Pediatric emergency medicine trisk 682

CLINICAL PEARLS AND PITFALLS
Tumor lysis syndrome can occur in patients who have undergone CAR-T
cell therapy and is managed similarly to other oncology patients with this
complication.
Cytokine release syndrome (CRS) presents with fever and multi-system
organ failure and can mimic the presentation of septic shock.
Neurotoxicity related to CAR-T cell therapy includes nonspecific
neurologic symptoms but can progress to coma.

Current Evidence
CAR-T cell therapy uses a patient’s genetically modified T cells to express anticancer surface receptors. Once developed, the CAR-T cells are infused back into the
patient where they encounter target antigen, leading to rapid proliferation and
release of cytokines. Over the subsequent 28 days, these patients are at high risk for
cytokine-mediated toxicities, particularly after the first 2 weeks, and can present
acutely ill. Though this cellular therapy is not universally available, it is becoming
more accessible and the ED clinician should be aware of this potential complication
in patients who have undergone this therapy.

Clinical Considerations
Clinical Recognition
Patients with CRS may appear to be in septic shock. Fever, chills, myalgias are
typically the earliest symptoms, and when severe are followed by tachycardia,
hypotension and signs of capillary leak including localized edema, pleural or
pericardial effusions, altered mental status, and shock. Neurotoxicity may occur
concurrent with CRS and includes nonspecific symptoms including headache,
confusion, and tremor. Severe neurotoxicity symptoms include hallucinations,
seizures, and signs of cerebral edema. Patients can progress to coma.
Clinical Assessment
As with any critically ill oncology patient, the stabilization of airway, breathing, and
circulation is the highest priority. Institutions using CAR-T cell therapy will likely
have protocols in place for the initial response to patients who present after CAR-T

cell infusion, and initial assessment and management should be approached in
conjunction with oncologic consultation. Laboratory assessment of organ function
including a CBC, electrolytes and management of renal function, as well as
measurement of inflammatory markers including ferritin and CRP. Neuroimaging
and CSF examination may be required in patients with neurotoxicity.


Management
Patients who present with signs of CRS may be indistinguishable from patients with
sepsis and concurrent treatment for presumed sepsis including administration of
broad-spectrum antibiotics is important. For mild symptoms, supportive care may be
sufficient. For patients with severe symptoms, evidence of organ dysfunction, or
life-threatening illness, the addition of glucocorticoids and/or tocilizumab (an anti–
IL-6 monoclonal antibody) may be indicated, in consultation with an oncologist. All
of these patients should be admitted and many will require a critical care setting.

METABOLIC COMPLICATIONS OF CANCER TREATMENT
Complications affecting metabolic balance and the endocrinologic system are
common in children with cancer. These may be because of the neoplastic disease
itself, as has been addressed in the sections on newly diagnosed cancer, or due to
complications from cancer therapy.
TLS is probably the most noteworthy example of metabolic derangement in the
setting of cancer (see “Leukemia” section). TLS can be present at the time of
diagnosis or develop as chemotherapy is initiated and tumor cells begin to die in
response. Prevention of tumor lysis relies on protecting the function of the kidneys
while preventing severe metabolic derangements ( Table 98.3 ). Hyperhydration
should be initiated to achieve brisk, dilute urine output. In addition to IV hydration,
all patients should receive therapy with either allopurinol (10 mg/kg/day with
maximum dose 300 mg) or rasburicase. Allopurinol is a xanthine oxidase inhibitor
that impairs the production of uric acid. Rasburicase, a recombinant urate-oxidase

enzyme, causes direct lysis of uric acid and leads to a rapid drop in uric acid levels.
The usual starting dose is 0.2 mg/kg IV. Rasburicase is indicated in patients who are
at higher risk of TLS complications such as patients with compromised renal
function or an extremely elevated uric acid level, who have advanced Burkitt
lymphoma, who cannot tolerate hydration (e.g., CNS hemorrhage or pre-existing
cardiac dysfunction), or whose uric acid is rising despite allopurinol. Rasburicase is
contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD)
deficiency as it can result in oxidative stress and hemolysis. Use of alkalinized
intravenous fluids is becoming less common as its efficacy is uncertain. If using
rasburicase, hydration with alkalinization is unnecessary.
Of note, not all electrolyte abnormalities in the setting of TLS should be corrected
( Table 98.3 ). Hyperphosphatemia can be treated using aluminum hydroxide as
frequently as every 2 to 4 hours. Hypophosphatemia should not be corrected unless
it is in a critically low range (less than 1 mEq/L). Serum potassium levels must be
aggressively monitored. Hyperkalemia in the setting of TLS should be managed as it
would be in other disease states (see Chapter 100 Renal and Electrolyte Emergencies
) with Kayexalate, insulin and glucose, and dialysis, if needed. Hypokalemia should


not be corrected unless the patient’s serum potassium falls in a critically low range
(less than 2 mEq/L), significant muscular weakness develops, or if hypokalemia is
associated with EKG changes. Hypocalcemia should remain uncorrected as well,
unless clinical signs or symptoms develop. Supplemental calcium may increase the
risk of formation of calcium phosphate precipitates in the kidney.
Renal tubular dysfunction is common in oncology patients. Patients may waste
electrolytes such as sodium, potassium, calcium, magnesium, and phosphorus
through their kidneys as a result of specific treatment exposures or prior renal injury.
Antifungal agents such as amphotericin and ambisome cause potassium wasting,
which may have clinical significance. Calcineurin inhibitors, such as tacrolimus or
cyclosporine, which may be used after stem cell transplantation, can cause

significant magnesium wasting. Patients with hypomagnesemia are more likely to
experience seizures when on calcineurin inhibitors so the magnesium should be kept
more than 1.8 mEq/L in these patients. In addition, patients with tumors of the CNS
may renally waste sodium so monitoring of serum sodium is crucial, especially in
the postoperative period.
Patients receiving drugs that cause salt wasting are often prescribed oral
electrolyte replacement. However, inability to tolerate oral medications or
nonadherence may allow electrolyte abnormalities to develop. Most of these
derangements are clinically asymptomatic with the notable exceptions of
hypocalcemia, which can cause tetany or cardiac arrhythmias and hyponatremia
resulting in refractory seizures. For the most part, management and replacement
strategies for these electrolyte abnormalities do not differ from children who do not
have cancer (see Chapter 100 Renal and Electrolyte Emergencies ). However, when
replacing calcium in pediatric oncology patients, the clinician should remember that
hypomagnesemia, a common side effect of cancer therapies, could complicate
efforts to address hypocalcemia.
Elevated blood sugar can be a transient side effect of corticosteroids as well as
asparaginase therapy. Asparaginase affects the body’s ability to make many proteins,
including insulin. In ALL treatment, steroids and asparaginase may be used together
and hyperglycemia may result. Treatment need not include insulin if dietary
measures alone are sufficient to control the serum blood sugar. If blood glucose is
greater than 250 mg/dL or is significant enough to cause glycosuria or ketonuria,
treatment with small doses of insulin may be considered. However, the approach to
insulin use in this setting should be conservative so as to limit the risks of
hypoglycemia. Diabetic ketoacidosis is rare in this situation.
High serum calcium levels are observed commonly in the setting of adult
malignancy but are rare in children with cancer. Hypercalcemia is usually related to
the tumor destroying bone or to ectopic production of parathyroid hormone by the

tumor itself. This complication is more common if patients are also taking calcium
supplements or calcium-containing medications such as antacids. If asymptomatic,
hypercalcemia does not always require intervention. When present, symptoms may
include nausea/vomiting, constipation, altered mental status, and renal failure.
Management in these cases is similar to strategies to address hypercalcemia outside
of the oncology setting (see Chapters 89 Endocrine Emergencies and 100 Renal and
Electrolyte Emergencies ). However, steroids should be avoided in patients with
known or suspected leukemia or lymphoma. Control of the underlying malignancy
is the best way to address the hypercalcemia.
SIADH can develop as a result of some cancers themselves, particularly those
involving the lungs or CNS, or from treatment with vincristine and
cyclophosphamide. Management of this complication hinges on fluid restriction and
does not differ from that of SIADH developing in other settings (see Chapter 100
Renal and Electrolyte Emergencies ).

PAIN
Goals of Treatment
Pain is a true emergency. The relief of pain is a critical element of caring for
children with cancer, and should be addressed even in patients who present to the
ED for other concerns.
CLINICAL PEARLS AND PITFALLS
NSAIDs and aspirin are generally avoided due to their antiplatelet activity.
Cancer patients are frequently not opioid naïve and may require higher
starting doses than are standard.

Current Evidence
Unfortunately, pain is a common symptom in oncology patients with data showing
that more than 30% of pediatric cancer patients have experienced pain in the
previous week. When pain leads to visits to the ED, it requires careful and
immediate management. Severe pain is a true emergency in and of itself, and also

may be particularly upsetting for cancer patients who may have already confronted
significant pain as part of their cancer diagnosis, who may anticipate or fear future
pain, and who may worry (usually needlessly) that their pain is a sign of progressive
cancer.
In some cases, pain may be related to the tumor itself and therefore often will
respond to chemotherapy or other cancer-directed therapies. Tumors can cause