Methemoglobinemia and hemolysis in a patient with G6PD deficiency treated with rasburicase

Authors


  • Conflict of interest: Nothing to report.

  • A physician or group of physicians considers presentation and evolution of a real clinical case, reacting to clinical information and data (boldface type). This is followed by a discussion/commentary

Correspondence to: Thomas E. Witzig, MD, Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Tel.: +507-266-2040. Fax: 507-266-9277. E-mail: witzig.thomas@mayo.edu

A 52-year-old African American male was admitted to the hospital for high-dose chemotherapy for refractory aggressive multiple myeloma (MM). He had previously progressed through bortezomib/dexamethasone and lenalidomide therapy. The most recent bone marrow biopsy showed approximately 90% kappa light chain-restricted plasma cells with a high proliferative rate (3.3% cells in S-phase). Admission labs prior to starting any therapy (Table1) were significant for uric acid 16.1 mg/dL (reference range, 3.7–8.0), creatinine 2.1 mg/dL (reference range, 0.8–1.3 and his baseline was 1.1), lactate dehydrogenase (LDH) 438 U/L (reference range, 122–222), phosphorus 6.2 mg/dL (reference range, 2.5–4.5), hemoglobin 7.1 g/dL (reference range, 13.5–17.5), and IgG kappa monoclonal protein of 4.1 g/dL. On admission, baseline pulse oximetry at the bedside was normal at 95% O2 saturation (SpO2). Due to baseline renal insufficiency and anticipated tumor lysis, intravenous (IV) fluids were started immediately followed by 6 mg of rasburicase on Day 1. High-dose IV cyclophosphamide (1,500 mg/m2) and 1,000 mg of methylprednisolone were administered in the early morning on Day 2.

Table 1. Laboratory Data from a Case of Rasburicase-Induced Methemoglobinemia and Hemolysis in a Patient with G6PD Deficiency and Anemia
Laboratory resultsNormal valuesDay 1Day 2Day 3Day 4Day 5
Hemoglobin (g/dL)13.5–17.57.18.88.28.08.37.37.7
Leukocyte (109/L)3.5–10.55.05.46.87.58.57.48.2
Platelets (109/L)50–1501019811489827170
Potassium (mmol/L)3.6–5.23.53.94.34.44.44.13.7
Calcium (mg/dL)8.9–10.110.69.59.6 9.89.89.7
Creatinine (mg/dL)0.8–1.32.12.01.9 1.81.61.5
Alanine amino-transferase (U/L)7–551938
Haptoglobin (mg/dL)30–20069<14
Phosphorus (mg/dL)2.5–4.56.24.05.24.64.64.3
Total bilirubin (mg/dL)0.1–1.00.30.612.33.6
Uric acid (mg/dL)3.7–8.016.17.44.82.3
Transfusion received 22 22

This patient presents with hyperuricemia and hyperphosphatemia with laboratory levels that meet Cairo–Bishop criteria of tumor lysis syndrome (TLS) even before chemotherapy was initiated [1, 2]. In addition, he also has an acute kidney injury (AKI) secondary to TLS occurring in the setting of refractory MM as manifested by high tumor burden, high plasma cell proliferative rate, increased serum LDH, and a very high uric acid with AKI.

Given the clinical features and baseline hyperuricemia and AKI, rasburicase should be administered to prevent worsening renal failure. A glucose-6-phosphatase dehydrogenase (G6PD) level is usually obtained in patients receiving rasburicase because rasburicase can induce hemolysis and cause methemoglobinemia in enzyme-deficient individuals. In our patient, the options were to give rasburicase or to provide prophylactic kidney dialysis without rasburicase. We proceeded with rasburicase given the need for immediate chemotherapy.

On hospital Day 2, bedside pulse oximetry showed significant hypoxemia (SpO2 75%), triggering an emergency consultation with the critical care team. The patient was evaluated and found to be quite comfortable on room air with a respiratory rate of 16 per minute without the use of accessory muscles of respiration; lung, cardiac, and mucous membrane examinations were normal. An arterial blood gas (ABG) was performed and the arterial blood was noted to be brown in color. ABG showed pH 7.39, pO2 104 mmHg, pCO2 39 mmHg, HCO3 24 mmol/L and methemoglobin 12.9% (normal range, 0–1.5%). At this point, the care team discussed the use of IV methylene blue.

Methemoglobinemia is one of the known side effects of rasburicase administration. In the setting of recent rasburicase administration, the low SpO2 with a normal physical examination in an asymptomatic patient makes the diagnosis of methemoglobinemia highly likely. There was no detectable blue skin color due to his African American ethnicity. ABG findings with the normal pO2 and increased methemoglobin confirmed the diagnosis.

Rasburicase can induce hemolysis in G6PD-deficient patients. Moreover, G6PD deficient patients who develop methemoglobinemia should not be given methylene blue as it can also induce hemolysis. Immediate treatment with methylene blue was considered in our patient, but avoided given his relatively moderate degree of methemoglobinemia, asymptomatic condition, and his unknown G6PD status at that time on Day 2. Ascorbic acid administration is the alternative method of treatment.

The patient was treated conservatively with ascorbic acid therapy 1,000 mg oral daily. The G6PD level returned deficient at 3.3 U/g Hb (normal, 8.8–13.4) and thus the patient did not receive methylene blue. Over the next 4 days, his methemoglobinemia resolved and his O2 saturation normalized (Fig. 1). Unfortunately, during this same time period, he developed progressive anemia requiring red blood cell support. Serum haptoglobin was normal at 69 mg/dL (reference range, 30–200) on Day 3 but became undetectable (<14) by Day 5. Bilirubin increased from 0.6 mg/dL on Day 2 to 3.6 mg/dL (reference range, 0.1–1.0 mg/dL) on Day 5; LDH increased from 438 U/L on Day 1 to 1,555 U/L on Day 5. The patient reported tea-colored urine. He was supported with a total of eight units of packed red blood cells over the next 4 days (Table1).

Image 1.

Trends in methemoglobin level (MetHb) and oxygen saturation (SpO2) with hospital day. SpO2 readings were obtained from a bedside pulse oximeter. Daily mean was calculated and plotted in this figure. Rasburicase was given on Day 1 and chemotherapy on Day 2.

The patient's low G6PD level explains the moderate hemolysis that he developed after rasburicase administration. It is important to note that there was an hemolysis-free interval between the rasburicase administration and the first clinical and laboratory signs of hemolysis. This is typical and must be remembered or else hemolysis may be missed during a short hospital admission.

Commentary

TLS is a potentially life-threatening condition characterized by hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia related to rapid cell death either spontaneously or from therapy. Hyperuricemia seen with TLS can potentially cause AKI or exacerbate chronic renal insufficiency from urate nephropathy[1, 2]. Development of AKI in turn results in considerable morbidity and even mortality. Apart from causing severe electrolyte imbalances that may necessitate dialysis, AKI also causes delays in initiation of chemotherapy and a dose reduction in chemotherapeutic agents [3]. Aggressive management of hyperuricemia with hydration, allopurinol administration prior to chemotherapy, and the use of rasburicase is therefore extremely important for optimal patient outcome [4]. Randomized controlled trials comparing allopurinol with rasburicase for TLS have shown greater reduction in uric acid levels, faster time to response, and better kidney function in patients who received rasburicase [5, 6]. Based on studies performed in the pediatric population [6], guidelines for management of TLS in adults suggest the use rasburicase over allopurinol when laboratory evidence of tumor lysis is present [4].

In red blood cells methemoglobin is generated as iron is oxidized from ferrous (Fe++) to ferric (Fe+++) iron. The ferric form of the methemoglobin molecule cannot bind to oxygen leading to tissue hypoxia. In normal individuals, 0.5–3% of hemoglobin will be auto-oxidized to methemoglobin each day. The body reverses this oxidation by two reduction pathways—the NADH-dependent pathway catalyzed by cytochrome b5 reductase, and the NADPH-dependent pathway. The latter is not physiologically active, and depends on extrinsically administered electron carriers to be activated, which plays a major role in treatment of methemoglobinemia [7].

Methemoglobinemia and hemolysis are known side effects of rasburicase that result from oxidative stress caused by hydrogen peroxide, a byproduct generated during the breakdown of uric acid to allantoin. Patients with G6PD deficiency have a decreased tolerance to oxidative stress and are therefore at a greater risk of hemolysis and methemoglobinemia with rasburicase [8]. Unfortunately, there are no comparable medication alternatives to rasburicase for the treatment of hyperuricemia in patients with a high risk of TLS.

Our patient presented with hyperuricemia and AKI secondary to TLS occurring in the setting of refractory MM and a very high uric acid with AKI prior to starting therapy. Rasburicase was emergently administered on Day 1 prior to chemotherapy and before the results of the G6PD assay were known. The goal was to reverse pre-existing AKI and prevent further kidney injury after the start of high-dose chemotherapy. Indeed, the rasburicase was effective, with a reduction in uric acid to 4.8 and 2.3 on Days 2 and 3, respectively. Serum creatinine also responded by decreasing from 2.1 to 1.9 by Day 2 and further to 1.4 by Day 6. Our patient did develop mild asymptomatic methemoglobinemia and moderate hemolysis requiring RBC transfusion, both of which resolved in the following week. In this case, the benefit of administering rasburicase emergently in an attempt to salvage the kidneys outweighed the risks of methemoglobinemia and hemolysis.

The association between rasburicase and methemoglobinemia has been reported in six other cases (Table 2). Interestingly, similar to our case, all six were males and three were in patients with G6PD deficiency. Five of six patients required support with blood products. Methylene blue was given in two cases, one in a patient with known G6PD deficiency [9-13]. In the three cases where G6PD deficiency was known, hemolysis also developed. In those three cases, as with our patient, the hemolysis did not appear until after the methemoglobinemia (over 30 hr after rasburicase administration) [10-12]. Rasburicase has a t1/2 of 18–24 hr and thus hydrogen peroxide may be generated for several days [8]. Clinicians should be aware of the delayed appearance of hemolysis after rasburicase as it can be missed in a short-period hospital admission.

Table 2. Review of Six Cases of Rasburicase-Induced Methemoglobinemia Along with Index Case
SourceSex/Age/EthnicityType of malignancyG6PD LevelUric acid on presentationPeak MetHbTreatment
Methylene blueAscorbic acidTransfusion
  1. G6PD: Glucose-6-phosphate dehydrogenase; MetHb: methemoglobin; NA: not available; AA: African American.
Bauters [9]Male/6/CaucasianAcute lymphoblastic leukemiaNormalNA17.3NoNoNo
Bhat [10]Male/12/LaotianAcute lymphoblastic leukemiaDeficient22.110.1YesNoYes
Borinstein [11]Male/14/CambodianBurkitt lymphoma/leukemiaDeficient16.212.6NoNoYes
Brownin [12]Male/50/AANoneDeficient14.69.8NoNoYes
Kizer [13]Male/NA/NAMycosis fungoidesNormal13.614.9NoNoYes
Kizer [13]Male/NA/NADiffuse large B cell lymphomaNormal14.021.5YesNoYes
Our caseMale/52/AAMultiple myelomaDeficient16.112.9NoYesYes

In severely hyperuricemic patients like ours with AKI from TLS, waiting for the results of G6PD may be impractical as it typically requires 24–48 hr for test results. In such cases, use of rasburicase may be justified, realizing that there is a known risk of methemoglobinemia and hemolysis. One should be constantly vigilant for both these conditions and be prepared to manage them. With the widespread routine use of bedside handheld pulse oximeters, methhemoglobinemia will likely be first noted as an asymptomatic drop in SpO2 by nursing staff and generate emergent calls for physician evaluation. The appearance of a blue skin discoloration is an immediate clue to the presence of methemoglobinemia; however, in our case the patient was African American and thus this important physical finding was not apparent. ABG is the appropriate diagnostic test and a brown color of the arterial blood is another useful clue to the presence of methemoglobinemia. It is important to point out that the findings on the bedside pulse oximeter in patients with methemoglobinemia are misleading. The oximeter only measures the relative absorbance of two wavelengths of light to differentiate oxyhemoglobin from deoxyhemoglobin; however, methemoglobin absorbs both of these wavelengths equally. Therefore, at high levels of methemoglobin, the pulse oximeter reads a SpO2 of 85%, which corresponds to equal absorbance of both wavelengths. Also important to note is that the partial pressure of oxygen (pO2) value on the ABG finding should be within the reference range in patients with methemoglobinemia [14].

Education of nursing and night shift staff is necessary to avoid undue alarm or immediate transfer to the intensive care unit without first evaluating the patient and performing an ABG. It is important to note that IV methylene blue ordinarily used in the treatment of severe (>20% methemoglobin) or symptomatic methemoglobinemia is ineffective in G6PD deficient patients since methylene blue works through the alternative pathway (NADPH dependent). Furthermore, methylene blue will exacerbate NADPH deficiency in such patients resulting in increased free radicals and a hemolytic crisis [15]. In such cases, ascorbic acid, a potent antioxidant and reducing agent, may be used instead [16].

Of note, all of the four reported G6PD deficient patients who received rasburicase developed only mild methemoglobinemia (Table 2). In our patient, the hemolysis was actually more problematic and although moderate and self-limited, the patient did require a total of 8 units of RBC during the hospitalization. It is likely that his transfusion requirements would have been much lower without the underlying MM that led to poor marrow reserve and pre-existent anemia.

In summary, there are many useful teaching points for physicians and nurses to be gleaned from this case that should be kept in mind when administering rasburicase:

  • Rasburicase can cause methemoglobinemia.
  • In patients with G6PD deficiency, rasburicase can cause mild methemoglobinemia and significant hemolysis.
  • Methylene blue should not be administered in asymptomatic cases and until after G6PD levels are shown to be normal.
  • Blue skin color change as a physical clue to methemoglobinemia is not helpful in Africans or African Americans.
  • Bedside pulse oximeters may give falsely low O2 saturation values in the presence of methemoglobin. The patient must be evaluated for clinical signs and symptoms of hypoxemia and ABG assessment for arterial blood color and methemoglobin levels.
  • The hemolysis seen after rasburicase administration in G6PD deficient patients is delayed, can be brisk usually requiring RBC transfusion, appears after the appearance of methemoglobinemia, and must be anticipated and followed until resolution.
  • Serum haptoglobin, bilirubin, and hemoglobin levels are important parameters to monitor for hemolysis in patients with malignancy receiving rasburicase. Reticulocyte counts and LDH are less useful due to marrow suppression and LDH production from tumor cells.

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