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Case Report: Severe Infusion Reaction to Rituximab
1. SEVERE INFUSION REACTION
TO RITUXIMAB
CASE REPORT
Hanna Yudchyts, Pharm D.
PGY-1 Pharmacy Resident
NSLIJ Lenox Hill Hospital
2. Objectives
Introduce patient case
Discuss metabolic abnormalities
Hyperkalemia
Lactic acidosis
Learn about Rituximab
Review infusion reaction
Discuss possible Tumor Lysis Syndrome (TLS)
3. History of Present Illness
Chief complaint: Anaphylaxis
HPI: JL is a 73 y/o F who presented to LHH
Emergency Department from oncology
infusion center on 08/14/13 with anaphylaxis
to Rituximab. During first infusion, she
experienced nausea and vomiting. The
infusion was stopped. Patient noted to have
some shortness of breath and tongue swelling.
EMS was called at 14:35. EMS arrived on the
scene at 14:38.
4. Past Medical History
Non-Hodgkin’s Lymphoma
• Mantle cell lymphoma, blastoid variant
• No previous treatment received
Diabetes Mellitus type 2
Hypertension
Hypercholesterolemia
Home Medications
Losartan
Metformin
Glipizide
Fenofibrate
Ezetimibe/Simvastatin
5. EMS Finding and Actions
Vital signs
Medications administered
Epinephrine 0.3 mg IM
Diphenhydramine 50 mg IV
Methylprednisolone 125 mg IV
Normal Saline 1 L IV
No improvement mental status decreased to
unresponsive. Patient was intubated and brought
to LHH emergency department at 15:30.
BP Pulse RR SpO2 BS
81/59 130 36 78 211
6. Upon Arrival at Emergency
Department
Stat medications given at 16:22
Sodium Chloride 0.9% IV 1 L bolus
Epinephrine 0.3 mg IM
Famotidine 20 mg IV
Propofol 5 mcg/kg/min, titrate to acceptable
sedation
Vasopressin 40 units IV
7. Initial Findings
89.8 617.5
24.8
214
Lactic Acid pH CO2 HCO3
15.2 6.79 58 9
130 99 38
8.2 8 4.05
•Urinalysis and blood cultures are negative
•ECG: wide complex tachycardia
Lab values received between 16:42-17:11
9. Hyperkalemia
Severe hyperkalemia can lead to:
Muscle weakness or paralysis
Cardiac conduction abnormalities
Cardiac arrhythmias
Treatment approaches:
Antagonizing the membrane effects of K+ with
Ca2+
Driving extracellular K+ into the cells
Removing excess K+ from the body
10. Stabilize Cardiac Membranes with
Calcium
Significant ECG findings or severe arrhythmias
Calcium Chloride
500-1000 mg
Calcium Gluconate
1000 mg
• IV infusion over 2-3 min
Effect of Ca2+ is transient treatments to shift
K+ into cells and to remove K+ are required
11. Shift Potassium into Cells
Insulin+ Glucose
Regular Insulin 10 units IV bolus + 50 ml of D50W
Beta 2 agonist
Albuterol 10-20 mg in 4 ml saline via nebulizer
Sodium Bicarbonate
Minimal effect on shifting K+ intracellularly
150 mEq in 1 L of D5W in water at 250 ml/h
The effect of shifting K+ into the cells is
transient, treatments to remove K+ are also
required
12. Strategies for Eliminating Potassium
Sodium Polystyrene Sulfonate (Kayexalate®)
Cation exchange resin
15-30 g PO
Diuretic
Limited short-term effect
Furosemide 20-40 mg IV
Hemodialysis
If above measures failed
Hyperkalemia is severe
Patient with renal failure
Marked tissue breakdown large amount of K+ released
form injured cells
13. Lactic Acidosis
Common cause of metabolic acidosis
Elevated plasma lactate concentration (>
4meq/L)
Elevated anion gap
Impaired
tissue
oxygenation
Increased
anaerobic
metabolism
Rise in
lactate
production
Decrease in
serum
bicarbonate
concentration
Decrease in
pH
Metabolic
acidosis
14. Acidosis Treatment
Who should be treated
pH < 7.10
Goal of therapy
Reversal of underlying cause
Goal for arterial pH > 7.10
Approach
1-2 mEq/kg Sodium Bicarbonate IV bolus
Repeat after 30-60 min if pH < 7.10
15. Treatment Progression
• K: 8.2
• pH: 6.79
• LA: 15.2
17:00
• Insulin Regular 10 units + D50W x 4
• Calcium Gluconate 1 amp x 4
• Sodium Bicarbonate 8.4% 1 amp x 4
• Normal Saline 1L x 4
• Sodium Bicarbonate drip (3 amp in
0.45%NS)
• Vancomycin 1 g + Zosyn 3.375 g IV
In
between…
• K:8.6
• pH: 6.94
• LA: 16
18:30
16. Treatment Progression
No improvement in metabolic abnormalities
despite medications administration
ICU team consulted
Emergency hemodialysis awaiting at ICU floor
During transportation patient developed
Ventricular Tachycardia and rushed back to ED
for CPR at 18:28
17.
18. During the CPR…
Patient was shocked 3 times
Received Epinephrine 1 mg x 3
Amiodarone 300 mg IV push
100 mEq (2 ampules) of Na+ bicarbonate
No pulse
Patient was declared deceased at 18:47
20. Rituximab
Murine/human monoclonal anitbody
FDA approved indications:
•Chronic lymphoid leukemia (CLL)
•Microscopic polyarteritis nodosa
•Non-Hodgkin’s lymphoma (NHL)
•Rheumatoid arthritis (RA)
•Wegener’s granulomatosis
Binds to the antigen CD20, located
on pre-B and mature B lymphocytes
CD20 is expressed on > 90% of B-
cell NHL, but not expressed on
normal plasma cells or normal tissue
23. Possible Tumor Lysis
Syndrome?
Lab values indicating TLS
K+: 8.2 mMol/L
SCr: 4.05 mg/dL
Ca2+: 7.3 mg/dL
No Uric Acid and Phosphate levels
Super acute onset within hours
Similar case reports
24. Case Reports of Acute TLS
Tumo
r type
Age
(sex)
WBC (x109) Immunotherapy Onset
TLS
(hours)
Outcome
CLL 26 (F) 112 Rituximab 375
mg/m2
24 Improved
NHL 41 (M) Rituximab 375
mg/m2
6 Improved
CLL 76 (M) 907 Rituximab 375
mg/m2
12 Expired
HL 36 (M) ABVD 2 Improved
25. Conclusion
Infusion reaction to Rituximab
Cardiac arrest Hyperkalemia Acute
kidney failure Possible tumor lysis
syndrome
More information needed to confirm TLS
Importance and timing of emergency
hemodialysis
26. References
1. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2012.
Available at www.rituxan.com
2. Bicarbonate therapy in lactic aciosis. In UpToDate, Wiederkehr M., Emmett M. Oct
3, 2012.
3. Advanced cardiac life support (ACLS) in adults. In UpToDate, Pozner C. Feb
4, 2013.
4. Yang H., Rosove M., Figlin R. Tumor Lysis Syndrome Occurring After the
Administration of Rituximab in Lymphoproliferative Disorders: High-Grade Non-
Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia. Am J Hem. 1999;
62:247-250.
5. Davidson M, Thakkar S, Hix J et al. Pathophysiology, clinical consequences, and
treatment of tumor lysis syndrome. Am J Med. 2004; 116:546-554.
6. McBride A, Westervelt P. Recognizing and managing the expanded risk of tumor lysis
syndrome in hematologic and solid malignancies. J Hemtol and Oncol. 2012; 5: 75.
7. Suzuki T., Takeuchi M., Saeki H., et al. Super-acute onset of tumor lysis syndrome
accompanied by hypercytokinemia during treatment of Hodgkin’s Lymphoma with ABVD
chemotherapy. Clin Ther. 2010 Mar;32(3): 527-31.
Notas do Editor
Patient was given another dose of EpiPen and more fluids. Propofol was started in order to put central line. However the blood pressure dropped to 74/52, Vasporessin was added on and dose of Propofol decreased. Famotidine was given to complete allergic reaction treatment, that is usually consists of Bendarly, Solumedrol and PepcidBitting on the tube propofol given
Severe hyperkalemia: K >7
CaCl preferably via a central line.CaCL contain three times the concentration of elemental Ca compared to Ca gluconate (13.6 vs 4.6 meq in 10 ml of 10 % solution) The effect of intravenous calcium administration begins within minutes but is relatively short-lived (30 to 60 minutes). As a result, calcium should not be administered as monotherapy for hyperkalemia but should rather be combined with therapies that drive extracellular potassium into cells
Lactic acidosis is the most common cause of metabolic acidosis in hospitalized patients. It is associated with an elevated anion gap and a plasma lactate concentration above 4 meq/L. Impaired tissue oxygenation, leading to increased anaerobic metabolism, is usually responsible for the rise in lactate production. Lactic acidosis causes a decrease in serum bicarbonate concentration that is similar in magnitude to the increase in the lactate concentration. Lactate is a metabolizable organic anion that, when oxidized, will generate bicarbonate
Patients with lactic acidosis and severe academia receive bicarbonate therapyThe primary aim of therapy is reversal of underlying disease. When using bicarb therapy in patients with lactic acidosis and severe academia the aim is to maintain the arterial pH >7. What is the normal pH 7.35-7.45Alternative of agents Carbicarb, thromethiamine
RITUXAN can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion, with time to onset of 30-120 minutes. Can occur: hypotension, angiodema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, MI, ventricular fibrillation, anaphylactoid evens, or deathAcute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, some fatal, can occur within 12-24 hours after the first infusion of RITUXAN. A high number of cirulating malignant cells ((≥25,000/mm3) or high tumor burden confers a greater risk of TLS