Low Hemoglobin Saturation in the Setting of Hyperuricemia

Clinical Challenge

A 75-year-old African American woman presented to the emergency department with one week of constipation and abdominal pain, characterized as diffuse, nonradiating, and cramp like. One month prior, the patient had a nephrectomy after the discovery of a high-grade neuroendocrine tumor on her left kidney. She had not yet received chemotherapy or radiation.

In the emergency department, the patient’s vital signs were within normal limits, and her hemoglobin saturation measured by pulse oximetry (Sp_O2) was 98% while breathing ambient air. Her neurological examination showed mild confusion but was otherwise normal. Breath sounds were normal and breathing was nonlabored. Her abdomen was soft and nondistended, with normal bowel sounds and mild tenderness to palpation, and she did not exhibit guarding or rebound pain. Her laboratory values were significant for: serum creatinine, 4.02 mg/dl; sodium, 128 mmol/L; calcium, 18.0 mg/dl; white blood cell count, 10,100/μl; hemoglobin, 9.9 g/dl; hematocrit, 30.4%; and uric acid, 23.6 mg/dl. There were several marked changes since the preceding month (Table 1). Phosphorus and albumin concentrations were normal at 2.7 mg/dl and 4.1 mg/dl, respectively. Computed tomography scan of the abdomen showed atelectasis of the lung bases, interval increase in lymphadenopathy, and a partially healed sacral fracture with mottled lucencies suggestive of metastatic disease. Chest radiograph (CXR) reported possible atelectasis versus infection at the left costophrenic angle. The patient was admitted, and her hypercalcemia was treated with intravenous fluids, subcutaneous calcitonin, and intravenous pamidronate.

Table 1.

Day 1 and Day 2 A.M. patient laboratory values

	1 Month Prior	Day 1	Day 2 A.M.
Serum creatinine, mg/dl	2.22	4.02	3.46
Uric acid, mg/dl	—	23.6	19.1
Sodium, mmol/L	137	128	133
Potassium, mmol/L	4.3	4.5	3.7
Calcium, mg/dl	9.5	18.0	14.6
Phosphorus, mg/dl	—	2.7	—
Hemoglobin, g/dl	8.9	9.9	8.1
Hematocrit, %	29.8	30.4	24.9

On hospital Day 2, because of persistently elevated uric acid levels (Table 1), the patient was treated with rasburicase 6 mg. Later that evening, the patient became acutely tachypneic with decreased Sp_O2 to 77%. The patient was initially placed on nasal cannula at 6 L/min and then on a Venturi mask with fraction of inspired oxygen 0.4, with minimal improvements in her Sp_O2. CXR and physical examination were unchanged.

Questions

1. What are the possible causes of an acute decrease in Sp_O2 for this patient?

2. What does the lack of response to supplemental oxygen suggest as to the cause of this patient’s low Sp_O2?

Clinical Reasoning

The differential diagnosis for this patient’s acute drop in Sp_O2 was broad and initially included pulmonary edema, pulmonary embolism, intrapulmonary or intracardiac shunting, metastatic disease to the lungs, pneumonia, and an abnormal hemoglobin. The CXR was not concerning for infection, pulmonary edema, or metastatic disease, and lung and cardiovascular examinations remained normal. Pulmonary embolism was considered but was believed to be less likely, given the lack of other suggestive signs and symptoms. Because her low hemoglobin saturation was unresponsive to supplemental oxygen, shunting was considered, but the absence of pulmonary infiltrates and lack of known vascular or intracardiac abnormalities made this unlikely. Abnormal hemoglobin function was then considered the most likely diagnosis, particularly after obtaining the results of the patient’s blood gas analysis.

Clinical Solution

While on a Venturi mask at fraction of inspired oxygen 0.4, an arterial blood gas with co-oximetry showed pH, 7.55; partial pressure of carbon dioxide, 28 mm Hg; partial pressure of oxygen (Po₂), 166 mm Hg; bicarbonate, 24.2 mmol/L; hemoglobin, 6.3 g/dl; arterial oxygen saturation (Sa_O2), 83.7%; and a methemoglobin (MHb) level of 14.7%. Subsequently, the patient received two units of packed red blood cells and intravenous ascorbic acid 1,500 mg. Because of concern that the patient might have glucose-6-phosphate dehydrogenase (G6PD) deficiency, methylene blue was not given. The next uric acid level normalized to 1.5 mg/dl and hemoglobin increased to 9.6 g/dl. The patient remained on nasal cannula for the next 24 hours and recovered without additional interventions. Eventually, the patient’s G6PD level was found to be 8.1 (reference range: 9.9–16.6 units/g hemoglobin).

Science behind the Solution

The primary indication for rasburicase is hyperuricemia associated with malignancy. Studies have shown that rasburicase is more effective than allopurinol at reducing and controlling plasma uric acid levels. Although typically well tolerated, rasburicase has been associated with significant adverse reactions, including hemolytic anemia and methemoglobinemia, especially in patients with G6PD deficiency. As a recombinant form of urate oxidase, rasburicase converts existing uric acid to its water-soluble metabolite allantoin, thus allowing for more rapid elimination (Figure 1). However, this reaction generates hydrogen peroxide (H₂O₂), which is a potent oxidizing agent that is normally counteracted by the reducing actions of nicotinamide adenine dinucleotide phosphate (NADPH → NADP) (Figure 2). In the absence of G6PD, NADP cannot undergo enzymatic conversion to NADPH. As a result, oxidation occurs within the heme moiety of erythrocytes from the ferrous (Fe²⁺) to the ferric (Fe³⁺) state, which converts hemoglobin to MHb. Unlike hemoglobin, MHb is unable to carry oxygen. Furthermore, the remaining hemoglobin molecules have an increased affinity for oxygen and are therefore less able to release oxygen to the tissues. As shown in Figure 3, this left shift of the oxyhemoglobin dissociation curve further impairs oxygen delivery and reduces the partial pressure of oxygen at an Sa_O2 of 50% (the P₅₀, shown as the intersection of the gray lines on the curves in Figure 3). The increased oxidative stress also leads to free radical formation and red cell destruction by macrophages. The combination of these phenomena ultimately results in both a functional and a hemolytic anemia.

Figure 1.

Enzymatic conversion of uric acid by rasburicase to allantoin with generation of hydrogen peroxide (H₂O₂) as a byproduct. Adapted from Browning and Kruse, 2005.

Figure 2.

Top: The formation of methemoglobin (ferric state) by hydrogen peroxide (H₂O₂) and the role of cytochrome b5 reductase in the regeneration of hemoglobin (ferrous state). Methylene blue is converted to leukomethylene blue to generate oxidized nicotinamide adenine dinucleotide phosphate (NADP), which reduces methemoglobin back to hemoglobin. Bottom: The role of glucose-6-phosphate dehydrogenase (G6PD) in reducing H₂O₂ via glutathione and NADP. Adapted from Browning and Kruse, 2005, and Wright and colleagues, 1999. GSH = reduced glutathione; GS-SG = oxidized glutathione; Hb = hemoglobin; MHb = methemoglobin; NAD⁺ = oxidized nicotinamide adenine dinucleotide; NADH = reduced nicotinamide adenine dinucleotide; NADPH = reduced nicotinamide adenine dinucloetide phosphate.

Figure 3.

Change in oxyhemoglobin dissociation curve with methemoglobinemia. The black line represents a normal curve with the partial pressure of oxygen at an oxygen saturation of 50% at approximately 27 mm Hg (P50, marked by the intersection of the gray lines on each curve). The dashed line represents the left-shifted oxyhemoglobin dissociation curve that occurs in the setting of clinically significant methemoglobinemia. The P50 is decreased to around 17 mm Hg as a result of the shift, and the maximal oxygen saturation is decreased as well.

MHb levels up to 2% are seen physiologically because of normal oxidative processes. Methemoglobin levels >15% produce symptoms such as lethargy, dyspnea, nausea, tachycardia, and cyanotic skin discoloration. Levels >70% are usually fatal. Because MHb levels are expressed as a percentage of total hemoglobin, symptoms may be more severe in patients with lower hemoglobin levels.

There are two commonly used methods to measure hemoglobin saturation. Pulse oximetry uses light-emitting diodes at two different wavelengths that are preferentially absorbed by oxygenated and deoxygenated hemoglobin to calculate the ratio of oxyhemoglobin to total hemoglobin. However, pulse oximetry does not detect wavelength absorption specific to methemoglobin and typically registers Sp_O2 in the range of 75% to 85% at high MHb levels.

Co-oximetry, which is performed as part of blood gas analysis, measures the relative absorbance of at least four different wavelengths of light and can therefore accurately differentiate and calculate the percentages of methemoglobin, carboxyhemoglobin, oxyhemoglobin, and deoxyhemoglobin (Figure 4). Because the measured Po₂ reflects only dissolved oxygen, it is unaffected by the presence of methemoglobin. Thus, dissociation between the measured Po₂ and the hemoglobin saturation measured by CO-oximetry strongly suggests the presence of an abnormal hemoglobin.

Figure 4.

Light absorption profile of different hemoglobin species. Red line represents oxyhemoglobin, blue line represents deoxyhemoglobin, green line represents methemoglobin. The vertical lines at 660 nm and 940 nm, respectively, represent the red and infrared wavelengths used in pulse oximeters. Adapted from Haymond and colleagues, 2005.

The treatment of methemoglobinemia consists of: 1) discontinuation of any offending drugs, 2) reducing the heme moiety from its ferric state to its ferrous state to restore adequate oxygen delivery, and 3) decreasing the effects of oxidative stress on erythrocytes. In general, asymptomatic patients with MHb levels < 20% do not warrant additional treatment aside from removal of the causative agent. Symptomatic patients should be assessed for airway and circulatory stability first. Initial treatment has historically been methylene blue, which is converted into leukomethylene blue via the NADPH-dependent methemoglobin reductase system. In turn, leukomethylene blue transfers an electron to ferric iron to reduce it to ferrous iron (Figure 2). However, because patients with G6PD deficiency also have NADPH deficiency, methylene blue is ineffective and can worsen oxidative stress, hemolysis, and methemoglobinemia. Caution should also be exercised when administering methylene blue to patients on serotonergic agents, as it can exacerbate serotonin syndrome. Other treatment modalities seek to directly restore reducing power via antioxidants such as ascorbic acid and N-acetylcysteine, both of which act as electron donors independent of NADPH. Last, red blood cell and exchange transfusions have also been successfully used in case reports.

In conclusion, this is one of few reported cases of a patient developing methemoglobinemia after receiving rasburicase. We believe that her hyperuricemia was caused by the combination of chronic kidney disease, prior use of furosemide and aspirin, a fructose-rich diet, and malnutrition, rather than tumor lysis. Our patient’s acute decrease in hemoglobin concentration was likely caused by rasburicase-induced hemolysis. Fortunately, we were able to draw a G6PD level before blood products were transfused and identify our patient’s G6PD deficiency. It may be of clinical benefit to have baseline G6PD status on file for patients with high-grade cancers or with large tumor burden in anticipation of treatment with rasburicase. We caution against the use of rasburicase and methylene blue in patients with unknown G6PD status, especially if they are of Mediterranean or African descent as they are at higher risk.

Answers

1. What are the possible causes of an acute decrease in Sp_O2 for this patient?

The differential for low Sp_O2 in malignancy is broad and includes infection, pulmonary embolism, pulmonary edema caused by chemotherapy-induced heart failure, lymphangitic carcinomatosis, and direct pulmonary toxicity of chemotherapy.

2. What does the lack of response to supplemental oxygen suggest as to the cause of this patient’s low Sp_O2?

Low hemoglobin saturation caused by right-to-left shunts is typically refractory to supplemental oxygen, because a portion of the deoxygenated venous blood returns to the systemic circulation without undergoing gas exchange in the lungs. Less commonly, aberrant hemoglobin species with reduced oxygen carrying capacity cause a similar presentation.