My name is Atsia Golnik, and I'm a pediatric intensivist at St. Jude Children's Research Hospital, and I'll be talking about oncologic and hematologic emergencies. I have nothing to disclose. The objectives of this talk are to recognize and manage common oncologic and hematologic emergencies and know the life-threatening complications of initial treatment of pediatric malignancies. Here's an overview of what I'll cover today. I'm going to give a quick introduction to pediatric oncocritical care, talk about critical complications of pediatric cancer, and then of cancer-directed therapy, and briefly mention hematologic emergencies. Equally important are things that I will not be discussing but are important and will be covered in other lectures. This includes sepsis and respiratory failure in pediatric cancer, which are the most common causes of ICU admission in these patients. Other types of SERS syndromes that these patients encounter or that have a hematologic origin. I won't be discussing neuro-oncology management and neurocritical care because that is covered elsewhere, and also won't be discussing complications of hematopoietic cell therapy and transplantation because that is a much broader topic that requires more time. This lecture is important because children with cancer frequently need critical care. The data in the U.S. is that one in every three to four patients with cancer will require PICU care during the course of their cancer-directed therapy. In VPS data, this accounts for about 7% of PICU admissions in the United States. Why is this? Children with cancer have a number of risk factors for critical illness. They obviously have immunosuppression, but also immune dysregulation with a dysregulated response to sepsis. They have also disruption of the natural barriers preventing many infections, and that is because they have multiple invasive lines, but also because they develop mucositis and other barrier injuries. Then, of course, there are many complications of either the underlying malignancy or the therapeutics that we use, the chemotherapeutics that we use to treat them that predispose these patients to organ dysfunction and critical illness. What do we know about these patients' outcomes? Luckily, they, with modern medicine, actually do quite well. The average length of stay for children with cancer in the ICU is five to eight days. Their mortality varies depending on studies, so U.S. data is 6.8% among all covers. A big recent meta-analysis shows 35% in high-resource settings worldwide, so it's certainly variable. However, we do know that this mortality is about three times higher than other general pediatric ICU patients, and maybe is improving over time, although there is evidence that this is not. Improvements in outcomes for these patients in children have not occurred at the same rate that similar improvements have occurred in oncology adult patients who require critical care. What are some risk factors for mortality in these patients? ICU admissions that are acute, meaning non-postoperative, have a higher mortality if the patient has relapsed oncologic disease or an underlying hematologic malignancies compared to solid tumors, and that's particularly true for patients with AML. Having received a stem cell transplant is a risk factor, as are infections, particularly fungal and viral infections. Some laboratory data that are associated with mortality are a high lactate and then thombocytopenias and neutropenias. Certainly more organ failure is related to mortality, and any need for ICU interventions such as mechanical ventilation or a renal replacement therapy. So to start with, let's talk about some common complications of childhood cancer. So the most common that many of you will encounter is hyperleukocytosis, so that's defined as a peripheral leukocyte count of greater than 100,000. Clinically, though, typically it is more likely to be symptomatic in AML if it's over 200,000 and ALL if it's over 300,000. This occurs in about 10% of patients with ALL and a higher percentage of those that present with AML, and does increase their risk of mortality in these diseases, particularly in AML. Hyperleukocytosis can have a number of complications that include CNS hemorrhage or thrombosis, pulmonary leukostasis, tumor lysis syndrome, renal failure, and coagulopathies. So what is the pathophysiology? The mechanism of symptomatic hyperleukocytosis is leukostasis, which occurs because there's adhesion between the lymphoblasts and endothelium in small vessels. It's important that this is not only because the blood is hyperviscous, certainly because you have an increased cell count, there is increased viscosity, but there's actually direct interaction between the cells and the endothelium. And AML, myeloid cells, myeloid blasts, are larger than lymphoblasts and are stickier because of production of cytokines, and so they are more likely to cause symptomatic hyperleukocytosis. And so I mentioned that there's leukostasis and also there's coagulopathy. And this occurs because there's a high cell turnover. The blasts are being produced but are also dying, and that causes release of tissue factor from the cells and activation of factor VII causing coagulopathy. So what are symptoms associated with hyperleukocytosis? Many cases of hyperleukocytosis, even with very high white counts, can be completely asymptomatic. You could have children presenting with a white cell count of a million and still have no symptoms. However, when symptoms do occur, those could be CNS symptoms, showing mental status changes, headaches, vision changes, or seizures, pulmonary, signs of pulmonary leukostasis, which present as dyspnea, hypoxia or pulmonary hemorrhage, and then other signs of leukostasis such as priapism or dactylitis. So what is the management? Management is initial, obviously, diagnosis, but then IV hyperhydration, and that is at about two to four times maintenance. It's also important to manage uric acid, and so that can be done by allopurinol or, if available, Respiracase. And because these patients can be coagulopathic and bleeding complications are common as well as thrombosis, it's important to correct thrombocytopenia, particularly below 20,000, and correct any other coagulopathies that are present. However, although patients are frequently anemic when presenting with leukemia, it is important to try to avoid red blood cell transmissions because that actually increases their risk of having thrombotic or leukostasis complications because it will increase the viscosity of the blood. And although previously there's a lot of talk about leukophoresis, in practice this actually is rarely indicated unless there is severe symptomatic leukostasis. Pediatric studies in ALL and AML have actually shown no improvement in either the rate of induction complications or mortality when comparing patients with hyperleukocytosis treated with leukophoresis versus those treated with supportive care. And part of the reason for this is because while leukophoresis will be effective initially by dropping the white cell count, often there's a large rebound in that cell count unless chemotherapy is started. And that's because there's ongoing production of cells because of the malignancy. And so it's because leukophoresis actually involves a lot of invasive lines and sedation in a high-risk patient, there's often a delay. And it is very important that if leukophoresis is used, it is not delay starting actual chemotherapy, which will be the definitive treatment for the hyperleukocytosis. And then in rare cases, if needed, if a blood transfusion is needed, for example, it is possible to do chemodilution using an exchange transfusion. But again, those things are extremely rare, and most patients with hyperleukocytosis can be managed with just supportive care. I mentioned that one of the common complications of hyperleukocytosis is tumor lysis syndrome, which is cellular death and release of intracellular contents into the bloodstream, resulting in a number of symptoms. This occurs fairly commonly in children with cancer, most often in those presenting with acute leukemia. And it carries the classic triad of hyperuricemia, hyperkalemia, and hyperphosphatemia, with secondary hypocalcemia. Tumor types that are most likely to develop tumor lysis syndrome are those that have a high growth fraction, meaning reproduced frequently, have a wide distribution, meaning a wide tumor volume, lots of cells, or are very sensitive to therapy, meaning will be destroyed quickly with treatment. And so the cancers that typically present or can present with tumor lysis syndrome include lymphomas, Burkitt's lymphoma, acute leukemias, lymphoblastic lymphoma, and Hodgkin's lymphoma. And the highest risk is within the first 72 hours of initiating therapy, inclusive of the actual presentation. Some patients will actually present in tumor lysis syndrome from the turnover of their high tumor burden. So what's the pathophysiology? I mentioned there is cellular breakdown of the tumor cells that releases DNA, which feed into purine catabolism, creating uric acid, which can precipitate in the renal tubules, causing renal injury. The DNA itself also is broken into nucleotides, which creates phosphate, and that causes calcium and phosphate unbalance, resulting in potential deposits in the kidneys and resulting in renal injury. And then finally, the actual cellular breakdown produces potassium, causing hyperkalemia, which can result in arrhythmias and neuromuscular irritability, and again, obviously, leading to renal failure. And the presence of renal failure actually exacerbates all of those three electrolyte abnormalities, causing a cycle. So what is the treatment? Important to identify at-risk patients, meaning those that are potentially a risk for developing tumor lysis syndrome with treatment. And for these patients, they need to have cardiopulmonary monitoring and frequent monitoring of electrolytes, including uric acid, every four to six hours during that high-risk period. If tumor lysis syndrome develops or is a risk, we use hyperhydration, usually two times maintenance. It's important to not have potassium, phosphorus, or calcium in the IV fluids. And although previously used, alkalization is actually not necessary and may be detrimental because it will facilitate precipitation of calcium and phos in the renal tubules, which may further the renal injury. Equally important is to maintain diuresis by either just hyperhydration or, if not enough, potentially diuretics. We want to do that to maintain an even fluid balance and achieving a urine-specific gravity that's quite low, meaning you're flushing the kidneys. And like I mentioned, you could use, at times, Lasix or mannitol if low urine output is present and the patient is not hypovolemic. A few notes about alpurnol and rispericase in the treatment of tumor lysis syndrome. Here you could see the pathway of purine catabolism to uric acid, which is the dangerous substance that may build up in the kidneys and cause renal injury. Alpurnol is a xanthine oxidase inhibitor, and it blocks formation of uric acid. And so it is something that is used prophylactically and therapeutically. Rispericase, however, which is urate oxidase, is a recombinant uric oxidase, meaning it promotes the breakdown of uric acid into allantoin, which is a highly soluble molecule excreted in the urine and not dangerous to the kidneys. This is rapidly effective but is much more expensive than alpurnol and is typically, for that reason, used to treat higher uric acid levels or patients who have a rapid increase in their uric acid levels. Important, however, it is contraindicated in patients with G6PD deficiency, and so it's important to know that if you're planning on using this medicine. So managing electrolytes in tumor lysis syndrome. For hyperkalemia, obviously, you want to monitor for any arrhythmias, and then the typical treatments for hyperkalemia, which include, if needed, if arrhythmia is present, calcium, insulin and glucose, K-axylate, and albuterol. And for hyperphosphatemia, typically, this is just managed with phosphate blinders. It is important to not replace calcium, even though the patients are typically hypokalcemic, unless they are symptomatic, meaning they have arrhythmias, tetany, or seizures. And this is because increasing, giving calcium in a patient who is very hyperphosphatemic can increase crystallization and formation of stones in the kidneys, which can worsen the AKI or tubular injury that already exists. Dialysis is, at times, needed in patients with tumor lysis syndrome, and that is for typical indications of dialysis, namely, that the patient has AKI with oliguria or unmanaged fluid overload, which is the most common reason that we end up using dialysis in tumor lysis syndrome, or, of course, if the patient has uncontrolled severe hyperphosphatemia or hyperkalemia that is not responsive to medical management. The next complication I want to talk about is acute promyelocytic leukemia differentiation syndrome, or APL differentiation syndrome, previously called retinoic acid syndrome. So APL is a type of AML, myeloid leukemia. It presents commonly in DIC with a profound coagulopathy, often with severe hypofibrinogenemia. Importantly, however, APL is very responsive to treatment with ATRA, or all-trans-retinoic acid, which promotes differentiation of those tumor cells. And so APL differentiation syndrome occurs commonly in about a quarter to a fifth of patients during induction, and we think that this is associated with rapid maturation of the BLAST cells in response to the retinoic acid treatment and release of cytokines, resulting in a capillary leak syndrome and endothelial damage. So symptoms are an organ injury as a result of this endothelial damage, which causes respiratory distress, infiltrates and x-ray, fever, edema, effusions throughout the body with hypotension and potentially shock, as well as renal failure. So treatment for APL differentiation syndrome, if it occurs, is actually dexamethasone. And in extreme cases, there are times when one would need to hold chemotherapy, but we would only do that in life-threatening complications, because obviously we need to treat the underlying cancer to ultimately save the patient. The next topic I want to cover is masses. So first, mediastinal masses. This is just to remind you of the three anatomic compartments of the mediastinum. You probably remember from your other boards that when we think of anterior mediastinal masses, we think of the four Ts, which are teratomas, germ cell tumors, thymomas, thyroid tumors, or terrible lymphomas. So those are leukemias or lymphomas. In the middle of the mediastinum, most commonly presentation would be a lymphoma. And in the posterior mediastinal in children, this is almost always a tumor of neurogenic origin, such a neuroblastoma, and at times can be a sarcoma. Of course, there are non-oncologic causes of mediastinal masses, such as infections, but here I'm just focusing on the oncologic causes. So many diseases present with mediastinal masses, but it's important to differentiate the presence of a mediastinal mass with symptomatic mediastinal masses. So while non-Hodgkin's lymphoma, Hodgkin's disease, and neuroblastoma are the most common diagnoses that will present with mediastinal masses, those that are most likely to be symptomatic with SVC syndrome are germ cell and sarcomas. So what are some of the signs and symptoms of patients presenting with mediastinal masses? The symptoms arise from obstruction of various parts of the mediastinum. So if there is obstruction of the airway, you can have presentation with shortness of breath, respiratory distress, cough, stridor, hoarseness, or voice changes. If there's obstruction of the esophagus, you can get dysphagia. You can get orthopnea either if there's obstruction of the airway or the vascular structure. And then if there is significant vascular obstruction, you can get chest pain and syncope. These symptoms often worsen in the supine position when the masses, if it's an anterior mediastinal mass, and it's important to look for symptoms of SVC syndrome or obstruction of the superior vena cava, which present as edema or cyanosis of the upper body, the head, neck, and arms, distention of superficial vessels in the upper body, clots in the upper blood vessels, and in severe cases, cerebral edema, or if there's significant obstruction of vascular return, hemodynamic instability. So mediastinal masses come up a lot because there are important anesthetic and management considerations in these patients, namely that these patients are extremely high sedation or anesthetic risk. And at all situations, local anesthesia is preferred, if possible, in order to do any procedures or diagnostic process that are needed for these patients. So why are particular anterior mediastinal masses of high risk? Well, there's a high risk of respiratory failure. So there's a mass that is currently in a semi-homeostatic situation with your physiology. Any decrease in your respiratory tone or change from negative to positive pressure ventilation can cause a complete loss of the airway. And depending on the location of the mass, if it's more distal, it may actually not be reversible with intubation if the external compression is lower than the endotracheal tube. And the risk of this is obviously, as I mentioned, higher in anterior mediastinal masses. Also in masses that cause more than 50% decrease in the tracheal cross-section from imaging and in patients who have postural symptoms. So because of this, it is important to try to maintain spontaneous breathing whenever possible if a procedure is needed and sedation is needed, and to avoid paralytics. So potential anesthetic strategies in order to sedate patients with mediastinal masses who are considered high risk are to conduct in a weak intubation, to use reinforced endotracheal tubes if the mass is infringing on the trachea, or consider rigid bronchoscopy to bypass the mass. Also, in either emergencies or for procedures, it's possible to try a lateral decubitus or prone position if it's an anterior mediaspinal mass to keep it from collapsing onto your mediastinal structures. And then obviously, in a severe emergency, an emergent sternotomy with manual elevation of the mass may be effective. And ECMO backup is often used to have available when general anesthesia is needed for these patients that are considered very high risk, in case they do have a cardiopulmonary event with sedation. Also, beyond the risk of the mass obstructing the airway, there's also risk of vascular compression or vascular compromise in acute development of SVC syndrome. And the mechanism is similar if you have a loss of muscular tone and change from negative to positive pressure ventilation in sedation. This can cause the mass to compress vascular structures, preventing venous return and causing hemodynamic compromise. And structures that are particularly susceptible to this are thin-walled structures. So the SVC, the right atrium, and the pulmonary artery. And volume expansion may be helpful if there's a small degree of compression as the initial therapeutic maneuver to try to overcome this. And also important, because many patients who are presenting with masses will ultimately need access, it's important to consider whether there is compression or thrombosis of central ventrils when considering where to place central lines. And then also, if you're worried about vascular compression of a mass in an emergency, it's important to have lower extremity access. Because if you have an upper extremity line, even a peripheral line, and you have compression of upper of the SVC, you're not going to be able to deliver medications to that patient through that line. And so lower extremity access may be a way to mitigate an emergency situation in those patients. So what is the appropriate pathway for diagnostic evaluation when you have a patient presenting with a mediastinal mass? Because of course, it's important to understand what is the underlying etiology in order to start therapy. And so this is kind of a list that's made from least invasive to most invasive in terms of what you can consider. And I'll talk about some of these specifically. So first, obviously, a chest X-ray, some blood work, so a CVC or chemistry, looking for some tumor markers, such as beta-HCG or alpha-feta protein, seeing if you can make a diagnosis through these non-invasive means. Next would be more advanced imaging, usually a CT. And then if a diagnosis is not able to be made using these, think about procedures that might be able to be done with local anesthesia, such as a bone marrow, aspirin biopsy, sampling of pleural fluid. Or if we need tissue biopsy aiming for peripheral lymph nodes or things that can be accessed without sedation. And so just a few notes about some of these diagnostic evaluations. So advanced imaging, such as a CT scanner or MRI, the issue here is that some patients may not be able to tolerate imaging if they have a significant amount of orthopnea. So they may not be able to tolerate lying flat. CT in this sense may be easier because it is a quicker scan. And it is helpful to evaluate the degree of airway compression and vascular compression. And so it's important to remember that it is possible with patients with symptomatic masses that hemodynamic or respiratory decompensation may occur in the supine position even if they're stable in an upright position. And so it is helpful sometimes to try to lay the patient flat before you put them in the scanner because if they're going to get symptomatic, you don't want that to happen in a CT scan. And sometimes these things can be negotiated by putting a patient in a lateral or prone position if they're better able to tolerate that position for imaging. And I mentioned tissue diagnosis is kind of the ultimate, the last step that we consider because we will try to make the diagnosis through non-invasive means. But if tissue is needed in order to make the diagnosis, we want to consider peripheral tissue that can be obtained through local anesthetic and thinking from the least invasive to the most invasive options. Again, because we are worried that sedation may cause cardiovascular respiratory collapse in these patients. So treatment obviously depends on what the underlying diagnosis is. If it is a leukemia or lymphoma, many of these are very rapidly responsive to steroids. However, it's really important to have an oncologic diagnosis before starting steroids even if a leukemia or lymphoma is considered because this causes necrosis, steroids cause necrosis in those cancers and alters the pathology. And so it may actually, if steroids are started before there's a definitive pathologic diagnosis, that may prevent the patient from actually getting a correct diagnosis of the underlying pathology. And then of course, depending on the pathology, chemotherapy and or radiation to treat the underlying cancer. Another type of tumor compression that commonly occurs is spinal cord compression, which can happen in three to five percent of patients who have oncologic diagnoses. Most commonly, this is because of a metastatic relapse of a cancer from another location. However, it can present in new onset cancers, particularly neuroblastoma or soft tissue sarcoma that are near the spine. And it is also seen in lymphomas, leukemias, and germ cell tumors. So what is the mechanism? This is either invasion of the spinal canal from a mass that is based in the vertebral body, pressing on the spinal cord, or direct extension of repaired vertebral mass. Also, these can be seeded through hematogenous spread. And there's the injury from the direct compression of the mass to the spinal cord, but also that is complicated by edema and possibly infarction if there's a vascular compression or compromise. And beyond the compression of the spinal cord, if there's leptomeningeal disease, this can cause meningeal irritation with cranial nerve dysfunction and CSF pleocytosis. So what are some signs and symptoms of spinal cord compression? These present with back pain, weakness, numbness, or timbling. One example would be an electrical sensation spreading from the spine to the arms or legs following neck flexion. Also, classically, bowel or bladder dysfunction. And if there's compression of the cervical or high thoracic region, you can get autonomic dysreflexia with bradycardia and hypertension. All of these things, however, are very difficult to assess in infants and toddlers who can't report these symptoms. And so there, we need to be cognizant of loss of milestones or delays in milestones. So evaluation, obviously, a complete physical exam is important, including an assessment of anal tone. And deficits, if present, can be made more obvious by straining, coughing, or raising lower extremities, meaning putting more pressure on the spinal cord. And in terms of imaging, MRI is the best diagnostic modality. Plain films will frequently miss the diagnosis. So management, dexamethasone is used on recognition of the pathology. It's used as a bolus followed by a maintenance dose. However, as I mentioned earlier, we need to have caution in using this in leukemia or lymphoma if that is on the differential diagnosis and this patient is having spinal symptoms on presentation. Because, as I mentioned, giving steroids in those diagnoses can actually prevent an accurate diagnosis. And so it's important to either obtain pathologic diagnosis before steroids are started, or if it is an emergency, try to obtain them as quickly as possible after, if you're worried that this could be on the differential diagnosis. And then, of course, we want to proceed with definitive treatment, which could be surgical resection, chemotherapy, or radiation therapy, depending on what the underlying cancer that's causing the compression. So here's a first case. An eight-year-old male presents with a two-week history of intermittent fever, weight loss, and easy bruising. Exam is significant for pale mucous membranes, mild tachycardia, and multiple bruises on the body. Initial blood work has a CVC with a white count of 230,000 with a hemoglobin of 6.3 and a platelet count of 25,000. Which of the following is unlikely to be present on this patient's blood chemistry? A, an elevated creatinine, hyperkalemia, hyperphosphatemia, hypercalcemia, or hyperuricemia? So I'll give you a second to think about that. So the answer here is hypercalcemia. So this patient likely has leukemia, obviously with a quite high white count with hyperleukocytosis. I mentioned that some patients who present with hyperleukocytosis can actually present in tumor lysis syndrome, so this patient's at risk for that. And if a patient is presenting with tumor lysis syndrome, you're going to have that classic triad of hyperkalemia, hyperphosphatemia, and hyperuricemia with hypocalcemia. And if there has been longstanding tumor lysis syndrome, the patient may already have an AKI, so that elevated creatinine. So now moving on to complications of cancer-directed therapy. So first I want to briefly mention febrile neutropenia. Definitions here, neutropenia is an ANC of less than 500 or less than 1,000 and expected to be less than 548 hours because of having received therapy. And fever is typically defined as an oral temperature that's greater than 38.3 once or two temperatures separated by over an hour over 38. And so febrile neutropenia is importantly a medical emergency. Patients present with fever and neutropenia or suspected neutropenia, we need to both conduct a very thorough infectious workup and start empiric broad-spectrum antibiotics based on the patient's underlying risk, both prior infections and presentation. In terms of etiology, any infection can cause febrile neutropenia, but what we worry about particularly are gram-negatives because those can be very rapidly fatal. And particularly in patients who have prolonged fever, we are also thinking about viral etiologies and fungal. And there is an increased risk, particularly of fungal infections and severe outcomes, with longer durations and severity of neutropenia. So these patients will present in the classic sepsis physiology and their management is similar, which I won't discuss at depth, only to mention that patients who have been receiving corticosteroids as part of their cancer-directed therapy often will have secondary adrenal insufficiency. And so we typically use stress dose steroids in shock more earlier in these patients because of their risk of adrenal suppression. The next thing, infectious etiology, I want to mention briefly is typhlitis, previously called neutropenic enterocolitis. This presents with abdominal pain, fever, and neutropenia. Also, patients can have abdominal dissension, diarrhea, nausea, vomiting, or GI bleeding. And symptoms typically improve with count recovery. This is fairly common in patients with leukemia, more commonly in AML, and carries a fairly high mortality rate, which is usually due to sepsis. So what is the pathophysiology? These patients have a number of insults to their gut. They receive chemotherapy. They are immunosuppressed. They often have mucositis. They also then will develop impaired blood flow to their gut and bacterial overgrowth, which leads to bowel wall edema, mucosal ulceration, and necrosis. And this typically involves the cecum or the transverse colon, although any part of the bowel can be affected. So how is this diagnosed? Typically, it's the clinical syndrome. However, you can see on imaging either CT or abdominal ultrasound, bowel wall edema, and in obviously severe cases, either pneumatosis or if there's perforation free air. In terms of pathogens causing infection, bacteremia and sepsis are common complications of typhlitis. Organisms include pseudomonas, E. coli, clostridium, staph, strep, enterococcus, but can be fungal, such as candida or aspergillus. Management of typhlitis, so mostly it's supportive care with bowel rest and parenteral nutrition, abdominal decompression, and broad-spectrum antibiotics covering gram-negatives, anaerobes, and fungi. And if, depending on the patient's underlying cancer and the chemotherapy they received, potentially GCSF to facilitate clout recovery, which usually resolves the colitis. And importantly, surgery is very rarely required, only if there is bowel necrosis, obstruction, perforation, or an abscess that needs to be treated. So next I want to talk about toxicities of specific chemotherapies, and this is the chemo man. These are the common chemotherapies that should trigger specific organs. We'll point out a few here, and then I'm going to go into detail. But many of us remember D-doxorubicin causing cardiotoxicity, or B-fobliomycin causing pulmonary fibrosis. I will go into some of these other ones, such as cisplatin and vincristine. But we know that chemotherapies that we use to treat cancer also have a number of systemic complications, and these can affect the central peripheral nervous system, the heart, the lungs, the bladder, the kidneys, the pancreas, and many others. And so let me talk about these, thinking about them in terms of organ systems. So first about the CNS. Patients receiving chemotherapy often present with encephalopathy or new onset seizures. Etiologies for this, it could be because of electrolyte derangements. So patients are at risk for posterior reversible encephalopathy syndrome, or PRESS, or there can be direct toxicity, CNS toxicity of chemotherapy. The agents most responsible for this are methotrexate, ifosfamide, ARA-C, and cytarabine, which also results in acute cerebellar syndrome. Treatment for patients who present with encephalopathy of seizures is typically supportive, meaning appropriate seizure management and correcting any electrolyte abnormalities, and if possible, discontinuing the offending agent. In terms of cardiac toxicity of chemotherapeutics, so the thing we've known the most about is cardiomyopathy related to anthracyclines, and this is a cumulative dose-dependent effect, meaning the higher the dose, the more you're exposed to, the more risk of cardiomyopathy you have. And so we previously think about late onset cardiomyopathy, meaning congestive heart failures years after therapy. However, there's also acute heart failure that occurs during therapy, and anthracyclines can be, such as doxorubicin or donorubicin, can be responsible for that. However, cyclophosphamide, 5-FU, are also agents that have been known to cause acute heart failure, and this can manifest as either left ventricular failure, arrhythmias, but also potentially pulmonary hypertension and diastolic dysfunction, which are things we see more often also. In terms of pulmonary toxicity of chemotherapy, I mentioned that trigger word is bleomycin, which can cause interstitial pneumonitis and pulmonary fibrosis. Radiation therapy is also responsible for those things, and reactions can occur chronically after therapy, however, can also be acute during therapy. And if they don't occur during the initial therapy, we can see those complications either months or potentially even years after the patient has been on chemotherapy, and so that's why it's important to know the patient's history of prior exposure if they are a cancer survivor. A number of agents affect the kidneys or the bladder. So there's a number of reasons why a patient with cancer may have renal injury, but some agents are directly responsible, such as aphosphamide or cisplatin or carboplatin can cause direct renal injury, resulting in AKI. However, also many agents will disrupt the kidney's ability to function, and so particularly what we frequently see is SIADH, resulting in renal loss of sodium and hyponatremia. And so the most common agents that are responsible for this are vincristine, cyclophosphamide, aphosphamide, cisplatin, and carboplatin. And so this is a presentation that might result in a patient coming in with nuanced seizures, for example, be found to have be profoundly hyponatremic, and this being the underlying etiology. And then there's also a number of agents that cause hemorrhagic cystitis, such as cyclophosphamide or aphosphamide, and this is managed with prophylaxis by hyperhydrating the patient and treating them with mesmine. Beyond those organ-specific complications, actually, some chemotherapeutics actually result in a shock state. So one thing to know is capillary leak syndrome, which is caused by ceterabine or erice or clofarabine, and this is a profound serocitis that presents, including pleural or pericardial effusions, pulmonary edema, and then a distributive shock with acute cardiac failure and other organ dysfunction. We think that this is secondary to direct endothelial injury and dysregulation of the inflammatory response. Also, a number of agents can cause anaphylactic shock, anaphylaxis, and so ones that are most, obviously anything can cause anaphylaxis, but the ones that are most associated with this are etoposide, any of the antibody therapies, which are the ones that typically end with MAB, and asparaginase. So just to note about asparaginase because that's something that comes up a lot. Pegasperidinase is frequently used in a number of cancers, but particularly in leukemia, acute leukemia, and this carries a number of complications. I already mentioned anaphylaxis. Thrombosis is another one, as well as fulminant liver failure, and I think probably the most, what many of you have heard of or probably managed is pancreatitis associated with pegasperidinase. Treatment for this is identical to the classic treatment of pancreatitis from other etiologies, and it is important to know that this can result in a more complicated course, including hemorrhagic pancreatitis or chronic pancreatitis. So another question, a 10-year-old female with ALL undergoing chemotherapy presents with new onset seizures. Which of the following is the least likely etiology of seizures in this patient? And your options are A, SCNS leukemic relapse, B, infectious meningitis, C, methotrexate toxicity, and D, hyponatremia from citerabine. So I'll let you think about that for a second. So the answer here is C for citerabine. Hyponatremia certainly is a potential reason why a patient might present with seizures, but citerabine is not one of the agents that is usually responsible for the SA8H. Agents we see more commonly are vincreasine, which is used in ALL therapy, so that would have been a potential option. Cyclophosphamide, ephosphamide, cisplatin, carboplatin, for example. The other three options are certainly things that may happen in a patient with leukemia that would cause seizures. So finally, just a note on hematologic emergencies, and particularly I wanted to mention acute chest syndrome. This is defined as an acute onset of respiratory symptoms, which can be cough, hypoxia, or rails, with a new infiltrate on chest x-ray. Classically, this is a right upper lobe or right middle lobe, but it can be any infiltrate, and this occurs in a patient who has sickle cell disease. The etiology of acute chest syndrome is usually infectious, but that often is an atypical bacteria or a pulmonary fat embolism, but it occurs, the patients are predisposed to this because they have sickling within their chest that predisposes them to infection. Management for acute chest syndrome is antibiotics, which is usually an IV cephalosporin and enteral macrolide. Supplemental oxygen to maintain saturation is greater than 95% because sickle cells are more likely to sickle with lower oxygen concentration, so we want to maintain higher oxygen saturation to prevent sickling. And if a patient is more than a gram, their hemoglobin is more than a gram below their baseline, to give them a simple transfusion to achieve their baseline hemoglobin. However, if the patient has progressive respiratory symptoms that is not unresponsive to oxygen therapy, an urgent exchange transfusion to reduce their sickling fraction is used. And so here is another case. 15-year-old male with a history of hemoglobin SS and multiple recent hospital admissions for pain crises presents with fever and cough. Chest x-ray demonstrates right upper lobe and right middle lobe consolidation. In the emergency room, the patient becomes acutely hypoxic, requiring intubation as transferred to the PICU, which is the most appropriate therapy. Transfuse two units of PacRib blood cells, an exchange transfusion, plasmapheresis, or invasive mechanical ventilation with permissive hypoxia. Let you think about that. So the answer here is B, as this patient meets the definition of acute chest syndrome and is actually in respiratory failure requiring mechanical ventilation. That is typically an indication to do an exchange transfusion, not a simple transfusion. Freezes has no role here. And this is a situation where you would not want to use permissive hypoxia because you would want to maintain that saturation above 95% to reduce the sickling fraction. So in summary, hopefully I have shared that children with cancer and other blood disorders frequently require critical care. However, we are able to achieve good outcomes in these patients if they receive appropriate supportive and critical care. And so for this reason, it is important for all of us to understand the diagnosis and management of critical complications of both malignancy and cancer-directed therapy in children. Thank you.

pediatric intensivist

oncologic emergencies

hematologic emergencies

children with cancer

complications

hyperleukocytosis

tumor lysis syndrome

APL differentiation syndrome