute pulmonary edema cardiac output. The treatment is supportive, diuresis, inotropic support. Patients really improve after a few days, as you saw in the prior case. And so there's no, like, you know, as we know with the pulmonary diffusion, you know, there's a guidelines not supported by robust, like how much you drain. So from European Society of Cardiology, you know, they recommend removing at least one liter of fluid at a time, not for you to develop PDAs. And in the World Journal of Cardiology, they recommend to remove enough to relieve symptoms and leave the drain, but there's no solid data on it. This is another gentleman, 58-year-old, with history of metastatic renal cell carcinoma under an immunotherapy with epilumab and nivolumab, you know, standard of care for these days for renal cell carcinoma with a dual immune checkpoint inhibitor therapy. Actually present with syncope, and was noted to have elevated troponin and CK. This was the EKG. So, you know, patient has complete heart block, admitted to the ICU for management of, like, shock with complete heart block. This was the echocardiogram. So if you see, like, you know, patient has a dilated right ventricle, and on the second clip you see, like, patient has a reduce in the LV function. So with a presentation of complete heart block with a decrease in the biventricular function, this patient has ICI-induced myopericarditis. So ICI-induced pericarditis and myopericarditis. You know, those both entities are there, but when you, once you, you know, once you see a lot of patients, because these are days ICIs are approved for most of the lung cancer types and, you know, renal cell carcinoma and melanoma. So you will see these patients coming to your ICU or to the hospital with this presentation. The incidences are on one person, and the workup include, like, EKG, troponin, you know, CRP, and having an echocardiography done. There's a high mortality. If you don't treat it, don't recognize it, you know, patients are going to die. High-dose IV corticosteroids are first-line therapy, especially pulse dose, giving one gram for three days, followed by a taper over three to four weeks, you know, and there's no guiding therapy how you should taper it down, but recommendations are you should guide it by symptoms and looking at their, like, inflammatory markers. And in refractory cases, you can use IVIG and a microfin on it. This is another patient, 48-year-old, history of stage 4 thymoma with progression of disease. They see pembrolizumab. She present with the progressive dyspnea. She had a prior surgery done for her thymoma. That's why you see the surgical incision. So she had new onset right-sided fusion on the right side. This is an EKG, you know, patient had a right bundle branch block with a high-degree AV block. It's an echocardiogram, you know, patient has a decrease in the LV function. So she was admitted for bradycardia and cardiogenic shock, required a pacemaker placement because, you know, initially had a temporary pacemaker, but since, you know, it was there for like a few days, then the permanent pacemaker was placed. During the course in the ICU, she had low blood vision, dysphagia, and positive antibodies for myasthenia gravis. Received extensive treatment, steroids, last, you know, inflixerab is because she was not getting better. And given her progression of disease, care was transitioned to comfort care. Malignant pleural effusion. So malignant pleural effusion is seen in around 15% of all cancer patients, you know, with annual incidence is more than 150,000. Majority of malignant pleural effusion are caused by metastatic disease, like lung and breast cancer, according for like 50 to 65%. And actually, they have a better prognosis in ovarian cancer patients. And cytology, we know it's a very well-established in the initial, it's not like 60% sensitive, but again, it depends upon, you know, how you prepare your sample, who's the cytologist, who's reading the interpretation, and the median survival is three to 12 months. So I'm going to go through a few cases, since it's the end of the session on the management of pleural effusion, so I'm not going to go a little bit deeper into that. We're going to present a few cases of ICU-admitted malignant pleural effusion. 53-year-old with active smoker, present with shortness of breath and pleuritic chest pain for one month. This is a chest X-ray, you know, complete opacification of right hemithorax, CT scan, you know, with a shift of medial stem towards the left side. So post-thoracentasis, you know, patient had a tripped lung, and the biopsy came positive for lung adenocarcinoma. So lung cancer is a common cause of malignant pleural effusion, with incidence around like 30%, and non-small cell cancer is the most common histological type. So another case, 35-year-old, present with a progressive dyspnea and hypoxia, and this is a chest X-ray and a CT scan on presentation, whiteout on the left side, with some, you know, shift of medial stem on the right side, and some compressive eclectasis. And patient underwent thoracentasis, and actually the cytology showed the patient had diffused large B-cell lymphoma. So lymphoma, you know, both Hodgkin and non-Hodgkin can lead to malignant pleural effusion, and in some cases it can be the initial presentation, and you see all like 10% cases of malignant pleural effusion secondary to lymphoma. It's a 75-year-old present with a chest pain with no significant past medical history for five days. This is the chest X-ray on presentation, underwent thoracentasis, patient had a tripped lung, you know, after, you know, some are like in patients who have malignant effusion, they get drained, you know, there's a high probability of developing a tripped lung. The chest X-ray CT scan showing the pleural-based mass, and the biopsy came positive for renal cell carcinoma. So in all these three cases, you see like the patient have present with effusion, and they get drained, and, you know, their initial presentation of pleural effusion malignancy presenting as an initial symptom. So, you know, conclusion, pleural and pericardial involvement in malignancy is common in metastatic cancer. In some cases, the initial presentation, as you saw in the previous few cases. If the cytology is positive, it's an independently poor prognostic factor, and there's a high risk of pericardial decompression syndrome if you drain a chronic malignant effusion, and early recognition and management is important. Thank you so much for your time. I'm going to invite my next speaker, Dr. Stephen Pestoris. Dr. Pestoris is a critical care program director. He's one of the inspiration, you know, I got trained under him, his leadership. Dr. Stephen Pestoris. Good morning. It's so nice to be on the same panel with two of my former fellows, and I'm very proud of them. So I'm going to talk about toxicities associated with checkpoint inhibitors and CAR T cell therapy. These are my disclosures, and these are my learning objectives. It's going to be a rapid fire 15, 16-minute presentation, so stay tuned. What are checkpoint inhibitors? Checkpoint inhibitors are a type of immunotherapy that recognize and attack cancer cells. They bind to immune checkpoint proteins to overcome the tumor-mediated inhibition of T cell function. There are three primary targets of checkpoint inhibitors. You have CTLA-4, cytotoxic T lymphocyte associated protein 4, that's the first red box on the left of the figure, PD-1, or programmed cell death 1, and PD-L1, programmed cell death ligand 1, the two red bars on top. CTLA-4 targets the priming of naive T cells, and inhibition of CTLA-4 decreases IL-2 and T cell proliferation. PD-1 and PD-L1, on the other hand, act on effector T lymphocytes, and inhibition of PD-L1 and PD-1 also allow the inhibition of T cell function that normally the tumors are mediating. There are about a dozen checkpoint inhibitors that have now been FDA approved since 2011. The initial ones were approved for melanoma, but they're finding their way in the treatment of non-small cell lung cancer, as well as urothelial cancer, breast cancer, as well as renal cell carcinoma. Despite their efficacy and general safety and tolerance, they can be associated with a variety of toxicities that are better termed as immune-related adverse events, or IRAEs. The timing of these AEs tend to be anywhere between a week to 12 months, usually a peak of six weeks after initiation of checkpoint inhibitor therapy. Practically every organ system in the body can be affected by checkpoint inhibitor toxicity. CTLA-4 toxicities tend to be greater than that of PD-1 and PD-L1 inhibitors, and usually the toxicities are higher and fatality rates are higher when combined CTLA-4 and PD-1 inhibitors are used. The mechanisms underlying toxicities from checkpoint inhibitors are many. They include increasing T-cell activity against antigens in the organs that are affected, to increasing levels of preexisting autoantibodies, as such may occur within the thyroid gland, to increasing levels of inflammatory cytokines, such as in the gut, and that's why you can get very bad colitis from checkpoint inhibitor therapy, or a complement mediated, as you might see in normal tissue, such as the brain. Shown here are four management guidelines from the American Society of Clinical Oncology and some of the international guidelines. I list them all here for your more detailed reference listing. They all just came out in the last couple of years. Let's talk about a case to highlight some of the toxicities that we will see in these patients. This 70-year-old man, stage 4 lung cancer, gets an anti-PD-1 immunotherapy. Six months after starting this therapy, he develops increasing dyspnea, fatigue, headache, and is hypoxic with a saturation of only 90%. Shown on the top left panel is his CT scan showing ground glass opacities. This patient was admitted, and empiric antibiotics were initially started, thinking that he might have a concomitant infection. Bronchoscopy with BAL, possibly lung biopsy, was also entertained, but he was empirically started on 1 milligram per kilogram of IV metal prednisone because ICI pneumonitis was very high on the differential diagnosis. Fortunately for the patient, he improved rather quickly. After two days, IV metal pred was switched to prednisone, 1 mg per kilogram, 60 milligrams daily. And a week later, his symptoms were essentially resolved. His CT scan, shown in the middle panel, shows near-complete resolution of the interstitial opacities that he had a week earlier. He continues on prednisone with a slow taper for about four weeks. And as you can see from his CT scan, top right, shows almost complete resolution of all the radiographic abnormalities. At this point, his steroid taper is completed, and the oncologist was beginning to think of restarting him back on the same immunotherapy regimen. So pneumonitis from checkpoint inhibitor therapy is uncommon, but can potentially be severe or fatal. With an overall incidence of about 5%, it tends to be lower when an anti-PD-1 or anti-PD-1 antibody is used as compared to that that includes an anti-CTLA-4 antibody. It's more common in patients with pre-existing lung cancer. Dyspnea, cough, and new oxygen requirements are classic signs and symptoms. 2.8 months is the usual timing, so about three months from the start of checkpoint inhibitor therapy to when you might start developing potentially pneumonitis. But this is a diagnosis of exclusion. You still have to rule out the more common causes of respiratory distress and hypoxemia in these patients, from pulmonary embolism, pneumonia, including COVID-19, congestive heart failure, COPD exacerbation, as well as malignant infiltration. The radiographic abnormalities are diffuse. They can include ground glass infiltrates, as I showed on the case earlier, to cryptogenic organizing pneumonia-like features, and even features that might have nodular patterns to them. Management is done by grade. So grades 1 to 5. 5 is death. Of course, 1 is relatively asymptomatic. And generally, those patients are just withheld from their checkpoint inhibitor therapy and followed clinically and radiographically to see if there's any improvement. For those with at least grade 2, 3, and 4, corticosteroids need to be added, usually prednisone 1 mg per kilogram, or more commonly in admitted patients, methylprednisolone 1 to 2 milligrams per kilogram per day. Again, because it's hard to differentiate whether the patient has pneumonitis or pneumonia, empiric antibiotics are commonly used in addition to steroids. Bronchoscopy with BAL may be considered, particularly those with grade 2 or 3, just to rule out an infection. And for refractory patients that don't respond to steroids, then infliximab, an anti-CNF inhibitor, can be used, or cyclophosphamide mycophenolate. Infliximab, you have to be cautious if the patient has liver dysfunction. And in patients with grade 4 pneumonitis from the checkpoint inhibitor, usually the oncologist will permanently discontinue that checkpoint inhibitor therapy. Neurologic toxicities are also something that may occur in these patients. They can be late, up to four months, or even longer. They can be central or peripheral. So you can have stroke-like syndromes, aseptic meningitis pictures, posterior reversible encephalopathy syndrome, shown on the CD of brain images here, where you have on MRI hyperintensities in the subcortical and periventricular areas. Or you can have a variety of peripheral neuromyopathies, Guillain-Barre-like syndromes, for example. And this can occur particularly with PD-1 inhibitor therapy. So steroids, again, are the treatment for these neurologic toxicities. We did a retrospective study along with Cleveland Clinic and MD Anderson Cancer Center and published a case series of 17 patients that developed severe neurotoxicities from checkpoint inhibitor therapy. About eight had peripheral nervous system abnormalities, mostly in the form of neuromuscular disorders, as I mentioned. And nine had central nervous system abnormalities, including seizures with concomitant encephalopathy. Two-thirds of these patients required mechanical ventilation, 35% vasopressors, and 18% required renal replacement therapy. These were sick patients. About 30% of the patients died in the hospital, 18% made full recovery neurologically, 41% partial, and 12%, unfortunately, did not recover. Other toxicities include colitis. We might see some of these patients if they have severe volume depletion and require tremendous amount of volume replacement. Steroids and fliximab are used in refractory cases. You heard Dr. Kumar's presentation on myocarditis in patients with checkpoint inhibitors. This can present also with chest pain or acute circulatory collapse. And as you can see from myocardial biopsies, there is significant lymphocytic infiltrate on biopsy specimens on these patients. Endocrine abnormalities are also quite common, from thyroid dysfunction, adrenal failure, to pituitary failure, dermatitis in the skin, and interstitial nephritis, as well as thrombotic microangiopathy, are some of the renal toxicities that you can see in these patients. The treatment for all of these toxicities is corticosteroids, again, methylpred, one milligram per kilogram, with a slow taper, five to 10 milligrams per week, for four to six weeks. Let's move over to CAR T-cell therapy. What are CAR T-cell therapy? Well, these are considered living drugs. They're genetically engineered fusion proteins that are manufactured on T-cells to attack certain antigens on many of our hematologic malignancies that are refracted to treatment. Shown in this figure are the different steps in the collection of stem cells and the manufacturing of CAR T-cells in the lab, and then the infusion of these CAR T-cells to patients after lympho-depleting chemotherapy. There are now at least seven FDA-approved CAR T-cell products. Many of these products are used for advanced or refractory or relapse acute lymphocytic leukemia or lymphoma, as well as B-cell lymphomas, mantle cell lymphomas, and more recently, multiple myeloma. Despite their efficacy, and now we have five to 10 years of efficacy with CAR T-cell therapy in certain disorders, we know that they can be associated with a variety of toxicities, from infusion-related reactions to the more common ones that you might see in your ICUs, such as cytokine release syndrome and neurotoxicity, now called immune effector cell-associated neurotoxicity syndrome. HLH, or hemophagocytic lymphohisterocytosis, is another dreadful complication. These patients can have prolonged cytopenias, B-cell aplasia, and resulting low gamma globulins, and will require supplemental IBIG, most commonly indefinitely in these patients. Let's talk about a case, again, just to highlight some of this toxicity. This is a 55-year-old man with relapsed, diffused large B-cell lymphoma, who receives an infusion of Axi-cell, CAR T-cell therapy. On day two, he develops fevers. Antibiotics are started. Infectious disease workup is done, and while waiting on cultures. On day three, he develops a very high fever of 39.5, is tachycardic to the 130s, gets fluid boluses for hypotension. His oxygen requirement starts increasing. His mental status and neurologic exam at this time are normal. He's presumed to have grade 2 cytokine release syndrome, and tocilizumab, an anti-IL-6 inhibitor, is given with resolution of fever, tachycardia, and hypoxia. On day six, however, he starts developing stuttering of speech, bilateral tremor, inattention, and somnolence. His CRP at this point is low. Head scan is negative. EEG does not show any seizures. He's transferred to our ICU and started on dexamethasone, 10 milligrams IV. He progresses with neurotoxicity, with word-finding difficulty, nonverbal, not following commands, and he becomes arousable only to persistent tactile stimulation. Hyponatremia, sodium of 123, is detected in his labs. At this point, dexamethasone 20 milligrams IV is given, and he's started on a standing 10q6 of dexamethasone. On day seven, he becomes more awake, but with ongoing aphasia and myoclonus. Neuro-puncture is done with normal pressure, normal cell count, elevated protein, and infectious disease workup is negative. Hours later, his mental status continues to improve. Steroids are tapered rapidly over three days. He continues to have word-finding difficulty and confusion over the next three days, but by day 14, all his neurologic exam returns to baseline. So the clinical take-home points from this case are that tocilizumab, anti-IL-6 inhibitor, can rapidly reverse most cases of cytokine release syndrome. Neurotoxicity can occur after CRS has resolved. Toci does not resolve severe neurotoxicity, but corticosteroids are the mainstay of treatment for severe neurotoxicity. Let's talk briefly about cytokine release syndrome. This is the most common adverse effect from cartesial therapy, characterized by fever, hypoxia, hypotension, like you might see with somebody with systemic inflammatory response. It tends to be most common in those with high disease burden of malignancy, such as those with ALL and Don Hodgkin's lymphoma. Patients who receive high doses of CAR T-cells are also at risk, particularly if they get CD28 versus 4-1BB as the co-stimulatory domain of the CAR T-cells, and particularly of those that receive fludarabine-based lymphodepleting chemotherapy. Onset and duration is variable. Symptoms generally occur within two to three days after the CAR T-cells are infused, and they tend to resolve within a few days, but some patients can take up to two to three weeks before they get better. Severe CRS can occur in up to 10% to 30% of cases. The pathogenesis and pathophysiology of CRS is very interesting. It's associated with activation of macrophages, T lymphocytes, and the T-cells. There's capillary leak. Activated macrophages and cytokine release is common with interferon gamma, as well as IL-6 and TNF are released in these patients, which gives you all the manifestations that you see with high fever, tachycardia, and hypoxia. Every organ system, again, can be involved. Fever, hypotension, and hypoxia are classic features. Laboratory findings are not required for diagnosis. They can be variable. CBC might only show neutropenia or low platelets. Inflammatory proteins, as well as cytokines, are elevated. Usually CRP, ferritin are high. IL-6, interferon gamma are elevated. Tumor lysis syndrome derangements can also be found. Hyperkalemia, hyperuricemia, hyperphosphatemia, and hypocalcemia can be associated as well. The grading has been standardized by the American Society of Transplantation and Cellular Therapeutics from grades one to four. Fever is universal across grades. The differentiating features are the presence of hypotension and hypoxia. We tend to see the patients that are at least grade two, three, or four. These patients tend to have hypotension that either is resolved with fluid but require maybe one presser, or if it's grade four, they require multiple vasopressors. On the other hand, patients that are hypoxic may require supplemental oxygen of, let's say, high-flow nasal cannula oxygen, less than six liters per minute. But if they're grade three, they require more, sometimes even Venturi masks or non-reusable masks. And patients with grade four can be very hypoxic, requiring non-invasive positive pressure ventilation or mechanical ventilation. Management, again, for grade one is usually supportive, hydration, resolution of fever with antipyretics, and close clinical and radiologic follow-up. Patients, however, that proceed to grade two will require IL-6 inhibitor, tocilizumab, given at least eight milligrams per kilogram in those that weigh over 30 kilos, not to exceed three doses in 24 hours. For those with grade three and four, you need to add steroids on top of tocilizumab. Panikinra has been shown more recently to be very, very useful in those with severe grade three or four CRS as well. ICANSS is the neurotoxicity syndrome that is seen with CAR T-cell therapy. This is linked to endothelial cell activation, impairment of blood-brain barrier integrity, resulting in white cells and cytokine infiltration into the cerebrospinal fluid. It typically occurs a few days after the CAR T-cell infusion, but can be up to 10 days. A prior severe episode of CRS is usually the major risk factor for neurotoxicity to develop. Other risk factors are if the patient is preexisting neurologic disease, a younger patient, higher disease burden, those that have significant doses of lymphodepleting regimen and prolonged cytopenia, and those that get CD28, co-stimulated CARs like Axacel or Braxacel, more than those that get 4-1BB, Tisacel, or Lysacel. The clinical symptoms can range just as in our case with word-finding difficulties, stuttering speech, tremors, seizures, but can proceed to somnolence and coma in severe cases. IL-6, IL-2, IL-15, interferon gamma, and TNF alpha are elevated if you're doing cytokine panel, and if you're getting CRP and ferritin, those levels are also elevated. The grading, just like for CRS, has been standardized by the ASCT, again, grade one to four. The ICE scores, the encephalopathy score, these are points given to the neurological exam, but the differentiating features, again, are the level of consciousness, the presence or absence of seizure, cerebral edema, and whether there's motor weakness or not. So again, we tend to see patients at at least grade two, three, or four. Grade three patients are those that can only awaken to tactile stimulation, and grade four are those that are essentially stuporous or comatose. Grade three patients may have partial seizures, grade four will have status. Cerebral or local edema will be present on brain imaging for grade three, and diffuse cerebral edema and signs of herniation that can be fatal can be seen in grade four patients. They can also have severe motor deficits. This is the ICE score. It's a series of different types of examination neurologically, from orientation, naming objects, following commands, writing, and attention span, and this gives you an idea, depending on the points, as to what the ICE score will be. Management, again, for lower grades is usually supportive, with hydration, with aspiration precautions. We do EEG, brain imaging studies, through that cerebral edema, and we give usually high-dose thiamine for neuroprotection. For those that have grade two, you need to give steroids. Again, this could be 10q6, 20q6, or methylprednisolone, one mg per kilogram, but for those with grade three or four, you have to step up to higher doses of dexamethasone, or even pulse-dosed steroids, like one gram for three days. Anakinra, again, it's very useful for refractory cases. Patients require intubation, mechanical ventilation, seizure treatment, and for those with cerebral edema, you need to give not only high-dose steroids, but measures to lower the ICP, such as hyperventilation, hypersmaller therapy with mannitol, or hypertonic saline. We did a retrospective cohort study at 11 centers, as part of our CAR-ICU initiative, published in 2021 in Critical Care Medicine. We looked at 105 patients who were treated with Axacel over the course of two years. About two-thirds of them had grade three to four toxicities. Vasopressors were required in 18%, mechanical ventilation in about 11%, and dialysis in about 3%. Eye score was less than 3 in 30% of these patients. Mortality was relatively low, at 8.6%. These were cases that were managed in oncologic centers that see these patients regularly and know how to manage these patients. What was interesting is that toxicity grade, or the level of organ support, had no impact on overall survival. However, the patients that get higher cumulative doses of steroids tended to have a decreased overall and progressive free survival. This study has been somewhat replicated by our French colleagues in France. Looking at the CAR-Test International Multi-Center Observational Cohort Study, they looked at 258 patients that got CAR-T cell, mostly Axacel, that required ICU admission. 90-day mortality was about 22%. They found three factors that were associated with 90-day mortality, and those were frailty, the presence of bacterial infection, and the need for lifesaving therapy within 24 hours of ICU admission. So in summary, just very briefly, life-threatening toxicities of checkpoint inhibitors can occur with varying frequency depending on the agent that's used and the underlying patient risk factors. Pulmonary, neurologic toxicities, cardiac toxicities can be common, and steroids remain the mainstay of treatment. CRS and ICANs, or neurotoxicity, are the most common complications that we see with patients getting CAR-T cell therapy. Treatment for those patients are usually tocilizumab, or siltoxamab, if you have siltoxamab available, as well as corticosteroids in grade three or four, CRS, as well as ICANs. I think most importantly, you need to have a very close relationship with your oncologist and CAR-T cell therapy folks, and your organ specialist, and have standardized protocols to best manage these patients. Thank you so much for your attention. Good morning, everybody. My topic of discussion today is going to be hemato-oncologic emergencies. I'm currently at the University of South Florida and have nothing to disclose. Using a couple of case-based scenarios, I will cover these lesson objectives. I will talk about malignant airway emergencies and malignant airway and vascular obstruction, discuss heme malignancy-associated emergencies like hyperleukocytosis, leukostasis, tumor lysis syndrome, and HLH, and also review some intracranial and spinal cord emergencies. While I won't have the opportunity to talk about all these emergencies, I will focus my attention on highlighting some of the key pathologies shown here and take you all through some case-based approaches of heme-onc emergencies in the ICU. We've heard both from Dr. Kumar and Dr. Pastores about pleuropericardial and immunotherapy-related toxicities in this population. Jumping straight into our first case, we have a 42-year-old man with a history of hypertension and hyperlipidemia and tobacco dependence with a history of cigarette use. He presents to the ED with new-onset cough, severe dyspnea on exertion, low-grade temperature, and he's also complaining of some weight loss over the last three months. Medical signs are as shown here, and on chest x-ray, we do find a widened mediastinum, and labs are significant for anemia, thrombocytopenia, and the rest of his labs are within normal limits. So what investigation would we like to perform next? How many in the audience would want to do number one? Hands up. Great. Fantastic. This is one of the representative cuts of the CAT scan images that we got for this patient. And as you can see, there is a malignant airway obstruction on hand. So malignant airway obstruction can be caused by either primary airway tumors or metastatic disease or direct tumor extension. Causes of primary airway tumors are squamous cell carcinomas, adenoid cystic carcinomas, and mucoepidermoid tumors. When we think about metastatic disease, common causes involve renal cell carcinoma, breast, colon, sarcomas, melanomas, and lymphomas. And lastly, direct extension from adjacent tumors can occur from lung cancer, esophageal cancer, thyroid, head, and neck, and mediastinal masses. These patients can also present in a multitude of ways. They can present with post-obstructive pneumonias or pneumonitis, lung collapse, or hemoptysis. When we think about massive hemoptysis, we define massive hemoptysis as expectorated blood anywhere from 200 to 1,000 cc over the course of 24 hours, and concomitant respiratory failure or insufficiency. Mortality with massive hemoptysis ranges from 13% to 18%, and it requires immediate intubation and bronchoscopic evaluation, or even IR evaluation for potential embolization. Differential diagnosis is varied from tumor-related causes, diffuse alveolar hemorrhage, and infectious causes such as tuberculosis or mysotomas, and iatrogenic causes as well. Cancer patients specifically are high risk for intubations in this category because of their tumor location, previous surgeries or previous radiotherapy, and coagulopathies. Our patients are also at very high risk of developing arrhythmias and bleeding from thrombocytopenia, antiplatelet agents such as Plavix and uremia, which all contribute to the high-risk nature of airway management and intubation in these patients. This is actually an example of a patient I encountered a couple of months ago, and given the location of the tumor, it was an all-hands-on-deck sort of approach to begin with. I had to get our anesthesia colleagues, head and neck colleagues, and interventional pulmonology colleagues on board very quickly to try and plan how this intubation was going to go. And I don't think it's wrong in this sense to get a rigid bronchoscopy to be very helpful in this unstable airway situation early on. And then sometimes patients are best served by primary tracheostomy at the onset. And if we are going to employ fiber-optic awake intubation, then having as many of our airway adjuncts at the bedside is important to begin with. Moving on, there are a lot of strategies we can administer at bedside prior to our interventional colleagues arriving to help us out with massive hemoptysis. One of these maneuvers is to place the patient in lateral decubitus position with the bleeding lung side down, and then followed by definitive airway management using a large ET tube to intubate and facilitate intervention and isolation of the non-bleeding lung when possible. When we do do our initial bronchoscopic evaluation, we can confirm the site of bleeding. We can use cold saline, epinephrine, and there's some emerging evidence to even use tranexamic acid in these group of patients so that when our IP specialists do arrive at bedside, they're able to help us out with hemostatic agents and endobronchial blockers and stents and other gadgets that they have at their disposal. I think it's also important to keep in mind that we can use our interventional radiology colleagues to call upon them to help us out with bronchial artery embolization as an intervention to manage massive hemoptysis with recognizing that anterior spinal artery embolization is a very rare and devastating complication of this procedure. So coming back to our patient, we're going back into the exam room to tell him the very devastating CAT scan results. But on our very astute physical exam, we find this on his exam. So I'm sure as everyone here rightly knows, this is likely SVC syndrome. And this patient actually progresses quite quickly requiring intubation and mechanical ventilation. So SVC syndrome really occurs due to extrinsic compression of the SVC or due to acute tumor thrombus in the SVC. And that leads to very high venous pressures, which then the body compensates by collateral vein dilatation to achieve blood return back to the heart. And that makes the neck area very high risk for bleeding. So SVC syndrome can be caused by both malignant and non-malignant causes. 90% of malignant causes are due to lung cancer, 50% of them are contributed by non-small cell lung cancer, and then 25% by small cell lung cancer, and a fraction of them by lymphoma. Among the non-malignant causes, implantable IV devices such as tunneled CVC catheters, and pacemaker leads have increased the prevalence of thrombosis-related SVC syndrome. Patients with this syndrome have physical exam findings which involve flacial plethora, neck and superficial vein dilatation, upper extremity edema, dyspnea, and orthopnea. And to diagnose these patients, we'll have to perform a CT with contrast, MRI, or venography. If SVC syndrome was left untreated, that would continue to increase venous congestion in the neck area, and that could lead to further airway compromise and cerebral edema. Some of the bedside strategies for management could include head of bed elevation, removal of CVC catheters if they have any, but really the cornerstone of management happens to be achieving and establishing patency of flow back to the SVC, and that can be achieved by either intravascular stents, radiotherapy, or chemotherapy. Routine anticoagulation is not suggested to improve outcomes, and the use of steroids is very controversial in this group of patients. I do want to point out that this, again, is a patient I took care of about four months ago. She's a very young 32-year-old with breast cancer who presented to our unit with SVC syndrome. She needed a stent-on-stent procedure, so she needed multiple IR procedures to reestablish patency of flow to her SVC. And then she got six doses of radiation and a dose of chemotherapy, after which her facial plethora and facial swelling got better. We got a tracheostomy in her and then were able to transition her care to a long-term care facility. I think it's important to also recognize that median survival once SVC syndrome is diagnosed is anywhere from six months to two years. So coming back to our case, our patient does well, miraculously, and has come off the ventilator. We extubate the patient, and 24 hours later, the patient actually starts to complain about bilateral lower extremity weakness, sensory deficits below the umbilicus, and new mental status changes with word-finding difficulties. We send the patient down for ACT head and neck, with and without contrast. We also get MRIs of the cervical, thoracic, and lumbosacral spine. And as you can see in these figures, we have a case of malignant spinal cord compression. So malignant spinal cord compression is really a surgical emergency, and we as intensivists really need to take it very seriously when we find it. Breast, prostate, and lung cancer are the big contributors to most of the instances of malignant spinal cord compression, while non-Hodgkin's lymphoma, renal cell, and multiple myeloma follow closely next. These patients can present with a very insidious onset of neck and back pain. 50% of them may also have bowel and bladder dysfunction. And on gadolinium-enhanced MRIs, most of these patients will also have thoracic, lumbosacral, multi-level involvement of the spine. The management really is threefold. Glucocorticoids early on to try and reduce cord edema. Neurosurgical consultation to establish spinal decompression and stabilization. And then external beam radiation therapy to achieve effective pain relief for these patients. I think as intensivists, again, at Bedside, we can use what we call the spine instability neoplastic score. It's available very readily on our phones, on MDCalc. And this is actually a figure of what the score looks like. This was something the Spine Oncology Study Group had brought to us about 10 years ago. And a score which is greater than or equal to seven constitutes a potentially unstable spine, while a score of greater than 12 definitely constitutes a very unstable spine. And so getting neurosurgical and our spine surgery colleagues involved early is paramount for these patients. This is actually from a really nice review article in Lancet Oncology back in 2005 that shows a plasma cytoma involving both the anterior and spinal elements and also vertebral body collapse. And this patient underwent surgery and fixation and thereafter had surgical bed irradiation with really good ambulatory effects and no neurological deficits after. So that brings me to the conclusion of my first case. Our patient ends up doing well. He gets steroids. He sees his hemong specialist outpatient and he's on his merry way. So coming to case two, this is a 32-year-old with a history of major depression and he's coming in with a new right lump noticed near his neck. He's also complaining of easy bruising over his legs, weight loss of 20 pounds over the last two months, and night sweats. And really his labs are significant for a white count of 240,000, a hemoglobin of 6.8, a platelet count of 68, and we have some metabolic acidosis on the blood gas. So what is this and, you know, how many of you would say all of the above? Yeah, so I would say all of the above. This could be any of these. And thinking about what happens to this patient very quickly, this is a portable chest x-ray after the intubation that we had to perform for this patient and when definitely we have a hematologic emergency on our hand. And this is hyperleukocytosis and leukostasis. Hyperleukocytosis is really when you have a WBC count greater than 100,000 in the setting of leukemia, and leukostasis really happens when you have signs and symptoms of decreased tissue perfusion. There is aggregation of blasts in the microvasculature causing tissue hypoxia, thrombosis, and potentially hemorrhage. These patients can present with altered sensorium, dyspnea, and pseudohypoxemia on the blood gas. The blood gas syringe itself has WBCs which are very hypermetabolic, and so the use of all the oxygen in the blood gas syringe falsely lowering the PaO2. So using the SpO2 at bedside is really what is recommended in these group of patients. And there are three approaches to using, three approaches to achieving cytoreductive therapy. One is induction chemo, which is favored unless a patient has renal insufficiency or severe electrolyte abnormalities. Leukophoresis is the second option. It's usually performed when you have in AML a WBC count greater than 50,000, and in ALL if your WBC count is greater than 250,000. But it's also very highly center dependent. There are centers that are very reluctant to do leukophoresis right off the bat. And it's important to understand that the data surrounding the outcomes comparing induction chemo and leukophoresis are pretty uniform. So a lot of centers will directly reach induction chemo before they do leukophoresis. And while we're waiting and debating the role of the above two strategies, it's very easy to start our patients on hydroxyurea in asymptomatic hyperleukocytosis. I think it's also very cognizant to hold transfusions in these group of patients because addition of any more red cells in the system can increase blood viscosity and stasis symptoms. So that's just something we want to be mindful of. Our case continues. So our patient gets a bone marrow biopsy, is presumptively diagnosed with AML, and he started on induction chemo. And six hours later, he develops hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia. And his ventilatory requirements have worsened as well. So this is tumor lysis. It is a rapid lysis of malignant cells, either spontaneously or after antidioplastic therapy, which releases toxic intracellular substances into the circulation. Risk factors include high tumor burden, high-dose chemotherapy, preexisting CKD or AKI, hypotension among a few. And then there are both clinical and laboratory criteria to diagnose TLS, but we really truly use the lab diagnosis, laboratory criteria, to diagnose this and treat this quickly. Management pearls really include maintaining aggressive IV hydration, maintaining high adequate urine flow with using loop diuretics if we need to, managing their electrolyte abnormalities aggressively, uric acid lowering treatments with allopurinol or Rasburicase, and also involving our nephrology colleagues early on if we find that the patients have refractory electrolyte abnormalities, despite our medical management. So as our case continues, our patient gets treated for TLS. He is given IV hydration, loop diuretics, Rasburicase is started. He ends up actually doing pretty well, and he gets discharged from the ICU back to the floor. He does good for about 14 days, and on day 14, a rapid response is called in the middle of the night. And when you get to the bedside, you find that there's a patient who is febrile. He's tachycardic. He's tachypneic. He's hypotensive. He's pale. He has dry mucous membranes. Capillary refill is prolonged. There's oozing from the site of the right IGA triple lumen catheter, and he's not making really good urine over the last six hours. So again, what is this? And I would hedge that it could be any of these, given all the insights we've heard from Dr. Pastores and Dr. Kumar so far today. But it could be HLH, which is, as Dr. Pastores mentioned earlier, it's a very challenging and obscure entity. There's uncontrolled T cell and macrophage activation. These patients can usually present with an undifferentiated clinical syndrome, which looks very similar to sepsis and septic shock. They can have cytopenias, hepatitis, AKI, neurological symptoms, coagulopathies, and DIC. HLH is broadly characterized between primary and secondary. And secondary HLH is life-threatening hyperinflammatory syndrome, which can be seen with malignancies, aggressive lymphomas, like NK cell lymphomas, hematopoietic stem cell transplant patients, autoimmune diseases, and a fraction of patients develop this even after CAR T cell therapy. So HLH portends a very high degree of mortality. These were the lab values for our patient after we sent some of the ferritin, triglyceride, fibrinogen, and soluble IL-2 levels for our patient. And as you can see, they're very high. In cancer-critically ill patients, it's very important that when we are trying to make the diagnosis of malignancy-associated HLH, we have to first establish if the patient has concomitant infection with other viruses like EBV, CMV, HIV, HHV-6 or 8, adenovirus, histoplasma, or COVID-19 even. So taking you all through the diagnostic criteria for HLH, this has been in the literature for the past two and a half, three decades. Our patient had fever. He had cytopenias. He had all the lab values that I showed previously. And so once we've established a diagnosis of HLH, I think there's a really nice algorithm by Dr. Henter's group a few years ago about recommendations of management of HLH. And I'd like to bring all your attention to the latter half, the right side of the algorithm, which talks about secondary HLH and malignancy-associated HLH, like this patient, where we would want to institute corticosteroids, plus-minus IBIG, and we also want to institute etoposide. But I think by the time we get to this part in the diagnosis and treatment, it's a very nuanced diagnosis and treatment involving all the specialists involved for the patient, like the BMT specialist, CAR-T specialist, heme and oncologist, and intensivist taking care of the patient is very important. There's also a lot of salvage therapies out there that are, you know, lots of research and evidence is coming out about these salvage therapies. One such salvage therapy is emapalumab. It's also called gamafant. It was approved by the FDA in 2018 to treat HLH in both adult and pediatric patients. And that's not something we used for this patient, but the patient received etoposide and corticosteroids for his HLH, and after a very prolonged ICU stay, he had a good outcome and left the ICU. That concludes my talk. I'd like to thank the CHEST organizing committee for giving me the opportunity to present this topic, and for those who are curious, that's a picture from my recent hiking trip to Iceland featuring an Arctic puffin. Thank you very much, everybody.

oncological critical care emergencies

pericardial effusion

tamponade

malignant pleural effusion

lung cancer

breast cancer

esophageal cancer

checkpoint inhibitors

CAR-T cell therapy

early recognition