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Heme-Onc Emergencies Workshop Management of the Hospitalized Patient San Francisco, CA November 2013

• J. Ben Davoren, MD, PhD

Clinical Professor of Medicine, UCSF Division of Hematology/Oncology This session will be an interactive, cased-based discussion of the diagnosis and management of important hematologic or oncologic emergencies that the hospitalist may need to manage. We will work through the cases to cover the objectives for this discussion including:

• Diagnosis and management of suspected spinal cord compression
• Diagnosis and management of suspected brain metastasis
• Management of hypercalcemia with or without renal failure
• Management of febrile neutropenia
• Differentiating causes of rapid onset thrombocytopenia
• Identifying and managing clinical versus laboratory tumor lysis syndrome
• Acute management of very high white blood cell counts

Handouts with additional information and answers will be provided at the session.

In addition, participants are encouraged to present their own diagnostic dilemmas and real life cases for discussion.

Suggested Real-time Reference Sources:

 Internet Free:  Emedicine.medscape.com (reference section)  www.merckmedicus.com (includes Harrison’s online & Hospital Medicine

• nline)

 Internet Cost:  UpToDate (www.utdol.com)  MDConsult (www.mdconsult.com)  Mobile Device Applications (Free):  Medscape (Diseases & Conditions)  Clinical Care Options Oncology inPractice (Freter & Haddadin Oncologic Emergencies section)

CASES

• 1. A 56 year old man with established castrate-resistant prostate cancer presents with

new motor weakness but intact bowel and bladder function. You are concerned about spinal cord compression.

• a. What evaluation is needed to make the diagnosis?
• b. While waiting for definitive therapy, what is the right empiric dose of

dexamethasone to administer and on what schedule?

• 2. The same patient receives radiation therapy for suspected cord compression and

clinically improves over the first two days, but then deteriorates.

• a. What else do you need to think about?
• b. Who else besides you needs to know?
• 3. A 51 year- old man with no past medical history presents with altered mental status,

weight loss, pancytopenia, and baseline emergency room labs show a high calcium and low albumin. What is the first thing you need to do?

• a. 80 mg IV furosemide
• b. 2L Normal Saline
• c. IV pamidronate 30-90 mg
• d. IV/ SQ calcitonin
• e. IV Solumedrol
• f. Something else
• 4. A similar patient presents with a high calcium and renal insufficiency, a CrCl less

than 30 ml/min.

• a. How does that limit your options in treating hypercalcemia?
• 5. A 77 year old woman with stable Chronic Lymphocytic Leukemia is admitted for

dehydration, fatigue, and anemia. On hospital day 2, a differential reveals a neutrophil count of 400 cells/mm3 just as the nurse calls that the patient has a temperature of 100.8F

• a. What is the first thing you need to do?
• b. Does that change if she has a permanent indwelling catheter?
• c. Should you administer filgrastim (G-CSF) to stimulate neutrophils?
• 6. You have just received signout on a 51 year old female admitted with community-

acquired pneumonia. She has yet to ‘turn the corner’ clinically. Before you see her, you get a stat page from the lab saying that her CBC shows a platelet count of 14,000/mm3. What do you want to know right now this minute?

• a. PT/PTT/fibrinogen to rule out DIC
• b. Yesterday’s platelet count to see how far it’s fallen
• c. Is the patient bleeding?
• d. Has this patient received heparin in any form in the last week?
• e. LDH to rule out TTP

• 7. If Heparin-Induced Thrombocytopenia (HIT) is the leading diagnosis in this patient,

how long should she receive warfarin anticoagulation after the platelet count has normalized with a thrombin inhibitor?

• a. If no clot, stop;

If clot, 3 months

• b. If no clot, 3-4 weeks;

If clot, 3 months

• c. If no clot, 3-4 weeks;

If clot, indefinite (at least 6 months)

• 8. If Thrombotic Thrombocytopenic Purpura (TTP) is the leading diagnosis in this

patient, how soon should there be clinical improvement with plasma exchange (apheresis)? How long should plasma exchange be continued?

• 9. If Disseminated Intravascular Coagulation (DIC) is the leading diagnosis in this

patient, when should heparin be considered in addition to supportive care?

• a. Once FFP, cryo and platelets given, give heparin to prevent further rise in

PT/INR

• b. When there is definite evidence of thromboembolism
• c. When factor/platelet replacement are ongoing but DIC labs are still abnormal
• d. When factor/platelet replacement are ongoing, DIC labs are abnormal, but only

if patient having clotting/bleeding

• 10. How would the possible diagnosis change if the patient were post-cardiac

catheterization and had received antiplatelet therapy with a gpIIb/IIIa inhibitor?

• 11. A previously healthy 64 year old man is admitted with fatigue, confusion, SOB, and

easy bruising for 5 days, associated with a WBC count of 128,000 cells/mm3, Hgb of 6.8 g/dL, platelets of 22,000/mm3, a plasma creatinine of 3.4 mg/dL, uric acid of 9 mg/dL and plasma potassium of 5.6 mmol/l, with a tentative diagnosis of Acute Myeloid Leukemia. What do you want to do first?

• a. Evaluate for DIC / Transfuse platelets
• b. Check tumor lysis labs and start allopurinol
• c. Give antibiotics for functional neutropenic fever & sepsis
• d. Call Renal to initiate dialysis for hyperkalemia
• e. Call IR for central catheter for leukapheresis
• f. Give chemotherapy to reduce WBC count
• 12. Medical Oncology decides to treat the patient above and begins fluids and allopurinol

to prevent tumor lysis syndrome.

• a. What should you watch for while you are on duty and the oncologist is away at

the race track?

• b. What is the role of empiric rasburicase to bring down the uric acid level and

what are the risks of using it?

Selected references:

Corticosteroid dose in spinal cord compression http://www.ncbi.nlm.nih.gov/pubmed/18420159 Lancet Neurol. 2008 May;7(5):459-66. doi: 10.1016/S1474-4422(08)70089-9. Metastatic epidural spinal cord compression. Cole JS, Patchell RA. Abstract Metastatic epidural spinal cord compression (MESCC) occurs when cancer metastasises to the spine or epidural space and causes secondary compression of the spinal cord. MESCC is a common complication

• f malignancy that affects almost 5% of patients with cancer. The most common symptom is back pain.

MESCC is a medical emergency that needs rapid diagnosis and treatment if permanent paralysis is to be prevented: the diagnosis of MESCC is best made with MRI; and corticosteroids, radiation therapy, and surgery are all established treatments. Future research will focus on prevention, improving detection, and the development of new treatments. PMID: 18420159 Hypercalcemia and pamidronate in renal insufficiency http://www.abstracts2view.com/endo/view.php?nu=ENDO12L_SAT-366 [SAT-366] Safety of Intravenous Pamidronate for Bone Hyperresorption in Patients with Chronic Critical Illness (CCI) and Chronic Kidney Disease (CKD) Rifka C Schulman, Chenbo Zhu, James H Godbold, Jeffrey I Mechanick. Objective: Chronic critical illness (CCI) occurs in survivors of acute critical illness remaining ventilator- dependent via tracheostomy. Pamidronate reduces bone hyperresorption in patients with CCI (1), but its use has been limited due to concerns about nephrotoxicity. The purpose of this study is to determine the safety of intravenous (IV) pamidronate on renal function in patients with CCI and CKD. Methods: A retrospective case series of patients admitted to The Mount Sinai Hospital Respiratory Care Unit from 2006-2010, identified patients who received IV pamidronate, administered for 24 hour urine N- telopeptide (NTx) ≥ 70 nmol BCE/mmol Cr or serum NTx > 40 nMBCE/L. Pamidronate 30-90mg was infused intravenously over 4 hours. Patients in both groups received calcium carbonate, ergocalciferol and calcitriol. Changes in glomerular filtration rate (GFR), estimated by the MDRD formula, and creatinine were tabulated for 4 CKD groups for those who did (N=115) and did not (N=200) receive pamidronate, respectively: no or mild CKD up to stage 2 (N=83, N=121), stage 3 CKD (N=13, N=28), stage 4 (N=3, N=30), and stage 5 on hemodialysis (N=16, N=21). Results: None of the pamidronate groups or doses showed significant reductions in GFR ≥ 25% immediately after, or at 7 or 14 days post-infusion. Median changes in GFR from baseline to 7 days per CKD group were 0% (P<0.0001), -4% (P=0.29), -4% (P=1) and -9% (P=0.02) after pamidronate, and 0%, 0%, 6% and 6%, in the control groups (P<0.05), respectively. Patients with increases in creatinine ≥ 0.5 or ≥ 1.0 mg/dl (for baseline creatinine < or ≥ 1.4 mg/dl, respectively) were 0%, 4.4%, 6.7% and 18.2%, in the pamidronate groups, and 0.8%, 2.4%, 8.8%, and 20.8%, in the control groups, respectively. Differences in creatinine change between the groups did not reach statistical significance (P=0.17, 0.06, 0.39, 0.78, respectively). Discussion: IV pamidronate was not associated with significant worsening of renal function, irrespective

• f CKD stage. Small fluctuations in renal function in this cohort of patients with multiple comorbidities

were not noted to be significant in the pamidronate group compared to the general CCI population. Conclusion: Pamidronate was not associated with short-term nephrotoxicity in patients with CCI, with or without CKD. It is hoped that these results will remove barriers to more aggressive management of metabolic bone disease in CCI, which may have salutary downstream effects on morbidity and mortality.

Filgrastim in established neutropenic fever http://www.ncbi.nlm.nih.gov/pubmed/15961767 J Clin Oncol. 2005 Jun 20;23(18):4198-214. Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of randomized controlled trials. Clark OA, Lyman GH, Castro AA, Clark LG, Djulbegovic B. Abstract PURPOSE: Current treatment for febrile neutropenia (FN) includes hospitalization for evaluation, empiric broad-spectrum antibiotics, and other supportive care. Clinical trials have reported conflicting results when studying whether the colony-stimulating factors (CSFs) improve outcomes in patients with

• FN. This Cochrane Collaboration review was undertaken to further evaluate the safety and efficacy of the

CSFs in patients with FN. METHODS: An exhaustive literature search was undertaken including major electronic databases (CANCERLIT, EMBASE, LILACS, MEDLINE, SCI, and the Cochrane Controlled Trials Register). All randomized controlled trials that compare CSFs plus antibiotics versus antibiotics alone for the treatment

• f established FN in adults and children were sought. A meta-analysis of the selected studies was

performed. RESULTS: More than 8,000 references were screened, with 13 studies meeting eligibility criteria for

• inclusion. The overall mortality was not influenced significantly by the use of CSF (odds ratio [OR] = 0.68;

95% CI, 0.43 to 1.08; P = .1). A marginally significant result was obtained for the use of CSF in reducing infection-related mortality (OR = 0.51; 95% CI, 0.26 to 1.00; P = .05). Patients treated with CSFs had a shorter length of hospitalization (hazard ratio [HR] = 0.63; 95% CI, 0.49 to 0.82; P = .0006) and a shorter time to neutrophil recovery (HR = 0.32; 95% CI, 0.23 to 0.46; P < .00001). CONCLUSION: The use of the CSFs in patients with established FN caused by cancer chemotherapy reduces the amount of time spent in hospital and the neutrophil recovery period. The possible influence

• f the CSFs on infection-related mortality requires further investigation.

Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapyand Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. http://www.ncbi.nlm.nih.gov/pubmed/17146606

• Chest. 2012 Feb;141(2 Suppl):e495S-530S. doi: 10.1378/chest.11-2303.

Linkins LA, Dans AL, Moores LK, Bona R, Davidson BL, Schulman S, Crowther M; American College of Chest Physicians. Abstract BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reaction that can lead to devastating thromboembolic complications, including pulmonary embolism, ischemic limb necrosis necessitating limb amputation, acute myocardial infarction, and stroke. RESULTS: Among the key recommendations for this article are the following: For patients receiving heparin in whom clinicians consider the risk of HIT to be > 1%, we suggest that platelet count monitoring be performed every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first) (Grade 2C). For patients receiving heparin in whom clinicians consider the risk of HIT to be < 1%, we suggest that platelet counts not be monitored (Grade 2C). In patients with HIT with thrombosis (HITT) or isolated HIT who have normal renal function, we suggest the use of argatroban or lepirudin or danaparoid over other nonheparin anticoagulants (Grade 2C). In patients with HITT and renal insufficiency, we suggest the use of argatroban over other nonheparin anticoagulants (Grade 2C). In patients with acute HIT or subacute HIT who require urgent cardiac surgery, we suggest the use of bivalirudin over other nonheparin anticoagulants or heparin plus antiplatelet agents (Grade 2C). CONCLUSIONS: Further studies evaluating the role of fondaparinux and the new oral anticoagulants in the treatment of HIT are needed.

Antiplatelet agents and acute thrombocytopenia http://www.ncbi.nlm.nih.gov/pubmed/17146606 Clin Res Cardiol. 2007 Feb;96(2):61-9. Epub 2006 Dec 8. Glycoprotein IIb/IIIa inhibitor-induced thrombocytopenia: diagnosis and treatment. Said SM, Hahn J, Schleyer E, Müller M, Fiedler GM, Buerke M, Prondzinsky R. Abstract Thrombocyte glycoprotein IIb/IIIa inhibitors prevent fibrinogen binding and thereby thrombocyte

• aggregation. The inhibition of thrombocyte activation at the damaged coronary plaque is the target of the

new therapeutic strategies in treating acute coronary syndrome. This reduces the ischemic complications associated with the non-STelevation myocardial infarction (NSTEMI) and percutaneous coronary intervention (PCI). Thrombocytopenia is a known complication of glycoprotein (GP) IIb/IIIa inhibitors. Although, in general, GP IIb/IIIa inhibitor-induced thrombocytopenia is a harmless side effect which responds readily to thrombocyte transfusion, it can occasionally be a very serious complication associated with serious bleeding. In addition patients developing thrombocytopenia have unfavorable outcome (e.g., death, myocardial infarction, bypass surgery or additional PCI) in comparison to patients without

• thrombocytopenia. Advanced age (> 65 years), low BMI and a low initial thrombocyte count

(<180,000/microl) are independent risk factors of thrombocytopenia. The risk of bleeding is higher with this form of thrombocytopenia not only due to the low thrombocyte count but also to the impaired function of the remaining thrombocytes. It is important to closely monitor platelet count during GP IIb/IIIa antagonist treatment. Platelet count monitoring two, six, twelve and 24 hour after starting the treatment reveals most cases of acute thrombocytopenia. Side effects can be avoided by the early discontinuation of the GP IIb/IIIa antagonist treatment. This article reviews the diagnosis and treatment

• f glycoprotein IIb/IIIa inhibitor-induced thrombocytopenia and summarizes the differential diagnosis

from heparin-induced thrombocytopenia and laboratory-related pseudothrombocytopenia. Tumor lysis syndrome consensus panel http://www.ncbi.nlm.nih.gov/pubmed/20331465 Br J Haematol. 2010 May;149(4):578-86. doi: 10.1111/j.1365-2141.2010.08143.x. Epub 2010 Mar 16. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Cairo MS, Coiffier B, Reiter A, Younes A; TLS Expert Panel. Abstract Tumour lysis syndrome (TLS) is a life-threatening oncological emergency characterized by metabolic abnormalities including hyperuricaemia, hyperphosphataemia, hyperkalaemia and hypocalcaemia. These metabolic complications predispose the cancer patient to clinical toxicities including renal insufficiency, cardiac arrhythmias, seizures, neurological complications and potentially sudden death. With the increased availability of newer therapeutic targeted agents, such as rasburicase (recombinant urate

• xidase), there are no published guidelines on the risk classification of TLS for individual patients at risk
• f developing this syndrome. We convened an international TLS expert consensus panel to develop

guidelines for a medical decision tree to assign low, intermediate and high risk to patients with cancer at risk for TLS. Risk factors included biological evidence of laboratory TLS (LTLS), proliferation, bulk and stage of malignant tumour and renal impairment and/or involvement at the time of TLS diagnosis. An international TLS consensus expert panel of paediatric and adult oncologists, experts in TLS pathophysiology and experts in TLS prophylaxis and management, developed a final model of low, intermediate and high risk TLS classification and associated TLS prophylaxis recommendations.

Consensus conference on the management of tumor lysis syndrome http://www.ncbi.nlm.nih.gov/pubmed/18838473 Patrizia Tosi,1 Giovanni Barosi,2 Carlo Lazzaro,3 Vincenzo Liso,4 Monia Marchetti,2 Enrica Morra,5 Andrea Pession,6 Giovanni Rosti,7 Antonio Santoro,8 Pier Luigi Zinzani,1 and Sante Tura1 ABSTRACT Tumor lysis syndrome is a potentially life threatening complication of massive cellular lysis in cancers. Identification of high-risk patients and early recognition of the syndrome is crucial in the institution of appropriate treatments. Drugs that act on the metabolic pathway of uric acid to allantoin, like allopurinol

• r rasburicase, are effective for prophylaxis and treatment of tumor lysis syndrome. Sound recom-

mendations should regulate diagnosis and drug application in the clinical setting. The current article reports the recommendations on the management of tumor lysis syndrome that were issued during a Consensus Conference project, and which were endorsed by the Italian Society of Hematology (SIE), the Italian Association of Pediatric Oncologists (AIEOP) and the Italian Society of Medical Oncology (AIOM). Current concepts on the pathophysiology, clinical features, and therapy of tumor lysis syndrome were evaluated by a Panel of 8 experts. A consensus was then developed for statements regarding key questions on tumor lysis syndrome management selected accord- ing to the criterion of relevance by group discussion. Hydration and rasburicase should be administered to adult cancer patients who are candidates for tumor-specific therapy and who carry a high risk of tumor lysis syndrome. Cancer patients with a low-risk of tumor lysis syndrome should instead receive hydration along with oral allopurinol. Hydration and rasburicase should also be administered to patients with clinical tumor lysis syndrome and to adults and high-risk children who develop laboratory tumor lysis syndrome. In conclusion, the Panel recommended rasburicase for tumor lysis syndrome prophylaxis in selected patients based on the drug efficacy profile. Methodologically rigorous studies are needed to clarify its cost-effectiveness profile. Management of Cardiac Tamponade http://www.ncbi.nlm.nih.gov/pubmed/21907951 Am J Cardiol. 2011 Dec 15;108(12):1820-5. doi: 10.1016/j.amjcard.2011.07.057. Epub 2011 Sep 10. Frequency of recurrence of pericardial tamponade in patients with extended versus nonextended pericardial catheter drainage. Rafique AM, Patel N, Biner S, Eshaghian S, Mendoza F, Cercek B, Siegel RJ. Abstract Recurrence of pericardial tamponade is relatively common after pericardiocentesis. We evaluated the clinical and procedural predictors of recurrent pericardial tamponade after pericardiocentesis. We included 157 consecutive patients with pericardial tamponade (age 62 ± 18 years, 54% men) who had undergone pericardiocentesis from 2000 to 2007. An intrapericardial catheter was used for prolonged drainage of the pericardial effusion (78% of cases) at the discretion of the operator. The overall recurrence rate 11.8 ± 0.6 months after pericardiocentesis was 20% and the mean interval to recurrence was 1.2 ± 2.1

• months. However, patients with extended catheter drainage had a reduced recurrence rate of 12%

compared to 52% in patients without extended drainage (p <0.001). In the Cox regression modeling, absence of extended drainage (hazard ratio [HR] 4.1, 95% confidence interval [CI] 1.7 to 10, p = 0.002), incomplete drainage of pericardial effusion (HR 9.7, 95% CI 3.6 to 22.7, p <0.001), loculated effusion (HR 11.1, 95% CI 2.9 to 43, p = 0.001), and malignancy (HR 3.3, 95% CI 1.8 to 10.3, p = 0.037) independently correlated with recurrence at 1 year. In conclusion, extended pericardial drainage after catheter placement is associated with a reduced recurrence of pericardial tamponade after pericardiocentesis.