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hematologic and oncologic emergencies

hematologic and oncologic emergencies. wes miller fellow, pediatric hematology and oncology october 31 2007. objectives: AMBITIOUS!. review common presentation, pathophysiogy and (emergent) management of the following the bleeding hemophiliac

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hematologic and oncologic emergencies

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  1. hematologic and oncologic emergencies wes miller fellow, pediatric hematology and oncology october 31 2007

  2. objectives: AMBITIOUS! • review common presentation, pathophysiogy and (emergent) management of the following • the bleeding hemophiliac • “the bleeding patient with immune thrombocytopenia purpura (ITP)” • tumor lysis syndrome in the patient with a new malignancy • hyperleukocytosis in acute leukemias or myeloproliferative disease (MPD) • typhlitis • superior vena cava syndrome in the patient with a mediastinal mass

  3. the sickler... • presents a whole new set of emergencies • potential for great morbidity and mortality • more familiar to most ED docs in Atlanta • not addressed here

  4. but, first... • THANKS for the job you do for out patients • we realize our patients are HIGH MAINTENANCE • our attitude on the phone is often one of caution • at risk population • subtleties matter

  5. the bleeding hemophiliac • 8 month old male • presented to PMD with 1 week hx of progressive bilateral LE weakness • diagnosed with GBS, sent to SR ED • at SR ED, noted to have multiple bruises over body (not just over shins), many nodular and hard • history of sublingualfrenular bleed x 10 days following mild trauma in past • history of 2 weeks of oozing at surgical site following neonatal circumcision • history of LP at 6 weeks of life for fever (RSV) • waxing and waning “bulging bruise” at site EVER SINCE

  6. the bleeding hemophiliac • family history negative for bleeding disorders • child with history of vit K ppx at birth, no warfarin or rat poison exposures, no recent antibiotics or diarrhea. • Formula fed; typical baby foods • PE: alert, smiling, clapping. VS wnl. no spontaneous movement of BLE, no withdrawal from painful stimuli, patellar areflexia • CBC normal, platelets robust • PT: 12.6 seconds (normal) • PTT: 125.6 seconds (not normal) • ultrasound: massive thoracolumbosacral paraspinal hematoma

  7. the bleeding hemophiliac

  8. the bleeding hemophiliac • normally, the known hemophiliac will present to your ED • hemophilia • A (“classic”): factor 8 deficiency • B (“christmas disease”): factor 9 deficiency • both coded on X chromosome • disease due to absent or dysfunctionalprotein • clinically INDISTINGUISHABLE • prevalence: 1 in 7500 males • hemophilia A seven times more common than hemophilia B

  9. the bleeding hemophiliac • hemophilia graded according to degree of factor dysfunctionality: • severe: <1% native activity • moderate: 1% - 5% native activity • mild: >5% native activity • where do hemophiliacs bleed? • everywhere!!! • mucocutaneous bleeds (epistaxes, oral, GI) • SOFT TISSUE BLEEDS • HEMARTHROSES!!!!! • muscle bleeds (ileopsoas!) • eyes, renal/GU, throat • CNS !!!!!!!

  10. the bleeding hemophiliac • treatment options • respective recombinant factor replacement(both F8 and F9 deficiency) • DDAVP (mild factor 8 deficiency) • FFP **** (factor 9 deficiency) • cryoprecipitate **** (factor 8 deficiency) • antifibrinolytics (amicar) • treatment strategies • “on demand” • primary prophylaxis • secondary prophylaxis

  11. the bleeding hemophiliac • DOSING SPECIFICS • recombinant factor 8 dosing: • 1 unit/kg of factor 8 raises the activity level 2% • recombinant factor 9 dosing: • 1.5 unit/kg of r-factor 9 raises the acvity level 1% • beware anaphylaxis in F9 replacement • FUNDAMENTAL PRINCIPLE: • when in doubt, treat!!!! • standard rule of thumb: • correct the bleeding hemophiliac child to 80% - 100% activity

  12. the bleeding hemophiliac • barriers to therapy: the dreaded factor inhibitor • 25% - 30% in F8 deficiency • 3% in F9 deficiency • options for patients with inhibitors • FEIBA • do not use antifibrinolytics with FEIBA • recombinant VIIa (novoseven) • antifibrinolytics (amicar)

  13. ITP • 3 y/o male presents with sudden onset, 1 day history full body petechiae and purpura • no epistaxis, melena, hematochezia, hematuria, no h/a, no emesis • no recent fever, no bony pains; excellent energy and appetite • no chronic medications, but mom gave robitussin 2 weeks ago for “cold” • mom frantic: just saw FoxNews special and wants to know if child dying of “meningitis”

  14. ITP • PE: vs wnl • child jumping up and down on exam bed • 8 year old brother then tackles patient who is giggling and about to fall off the bed • head to toe petechia and purpura • OC with multiple purpura, none oozing • CN exam normal, neuro exam normal • no HSM • CBC with differential: • WBC 6k/microL, relative lymphocytosis, 10% atypical lymphocytes, ANC 2000 • hgb 11.8 g/dL • platelets <10k/microL

  15. ITP • the most common AI disorder affecting a hematologic element (1:10,000 kids/year) • peak age: 2 - 6 years • males = females (children) • 2 flavors: • acute (spontaneous resolution < 6 months) • chronic (persistance > 6 months)

  16. ITP • cause: macrophagic destruction of antibody-sensitized platelets • occurs in RES • primary site: spleen • clinical course • usually, antecedent viral illness/vaccination in weeks prior to onset • abrupt onset bleeding/bruising • otherwise HEALTHY kid

  17. ITP • how low do they go?? • plts < 20K: over 80% • usually isolated: expect normal WBC, hgb • anemia in 15% of cases: extracorporeal losses • splenomegaly? • palpable spleen present in 10% • peripheral smear “mandatory” • confirm true t’penia (rule out spurious!) • may see large plts • important negatives: • no WBC abnormalities • no evidence of MAHA • no evidence of AIHA • other work-up: • direct antibody test (DAT/direct Coomb’s) • ABO/Rh blood type

  18. ITP treatment intracranial hemorrhage risk

  19. ITP • where, exactly, do ITP kiddos bleed?? • “most” with petechiae/ecchymoses/purpura • epistaxis/oral wet purpura in < 30% • GI (melena/hematochezia), hematuria in < 10% • menorrhagia in appropriate age group • ICH: 0.1% - 0.9% • how prone to serious bleeding are ITP patients?? • not very!!! • concept of total body platelet mass • bone marrow: LOTS of megakaryocytes! • compare to other thrombocytopenic contexts • iatrogenic post chemo! • risk stratification with absolute platelet count • < 20K/microL: greatest • 20K - 50K/microL: moderate • >50K : insignificant

  20. ITP • reasons to treat: • suspected ICH • known ITP with significant trauma • recurrent or unabating mucosal bleeding • anemia secondary to loss • rarely: extenuating social situation • NOT reasons to treat: • parental anxiety • petechiae or purpura, no matter how florid

  21. ITP • management armamentarium • educate, educate, educate • anticipatory guidance • counsel to avoid antiplatelet meds (ASA, NSAIDs) • Platelets are NOT TYPICALLY HELPFUL**** • observation is commonest strategy • WinRho: monoclonal anti-Rho D antigen antibody • only for non-anemic, DAT negative, Rh+ patients • IVIG • steroids***** • other immunomodulatory agents • splenectomy

  22. ITP • to marrow or not to marrow??? • good concensus: do not marrow if • clinical gestalt consistent with ITP • plan observation alone • plan IVIG and/or anti-D therapy • debatable • plan corticosteroid treatment (even in kids with clinical constellation classic for ITP) • good concensus: marrow if atypical clinical picture • natural history: • resolution in 50% by 4 - 8 weeks • resolution in 65% by 3 months • resolution in 75% by 6 months • 1/3 of “chronic” patients will spontaneously resolve • factors associated with chronicity: • females • age older than 10 (also very young?) • insidious onset

  23. tumor lysis syndrome (TLS) • 8 year old male presents with rapidly distending abdomen, first noticed 4 days ago • febrile, anorexic, pale; stooled yesterday; decreasing UOP • PE: mild distress, large palpable discreet mass in right lower abdomen • CT: large mass near ileocecum • CBC: • WBC 10 K/microL • 3% blasts • mild anemia. • chemistries: • LDH 22,000 U/L (quite high) • uric acid: 12 mg/dL (quite high) • K: 6.1 mmol/L (elevated) • creatinine: 1.3 mg/dL (elevated) • phos: 9 mg/dL (elevated)

  24. TLS high [K+] purines high [phos]

  25. TLS • sudden burden of intravascaular potassium, phosphate and uric acid spilled by dying tumor cells • rhabdomyolysis • crush injuries • thermal injuries (burns/hypothermic exposure) • secondary to massive synchronous release of intracellular contents into extracellular space • typically seen at initiation of therapy for new malignancy, but MAY BE SEEN AT PRESENTATION • consequences: • acute renal failure (urate and CaPhos crystal tubulopathy) • cardiac dysrhythmias • acute hypocalcemia

  26. TLS • identifying patients at risk: • lymphomas: • classically, Burkitt’s lymphoma (practically, any NHL with short doubling time and bulky disease) • leukemias: • especially with high peripheral WBC (>100k/microL) • especially with large extramedullary disease burden: massive HSM, bulky T cell leukemia/lymphoblastic lymphoma • especially with nephromegaly: suggests leukemic renal parenchymal involvement • lymphoproliferative disorders • CML, JMML

  27. TLS • interventions: • hyper-hydration: • beware of oliguria • 2-3 x maintenance of NON POTASSIUM CONTAINING IVF • ?alkalanization • NOT AT CHOA • kayexelate (ideally, oral only), concomitant insulin and glucose, albuterol, CaGluconate**** • renagel • be CAUTIOUS: give supplemental calcium only with EKG changes with hyperkalemia or symptomatic hypocalcemia • goal: keep calcium-phosphate product LOW (<60)

  28. TLS • interventions: • allopurinol • inhibits hypoxanthine oxidase • enzyme critical in metabolic pathway from purine → → →uric acid • rasburicase • urate oxidase • converts uric acid to soluble metabolite (allantoin) • $$$$$ • consult with heme/onc before giving • begin treating malignancy!!!!

  29. hyperleukocytosis • 7 year old male presents to SR ED with CC of decreased energy x 7 days, unresponsive today • exam: • combative, confused, averbal • pupils anisocoric, but responsive • hemiparesis • pallor • tachycardic with gallop • massive HSM • CBC: • WBC: 327K/microL, 94% blasts • hgb: 4.6 g/dL • plts: 16K/microL • DIC panel: • PT: 24 seconds (prolonged) • PTT: 28 seconds (normal) • firbrinogen: 60 (low) • DDimers: 4100 (elevated)

  30. hyperleukocytosis

  31. hyperleukocytosis • patient intubated • surgery emergently consulted to place vas-cath • patient leukapheresed x multiple cycles in PICU • flow cytometry: acute T-cell lymphoblastic leukemia • progressed to renal failure, CVVH • worsening neurologic picture, unilateral fixed pupil • neurosurgery: cranial flap

  32. hyperleukocytosis

  33. hyperleukocytosis • presence of excessive blastemia in the leukemic • defined by peripheral WBC of at least 100K/microL • risk of symptomatology greatly increased for counts of 300K/microL or more • risk of symptomatology greatly increased in AML and CML with increased circulating myeloblasts • seen in • AML: 5%- 20% at presentation • ALL: 9% - 13% at presentation • CML: nearly all patients at presentation

  34. hyperleukocytosis • pathophysiology: • supraphysiologic whole blood viscosity: LEUKOSTASIS • aggregation of blasts in microvasculature • rheologic properties of MYELOBLASTScontribute to worse outcomes in AML or CML • larger than lymphoblasts • less distensible than lymphoblasts • “stickier” than lymphoblasts

  35. hyperleukocytosis • Pathophysiology • inappropriate activation of soluble phase clotting cascade • microvascular occlusion • distal ischemic injury/metabolic acidosis • MAHA (on top of myelophthistic cytopenias) • DIC • reperfusion hemorrhage • MSOF (CNS, pulmonary, renal, hepatic, cardiac, dactylitis, priapism, etc.)

  36. hyperleukocytosis • Interventions   DECREASE WHOLE BLOOD VISCOSITY: • primary intervention: CYTOREDUCTION • leukapheresis • cytoreductive chemotherapy • immediately notify heme/onc • we will urgently activate ARC cytapheresis folks • in the meantime, tip balance to LESS viscosity • immediately begin hyper-hydration (2-3 x maintenance) with non-K+ containing IVF • AVOID PRBC transfusions! • markedly increase whole blood viscosity • if necessary, transfuse with ceiling hgb of 8-9 g/dL • may transfuse platelets liberally if necessary

  37. hyperleukocytosis • interventions: • correct coagulopathy??? • depends! • make plans for urgent placement of vas-cath • manage TLS • who gets leukapheresed? • ANY PATIENT WHO IS SYMPTOMATIC FROM SUSPECTED LEUKOSTASIS SYNDROME • asymptomatic patients: • suspected AML: WBC > 100K/microL • suspected ALL: WBC > 200K/microL • suspected CML: WBC > 200K/microL

  38. typhlitis • 4 year old female • fever to 103, abdominal pain, emesis, bloody diarrhea x one day • undergoing induction chemotherapy for standard risk, B-precursor ALL • finished 2 week steroid course 3 days go • exam: • toxic appearing • tachycardic and hypotensive • mild abdominal distension, hypoactive bowel sounds • guarding on abdominal exam with marked TTP in RLQ • Central capillary refill > 5 seconds • KUB and cross-table lateral: no free air, possible pneumatosis intestinalis noted • CT abdomen: marked cecal bowel wall thickening, peumoatosis intestinalis present

  39. typhlitis • inflammation of the bowel wall, especially at the level of the cecum • seen in children with PROLONGED and PROFOUND neutropenia • Increased risk following chemotherapeutic drugs which cause mucositis • pathogenesis is essentially parallel to neonatal NEC (nectrotizing enterocolitis) • transmural bacterial translocation: PI • risk of bowel perforation • risk of translocated bacteremia: SIRS • pseudomonas aeruginosa • clostridium septicum

  40. typhlitis • at risk patients: • leukemics or NHL patients in induction • may be seen in consolidation for higher intensity regimens • following systemic cytarabine (ARA-C) therapy • especially post high dose cytarabine • any patient with prolonged, profound neutropenia • beware the child “in leukemic induction, coming off steroids, with sudden fever and acute abdomen/signficant RLQ pain”

  41. typhlitis • interventions: • fluid resuscitation • blood culture; stool culture if available • avoid rectal exam • empiric broad spectrum antibiotics (GP, GN, anaerobic coverage) • vancomycin, meropenem +/- aminoglycoside • evaluate for perforation (KUB/CT) • surgery consult if present • inotropic support for hypotension unresponsive to fluid resuscitation

  42. superior vena cava syndrome • 12 year old male, previously healthy • 6 week history of worsening cough • treated 1 week into symptoms with 2 weeks of systemic steroids for “bronchitis” • initially cough improved and felt much better • now worsening • 20 pound weight loss • past week: • worsening orthopnea (sleeping upright in chair) • fevers • past 2 days: • expanding mass in supraclavicular area

  43. SVCS • exam: • alert and non-toxic; completely oriented • facial edema • no stridor, not dyspneic • tachypneic, absent breath sounds R lung • palpable, firm nodes in right supraclavicular chain • splenomegaly

  44. SVCS

  45. SVCS

  46. SVCS • CBC: • WBC: 12K/microL, 13% blasts • hgb: 11.9 g/dL • plts: 144K/microL • quantitative βhCG (tumor marker): normal • quantitative AFP (tumor marker): normal • stat peripheral flow: T cell acute lymphoblastic lymphoma (leukemia?)

  47. SVCS • Interventions: • ICU observation • begun on empiric high dose solumedrol • based upon presence of blasts in smear • next day, begun on induction chemotherapy per flow cytometric diagnosis

  48. SVCS • signs and symptoms from impedence to flow in the SVC • plethora • facial edema • JVD • dyspnea • orthopnea • cough • stridor • for advanced SVC obstruction, may see • confusion • lethargy • headache • vision changes • usually, abnormal SVC flow results from extravascular compression, not a primary intraluminal thrombus

  49. SVCS • causes: mediastinal badness • malignancy • NHL (70% of malignant causes of SVCS) • HL • neuroblastoma • leukemias*** • germ cell tumors • granulomatous disease • aortic aneurysms • primary SVC thrombus

  50. SVCS • accurate diagnosis is critical... • ...however, tissue acquisition can be problematic • do NOT sedate • do NOT give anxiolytics • avoid anything which will compromise • muscular tone • venous return • an already taxed cardiopulmonary state

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