Hem/Onc EmergenciesCreated by: Peter Newburger, MD

Edited by: Venee Tubman, MD

Oncologic Emergencies

• Oncologic emergencies may represent the initial complaint!!

• Review pathophysiology, clinical manifestations and management– Tumor Lysis Syndrome– Hyperleukocytosis– Hypercalcemia– Superior Vena Cava Syndrome– Spinal Cord Compression

Tumor Lysis Syndrome (TLS)

• A potentially fatal metabolic complication that results from the rapid destruction of tumor cells, leading to:– hyperuricemia– hyperkalemia– hyperphosphatemia– hypocalcemia

Risk Factors for TLS

• Large tumor burden– acute leukemias with high WBC– aggressive large lymphomas (esp. Burkitt’s)– bulky solid tumors

• High tumor growth fraction

• High sensitivity to chemotherapy

• Elevated LDH

• Compromised baseline renal function– can be due to TLS prior to therapy

Prevention of TLS• Hydration without K at ≥3000 ml /m2/day; sustain

– urine output ≥100 ml/m2/hour

– urine specific gravity < 1.010

• Alkalinization: NaBicarb 50-75 mEq/L; maintain

– urine pH 7.0-7.5

– serum bicarb < 30

• Allopurinol 100 mg/m2/day in divided doses

Clinical Manifestations of TLS

• Hyperuricemia: lethargy, nausea, vomiting• Hyperphosphatemia and resultant

hypocalcemia: Anorexia, cramping, vomiting,• spasm, tetany, seizures, altered consciousness,

cardiac arrest.• Hyperkalemia: Widened QRS and peaked T

waves, watch for arrhythmias.• Acute renal failure

Treatment of TLS• Hyperkalemia

– Stop K+ Intake – Ca gluconate (100-200 mg/kg/dose)– Alkalinization – Insulin (1u/kg) with glucose (2 ml/kg of 25%) infusion– Ion exchange resin (1gm/kg) PO or PR

• Hyperphosphatemia and hypocalcemia– Aluminum hydroxide 50 mg/Kg orally q8h– Hydration + Diuresis – Urine pH 7-7.5 (pH >8 calcium phosphate stones)

Treatment of TLS

Dialysis Criteria:

• K+ > 6 mEq/L• Uric acid >10 mg/dl• Creatinine >10 X normal• Phosphorus > 10 mg/dl• Symptomatic hypocalcemia• Uncontrolled hypertension

Too many white cells: Hyperleukocytosis

• Peripheral WBC > 100,000 / ml

• Incidence: ALL 9 to 13% at presentationAML 5 to 22% at presentationCML almost all in chronic phase

• Mortality: during induction– 23 % in AML – 5 % in ALL

Pathophysiology of Hyperleukocytosis

• Increased blood viscosity blast cell aggregates & thrombi in microcirculation– Viscosity is a function of total red cell and white

cell volumes

• Blasts are larger in size, less deformable, & may have abnormal adhesion molecules

Clinical Manifestations of Hyperleukocytosis/

Hyperviscosity• CNS: Blurred vision, agitation, stupor, confusion,

headache, papilledema, ataxia

• Pulmonary: SOB, cyanosis and patchy infiltrates on CXR and right heart failure

• Renal: Oliguria, anuria and electrolyte abnormalities

• GU: Priapism

• Heme: Thrombosis and bleeding (DIC, fibrinolysis)

• Tumor lysis syndrome (without lysis)

Treatment of Hyperleukocytosis

1. Hydration: 3000 ml / M2 / day (2x maintenance), urine output = 100ml / M2 / hr; avoid diuretics

2. Allopurinol 300-600 mg/M2 or 10-20 mg/kg/24 day 3. Platelets and FFP to maintain plt > 20,000 / l and to correct

coagulopathy

4. Leukapheresis: a short term solution Problems include rapid rebound of WBC and cardiovascular instability

5. Chemotherapy: treat the underlying disease

6. (Red cell transfusion): increases blood viscosity – hematocrit should not be raised above 30%

Hypercalcemia (serum Ca > 10.5)

• Incidence: 0.4- 0.7%– Osteolytic Bone Tumors: Primary or Metastatic– Tumors: ALL, NHL, Ewing’s, neuroblastoma,

rhabdomyosarcoma, renal rhabdoid tumors, small cell carcinoma of ovary

• Bone demineralization due to– direct bone destruction– humoral factors and cytokine release: PTHrP, TGF-α and -β, IL-1, IL-6, TNF-α and -β

Clinical Manifestations of Hypercalcemia

• spiral of dehydration and Ca++

– Anorexia, malaise, drowsiness, coma– Nausea/vomiting, constipation, ileus– Polyuria– Bradycardia, arrythmias– pruritis, pancreatitis, DIC

Treatment of Hypercalcemia:

Emergency: Ca >14 mg/dl

• Treat underlying malignancy Calcium excretion

– Diuresis with NS and Lasix

Calcium mobilization from the bones – Bisphosphanates – Pamidronate

– Calcitonin + Mithramycin (only short-term)

Calcium absorption from the gut– Oral sodium phosphate

• Dialysis

Superior Vena Cava SyndromeSuperior Mediastinal Syndrome if compression of SVC + trachea

SYMPTOMS• headache, fullness in ears, distorted vision, drowsiness,

nightmares • cough, dyspnea, wheezing, stridor

SIGNS• plethora with swelling and flushing of face and neck• conjunctival edema and injection• cyanosis of face and upper extremities, engorgement of

collateral veins• seizures, stupor

CXR: Mediastinal mass ± pleural or pericardial effusions

SVC Syndrome• The terrible T’s:

T-cell lymphoma, T-cell ALL, malignant teratoma, thyroid cancer, thymoma

• Less commonly:– Hodgkin’s, pre-B NHL– Neuroblastoma– Rhabdomyosacroma– Ewing’s sarcoma

Superior Vena Cava Syndrome:Management

• Anesthesia is extremely risky – difficult intubation– respiratory failure that can be aggravated by a

decrease in respiratory muscle tone– reduced venous return and cardiac output that

can be aggravated by vasodilatation

• Diagnostic tissue should be obtained if the patient has an easily accessible site of disease (e.g. pleural effusion, ascites, bone marrow, lymph node)

Superior Vena Cava Syndrome:Management

Steroids: histological samples must be obtained within 24-48 hr

Chemotherapy: after tissue diagnosis

Spinal Cord CompressionOccurs in ~4% of children with cancer

Origin:• Tumor in epidural or subarachnoid space• Metastatic vertebral disease with cord compression• Spread to epidural space through foramina

Diseases that cause spinal cord compression:• Sarcomas (Ewing’s, Osteo, Rhabdo etc)• Neuroblastoma, lymphoma, leukemia – can be

presenting complaint

Symptoms/signs: • Back pain 80%, local or radicular in distribution• Sensory abnormalities• Localized tenderness to percussion 80%

Treatment: Depends on tumor (usually surgery or XRT)

CHF and Tamponade

• Cardiomyopathy due to radiation, BMT, or anthracyclines

• Tumor thrombus with Wilm’s tumor

• Pericardial effusion due to malignancy (1º or 2º) or infection

• Pericardial fibrosis due to radiation, tumor infiltration, or infection

Treatment: ask a cardiologist!

White Blood Cells

Too few

ANC Clinical Significance >1500 Normal

1000-1500 Statistically abnormal but not clinically significant

500-1000 Slight predisposition to infection

200-500 Significant predisposition to infection; IV antibiotics for fever

<200 Very high risk of infection, including opportunistic agents; decreased signs of inflammation; aggressive in-patient treatment

Contributing factors

Disruption of integumentary barriers

Altered microbial colonization

Lymphopenia, immunosuppression

Other factors: mechanical obstruction malnutrition splenectomy

Fever and Neutropenia

• Fever ≥ 38.5C or sustained ≥ 38.0C

• ANC ≤ 500

• Localizing signs/symptoms may be diminished or absent

• Afebrile neutropenia: localized infection with diminished local reaction and no fever

Initial Empiric Treatment of Fever/ Neutropenia

PROMPT INITIATION: Single most important issue. Every patient who presents with fever and neutropenia is considered septic until proven otherwise

Mortality for gram negative sepsis down from 80% to 10%

Initial Empiric Treatment of Fever/ Neutropenia

80-95% of documented pathogens are bacteria Gram positive: Staph aureus, SNA, MRSA, Strep viridans Gram negative: E coli, Enterobacter, Klebsiella,

Acinetobacter, Pseudomonas

Broad spectrum regimen: Ampicillin and gentamycin Consider changing or adding cephalosporin (e.g.

cetriaxone) Consider adding metronidazole for anaerobe

coverage Consider adding ketoconazole for fungal coverage

• Remember PCP prophylaxis

Red Blood Cells

Too few

Anemia – Emergencies

• Blood loss

• Destruction– Acute hemolysis

• Lack of production– Hypoplastic crisis in chronic hemolytic anemia

• Sequestration– Splenic sequestration in sickle cell

• Other sickle crises

Anemia – blood loss

• Neonatal blood loss– Feto-maternal (Betke-Kleihauer stain for fetal

Hgb)– Twin-to-twin– Obstetrical accidents– Internal hemorrhage

• Older children: “All bleeding eventually stops”– If anemia is the presenting problem, then the bleeding

is chronic, not acute

Anemia – hemolysis• Signs: anemia with hyperbilirubinemia

and/or hemoglobinuria

• Etiology:– Immune

• autoimmune, isoimmune• paroxysmal cold hemoglobinuria (cold antibody)

– Microangiopathic• DIC, HUS/TTP • thrombocytopenia, schistocytes

– Primary RBC disorders: HS, sickle, G6PD, etc. (save green- & purple-tops before transfusion!)

Anemia – hemolysis

Treatment: RBC transfusion (± exchange for newborn)

– Emergency crossmatch: 45-60 min

– Type-specific blood: 10 min

– O-negative blood: immediate

Warm blood for PCH

Steroids for autoimmune hemolysis

Anemia – hypoplastic

• Primary: (rarely an emergency; RBCs drop slowly)

– Congenital hypoplastic anemia

– TEC (Transient Erythroblastopenia of Childhood)

• Secondary: (in the setting of chronic hemolysis)

RBC production due to virus (Parvo B19), drug, etc.

– RBC lifetime short, baseline low

– rapid & serious drop in H/H

• Treatment: transfusion

Platelets

Too many

(“D.V.” – don’t vorry)

Platelets

Too few

(sometimes worry)

Thrombocytopenia• Destructive

– Immune (ITP, isoimmune, maternal autoimmune)– DIC– Hemangioma (large, cavernous)– Neonatal thrombosis– NEC, asphyxia, RDS

• Hypoproductive– Chemotherapy– Leukemia, neuroblastoma, other marrow malignancy– TAR, amegakaryocytic thrombocytopenia– Fanconi’s anemia

• Sequestration – rarely significant clinically

Clotting

Too much

Paul Monagle, Anthony Chan, Patti Massicotte, Elizabeth Chalmers and Alan D. MichelsonAntithrombotic Therapy in Children: The Seventh ACCP Conference on Antithrombotic and Thrombolytic TherapyChest 2004;126;645-687

Venous Thrombosis

• Catheter-related in 50% of children and 80% of newborns

• Renal vein thrombosis (in newborn)• Homozygous protein S or C deficiency

– Neonatal purpura fulminans, CVA, eye damage, large vessel thrombosis

• Congenital thrombophilia (AT3 deficiency, factor V-Leiden, prothrombin G20210A)

– DVT rare before age 15

Venous Thrombosis

Treatment• tPA for clot within CVL

• Heparin – Loading: 75 U/kg IV– Maintenance: 20 U/kg/hr (age > 1 yr)– Adjust to keep PTT = 60-85 sec

• Follow with LMWH or coumadin

• Evaluate for thrombophilia

Tests for Thrombophilia• Antithrombin activity *• Protein C: activity *• Protein S: free antigen *• Factor V Leiden:

– Activated protein C resistance (aPCr) screen– If +, confirm by genotyping

• Prothrombin G20210A: genotype• Homocysteine: fasting serum • Lipoprotein(a)• Phospholipid antibody

– anticardiolipin IgG & IgM – Lupus anticoagulant *

Draw prior to anticoagulant therapy

Arterial ThrombosisTreatment• Heparin • Platelet inhibitors

– Aspirin– Clopidogrel (Plavix)

• Thrombolytic therapy – tPA– Streptokinase, urokinase

• Thrombectomy• Call: Alan Michelson

or 1-800-NO-CLOTS

Clotting

Too little

Bleeding/bruising: ER evaluation

• Child in ER with shock and purpura :DIC/ meningitis/ sepsis

• Well-appearing child with multiple bruises, petechiae ± mucosal bleeding:

ITP• Child with large hemarthrosis or hematoma:

hemophilia

Family history, past medical historyCultures, antibiotics (STAT) if sepsis consideredCBC, differentialPT, aPTT, freeze plasma for future factor levels if

hemophilia considered

Bleeding/bruising

• Thrombocytopenia or platelet disorder:Petechiae

Ecchymoses

Spontaneous mucosal bleeding

• Hemophilia or other humoral disorder:Hemarthrosis

Hematoma

Bleeding with trauma (cutaneous or mucosal)

Hemophilia: Treatment principles

Treat first, ask questions later!Family usually brings their own factor supply to

ER; if not, use the limited supply in the blood bank

When calculating dose, round up to the whole vial – never discard “excess”

Hemophilia: Treatment

Factor 8: 1 unit/kg yields 2% rise in factor level, with 12-hr half life

Factor 9: 1 unit/kg yields 1% rise in factor level, with 24-hr half life

Goals: % replacement

Severe bleed or surgery 100

Hemarthrosis 50-100

Minor soft tissue bleed ~40

Hemophilia: Treatment

Oral bleeding, tooth extraction• Single dose of factor (to 50-100% level)

• Amicar (ε-amino caproic acid)– 100-200 mg/kg (max 10 g) loading dose– 50-100 mg/kg (max 5 g) p.o. q6h for 7-10 days

Contraindicated for urinary tract bleeding

von Willebrand’s: DiagnosisConsider vWD in cases of:• Easy bruising, normal platelet count• Menorrhagia• Recurrent epistaxis• Family history of vWD or above Sx

Laboratory tests:• Recheck platelet count• vW antigen• vW (ristocetin cofactor) activity• Factor 8 activity

Is “mild von Willebrand’s disease” a disease?Sadler E: VonWillebrand disease type 1: a diagnosis in search of a disease Blood. 2003;101:2089-

2093

von Willebrand’s: Treatment

Factor replacement – dosage as for factor 8– Humate P, Alfanate (factor 8 preps with high vW levels)– Cryoprecipitate

DDAVP: releases endothelial stores in mild or moderate vWD– DDAVP trial to demonstrate response– 0.3 mcg/kg in 50 ml NS over 30 min– 150-300 mcg intranasal (Stimate®)– Repeat QD for only 1-2 days– Risk of hyponatremia, seizures

Mannucci PM: Treatment of von Willebrand’s Disease. N Engl J Med 2004;351:683-94.

Treatment of TLS• Urate oxidase (Rasburicase, Elitek®)

– Recombinant enzyme from Aspergillus flavus

– Reaction product: H2O2

check G6PD pre-treatment

• Antihyperuricemic effect– rapid onset of action– transforms uric acid into allantoin:

• very soluble compound• excreted by the kidneys

• $15,000 for 4-day course

Antibiotic Treatment of Fever/ Neutropenia

Additional considerations: CVL

Cover gram positives

(Nafcillin, Vancomycin)

Abdominal/GI symptoms or signs

– Cover anaerobes, Clostridia

(clindamycin, Zosyn)

Red Blood Cells

Too many

Neonatal Polycythemia

• Definition: Hct > 65%

• Preferred methods:– Venous blood

– Spun Hct

• Viscosity = f(Hct)– Linear at Hct < 65%

– Logarithmic at Hct > 65%

Neonatal Polycythemia

• Clinical Sx & signs – 50% asymptomatic– Plethora (red not blue)– Poor feeding– Lethargy– Tachypnea– Hypotonia– Irritability– Slow capillary refill

Neonatal PolycythemiaEtiology

• Primary– Intra-uterine hypoxia

– IDM

– Thyrotoxicosis, adrenal hyperplasia

– Trisomies 13, 18, 21

– Beckwith-Wiedemann Syndrome

• Secondary– Delayed cord clamping

– Twin-twin transfusion

– Dehydration

Neonatal PolycythemiaTreatment

• Increased fluid intake

• Correct accompanying metabolic abnormalities– glucose

– calcium

– oxygen

• Partial exchange transfusion

Anemia – Emergencies

Splenic sequestration in sickle cell disease

Very rapid development of– Shock– Anemia – ± thrombocytopenia– Markedly enlarged spleen

Patient M.C.

9/5/02 9/6/02

HGB 6.8 2.4

HCT 20.0 6.6

PLT 216 11

Anemia – Emergencies

Splenic sequestration in sickle cell disease

Treatment:

• Transfusion

• Maintain on chronic transfusion until …

• Elective splenectomy

Sickle Cell:Vaso-occlusive (Pain) Crisis

• Frequency inversely proportional to [Hgb F]

• Gnawing and throbbing, swelling, redness, warmth and tenderness

• Any part of the body: most frequent LS spine, knee, shoulder, elbow and femur

• Dactylitis in infants

• ± Fever

Sickle Cell:Vaso-occlusive Crisis

Treatment• Prompt hydration• Opiates:

–Adequate doses–Continuous infusion or PCA–Concurrent laxative

• NSAID (e.g. Toradol)• Steroids (Prednisone 15 mg/kg qd x 2)

Sickle Cell:Acute Chest Syndrome

• Def’n: New infiltrate on CXR + one or more:

–Fever >38.5C–Chest pain–Cough–Wheezing–Hypoxemia

• Pathophysiology:–Infection vs. infarction

Sickle Cell:Acute Chest Syndrome

Treatment:

– O2: if SaO2 < 3-5% points below baseline

– Broad spectrum antibiotics plus a macrolide– Pain medication (morphine, toradol)

– enough to decrease splinting, but avoid hypoventilation

– Bronchodilators for wheezing– Steroids – taper slowly– Hydration: Correct deficit and then 1x maintenance– Diuretic if fluid overloaded– Transfusion, simple or exchange

Sickle Cell:Stroke

• Incidence: 10% of sickle patients by age 20– highest at ages 2-10 – 20% incidence of “silent stroke”

• Large vessel thrombosis: intracranial arterial stenosis or obstruction (internal carotids, proximal middle cerebral or ant cerebral arteries)

• Sx: Hemiparesis, speech defects, focal seizures and abnormal gait; chronic cognitive deficits

• Dx: MRI or MRA• Mortality: 20%• Recurrence: 90% without chronic transfusion

Sickle Cell:Stroke

• Treatment: – Exchange transfusion (start with simple Tx while

arranging exchange) DO NOT DELAY INITIATING TRANSFUSION

THERAPY WHILE WAITING FOR IMAGING STUDIES IF SIGNS OR SYMPTOMS ARE CONSISTENT WITH STROKE

– Chronic transfusion (for how long???)

• Prevention:– Screening by transcranial doppler ultrasound– Chronic transfusion for flow velocity >200 cm/sec

Sickle Cell:Priapism

• Painful erection for more than one hour with urinary retention

• Long-term sexual dysfunction in 46%

• Treatment:– Conservative: Hydration, analgesia,

transfusion, pseudoephedrine– Surgical: Penile aspiration and

pseudoephedrine irrigation or creation of a fistula between glans and corpora cavernosa

ThrombocytopeniaTreatment

• Destructive– Severe complications extremely rare in ITP– Do NOT transfuse platelets unless:

• Isoimmune (random or washed maternal platelets)• Life-threatening bleeding in ITP• Clinically significant bleeding in TTP, HUS, DIC, etc.

– ITP: steroids, IVIG, anti-D– Emergency: splenectomy

• Hypoproductive– Transfuse platelets (at what platelet “trigger”?)

• Sequestration – transfuse if necessary (e.g. bleeding, surgery)

• White blood cells (or tumor cells)– Too many / too few

• Red blood cells– Too many / too few

• Platelets– Too many / too few

• Clotting– Too much/ too little