The second topic is pediatric hematologic and oncologic emergencies, same disclosures. So I'm going to talk about how to recognize and manage common complications of cancer and other blood disorders and the complications of treatment for pediatric malignancies. So the way that I've organized this talk is to think about the complications of cancer itself. And those are the four topics I'll talk about, each one separately. Then talk about the complications of cancer-directed therapy. And then a note about hematologic emergencies. This is not an inclusive list, but I have 20 minutes, so I did my best. What I didn't include in this lecture, but is covered in other lectures in this course, are sepsis, which you already heard about, and respiratory failure and how to manage that in children with cancer, neuro-oncology management and neurocritical care, and then complications of cellular therapies. And that will be covered in a different talk. So the first part of this is complications of pediatric cancer, so patients presenting with cancer or having relapsed or refractory disease. So the first one I wanted to talk about was hyperleukocytosis. So the formal definition here is greater than 100,000 white cells, but is only really clinically significant or symptomatic at greater than 200 in AML and more than 300 in ALL. The reason for the lower white count becoming more symptomatic for AML is those cells are bigger and stickier. And this is pretty common in patients presenting with leukemia. So the complications you have to worry about or conversely think about if you see are hemorrhage, CNS hemorrhage, orthorhombosis, pulmonary leukocytosis, that presents kind of like ARDS, tumor lasis syndrome, which we'll talk about, renal failure, and coagulopathy. So the pathophysiology, and there's a picture there of leukostasis. So this is adhesive interactions between the lymphoblats and the endothelium, not just hyperviscosity. So we often think about the hyperviscosity of the cell because they have more cells in it, but it's also the interaction between the cells. So as I mentioned, myeloid blasts are bigger and stickier, and so they're more likely to have symptomatic leukocytosis. And this can happen in the setting of high blasts or high cell turnover. You also get release of tumor tissue factor and activation of factor VII, which gives you the coagulopathy. So this is both the risk of clotting because of the adhesion to the endothelium and the large cell count, as well as the risk of bleeding because of the coagulopathy. So management, I think this is hopefully bread and butter for you, but we hydrate those patients. Manage complications of tumor lysis, which I'll talk about in the next slides with allopurinol and raspberry case if that's available. Treating thrombocytopenia because of the risk of bleeding and coagulopathy, but typically not treating anemia unless it is symptomatic because of that risk of hyperviscosity. And really, the definitive therapy for hyperleukocytosis is cytoreduction, which is typically done either through steroids or starting chemotherapy. Although practices are different in different hospitals, as I've learned, leukophoresis is rarely indicated unless there's severe leukostasis and the patient is symptomatic or unresponsive to chemoreduction. So there's good studies in leukemias that show no improvement in outcomes in complications or in mortality comparing leukophoresis or early cancer directed therapy. And if you think of the mechanism of what leukophoresis is doing is you're removing the white cells, but you're not treating the underlying cause. So the patients will often rebound unless you're doing cancer directed therapy. And practically speaking, if you think about what has to happen for a patient to receive leukophoresis, if you're pursuing that route, you're often delaying cancer directed therapy. So that is probably the mechanism of why the outcomes don't improve. And one option that if you're trying to, if you need to give blood, but you are not able to leukoreduce quickly is an exchange transfusion to prevent the complications of transfusion. So start chemotherapy and hydrate the patient as the solution. So often concurrently, if you have a high white cell count, you have a high tumor burden. So often patients will present with tumor lysis syndrome or develop tumor lysis syndrome when you start treatment. So the mechanism of this is release of intercellular contents of cells die. And so the classic triad that you're going to see in the patient and in board's questions is hyperuricemia, hyperkalemia, and hyperphosphatemia with a secondary hypocalcemia. So this is pretty common, most common in leukemias or lymphomas, but can present in any patient with a high tumor burden where you have high cell turnover, either at presentation or in response to treatment. So this is often an early complication of cancer treatment. So management, monitoring patients who are at high risk. So practically, we're doing frequent labs. Classically, we're putting them on hyperhydration. You want to make sure the fluids don't have potassium or phos for obvious reasons, because those things are elevated, or calcium, because you can precipitate. And I think the old teaching in the past has been to alkalize these patients. However, that actually increases the risk of precipitating calcium phos in the renal tubules, which would worsen the renal injuries. So now the practice is not to alkalize, just to hydrate. And then we want to maintain diuresis, monitoring urine output, as well as giving them hyperhydration. So sometimes these patients do end up requiring diuretics, and then, of course, alanol and respiricase to manage the uric acid. So a note on electrolyte management, because I think these come up on board questions fairly regularly. So complications that arrive from tumor lysis syndrome, classically hyperkalemia, so you're going to treat that, like any patient with hyperkalemia, with the same treatment you would use. A note about calcium, so in a patient who has a high phos, if you give them and replace their calcium, if they're not symptomatic, you can precipitate calcium phos crystallization, which would worsen their renal injuries. So typically, you wouldn't give, obviously, if they're having symptomatic hyperkalemia, you treat that. But in non-symptomatic patients, you wouldn't treat that typically on its own. And then for hyperphos, phos binders, there's no other way to remove phosphate except with dialysis. So indications for dialysis and tumor lysis syndrome, these are typically what happens. The most common is AKI with oliguria and fluid overload. So you're hyperhydrating the patient, they've sustained a renal injury from tumor lysis syndrome, and they're not able to maintain urine output. So that's the most common reason we end up starting dialysis on these patients. And then, of course, uncontrolled hyperphosphatemia or with symptomatic hypocalcemia and then hyperkalemia. And classically, these patients will go on continuous renal replacement because, of course, the source of the problem is a continuous release of either calcium or phos rather than an acute insult. So if you drop their calcium, sorry, their phos or their potassium abruptly, they'll let you rebound if you're continuing therapy. So the next cancer complication is mediastinal masses. So I think this is, if you remember back to physiology, we think about the anterior four Ts, depending on where the mass is in the mediastinum. So anterior, in the middle mediastinum, or in the posterior mediastinum. And that impacts how symptomatic or potentially symptomatic the mass is, as well as what the underlying etiology is. So anterior, thinking more heme malignancies, although certainly it could be other solid tumor. In the middle, more lymphoma. And then in the posterior, it's almost always neurogenic or sarcoma. So what are the classic presentations of mediastinal masses? So thinking about obstruction of either your respiratory or your venous systems. So if it's respiratory, shortness of breath. Respiratory distress. Cough. Strider. Voice changes. That's a good tip off. Dysphagia and orthopnea. As well as, obviously, chest pain or syncope if it's severe. These symptoms are worse in the supine position. So a patient who is symptomatic laying down, but feels better when they're sitting up or unable to lay down comfortably. That's a big danger sign. And then they can present with SVC syndrome, which would be classically edema, cyanosis of the head, neck, or arms. Dissension of vessels in the face or neck. And then they can either present, the SVC syndrome can be from the mass, can be from thrombosis secondary to the mass. And so management, this comes up a lot on boards because these are patients that are a very high anesthetic risk. And so often the questions have to do with what would be the best way to get a diagnosis in these patients. And so the answer to those questions is whatever the least invasive way possible. Because these patients are really high risk in general anesthesia. And so the risk is twofold. The risk is, first, for respiratory failure. So any decrease in respiratory tone, for example, when you give paralytic or sedation, may cause a complete loss of airway from the mass obstructing physically the airway. And this is the highest risk is with the anterior mediastinal masses, especially in a supine patient, just you might think mechanics. And there's a trigger that the patient's at highest risk is if there's more than 50% decrease in cross-section on imaging, or if a patient has severe postural symptoms, meaning they're very symptomatic, laying flat. And importantly, reversing the paralytic may not fully restore the problem, so it's not always salvageable. And also, even intubating the patient may not reverse the mechanism because the mass obstruction may be distal to where your airway is. And so for that reason, and for both of these, the best sedation mechanism is no sedation or minimal sedation without paralytic. And so the same idea applies with venous compression from the mass. So thinking about the mass causing compression not only of respiratory structures, but also of vascular structures in the chest and upper body. And so same mechanism, the loss of the muscle tone and positive pressure ventilation can cause vascular compression and hemodynamic compromise. And if that happens in an acute setting, the treatment is vascular volume expansion and reversing, whatever it was that caused it, if possible. And that's something that in practical settings we often consider when you're placing lines, because if you have a mediastinal mass where you're sedating and you have an upper extremity line, if there's a high risk of vascular occlusion, you might not have access to that vascular access in an emergency. And so that would be an example for a patient who would benefit from lower extremity access to resuscitate them if needed. And so for diagnosis, as much as possible, trying to make a definitive diagnosis peripherally through peripheral blood, if it's a hematologic malignancy, or on imaging. A note in imaging is that some patients may not be able to tolerate laying flat for a CT or MRI. So a shorter, more definitive scan may be better in that setting. And then often the question is around tissue diagnosis and sedation around tissue diagnosis. Are you going to go from least to most invasive to try to get your diagnosis? And so treatment, of course, is definitive treatment for the underlying malignancy. And depending on what that is, it can be steroids, chemotherapy, and or radiation. And a note to remember that any of these patients, if you don't have a definitive diagnosis, steroids are tricky because it limits your ability to get a definitive diagnosis if you wait too long between starting the steroids and whenever you're getting your tissue sample. And so that obviously needs to be done with oncology together. And so the last bit is spinal cord compression from a solid tumor. Mostly in children, these are metastatic or relapsed disease. The common ones that we see are neuroblastoma or soft tissue sarcomas, but they can be other types of tumors and are presenting with neurologic symptoms. So pain, weakness, numbness or tingling. And in a toddler who's often not able to communicate those things, it's classically loss of milestones or going from walking to sitting or not being able to sit. And so management is steroids to relieve any immediate compression that is limb threatening or functional threatening. And it's classically bolus followed by maintenance. But again, that caution that if you're not sure what the diagnosis is, you have a very short time between giving steroids and obtaining tissue to make the diagnosis. Or that can impact the long-term prognosis of that patient. And then depending on the diagnosis, some combination of surgery, chemo, or radiation. So those are a summary of complications that cause critical illness from presentation of cancer. And then the second piece of the talk is looking at complications of cancer directed therapy, which I think is what we largely see within our ICUs. So Scott touched on this briefly as you think about the most common presentation of a child with cancer in our ICUs, probably sepsis. And what the functional diagnosis is often febrile neutropenia. And so that carries a very specific diagnosis of what is neutropenia and what is fever in that setting. This is obviously a medical emergency, even more so than a healthy child who's presenting with these symptoms. It's really important to start the infectious work up and start broad-spectrum antibiotics. So that does come up on tests. You want to start an empiric regimen that is, especially in a critically ill patient, that's broadly against gram negatives, including pseudomonas and gram positives that are causing that, not waiting for a definitive diagnosis. And then the rest is a classic management of sepsis, like what you've heard in earlier lectures. The one thing I will say, and this is, I think, less controversial in children with cancer have seen a lot of steroids. Often, corticosteroids are used in resuscitating these patients a lot sooner than they are in general pediatric patients who are presenting with sepsis because of the higher risk of adrenal insufficiency. The second complication that I think comes up pretty fairly regularly as a complication, again, of cancer treatment is typhlitis or neutropenic enterocolitis is the formal term. So that's presenting with fever, abdominal pain, and neutropenia. So it's febrile neutropenia with abdominal symptoms. Can also have abdominal distension, diarrhea, nausea, vomiting, can have GI bleeding as the presentation. And often, this improves with count recovery. So this is pretty common, particularly in leukemias, especially with leukemias that are getting a more intensive immunosuppressive regimen, like AML, or relapsed disease. And carries a relatively high mortality, depending on the setting, from sepsis. And so the pathophysiology is that the chemotherapy causes immunosuppression, but also damages the mucosa. There's impaired blood flow and bacterial overgrowth. And that causes bowel wall edema, and then the risk of translocation of bacteria into the bloodstream, which is the mechanism of sepsis and bacteremia in those patients. So diagnosis is a clinical syndrome. Often, it's diagnosed by ultrasound based on the intestinal thickness. And in severe cases, you could see pneumatosis or free air, but largely, we're not getting to that state. In terms of the bacteremia or the sepsis complications that happened, if that translocation occurs, is gut flora, but can be caused by fungus. And so management is largely supportive care, with bowel rest and TPN, abdominal decompression, if there's ileus, and antibiotics. And then, depending on the underlying cancer, potentially treatment to facilitate count recovery, which will then resolve the process. It's very unusual to require surgery for this, only in cases of necrosis, obstruction, perforation, or abscess. And then the last part of complications is direct complications of cancer therapies. And so I think probably everyone has seen The Chemo Man, which talks about different organ complications of different chemotherapies. The way that I've organized this, because this is another thing that can just, like, lists are really hard to teach in a talk, is I've organized these as organ system-based disorders that may happen as a result of specific cancer-directed treatment. Hopefully that will help kind of ground it in something practical. So first, thinking about CNS complications of cancer-directed therapy. So this presents as encephalopathy or seizures. So the most common is because of electrolyte derangements, secondary to the cancer treatment. Another syndrome that's seen often is PRESS, in the setting of hypertension or not, presenting with nuanced seizures. And then direct encephalopathy and CNS toxicity from certain chemotherapies, methotrexate being the most common. But then you see the list there. And treatment here is largely supportive care and correcting any of the electrolyte disorders that may be causing it, as well as discontinuing whatever we think is the mechanism. Moving to cardiac complications. So I think what we learn in medical school is the risk of cardiomyopathy from anthracyclines. And this is a cumulative dose-dependent effect and happens years after therapy. That's not usually what we're seeing in our ICUs in the acute therapy stage. But you do often see acute heart failure, acute cardiomyopathy during therapy, which can be from anthracyclines, but can be from a disordered response to critical illness in the setting of a heart that's seen rounds of other chemotherapies. And so you can see any kind of cardiac dysfunction, LV failure classically, but also diastolic dysfunction, pulmonary hypertension, and arrhythmias. Pulmonary toxicity. So again, I think the classic what we learn in medical school is the interstitial pneumonitis from gliomycin. But that happens remotely, past therapy. But there's a lot of acute complications of chemotherapy. I think the one that we see the most often that's a direct acute complication is from radiation therapy. But also, you may see more of an acute on chronic presentation of a patient who's developing respiratory failure on top of having a chronic history as a result of treatment. So renal. This can come in two flavors. One is acute renal injury directly from chemotherapy agents. And then the second is having SIADH acquired as a result of renal dysfunction from chemotherapy. And so those patients often present as a result of increased sodium losses in the kidney will present with hyponatremia, presenting classically with CNS changes, going back to that first slide. And those are agents that are associated with that. I talked about cardiac heart failure. But there's also, especially in the newer regiments, and I think this is stuff that you guys have seen within your ICU and training, a lot of the newer cancer therapies present with shock, with distributive shock, capillary leak syndrome, or anaphylaxis. And so ARC and clofarabine are two that classically present with capillary leak syndrome. So these patients will have serocitis, distributive shock, and acute heart failure and renal failure. This is secondary to endothelial injury and dysregulation of the inflammatory response is classically reversible. So if you can support the patient through that shock period, stop the offending agents, they will get better. And then a lot of the agents we're using in treatment can have an acute anaphylactic reaction, presents like anaphylaxis for many other sources, treated in the same way as well. And then just a note on asparaginase, because I think this one likes to frequent board exams, because it has a very specific side effect profile that presents with critical illness. So this is a classic of treatment for ALL. There are multiple potential complications that result in critical illness from asparaginase, anaphylaxis being one, thrombosis being another, and liver failure. But I think what we classically see is pancreatitis. So it would be a patient with ALL who's on therapy, who's presenting with acute pancreatitis, who has received asparaginase. And so the good thing is the treatment of that is actually the same as the treatment of pancreatitis in a different kind of patient. It's just recognizing that association, that that's what the mechanism is. And so then a note on hematologic emergencies. I don't have time to be exhaustive, but I did want to mention something that I think we see a lot and will come up on board exams, which is acute chest syndrome. So this is, of course, a respiratory complication of sickle cell disease. The definition is presentation of respiratory symptoms with a new infiltrate on chest x-ray. And it is infectious, classically, atypical bacteria, but can be a fat ablism or a direct result of sickling in the lungs. So this is managed with antibiotics, a broad spectrum for community-acquired pneumonia, plus or minus staph aureus directed, depending on the severity of illness, and then with oxygen to reverse the sickling process, and often simple transfusion to get the patient back to their baseline. However, in a patient who's critically ill, who's developing respiratory symptoms that are not responsive to that basic therapy, the next step would be an exchange transfusion. And I think that's the question that usually comes up. OK, so with that, I will stop. So in these slides, hopefully I showed that children with cancer and blood disorders frequently develop critical illness that require critical care. And it's important to understand the diagnosis and management of those disorders for good outcomes. That's it. Thank you.

pediatric emergencies

cancer complications

hematologic emergencies

chemotherapy toxicities

supportive care

oncology management