Oncological Emergencies in hospital setting

Oncology

1. OnCOLOGICAL EMERGENCIES Dr Shreeprada Moderator-Dr Narendra K Chaudhary

2. Table 1 Common oncologic emergencies i Metabolic emergencies Tumor lysis syndrome Hypercalcemia ii Cardiothoracic emergencies Superior vena cava syndrome and superior mediastinal syndrome Pleural and pericardial effusion Cardiac tamponade Massive hemoptysis Pneumothorax, pneumomediastinum ATRA syndrome (seen in acute promyelocytic leukemia ) iii. Hyperleukocytosis Pulmonary leucocytosis CNS leukostasis iv. Infectious complications Febrile Neutropenia v. Associated with cytopenias /abnormal hemostasis vi. Genitourinary emergencies Hypertension, Hematuria Oliguria Hemorrhagic cystitis Acute renal failure vii. Abdominal emergencies Hemorrhage Mechanical obstruction/Perforation Inflammation viii. Neuralgic emergencies Direct emergency of malignancy Raised intracranial pressure Reference- Seth R Bhat AS Management of common oncological emergencies- The Indian journal of pediatrics 2011 Jun

3. TUMOR LYSIS SYNDROME Tumor lysis syndrome, described as the acute metabolic derangements that occur due to breakdown of tumor cells -Spontaneously (Spontaneous TLS) -Or secondary to initiation of chemotherapy (12-72hrs of starting chemotherapy) Reference- Seth R Bhat AS Management of common oncological emergencies- The Indian journal of pediatrics 2011 Jun

4. Pathophysiology Spontaneous or therapy induced lysis of tumor cells DNA ↑ Potassium ↑ P hosphate Cytokines ↑ Uric acid Accumulation in renal parenchyma Hypotension Inflammation Acute kidney injury Release of intracellular content ↓ Calcium Sudden cardiac death

5. Cairo-Bishop Definition of Clinical and Laboratory TLS L aboratory tumor lysis syndrome (≥2) (1) Uric acid: ≥8mg/dl (2) Potassium: ≥6mg/dl (3) Phosphorous: ≥6.5mg/dl (4) Calcium: < 7mg/dl or iCa <1.12 mmol/L C linical tumor lysis syndrome (LTLS plus any ≥1) (1) Creatinine: Serum creatinine rise from baseline by 0.3 mg/dL or 1.5 x ULN or Oliguria < 0.5 ml/kg/ hr (2 )Cardiac arrhythmia/sudden death (3) Seizure or 25% increase from baseline

6. Risk for Tumor lysis Syndrome Grading of Clinical TLS High Risk Intermediate risk Low Burkitt Lymphoma, Lymphoblastic Lymphoma DLBCL Indolent NHL ALL with TLC≥ 1 lac ALL with TLC 50k-1 lac ALL with TLC≤50k AML with TLC≥50K AML with TLC 10k-50K Bulky tumor Rapid response to tumor Remainder of patients Grade Serum Creatinine (ULN) Cardiac Arrythmia Seizure ≤1.5 None None 1 1.5 +, interventions not needed None 2 1.5-3 Non urgent 1, GTCS, controlled with medication, focal –not affecting ADL 3 3-6 Symptomatic, incompletely controlled with medicine, controlled with device Altered consciousness, partially controlled with medication, breakthrough seizures 4 >6 Life threatening arrythmia Prolonged, repetitive seizures, difficult to control(status) 5 Death Death Death Reference-AIIMS PICU protocol

7. Prevention OF tls Vigorous hydration 3 Litres/m 2 /day 48 h prior to therapy and at least 48-72 hours thereafter Half DNS with NO ADDED ELECTROLYTES Allopurinol 10 mg/kg/day PO in 2-3 divided doses (max 800 mg/day, 100 mg tablets available) Strict input-output monitoring Target urine output of 2-4 ml/kg/hr Watch for fluid overload (vitals, puffiness, liver span, input-output) furosemide 0.5 mg/kg/dose q 8–12 h if output less/ fluid overload Baseline and repeat testing High risk or established – q6-12h At risk but no evidence as yet – q24h

8. Treatment of established TLS Hyperhydration Monitoring: clinical, ECG Manage individual electrolyte disturbances Renal replacement in refractory cases.

9. hyperkalemia Cardiac stabilization if ECG abnormality 2 ml/kg 10% calcium gluconate ↓ ECG monitoring Shift K to intracellular compartment 1. salbutamol nebulization 2. 0.1 U reg insulin + 2 ml/kg 25% dextrose 3. NaHCO3 1-2 mEq /kg IV Gut binding Kayexalate(sodium polystyrene sulfonate) 1 g/kg PO q 6 hourly

10. Hyperuricemia Hyperhydrate Rasburicase 0.15-0.2 mg/kg IV in 50ml NS over 30 min OD Usually 1-2 doses (or even 1 vial) would suffice Life threatening hemolysis in G6PD deficiency Send serum uric acid sample on ice & process within 4 h Allopurinol cannot reduce established hyperuricemia but prevent further synthesis

11. Hyperphosphatemia Increase hydration Aluminium hydroxide 50-150 mg/kg/day PO in 4 divided doses ( gelusil ) Tab. Sevelamer (400 mg) 20-40 mg/kg/dose q 8 h PO

12. Hypocalcemia DO NOT TREAT ASYMPTOMATIC LAB HYPOCALCEMIA [Calcium x phosphate] > 60  deposits in kidney → AKI If symptomatic (cardiac/ neuromuscular) 10% Calcium gluconate 0.5ml-1ml/kg slow infusion ↓ ECG monitoring

13. Renal replacement therapy Indications(Refractory dyselectrolemia ) Potassium > 6 mEq /L Uric acid > 10 mg/dL Phosphorus > 10 mg/dL Acute oliguric/anuric renal failure Pulmonary edema /Signs of fluid overload Options Continuous renal replacement/ hemofiltration preferred Hemodialysis in hemodynamically stable older children Timely preventive measures may avoid need of dialysis

14. HYPERLEUCOCYTOSIS Total Leucocyte Count >1 Lac Generally seen in – AML, ALL , rarely CML Risk Factors – Age less than 1 year AML M4 M5 Cytogenetic abnormalities like Philadelphia Chromosome, 11q23, t(4,11) T ALL with mediastinal mass / T ALL with hypoploidy Blast phase of CML Reference –AIIMS PICU Protocol

15. Leucostasis Thrombosis Secondary hemmorrhage Metabolic derangement of tumor lysis Consequences Increase in blood viscosity Leukemic cell aggregate formation Adhesive interaction between damaged endothelium and leukemic blast Decrease tissue perfusion and hypoxia Reference –AIIMS PICU Protocol

16. Interventions after hospitalization Intravenous hydration (2-4 times the maintenance therapy) Alkalinization with sodium bicarbonate Allopurinol (10mg/kg/day in 3 divided doses) Desired platelet count is 20,000 per cubic mm to prevent cerebral hemorrhage Avoid packed red cell transfusion if child is hemodyanamically stable Systemic chemotherapy - as soon as child is metabolically stable. . Leukopheresis - Older children , Exchange Transfusion – infants Reference –AIIMS PICU Protocol Clinical Features CNS – Altered sensorium , Blurred vision , Stupor, Papilledema, Coma, Bleed, infarct Pulmonary- Tachypnea , hypoxia , Cyanosis, Dyspnea CXR-pulmonary infilterates GUT- Oliguria, Anuria, Priaprism Vascular – DIC, MI, Renal Vein thrombosis, Retinal Hemmorrhages

17. Leukoreductive procedures

18. SUPERIOR Vena cava syndrome and superior mediastinal syndrome SVCS denotes compression, obstruction or thrombosis of SVC and SMS denotes SVCS and tracheal compression. Etiology- Intrinsic causes- Vasular thrombosis, post catherisation Extrinsic causes- Malignant Anterior Mediastinal Tumor Seen in HL, NHL, T cell ALL (more commonly), Teratoma, Germ cell tumor, Thyroid cancer, Thymoma(less commonly) Clinical manifestations SVCS- Swelling and plethora of face, cyanosis of face/neck/upper limb Conjuctival suffusion, Horner syndrome, Altered sensorium, pleural and Pericardial effusion SMS- Dyspnea, orthopnea, stridor, Wheeze, Hoarsness of voice, Dysphagia, chest pain syncope Reference-AIIMS PICU Protocol

19. SMS/SVCS CXR- mass,widened mediastinum, tracheal deviation, pleural effusion CBC/initial Investigations- Blasts, TLS profile, BMA under LA ECG, ECHO,PFT Diagnostic Treat Avoid 3S Supine position Sedation Stress Steroids, Cytoreductive chemotherapy Not diagnostic Differentials Assess Anesthesia risk High Low Biopsy Empirical Chemotherapy Reassess after 4-6 hours Low risk - biopsy High risk- Continue empirical treatment Intrinsic thrombosis- Unfractionated Heparin/ LMWH Reference AIIMS PICU protocol Reference-AIIMS PICU Protocol

20. Neutropenic enterocolitis( typhilitis ) Most common GI emergency in pediatric oncology It is a necrotizing colitis limited to terminal ileum and caecum, seen in hematological emergencies and stem cell transplant recepients . Pathogens associated are – Pseudomonas, E coli, Staphylococcus, Streptococcus. Pathogenesis- Cytotoxic chemotherapy  Mucosal injury and impaired host defense  Bowel invasion  transmural bowel wall inflammation and necrosis Leading to Peritonitis C/F- Acute onset Right lower Abdominal pain(90%) Perforation Right Lower abdominal mass Necrosis of bowel Fever, Diarrhea, Nausea, Emesis Septic Shock Features of perforation and shock Reference-AIIMS PICU Protocol

21. Investigations- Xray- Pneumatosis Intestinalis Bowel wall thickening( thickening >3mm in any segment of bowel for at least 30mm length ) Pneumoperitoneum Screning investigation – Ultrasonography thick bowel in caecal region IOC/most accurate- CT scan shows diffuse thickening of caecal wall Barium enema Treatment- NPO, IV fluids, Correction of dyselectrolemia if any, Broad Spectrum Antibiotics Surgical intervention ( Resection colostomy ) – if Persistent GI bleed, Perforation Bowel Infarction Reference-AIIMS PICU Protocol

22. Neurological emergencies(spinal cord compression) Uncommon in children Associated tumors- Ewings Sarcoma, Hodgkin Lymphoma, Germ cell tumor, Neuroblastoma. Mechanism- Direct extension of tumor Metastatic spread Drops metastasis Clinical Features-Back pain with/without radicular symptoms , sensory disturbances, motor weakness, bowel and bladder involvement(later) Investigations- Xray spine –detects vertebral mets , IOC- MRI Reference-AIIMS PICU Protocol

23. Treatment- Inj Dexamethasone (decreases local edema) (1mg/ kg emergencency MRI,) (symptoms without any neurological examination lower dose of dexamethasone 0.25-0.5mg/kg every 6 hr followed by MRI ) Chemotherapy in Chemosensitive tumors and radiotherapy in radiosensitive tumors. Surgery- Laminectomy if nature of tumor is not known. Reference-AIIMS PICU Protocol

24. Apml -differentiation syndrome Also known as Retinoic Acid Syndrome Seen in patients with APML treated with ATRA/ATO Pathogenesis  Leading to SIRS, occlusion of microcirculation, tissue infilteration ATRA differentiation of promyelocytes which release- IL-6, IL-8, IL-1B, TNF-alpha(proinflammatory cytokines) Release of Cathepsin G increase capillary permeability and endothelial dysfunction Increase adhesion of blasts to endothelium causes endothelial damage. Reference-AIIMS PICU Protocol

25. Symptoms- 2 days to weeks (median day 12) Fever, weight gain, edema, pleural and pericardial effusion, pulmonary infilterates , hypotension , renal failure D/d- Sepsis, pneumonia, fluid overload, Renal failure, CHF, Pulmonary hemmorrhage Treatment- Prophylactic therapy with Dexamethasone(2.5mg/m2/12h) TLC >5000-10000/mm3 Treatment for DS- Dexamethasone(10mg/m2/12h) Supportive management Temporary discontinuation of ATRA/ATO if life threatening Renal or pulmonary Dysfunction is present. Reference-AIIMS PICU Protocol

26. FEBRILE neutropenia Defination - Oral-single value of ≥101F, Axillary temp ≥ 100.4F for more than 1 hour Neutropenia- ANC≤500 / ≤ 1000 and predicted decrease to <500 within next 48 hours. Can have fever/ hypothermia/ no fever(due to treatment with steroids as part of chemotherapy treatment)

27. High risk feature= Younger age (<5 years) ALL in Induction AML Burkitt’s lymphoma Bone marrow relapse in leukemia First 30 days of allogenic hematopoietic stem cell transplantation Clinical focus of infection, vomiting ,abdominal pain, severe mucositis Altered mental status, hypotension, hypoxia (SpO 2 <94%), renal or hepatic insufficiency Presence of central venous catheter Anticipated duration of neutropenia more than7 days Profound neutropenia (ANC<0.1x10 9 /L), absolute monocyte counts <0.1x10 9 /L New chest X-ray findings CRP more than50 mg/L

28. Febrile neutropenia-Initial management Low risk High risk OPD Inpatient(IV) If able to take orally Access to Emergency is present Physician decision Oral Levofloxacin/ciprofloxacin/ Cefixime/Amoxiclav 24 hrly Ceftriaxone 12 hrly cefipime Observe for 4-24 hrs Patient stable Documented infection GI intolerance Physician decision Early stepdown of antibiotics, Oral Antibiotics Change to oral antibiotics After 24 hours if pt stable Inpatient/IV antibiotic/ Emperical antibiotic Monotherapy Piptaz Cefoperazone-sulbactum Cefepime Adjust antibiotic according to clinical/ Radiological/Culture Abdominal symptoms-Metronidazole Diffuse lung infilterate -PJP-high dose cotrimoxazole Focal lung infilterate -fungal-Antifungal Gram negative/Pneumonia/clinically unstable- carbapenem/add Amikacin MRSA/Hypotension/Severe mucositis/soft tissue Infection/suspected cental line infection-Vancomycin CRO-colistin

29. 24-72 hours of Empirical Antibiotics Responding Afebrile >24 hr Consider stopping antibiotics Initial Low risk Stop Antibiotics after 72hrs Irrespective of marrow recovery Consider discharge Initial High risk Clinically stable Continue Antibiotics till ANC >500 Unexplained fever/Blood culture sterile@48hrs Documented infection Modify antibiotics a/c culture/ Clinical/Radiological Continue antibiotics till 7-14 days Till ANC>500 7 days after negative blood culture Resolution of focus of infection Not responding Recurrent Infection Unexplained fever Clinically stable Continue same antibiotic Search for focus of infection Clinically Unstable Review AB coverage For ESBL, CRO, MRSA 2 nd line-Mero 3 rd line - Colistin Search focus of infection Empirical antifungal>96hrs Documented infection Modify AB a/c site of infection Not responding responding Continue antibiotics till 7-14 days Till ANC>500 7 days after negative bloodculture Resolution of focus of infection

30. INVASIVE FUNGAL DISEASE High risk- FN with AML Relapse ALL Solid tumors Highly Myelosuppresive Allogenic BMT Fever.96 hr on empirical AB Expected neutropenia>10 days Diagnosis- Blood, BAL, scrapings. Tissue culture CT thorax – Aspergillus typical nodular lesions And ground glass halo sign and typical crescents or cavities CT sinus≥2years USG screening- liver,spleen Candida and aspergillus causes- multiple hepatosplenic lesions, skin nodules and endoca rditis 2D ECHO- Vegetations Galactomannan- Aspergillosis Empirical treatment- Caspofungin /Liposomal AMB in FN Voriconazole-Aspergillosis Fluconazole-candida

31. References AIIMS PICU Protocol Seth R Bhat AS Management of common oncological emergencies- The Indian journal of pediatrics 2011 Jun Management of Febrile Neutropenia Dr Narendra Chaudhary Dr Nuthan Kumar Dr Leni G Mathew-Indian Journal of Practical Pediatrics 2015

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