Pediatric Oncologic Emergencies

Table I.

Treatment	Onset	Duration
IV Bicarbonate	Immediate	10 minutes
IV Calcium	Immediate	10 minutes
Albuterol NMT	20 minutes	Duration of treatment
Insulin and glucose infusion	30 minutes	Duration of treatment
Furosamide	1-2 hours	6 hours
Kayexalate	12-24 hours	12-24 hours
Dialysis

C. Assess risk level of TLS (see below).

• Low Risk: low risk tumor, no lab evidence of TLS, no renal dysfunction:

  Treat with IV hydration with or without allopurinol at physician’s discretion.

• Intermediate risk: (intermediate risk tumor or low risk tumor with laboratory evidence of TLS, or low risk tumor with renal dysfunction at presentation):

  Treat with IV hydration and allopurinol.

• High risk of TLS: (high risk tumors, or low risk or intermediate risk tumors with laboratory evidence of TLS or renal dysfunction at presentation):

  Treat with IV hydration and rasburicase.

D. Renal failure

• Hydration as described above

• Close monitoring of urine output and BUN/creatinine

• Close monitoring of electrolytes

• Early consideration of nephrology consult and dialysis

Hyperleukocytosis

• Evaluate for TLS as above

• Assess for MM as below

• Assess respiratory status and CNS status

• Initiate IVF at 1.5 maintenance

• Hyperleukocytosis requires rapid reduction for the following cases.

  Lymphoid malignancy: WBC > 300,000

  Myeloid malignancy: WBC >200,000

  Chronic myelogenous leukemia (CML): WBC> 300,000

• If deemed a medical emergency, at risk for significant side effects, consider initial therapy as follows:

  <10 kg and – symptomatic, or at high risk of complications:

  Begin chemotherapy in consultation with pediatric oncology

  Consider CVL placement for steps c and d below

  Consultation with the local red cross or pheresis service to see if the patient is a candidate for leukopheresis

  If not, consider double exchange transfusion:

  Estimated volume of total exchange is 160 cc/kg.

  The hematocrit of PRBC (usually 60-70%) must be dropped to appropriate levels using NS or albumin.

  In general the hematocrit of the exchanged blood should not be higher than 30. If the patients hematocrit is <15, do not raise the hematocrit by more than 10% over the original Hct (ex: if the original Hct is 12%, final Hct after exchange transfusion should not be more than 22%). If the hematocrite is raised above 30%, the risk of vascular occlusion due to increased viscosity will increase, especially in AML.

  Two lines must be established, one to pull blood from, and one to put blood into. A double lumen CVL will work if blood is taken from the proximal opening and placed into the distal opening.

  Small amounts of the patient’s blood 3-5 cc (depending on the patient’s size) should be pulled from one line. Then small aliquots of PRBC (the same volume as taken), reconstituted to the appropriate hemoglobin should be infused in the other line. Aliquats should be placed and withdrawn every 3-5 minutes until 160 cc/kg is infused.

  Calcium supplements may be needed due to the anticoagulant (citrate) in the PRBC to help prevent coagulopathy.

  Large volume exchange transfusion can exacerbate DIC. Be prepared to transfuse fresh frozen plasma if needed.

  >10 kg and – symptomatic or at high risk for complications:

  Begin chemotherapy in consultation with pediatric oncology

  Consider CVL placement for steps c and d below

  Consultation with the local red cross or pheresis service to see if the patient is a candidate for leukopheresis

  If not available consider double volume exchange described above

• Continue pheresis daily until total white count is under 100,000; Exchange transfusions cannot be done daily without high risk of DIC.

• Continue chemotherapy until determined by pediatric oncology.

MM

• Evaluate for TLS as above.

• Maintain position of comfort for the patient and prevent the patient from becoming anxious or agitated.

• Consult hematology oncology for emergent management.

• Diagnostic procedures should be done without sedation, using local anesthesia if possible. If diagnosis can be made via blood sample, this is ideal (blasts for leukemia/lymphoma, VMA and HVA for neuroblastoma, serum alpha-fetoprotein and beta hCG for germ cell tumors).

• If the mass is an anterior mediastinal mass, and the patient is judged to be too unstable for diagnostic procedures, steroids should be initiated immediately at a dose of 40 mg/m2/day. TLS should be expected after steroid treatment.

• If the mass is a posterior mediastenal mass, there should not be airway compromise, although there can be spinal cord compression. If emergent treatment is needed, the use of a general sarcoma treatment regimen should be considered such as vincristine, actinomycin-D and cyclophosphamide, or vincristine, doxorubicin, or cyclophosphamide.

• In our institution, the following criteria are used to assess if a patient is safe for general anesthesia:

  CT scan (or other cross sectional imaging) with less than 50% tracheal narrowing due to compression.

  Peak expiratory flow of >50% expected. If either of these measurements is out of range the patient is at high risk of losing their airway during sedation.

• Assessment of the pulmonary artery may also prove important. There are many reports of sudden death in the OR due to possible pulmonary artery compression in patients with mediastinal masses. There are no clinical criteria to assess whether a patient is at risk.

SVCS

• Assessment of neurologic status and pulmonary status.

• Determine the mechanism of obstruction, whether intravascular (thrombosis) or extravascular (compression).

• For intravascular initiate anticoagulation with either a heparin drip or LMWH per institutional guidelines. Other therapies such as thrombolysis must be considered in each case according to severity of the patient and the institutional resources.

• For external compression, assess for MM and TLS as above. Emergent chemotherapy may be needed if the patient is having changes in mental status or evidence of venous infarcts in the CNS.

FN

• Rapid assessment with vital signs and physical exam to determine perfusion status. If patient is in compensated or decompensated shock, consider those algorithms listed elsewhere in the module.

• Immediate access of CVL with blood cultures and diagnostic blood tests needed by the assessing team.

• Immediate administration of an antipseudomonal IV antibiotic (3rd generation antipseudomonal cephalosporin, antipseudomonal synthetic penicillin, or a carbopenems).

• Risk assessment for other antibiotics:

  Low risk: Antipseudomonal IV antibiotic is sufficient

  Chemotherapy < 7 days ago; period of expected neutropenia < 14 days (therefore BMT and AML patients are never considered low risk)

  No mucositis, and no history of drugs that cause severe mucositis (ex high dose cytarabine)

  No abdominal or perirectal pain

  No evidence of CVL infection (chills with flushing, recent line access)

  Solid tumor, or ALL/lymphoma that is past the induction period

  High risk: As above, plus gram positive coverage, usually vancomycin

  ALL or lymphoma in induction; AML at any time while in therapy (extended periods of neutropenia)

  Mucositis

  Evidence of line sepsis

  Abdominal source: antipseudomonal coverage and anaerobic coverage, and gram positive coverage

  Documented abscess

  Abdominal pain or perirectal pain

  Oral infections

  Unstable with signs and symptoms of shock: antipseudomonal antibiotic with an aminoglycoside for double gram negative coverage, anaerobic coverage and gram positive coverage

  Evidence of shock, compensated or uncompensated, either before or after initial antibiotic dose

Typhlitis

• Follow FN protocols as explained above. If typhlitis is suspected coverage should be started for gram positive organisms, anaerobes, and gram negative organisms including pseudomonas.

• Assessment of possible surgical abdomen. If rebound or guarding is seen, abdominal imaging should be considered, and surgical consultation should be obtained.

• Treatment of pain which may be severe enough to warrant narcotics and patient-controlled analgesia devices.

• Management of constipation, which can be worsened with the use of narcotics. Constipation can make the side effects of typhlitis more likely.

• If prolonged stay is anticipated, consider TPN for nutritional support.

SCC

• Full neurologic exam with both sensory and motor to determine the level of compression; palpation of the back and spine to determine if there is point tenderness which might suggest the level of compression.

• Rapid imaging of the spine, usually with MRI, although CT may be adequate.

• Rapid consultation with hematology oncology and neurosurgery to decide best treatment options as a team

• Neurosurgery may want to treat with steroids per spinal injury protocols. Note that assessment of TLS should be done prior to and after the steroid dose if the suspected malignancy is lymphoid. Diagnosis may be compromised by steroids.

• Treatment should be initiated as soon as possible, especially if the loss of function was rapid and recent (hours to days). Treatment should be decided on a patient by patient basis. Acceptable options include emergent laminectomy, emergent chemotherapy, or emergent radiation therapy. Generally surgery or chemotherapy are the first line options. In certain malignancies, such as neuroblastoma, there is evidence that chemotherapy is as effective as surgery.

Management points not to be missed

TLS

a. Checklist:

• Establish history of UOP

• Begin IVF at 1.5 maintenance

• Frequent assessment of electrolytes, LDH and renal function

• Emergent treatment for elevated potassium

• Risk assessment of TLS as described above with appropriate therapy initiated

• Manage secondary effect of hypocalcemia and hyperphosphatemia

• Consult hematology oncology for chemotherapy

• Consult nephrology for renal failure or hyperkalemia

b. Do not forget:

• Do not forget to assess UOP prior to initiating IV hydration

• Do not put potassium into the IVF until you are sure the risk of TLS has passed

• Frequent assessment of electrolytes

• Early nephrology consultation for dialysis if in renal failure

• Do not assume high potassiums are due to hemolysis

Hyperleukocytosis

a. Checklist:

• Rapid assessment of TLS, MM, neurologic status and respiratory status

• Begin IVF at 1.5 maintenance

• Initiate an exchange transfusion if patient is symptomatic or WBC is high enough

  Contact local pheresis service if available

  Order appropriate volume of PRBC, and order it reconstituted to the appropriate hematocrit with either NS or albumin

  Establish venous access

• Consult hematology oncology for chemotherapy recommendations

  Do not forget

  Associated with TLS and MM

  Getting the blood for an exchange transfusion may take several hours depending on the location. Activate the blood bank as soon as possible if an exchange transfusion is needed.

  Knowing your local pheresis service ahead of time can save hours in an emergent situation.

  Line access is a critical part of pheresis. Make sure that you check with your service for their line

MM

a. Checklist:

• If suspected, rapid CXR to confirm mass

• Maintain the patient in a position of comfort, avoiding agitation and anxiety

• Avoid general anesthesia or sedation

• Consult hematology oncology for appropriate chemotherapy

• Non-invasive means of diagnosis if possible (peripheral blood with leukemic cells, or serum tumor markers)

• Minimally invasive diagnostic procedures if necessary

• CT scan of chest and peak expiratory flow rate if general anesthesia is considered critical

b. Do not forget:

• General anesthesia will remove the increased work of breathing and the accessory respiratory muscles. In addition patient will generally be lying on their back. If a mediastinal mass occludes the airway, generally it is below the level of intubation. This leaves ECMO as the only sure way to establish gas exchange. Avoid general anesthesia.

• Pulmonary artery compression is being recognized more frequently as a cause of sudden death during general anesthesia. There are no standards to judge compression, and this must be evaluated on a case by case basis.

SVCS

a. Checklist:

• Assess for MM and TLS.

• Establish mechanism of SVCS, whether it is due to external compression or intraluminal obstruction, generally with cross sectional imaging.

• Emergent therapy may be needed if venous infarction is occurring in the CNS. Therapy is determined by the mechanism of SVCS

  Thrombosis: Initiate anticoagulation with heparin (either unfractionated drip or LMWH) or other anticoagulant agent deemed appropriate. Consider thrombolysis of the SVC on a case by case basis if there is evidence of CNS infarction.

  External compression (mass): Consider emergent treatment with chemotherapy, radiation or surgery based on the suspected malignancy and the clinical situation

b. Do not forget:

• In children this can generally be managed conservatively by treating the patients primary tumor with front line therapy.

FN

a. Checklist:

• Rapid assessment and triage once the patient presents.

• Immediate access of CVL if present, and pan culture as appropriate to clinical presentation.

• Immediate treatment with a antipseudomonal IV antibiotic.

• Further history and physical to assess risk group and need for additional coverage (anaerobic, gram positive, additional gram negative coverage).

• Frequent assessment of patient for signs and symptoms of shock (inadequate tissue perfusion).

b. Do not forget

• Mucositis, abdominal pain, cellulitis, line infection, and perirectal abscess require expanded antibiotic coverage.

• Patient must be watched closely for the first 24-36 hours after presentation to ensure that signs and symptoms of shock do not develop.

• Although FN protocols treat the most common infection, i.e. bacterial infection, in neutropenic patients, remember that other organisms, such as viruses and fungus, may also cause fever in these patients.

Typhlitis

a. Checklist:

• Follow appropriate FN guidelines

• Assessment of a surgical abdomen with exam and imaging

• Pain control

• Management of constipation or diarrhea

• Management of nutrition with prolonged stay

b. Do not forget:

• Typhlitis increases risk of sepsis and associated conditions such as DIC

• Pneumatosis, perforation and GI bleed may complicate severe typhlitis

SCC

a. Checklist:

• Decision making should be a team approach with neurosurgery, oncology and radiation oncology. There are tumors where chemotherapy will work as well as surgery.

• Do not delay in the imaging of these patients.

• Neurologic assessment should include rectal tone.

b. Do not forget:

• Five percent of patients with malignancy will have SCC.

• If steroids are given, recognize that they may cause TLS and delay the diagnosis of lymphoid malignancies.

3. Diagnosis

Diagnostic criteria and tests

All of these disorders are considered in the setting of a new or relapsed malignant diagnosis. Many times the challenge is to make the primary diagnosis of malignancy. Once a diagnosis of malignancy is made, these complications of malignancy should routinely be assessed.

TLS

• Diagnostic criteria

  Risk assessment of the cancer (diagnosis)

  Clinical judgment based on presentation

  Evaluation of the peripheral smear

  Peripheral blood flow cytometry

  Assessment of LDH

  The diagnosis of a malignancy, particularly lymphoid, is enough to initiate prophylactic treatment of potential TLS.

  Low risk pediatric malignancies

  Solid tumors without laboratory evidence of TLS

  Acute myelogenous leukemia (AML) with WBC <25 thousand and LDH <2x Upper limits of normal (ULN)

  Lymphomas other than lymphoblastic lymphoma (LL), Burkett’s lymphoma (BL) or leukemia, and anaplastic large cell lymphoma (ALCL)

  Intermediate risk pediatric malignancies

  Low risk malignancies with laboratory evidence of TLS

  Low risk malignancies with laboratory or clinical evidence of renal dysfunction

  AML with WBC >25 and <100 thousand OR

  AML with WBC <25 thousand with LDH >2x ULN

  Acute lymphoblastic leukemia (ALL) with WBC <100 thousand and LDH <2x ULN

  BL, low stage and with LDH <2x ULN

  LL low stage (I/II) and LDH <2x ULN

  Childhood ALCL high stage (III/IV)

  High risk pediatric malignancies:

  Intermediate risk malignancies with laboratory evidence of TLS

  Intermediate risk malignancies with laboratory or clinical evidence of renal dysfunction

  AML with WBC >100 thousand

  ALL with LDH >2x ULN

  ALL with WBC >100 thousand

  LL high stage (III/IV)

  LL with LDH >2x ULN

  Burkett’s Leukemia

  BL any stage with LDH >2x ULN

  BL high stage (III/IV)

  Assessment of laboratory evidence of TLS

  Elevation of any of the following electrolytes above the upper limits of normal at presentation indicates laboratory evidence of TLS

  Uric Acid

  Phosphorous

  Potassium

  If these are elevated, low risk patients should be elevated to intermediate risk at least, and intermediate risk of TLS based on disease is increased to high risk

  Assessment of renal function

  Elevation of BUN or creatinine above the upper limits of normal at presentation

  Clinical evidence of renal dysfunction (decreased urine output primarily)

• Initial lab assessment

  Serum electrolytes (potassium, calcium, and phosphorous are most important)

  Uric acid

  BUN

  Creatinine

  LDH

• EKG if potassium is elevated

• Imaging

  Generally not indicated

  Consider renal US if TLS is severe and not responding as expected. Other causes of renal failure my exist (ex obstructive uropathy) which may have other treatments

• Frequent reassessment of labs above

Hyperleukocytosis

• Diagnostic criteria

  Routine CBC will demonstrate hyperleukocytosis. Should make sure that the cytometer is able to read WBC >100,000 – many office practices will not have a machine that can read that high. Also need to correct for nucleated RBC’s, although that is not usually an issue for WBC>100,000

MM

• Diagnostic criteria

  Any clinical evidence of extra or intra thoracic obstruction in the setting of a new diagnosis

  Any imaging modality which demonstrates a thoracic mass

• Diagnosis

  Physical exam finding of a neck mass with tracheal deviation, or tracheal deviation or stridor alone in the setting of a new diagnosis

  CXR is generally adequate to diagnose that a mass is present

  CT of chest with contrast will give more information about degree of tracheal compression and allow at least partial assessment of pulmonary artery compression. Patient must be able to lie flat for this test.

  Peak expiratory force may be obtained to see if there is significant airway compromise

SVCS

• Diagnostic criteria

  Findings of upper body edema, or neurologic changes and imaging that demonstrates compression or occlusion of the superior vena cava

• Diagnosis

  Generally requires imaging of the superior vena cava and is feeding tributaries. This may be done with a contrasted CT, contrasted MRI, MRV, or venogram.

FN

• Diagnostic criteria

  Any patient with an absolute neutrophil count (ANC) of <750 with signs or symptoms of fever or shock.

  Note that fever is not an absolute criteria for diagnosing a neutropenic patient with FN and initiating antibiotic treatment, and that certain treatments such as dexamethasone, may mask fever in a septic patient.

• Diagnosis

  CBC with differential demonstrating an ANC <750

  Fever or clinical signs and symptoms demonstrating possible infection. When in doubt, treat

Typhlitis

• Diagnostic Criteria

  Abdominal pain in the setting of neutropenia

• Diagnostic tests

  This is a primarily a clinical diagnosis

  KUB may demonstrate obstruction or pneumatosis

  Contrasted CT may demonstrate thickened walls in small or large bowel, traditionally, but not restricted to the cecum

SCC

• Diagnostic Criteria

  Neurologic findings compatible with compression of the spinal cord is sufficient to make a diagnosis

• Diagnostic test

  MRI or CT of the spine

Confirmatory tests

TLS

• Image of EKG changes with hyperkalemia

Hyperleukocytosis

Smear? Not very helpful

MM

• X-ray

• One CT

SVCS

• One CT

FN

• Smear?

Typhlitis

• CT of thickened bowel walls

SCC

• MRI of SCC

Side effects

As stated above, the complexity of these side effects is diagnosing the underlying malignancy. Once that is diagnosed, these side effects should be routinely assessed. Therefore these are relatively specific. There may be other confounding complications which are listed with the specific disease.

TLS

• Obstructive uropathy

• Without malignancy diagnosis, rhabdomyolysis (same mechanism for renal failure)

Hyperleukocytosis

• leukemoid reaction due to inflammation such as sepsis (rarely reaches 100,000). Does not require treatment itself, just for the underlying inflammatory condition.

• Transient myeloproliferative disorder (TMD) which occurs within the first year of life in patients with trisomy 21. Rarely these progress directly to leukemia over time. The natural course is for the white count to rise over weeks to months, sometimes over 100,000, possible with associated hepatosplenomegaly and lymphadenopathy, and then to gradually fall back to normal levels on its own without therapy. The entire time course may take 6-8 months or less. The patients with TMD need to be followed very closely afterwards as their risk of developing future leukemia is 25%.

MM

• Any mass occupying lesion of the upper chest which could displace the trachea, such as an organized upper lobe pleural effusion or parenchymal consolidation.

SVCS

• Obstruction of SVC may produce CNS symptoms.

FN

• Adrenal insufficiency may contribute to hypotension especially if prolonged steroids have recently been used and weaned

Typhlitis

• Any disorder leading to acute abdomen including common disorders such as appendicitis

SCC

• Disorders which affect the spinal cord without mass effect such as transverse myelitis can present with similar neurologic features, but without associated back pain.

4. Specific Treatment

TLS

• Diagnosis of the malignancy and Initiation of chemotherapy

• Assessment of MM and hyperleukocytosis

• Prevention of renal failure

  IV hydration at 1.5 – 2.5 maintenance

  Treatment by risk group above

  Close monitoring of electrolytes, uric acid and renal function

  Early consideration of dialysis if renal failure is progressive

• Electrolyte disturbances

  Oral calcium for hypocalcemia. Use IV calcium only if there is a risk of immediate injury to the patient

  Oral phosphate binders to prevent further absorption of phosphorous

  Early initiation of dialysis if renal failure is progressive

  For symptomatic hyperkalemia (EKG changes) therapy as listed in the table above

Hyperleukocytosis

• Assessment of MM and TLS

• Diagnosis of the malignancy.

  Therapy may be held or reduced due to the risk of TLS, until exchange transfusion is able to reduce the total WBC in order to prevent TLS.

• c. Determine the type of exchange transfusion needed based on patient’s weight and institutional resources

  Double volume exchange using pheresis

  Manual double volume exchange transfusion

• Activate the blood bank as soon as possible, as an exchange transfusion requires 160 cc/kg of blood which has been reconstituted to the appropriate hematocrit using either normal saline or albumin

• Establish good peripheral or central venous access depending on the requirements of the local pheresis service or clinical need

MM

• Rapid assessment of the airway. If there are associated signs and symptoms of airway compromise prepare for emergent therapy of the tumor in consultation with hematology oncology and possible radiation oncology

  The majority of anterior mediastinal masses that cause airway compression are lymphoid malignancies (T-cell leukemia or lymphoma, Hodgkin’s disease) which will respond rapidly to steroids. Prednisone is generally dosed at 60 mg/m2/day in divided doses.

• Consider airway support that can assist the conscious patient such as continuous positive airway pressure (CPAP or BiPAP, not intubation which requires sedation) or heliox

• Assessment of hyperleukocytosis and TLS, especially if steroids are initiated

• Avoid anxiety provoking procedures, and allow the patient to find their position of comfort

• Avoid deep sedation and general anesthesia

• Consider further assessment of the airway if the patient is not acute

  Chest CT to assess degree of tracheal and pulmonary artery compression

  Forced peak expiratory flow

  If tracheal compression is <50% of expected diameter, and FPEF is >50 of expected, and there is not concerning PA compression on CT, patient may be a candidate for general anesthesia and biopsy.

• Diagnosis from peripheral blood (smear interpretation, flow cytometry, tumor markers) or diagnostic procedure under local anesthesia (ex excisional lymph node biopsy) to confirm diagnosis if possible.

SVCS

• Rapid assessment of the neurologic status of a patient with upper extremity edema, emphasizing mental status and focal neurologic deficits

• Assessment of TLS and MM as above

• Appropriate imaging to determine if the cause of SVCS is due to intraluminal obstruction (ie thrombosis) or extraluminal compression

  If SVCS is due to thrombosis, initiate heparin drip or LMWH per institutional guidelines. Be sure to evaluate for possible contraindications to heparin, such as intracranial bleed, if clinical suspicion exists.

  If SVCS is due to extraluminal compression, consult hematology oncology and radiation oncology to initiate appropriate therapy. Therapy may need to be emergent without biopsy if patient is showing rapid neurologic deterioration.

FN

• Rapid triage and assessment of the patient who presents with fever or signs and symptoms of shock with a recent history of chemotherapy

• Immediately access the CVL to obtain cultures and appropriate blood work

• Immediately administer an appropriate antipseudomonal IV antibiotic, even if the patient’s blood work is not yet back

• If signs and symptoms of shock develop initiate supportive measures (airway management, fluid management, pressors, etc) and broaden antibiotic coverage as described above

• Extended history and physical to appropriately determine the patient’s risk group as listed above and expand antibiotic coverage as described above

• Admission and close monitoring for shock prior to and after the start of antibiotics

• Hospital observation until discharge criteria have been met. In our institution this would be negative cultures for at least 48 hours, afebrile for at least 24 hours, and evidence of count recovery. If the stay is associated with any signs or symptoms of shock, or if an organism is cultured, longer courses of antibiotics may be appropriate, even after count recovery.

Typhlitis

• Rapid assessment and treatment as outlined under FN

• Appropriate assessment of the abdomen. If guarding or rebound is present appropriate imaging and surgical consultation should be obtained immediately

• Initiate appropriate levels of pain control

• Manage associated symptoms such as diarrhea or constipation

• If prolonged course is expected, should assess nutritional needs and determine if TPN is appropriate

SCC

• Suspected when the history or neurologic exam demonstrates a sensory level, or decreased strength and increased reflexes bilaterally below a specific spinal level. Rectal tone should be assessed, as well as any recent history of urinary or fecal incontinence. Physical should also assess for point tenderness over the spine.

• Emergent imaging of the spine if SCC is suspected with either MRI or CT.

• Consider spinal injury doses of steroids. Remember that steroids may make the diagnosis of a lymphoid malignancy impossible, and may precipitate or worsen TLS.

• Emergent consultation with neurosurgery, hematology oncology, and radiation oncology to determine the best course of action to relieve the compression. In some cases chemotherapy may be as effective as neurosurgery.

Drugs and dosages

TLS

• Hyperuricemia

  Allopurinol

  <10yo: 10 mg/kg/day divided 2-3x’s a day, max 800 mg/day

  >10 yo and adults: 600-800 mg/day divided 2-3x’s a day

  Rasburicase

  0.2 mg/kg/dose IV once daily for up to 5 days

  Contraindicated with G6PD deficiency

• Treatment of electrolytes

  Oral calcium supplements based on institutional preference

  Calcium gluconate (IV) – not recommended unless concern of immediate harm to the patient due to complications of hypercalcemia

  Amphogel

  20-150 mg/kg/day divided every 4-6 hours

• Treatment of hyperkalemia

  Sodium bicarbonate (IV) based on institutional policy

  Calcium gluconate (IV) based on institutional policy

  Albuterol

  0.3 mg/kg/hour via continuous nebulization

  Insulin and glucose

  Glucose 0.5-1 g/kg combined with

  Regular insulin 1gm per 4 gram of dextrose infused over 2 hours. This should be a continuous infusion until hyperkalemia is resolved

  Note this may need correction for renal impairment

  Lasix

  1-2 mg/kg IV every 6 hours

  Note this is only used to encourage excretion of potassium, not to maintain urine output

  Kayexolate

Hyperleukocytosis

• ALL

  Steroids at 40-60 mg/m2/day

• AML

  Low dose cytarabine

• CML

  Hydroxyurea

  Low dose cytarabine

SVCS

• Anticoagulation

  Heparin drip

  LMWH

FN

• Appropriate antipseudomonal IV antibiotics

  Ceftazadime

  Piperacillin

  Pipercillin and clavulanate

  Ticarcillin

  Ticarcillin and

  Imipenem

  Meropenem

• Gram positive coverage

  Vancomycin

  Linezolid

• Anaerobic Coverage

  Clindamycin

  Metronidazole

  Imipenem

  Meropenem

• Aminoglycosides

  Gentamycin

  Tobramycin

  Amikacin

• Growth Factors

  Granulocyte culture stimulating factor (GCSF)

  Granulocyte Monocyte culture stimulating factor (GMCSF)

Typhlitis

• Pain

  Oral

  Rapid release

  Hydrocodone

  Oxycodone

  Sustained release

  Oxycontin

  Methadone

  IV

  Morphine

  Dilaudid

  Fentanyl

  PCA delivery systems

SCC

• Steroids

• Chemotherapy

• Radiation

Refractory cases

TLS

In the setting or refractory renal failure or hyperkalemia, despite all measure listed above, dialysis or CVVH remains the final treatment until renal function recovers. As long as the malignancy responds to chemotherapy, renal function is very likely to return to baseline, although the time frame for that is variable.

Hyperleukocytosis

Plasmapheresis should always be considered for WBC counts that exceed mentioned thresholds. Remember that WBC live in the interstitial space as well as the vascular space. Therefore, many patients will experience a rebound after the initial reduction 12 to 24 hours following the procedure. Therefore pheresis once a day for several days in a row may be needed.

Initial therapy should also be introduced, and treatment of TLS should be established quickly.

In the setting of ALL, very few initial presentations will be steroid refractory. Therefore treatment with steroids, after plasmapheresis, in addition to treatment of TLS, should be effective.

CML is very responsive to oral hydroxyurea and low dose cytarabine. These medications will gently reduce the total tumor burden while imatinib is started for definitive control, and TLS measures are being followed. If the patient doesn’t respond to these three medications, blast crisis in CML (the transition of CML to AML) should be considered, as the AML occurring after CML is particularly refractory, and may require full dose AML chemotherapy for control.

Plasmapheresis may also be used in CML to control the WBC, although its benefits are not prospectively studied in the pediatric population in CML.

In the setting of relapsed ALL, or AML, however, low dose or partial dose therapy may not control the disease due to disease resistance. Therefore plasmapheresis with treatment of TLS is the standard for these entities, with initiation of full dose chemotherapy to induce remission.

For T-cell leukemia, only 50% of relapses make it back into remission despite reinduction therapy, and very few survive long term even with allogeneic transplant. Therefore, full dose chemotherapy is warranted if steroids alone fail to reduce the WBC count.

AML, new or relapsed, tends to be more resistant to treatment. Therefore full induction therapy is warranted in almost all situations.

MM

Emergent treatment with steroids, chemotherapy, and radiation for patients who are felt to have a high risk of losing their airway. If a patient loses his/her airway below the level of intubation, that patient will need to be placed on ECMO emergently as intubation cannot relieve the obstruction.

SVCS

a. External compression of the SVC is generally removed using chemotherapy or radiation, depending on the tumor type. If the event that these modalities are not effective, emergent debulking of the mass with surgery is an option. Consultation with pediatric surgery, or with the appropriate subspecialty surgeon should be considered.

b. Occlusive or near occlusive thrombosis of the SVC is generally handled with heparin, either by IV drip, or with subcutaneous LMWH. If a patient’s neurologic status is deteriorating without CNS hemorrhage (venous infarction), then thrombolytics, either catheter directed or systemic can be considered although there is significant risk of bleeding with these medications. Generally hematology, interventional radiology, interventional cardiology or vascular surgery have the most experience with thrombolytics, although this is institution specific.

If there is evidence of CNS hemorrhage or infarction, thrombolytics are contraindicated, and heparin therapy is controversial. Surgical thrombectomy, either by general or vascular surgery, interventional radiology, or interventional cardiology should be considered.

FN

Refractory cases of FN become sepsis. Consideration can be given to the use of WBC growth factors such as GCSF and GMCSF, as well as granulocyte infusions. There is no clear data that any of these interventions improve the outcome of a neutropenic patient with sepsis.

Typhlitis

Rigorous treatment of pain with PCA is the standard of care. Treatment of associated sepsis as per FN guidelines initially and sepsis guidelines if the infection progresses. Complications of typhlitis include obstruction, perforation and gastrointestinal bleeding. If those side effects occur, consult pediatric surgery for management recommendations and possible surgery.

SCC

Treatment options as stated above include initial steroids, chemotherapy, radiation, and at our institution, surgery as a last resort. If steroids, chemotherapy and or radiation have failed, laminectomy or laminotomy should be considered. Note that the longer the patient has loss of function, the less likely to recover. Therefore, hematology oncology and neurosurgery should be on board as soon as this is discovered in order to make rapid decisions both initially and during reassessment.

Historically treatment has been laminectomy with removal of the tumor from the spinal canal. in the last ten years, there is a growing recognition that chemotherapy for many pediatric tumors may be efficacious as surgery. Given that the patient is going to have the chemotherapy regardless, many pediatric oncologists are pushing for chemotherapy upfront rather than surgery. Long term complications of laminectomy is primarily mild to severe scoliosis depending on the length of the laminectomy. If a patient can avoid this complication that would be preferable. This decision requires a multidisciplinary discussion.

5. Disease monitoring, follow-up and disposition

Monitoring and disposition

TLS

• monitoring

  Frequent monitoring of electrolytes, uric acid, and renal function up to every 4 hours for severe cases. As the first days of therapy pass, and tumor burden drops with therapy, these can be dropped in frequency

  Periodic EKG for potassiums greater than 6 (Units)

  Close monitoring of fluid balance and urine output

• Follow-up and disposition

  For patients who avoid dialysis, once the tumor burden has been reduced with chemotherapy, the patient can be transferred from the unit to the hematology oncology service. Mild renal injury, determined by increasing creatinine, generally recover fully.

  For those patients who required dialysis and CVVH, full recovery is generally the rule. Hematology oncology and nephrology services will determine the ultimate disposition.

Hyperleukocytosis

• Monitoring

  Frequent monitoring for TLS as above

  With plasmapheresis or manual exchange transfusion, calcium levels can drop due to the anticoagulants used during pheresis, or stored with the PRBC. Monitor calciums before and after exchange transfusions

  Frequent neuro checks to watch for intracranial events

• Follow-up and disposition

  Once the WBC has been reduced, either with pheresis or chemotherapy, the patient can be transferred to the hematology service. Hyperleukocytosis establishes that the patient has a high risk leukemia. Overall survival can be anywhere from 30-70% depending on the leukemia classification.

  Transfer to the hematology service once TLS has resolved, as above.

MM

• Monitoring

  Frequent assessment of the airway with simple clinical exam, and possibly peak expiratory flow rates

  Avoid sedating medications

• Follow-up and disposition

  Frequent monitoring for TLS as above

  For those patients successfully treated without airway compromise, clinical exam should predict when they are able to be transferred to the hematology oncology service. Simple chest X-rays will demonstrated the shrinkage of an anterior mediastinal mass originating in the thymus, and potentially hilar adenopathy. Imaging with CT scan may be necessary to determine if a posterior mediastinal mass is shrinking, but these are less likely to cause airway compromise.

  Survival of patients with MM who did not obstruct is dependent on the underlying malignancy

  For those patients who require procedures such as ECMO, please refer to the ECMO section for disposition

SVCS

• Monitoring:

  For extravascular compression

  Monitoring of TLS as above

  Monitoring of the neurologic status to ensure that the patient is not having focal neurologic events or changes in mental status.

  2. For intravascular obstruction (blood clot)

  Monitoring of TLS as above

  Monitoring of the neurologic status to ensure that the patient is not having focal neurologic events or changes in mental status

  Monitoring of heparin, whether heparin drip or LMWH, should be done per institutional standards. LMWH in generally checked with an activated factor X level (Factor Xa level), and heparin drips can be followed with PTTs or Factor Xa levels. Heparin drips require much more frequent monitoring (every four hour PTTs) until target anticoagulation is achieved. Then heparin drips are monitored every 24 hours generally.

  In our institution, imaging of the clot within 72 hours of initiating anticoagulation is done to ensure that the clot is not enlarging. If enlarging, despite therapeutic levels of heparin, other treatments discussed above should be considered.

  Assessment of inheritable causes of thrombosis (factor V leiden, prothrombin gene mutation, Proteins S deficiency, protein C deficiency, ATIII deficiency) should be considered on a case by case basis, after a thorough family history has been obtained.

• Follow-up and disposition:

  Once extravascular compression has been relieved, whether by chemotherapy, radiation, surgery or a combination, the patient may be transferred to the hematology oncology service for further therapy. Prognosis is dependent on the underlying malignancy.

  Once intravascular compression is successfully anticoagulated, and the clot is documented as stable without propagation, the patient can be transferred to the hematology oncology service. Usually heparin drips are converted to either LMWH or oral warfarin for long term anticoagulation. In our institution, once a clot is demonstrated, anticoagulation is continued for a minimum of three months unless there is a medical contraindication. Prognosis is dependent on the underlying malignancy.

FN

• Monitoring

  Once the patient is triaged and the appropriate antibiotics have been selected, the patient should be monitored with frequent vital signs and exact measurements on input and output. Signs and symptoms of shock should be treated aggressively as per the sepsis guidelines, first with fluids and then with other medications such as dopamine and possibly hydrocortisone based on recent therapy.

  Generally, signs of shock would present within 72 hours of the first dose of antibiotic if related to the original fever. However, secondary infections should be watched for, and other types of infections which are unresponsive to antibiotics (viral, fungal, etc) should be considered if the fever continued despite appropriate antibiotic selection.

  For patients admitted on a single anti pseudomonal antibiotic (low risk) at our institution, we will continue to add antibiotics over the first five days after admission. If the fever continues past 48 hours after admission we will add vancomycin. If the fever continues beyond 72-96 hours we consider adding an aminoglycoside. And if the fever continues beyond 5 days after admission and appropriate antibiotics, we add empiric antifungal coverage,

  The use of broad spectrum antibiotics can predispose the patient to fungal infections. In general, there are two types of fungal infections, candidal infections, and molds (ex: aspergillus). Our first line antifungal is liposomal amphotericin (Ambisome) as it has fewer side effects and has the broadest spectrum of coverage.

• Disposition

  We use three criteria for discharge after fever neutropenia: Resolution of fever for at least 24 hours. Cultures negative for at least 48 hours. Evidence of count recovery for two to three days in a row.

  Transfer from the ICU only requires that the patient is stable without signs or symptoms of shock.

Typhlitis

• Monitoring

  Symptoms may improve with the initiation of antibiotics and pain control; however, severe cases of typhlitis may take weeks for the patient to fully recover (no abdominal pain, normal diet). Close monitoring of the abdominal exam is warranted to ensure that acute abdomen does not develop, This may be difficult to assess in the setting of narcotic use.

  Weight must be watched in the setting of decreased oral intake. Use of enteral feeds through a nasogastric tube may be considered, but many times is difficult because of increased pain. In the setting of pneumatosis or obstruction, NG feeds are generally contraindicated. Early initiation of total parenteral nutrition should be considered if the patient is not eating adequately.

  Generally, symptoms should begin to improve with count recovery.

• Disposition

  Discharge is very dependent on the patient. We generally would like the patient on oral pain medication. Generally we would like the patient to be taking a regular diet, although this is variable.

  Transfer from the ICU can occur when the patient is stable on therapy, without signs of an acute abdomen or sepsis

SCC

• Monitoring

  Monitoring mainly consists of frequent neurological assessments.

  For patients with intravascular thrombosis, initial monitoring of the heparin drip should occur relatively frequently per institutional guidelines, until therapeutic levels of heparin are achieved and stable. For patients on LMWH, monitoring is generally done every twenty four hours (every two doses) until therapeutic levels are established.

• Disposition

  Discharge for the ICU only requires that the patient’s neurologic status is stable and not getting worse. In addition, many hospitals have internal standards as to where a heparin drip can be managed within the hospital.

  Discharge from the hospital is determined by the treatment of the underlying malignancy.

Incorrect diagnosis

TLS

• if markers of TLS are not abnormal (uric acid, calcium, phosphorus), but renal failure is evident in the setting of malignancy, then other causes of renal failure should be considered, such as obstructive renal failure.

• If there is evidence of TLS in the setting of renal insufficiency or failure, but no malignancy can be found, consider other conditions with massive rapid cell death such as rhabdomyolysis.

Hyperleukocytosis

• Nucleated red cells (states of high marrow output such as inborn or autoimmune hemolytic anemia) can be misread on a CBC as WBC, falsely elevating the WBC count. Review of the smear will demonstrate nucleated RBC and possibly abnormal red cell forms depending on the cause of the hemolytic anemia.

• Leukemoid reactions (elevated WBC due to an inflammatory but non-malignant condition such as sepsis) can elevate the white count acutely. On smear, the white cells will show reactive and immature forms, but at all levels of development. Many times granulocyte cell lines predominate (segs, bands, and their precursors). Treatment for the underlying condition will generally improve the white count within several days. Other markers of TLS should be negative as long as renal function is adequate.

• Transient myeloproliferative disorder may occur in young patients with trisomy 21. This condition is associated with an elevated WBC with blast forms in the marrow and peripheral blood, and looks like new onset AML. The history of trisomy 21 is important, however, and point to TMD vs frank AML.In general, the white count generally does not go above 100,000 (units), but can. Physical exam can show splenomegaly and other signs consistent with AML. Infrequently these patients are treated with low dose cytarabine or hydroxyurea if the WBC is felt to be too high (generally over 100,000). This condition spontaneously resolves within weeks to months, but these patients then have a 25% risk of developing AML later in life.

MM

• Usually there is not an argument that there is some type of lesion on CXR causing a mass effect. The concern is usually whether that lesion is malignant, structural, or infectious. Regardless, airway precautions should always be followed if there is a question of tracheal compression while other diagnostic imaging and surgery is pursued.

SVCS

• For extravascular compression please see MM above.

• For intravascular thrombosis, the level of thrombosis needs to be fully evaluated. Cardiac involvement, or jugular extension may require further consultation with other services such as cardiology, thoracic surgery, or vascular surgery.

• Please note that if SVCS is suspected and there is an acute change of mental status, evaluation for other causes of acute mental status change should be considered in addition to SVCS.

FN

• Artifactual neutropenia can be caused by margination of PMNs. This can occur with acute stress such as infection or with steroid administration. In reality these patients have adequate numbers of granulocytes, and respond appropriately to infection.

• Autoimmune causes of neutropenia should be considered in the patient with a long history of illness, not otherwise diagnosed. These patients can have variable responses to infection; they may be completely appropriate, or may act as a fully neutropenic patient. We recommend treating all patients with neutropenia and fever as immunodeficient until proven otherwise.

• All oncology patients with recent history of chemotherapy should be assumed neutropenic and treated appropriately prior to CBC results being obtained

Typhlitis

• Common causes of acute abdomen should always be considered and potentially ruled out when considering the diagnosis of typhlitis. These include but are not limited to acute appendicitis, peritonitis, cholelithiasis, pyelonephritis, and in the sexually active teenager, PID and pregnancy.

SCC

• As with many other oncologic emergencies, the question is not whether the condition exists, but whether it is a malignant process causing the spinal cord compression. Spinal cord compression can be caused by many different processes such as bleed, trauma, fluid collection, abscess, and benign neoplasms. These different etiologies should be answered by MRI of the spine.

• Transverse myelitis can present very similarly to malignancy, but is an intrinsic process to the cord itself.

Follow-up

TLS

• Generally the process resolves within two to seven days of the start of therapy

• If renal function returns to baseline no specific follow-up is needed

• Follow-up per oncology and nephrology

Hyperleukocytosis

• Generally the process resolves with initiation of chemotherapy within two to seven days

• Follow-up per oncology

MM

• No specific follow-up is needed for this condition.

• Follow-up per oncology

SVCS

• For extravascular compression, follow-up is per surgery, radiation oncology, and oncology depending on the treatment used. No specific long term follow-up is needed beyond treatment.

• For intravascular thrombosis, anticoagulation should remain in place for 3 months at therapeutic doses if there are contraindications. This will require monitoring per the type of anticoagulation used.

FN

• Once the neutropenia resolves, there is no need for further follow-up beyond normal oncology follow-up

Typhlitis

• Depending on the severity of the condition specific treatments may require specific follow-up such as weaning pain medications and outpatient TPN. Beyond these treatments, no further specific follow-up is needed beyond normal oncology follow-up.

SCC

• Follow-up is dependent on the status of the patient. If dysfunction remains after initial treatment, referral to physical therapy and rehabilitation centers may be warranted. Long term follow-up with neurology should be considered to follow status. Otherwise, oncology follow-up should be adequate

Pathophysiology

TLS

TLS is the result of rapid cell lysis. Malignancy, especially hematologic malignancy, is characterized by increased cell proliferation, and increased cell death. TLS results when the byproducts of this rapid cell death exceed the capacity of the renal clearance. Specifically, these by-products are uric acid, the result of purine degradation, phosphorous and potassium.

a. Purine metabolism and uric acid

To review, purines are degraded to xanthine and hypoxanthine, which is then converted to uric acid by xanthine oxidase. Degradation in primates stops at that point. Urine acid is relatively insoluble which is the primary problem in TLS.

The pKa of uric acid is 5.75, which means that below a urine pH of 5.75 uric acid is in its neutral form, which limits its solubility in urine. A pH above 5.5 causes uric acid to release a hydrogen molecule, converting the molecule to urate, facilitating its solubility. At a pH of 7, approximately 98% is in its urate state. This is why bicarbonate has historically been used to alkalinize the urine.

Uric acid is primarily secreted into the nephron. Uric acid is freely filtered by the glomerulus, but is what is secreted is almost complete reabsorbed in the proximal tubule. Seventy percent of uric acid is removed by the kidney, 30% by the hepatobiliary route.

Hydration is very important in controlling uric acid excretion. If more urine can be created this allows more uric acid to be dissolved, and therefore excreted in the urine.

Allopurinol inhibits xanthine oxidate, preventing the creation of uric acid. Hypoxanthine is much more soluble than uric acid facilitating excretion. Xanthine is less soluble that uric acid, and may still contribute to renal failure in severe cases.

Rasburicase is an enzyme that is present in all mammals. In primates, there has been a missense mutation in the promoter of the gene which prevents its transcription. The enzyme continues the metabolism of uric acid further into allantoin, which is very soluble.

b. Phosphorous and calcium

Phosphorous generally maintains a zero balance on a daily basis; gut absorption is equaled by renal excretion. Generally a well functioning kidney can excrete heavy phosphorous loads. However, when there is a phosphorous challenge as in TLS, especially in association with renal insufficiency and/or dehydration, the kidney may be unable to excrete the phosphorous load, mostly due to decreased renal perfusion (prerenal and renal).

If the product of the calcium concentration and phosphorous concentration reaches 60, calcium phosphate crystals begin to precipitate. This can especially occur in the kidney where alkaline pH and elevated concentrations of the minerals may worsen renal failure. If the pH of the urine is >8.5, this will increase precipitation, which is why alkalinization of the urine is somewhat controversial.

c. Calcium

Hypocalcemia primarily results from elevated phosphorous levels and precipitation. Calcium is used as a signaling molecule in skeletal muscle, cardiac muscle, and the central nervous system (among others). Low levels of calcium result first in skeletal muscle spasm (at serum levels of 6-7 (units)). Levels between 5-6 can be associated with decreased cardiac function and arrhythmia, and would be considered an emergent reason for treatment with IV calcium. Levels less than 5 (units) are associated with seizures that will abate only with increased levels of calcium.

d. Potassium

Hyperleukocytosis

The pathophysiology of hyperleukocytosis is related to the underlying malignancy.

With ALL, the malignant cells are very susceptible to treatment with chemotherapy and steroids. Therefore, even small amounts of treatment can cause a large drop in the total WBC. For that reason, TLS is the main side effect of ALL related hyperleukocytosis.

With AML, the malignant cells are more resistant to treatment. Therefore, TLS less of a problem in AML with bulky disease or hyperleukocytosis. Instead, total blood viscosity becomes more significant and risk of vaso-occlusion, especially in the lung and the CNS increases.

Specifically in AML M3 (acute promyelocytic leukemia or APML) the leukemic blasts express fibrinolytic enzymes on the cell surface. These patients frequently present with bleeding and clinical DIC. The bleeding can be life threatening if in the lungs or intestines. CNS bleeds and infarction are both reported.

MM

Large masses in the chest can exert pressure of the trachea or the mainstem bronchi, increasing airway resistance, and compromising gas exchange.

Masses that occur in the neck outside of the rib cage generally present with stridor, usually inspiratory. As the diaphragm generates negative pressure, the upper trachea experiences a collapsing force during inspiration which is responsible for stridor. Within the chest, the expansion of the chest wall counters the negative force of inspiration, and pulls the airway open, so there are usually no inspiratory sounds. However on expiration the chest wall exerts pressure on the airway, causing a choke point where the positive pressure of the airway (expiration by the diaphragm) equals the pressure being exerted by the chest wall.

This is exacerbated by the external compression of the mass, so that wheezing may be heard. Wheezing from a large airway is different from small airway wheezing (as in RAD). The wheezing may sound like a whistling, and be more of a solitary sound, located in one section of the chest.

The trachea of the neck has thick cartilage rings that prevent compression in all but the most extreme cases.

The body compensates primarily for intrathoracic mass by increasing use of accessory muscles, applying more force to bypass the obstruction. In the case of anterior mediastinal masses, the patient may also assume a tripod position, or position of comfort, which leans the mass forward and off the trachea. Sedating the patient removes both of these compensatory mechanisms.

Lastly, there have been deaths from MM attributed to pulmonary artery compression. There is no way to assess compromise of pulmonary artery flow at this time.

SVCS

SVCS implies that the SVC is either partial or completely obstructed, either due to internal obstruction (thrombosis) or external compression.

The hallmark of venous obstruction is swelling and congestion distal to the occlusion, and this would involve one or both upper extremities and the head and neck. There is not a good system of collaterals available for the upper circulation. Therefore venous pressure may rise to systemic pressures in the setting of complete obstruction.

In this scenario, as venous pressures rise to match systemic pressures, the patient may experience venous infarcts. Arterial perfusion is impaired as venous pressures rise, and the pressure gradient across the capillary approaches zero. On pathology or imaging, enlarged venules can be noted, which is the hallmark of this condition.

Factors leading to thrombosis relate to Virchow’s triad: hypercoagulability (from the cancer itself, CVL placement, etc), stasis (compression by the tumor, or obstruction due to clot), and endothelial injury (thrombosis). Pediatric malignancy can cause SVCS due to one or all of these categories. It is important to distinguish the cause as treatment can change with the cause. For example, a clot may be treated with line removal, and heparin or TPA; compression may need to be treated with stent placement or surgical decompression if possible.

FN

Translocation of bacteria from our skin, GI tract, or respiratory tree occurs every day in most individuals. However, only a small percentage of these occurrences are associated with illness. This is due to an immediate response of the innate immune system. Neutrophils comprise the major cellular response to acute bacteremia, and when they are absent, these common bacteremias can lead to life threatening infection.

Neutrophils divide and mature in the bone marrow over a 21-day period, which incidentally is why traditionally chemotherapy is given in 3-week cycles to allow recovery.

The growth period begins with rapid expansion lasting for about 11-14 days. During this period, the neutrophils are maturing, but also have the ability to expand and divide. The last 7-10 days in the marrow, these cells continue to mature, but lose their ability to divide. This 7-10 day maturation window explains why patients do not become neutropenic immediately upon receiving chemotherapy: since these cells are only maturing and not dividing, they are not sensitive to the affects of chemotherapy, which attacks rapidly dividing cells.

Once these maturing cells in the bone marrow are depleted, the patient becomes neutropenic, usually 7-10 days after chemotherapy.

Once the chemotherapy is completed the bone marrow immediately begins regenerating, creating new neutrophils (and all of the other cell lines). But there is a 21-day window till those cells are mature enough to be found in the peripheral circulation. This usually leaves a 10-14 day window of neutropenia.

During that time period the patient is at increased risk of spontaneous bacterial infection. If other aspects of the immune system are compromised (mucosal breakdown for example) that risk will be increased.

Typhlitis

Typhlitis occurs when bacterial are able to translocate from the lumen of the gut to the wall of the intestine. In the early 80s when this condition was defined, it was identified with RLQ pain similar to that identified with appendicitis. Therefore the original definitions of typhlitis located the bacterial infection of the gut primarily to the cecum. Today this condition is recognized to occur throughout the length of the intestine. This has been referred to bacterial overgrowth within the intestine.

There can be a component of bacterial overgrowth with pathogenic bacteria that are normally restricted in their growth by neutrophils, but even routine bacteria become dangerous in this situation.

Infection of the intestinal wall leads to edema and inflammation. Radiographically the intestine can show ileus and pneumatosis. Invasion of the intestinal wall can have an increased risk of bacteremia. Swelling and edema can lead to GI bleed and perforation in the most severe cases.

SCC

There are many mechanisms of SCC, and many of them can be caused by oncological conditions. Compression from a bony metastasis to the spine, chloroma formation, or direct invasion of the spinal space from a paraspinal mass with extension through the neural foramen is one mechanism. This can be complicated by local edema and swelling of the spinal cord itself.

Treatment such as radiation can cause injury to the cord causing swelling as described above.

Infections, such as meningitis or epidural abscesses can cause compression to the cord.

Fracture of vertebral bodies due to bony metastases or ALL can rarely lead to cord compression.

Historically treatment has been laminectomy with removal of the tumor from the spinal canal. in the last ten years, there is a growing recognition that chemotherapy for many pediatric tumors may be as efficacious as surgery.

Given that the patient is going to have the chemotherapy regardless, many pediatric oncologists are pushing for chemotherapy upfront rather than surgery. Long term complications of laminectomy is primarily mild to severe scoliosis depending on the length of the laminectomy. If a patient can avoid this complication that would be preferable.

Epidemiology

NA

Prognosis

TLS

The outcome of mild to moderate TLS which is handled with hydration, treatment for uric acid, and treatment of the malignancy rarely if ever has long term complications. Even TLS severe enough to require dialysis generally reverses without long term complications.

Hyperleukocytosis

The prognosis of hyperleukocytosis relates to the underlying disease and the complications that occur during the presentation (TLS, stroke, ARDS). Generally outcome of patients with hyperleukocytosis is excellent, as long as the aforementioned complications have not occurred.

MM

The prognosis of MM relates to the underlying disease and the complications that occur during the presentation (respiratory failure). Generally outcome of patients with MM is excellent, as long as the aforementioned complications have not occurred.

SVCS

The prognosis of SVCS relates to the underlying disease and the complications that occur during the presentation (venous thrombosis, venous infarcts). Generally outcome of patients with SVCS is excellent, as long as the aforementioned complications have not occurred.

FN

The prognosis of FN relates to the underlying disease and the complications that occur during the presentation (sepsis). Generally outcome of patients with FN is excellent, as long as the aforementioned complications have not occurred.

Typhlitis

The prognosis of typhlitis relates to the underlying disease and the complications that occur during the presentation (ileus, pain, infection, perforation, GI bleed). Generally outcome of patients with typhlitis is excellent, as long as the aforementioned complications have not occurred.

SCC

Outcome of SCC depends on many variables, including tumor compression, duration of symptoms and underlying tumor.

Special considerations for nursing and allied health professionals.

NA

What's the evidence?

Cairo, MS, Coiffier, B, Reiter, A, Younes, A. “Recommendations for the evaluation of risk and prophylaxis of tumor lysis syndrome (TLS) in adults and children with malignant disease: an expert TLS panel consensus”. Brit J Haematol. vol. 149. 2010. pp. 578-86. (Good multidisciplinary summary by expert panel.)

Coffier, B, Altman, A, Pui, CH, Younes, A, Cairo, MS. “Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence based review”. J Clin Oncol 2008 June. vol. 26. 1. pp. 2767-78.

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