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Volume 07 No. 06
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Sleep Medicine Pearls

Unexplained Hypoxemia

http://dx.doi.org/10.5664/jcsm.1484

Kristin C. Spoon, M.D.; Kannan Ramar, M.D.
Mayo Clinic, Rochester, MN

A 56-year-old white female was referred to our sleep center upon dismissal from the hospital following an episode of hypercapnic respiratory failure secondary to neuromuscular weakness in the setting of newly diagnosed inflammatory myopathy. She was started on azathioprine and 60 mg of prednisone, along with dapsone for Pneumocystis jiroveci prophylaxis, as treatment for her inflammatory myopathy.

A deviated nasal septum and crowded oropharynx with reduced lateral dimension were noted on oral-nasal exam. Chest exam, chest radiograph, and echocardiogram were normal. Pulmonary function testing showed a restrictive pattern, with a vital capacity of 26% (0.81) and decreased maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) of 50% and 34%, respectively. Arterial blood gas analysis during wakefulness at this stage revealed pH of 7.44, and PaCO2 of 42. Signs of hypercapnia were noted during wakefulness when nocturnal oxygen therapy at 2 liters/minute was started due to signs of sleep related hypoxemia (based on overnight oximetry findings) by the primary care team (pH 7.43, PaCO2 51).

The patient was referred to our sleep center a few days after she was started on immunosuppressive therapy (her symptoms of weakness were improving by then) for further evaluation of sleep disordered breathing (for possible sleep related hypoventilation/hypoxemia) and for possible bilevel positive airway pressure (BPAP) titration. Overnight polysomnogram (PSG) performed revealed no evidence for sleep disordered breathing or sleep related hypoxemia. An arterial blood gas analysis the following day during wakefulness showed: pH 7.51; PaO2 78; PaCO2 38; HCO3 29; and SaO2 98%.

She returned a week later in follow up relating modest improvement in her symptoms of dyspnea, fatigue, and sleepiness. Repeat overnight oximetry was performed (SpO2 88%) prior to a scheduled PSG, in the anticipation that she may have developed sleep disordered breathing and a need for BPAP (Figure 1). An arterial blood gas analysis (ABG) during wakefulness was performed based on the abnormal findings on the overnight oximetry, which revealed pH 7.43; PaO2 84.1; pCO2 41.9; HCO3 of 27; and SaO2 88.5%.

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Figure 1

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What is the explanation for the low baseline arterial oxygen saturation (SaO2)?

Diagnosis: Low SaO2 due to acquired methemoglobinemia secondary to treatment with dapsone.

Methemoglobin is an altered state of hemoglobin in which the ferrous (Fe2+) irons of heme are oxidized to the ferric (Fe3+) state, binding a water molecule instead of oxygen. Additionally, the oxygen affinity of any remaining ferrous hemes in the hemoglobin tetramer is increased, thereby shifting the oxygen dissociation curve to the left resulting in functional anemia and impaired oxygen delivery to tissues.

In normal individuals, autooxidation of hemoglobin to methemoglobin occurs spontaneously at a slow rate, and subsequent reduction of methemoglobin occurs by protective enzyme systems which maintain a steady-state level of methemoglobin of about 1% of total hemoglobin in normal individuals. An increase occurs due to either increased methemoglobin production or decreased methemoglobin clearance through reduction.

Most cases of methemoglobinemia are acquired, resulting from exposure to exogenous oxidizing agents, with many drugs and their metabolites having been implicated. Dapsone and local anesthetic agents such as benzocaine appear to be the most commonly reported causes of acquired methemoglobinemia.2

Signs and symptoms of acute acquired methemoglobinemia depend on the levels of methemoglobinemia. Signs include cyanosis of the skin and mucous membranes and chocolate-brown blood on ABG with normal arterial PaO2 values. Symptoms include headache and fatigue progressing to dyspnea, nausea, tachycardia, lethargy, and deteriorating consciousness. Higher levels may lead to cardiac arrhythmias and circulatory failure. Diagnosis should be confirmed by measurement of methemoglobin levels on arterial blood sampling via a co-oximeter to detect the different absorption spectrum of methemoglobin (peak absorbance at 631 nm). Higher levels of methemoglobin are associated with pulse oximetry (SpO2) values closer to 85%, due to near equal absorption at the two frequencies of radiation used by the pulse oximeters (660 and 940 nm).3

Treatment of acquired cases of methemoglobinemia involves discontinuing the offending agent. If the patient is asymptomatic and methemoglobin level is less than 20%, no other therapy may be required. However, if the level is greater than 20% or if the patient is symptomatic, specific therapy with methylene blue is indicated. Methylene blue should not be administered to patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency; in such cases, moderate doses of ascorbic acid can be given. Severely affected patients may benefit from adjunctive treatment with exchange transfusion and/or hyperbaric oxygen.

In our patient, the arterial blood gas findings at return visit (presented previously) showed a pH of 7.43, partial pressure of carbon dioxide (PaCO2) of 41.9 mm Hg, partial pressure of oxygen (PaO2) of 84.1, an elevated methemoglobin level of 5.6% (by co-oximeter), and a fraction of oxygenated hemoglobin (FO2Hb) of 88.5%, where the FO2Hb is the fraction of the total hemoglobin that is bound to oxygen. The terminology used when oxygen saturations are measured by the co-oximeter/ABG can be confusing. Most laboratories define SaO2 as the percentage of hemoglobin that is available for oxygen binding, i.e., SaO2 = 100 × oxyhemoglobin / (oxyhemoglobin + deoxyhemoglobin); while FO2Hb = 100 × oxyhemoglobin / (oxyhemoglobin + deoxyhemoglobin + carboxyhemoglobin + methemoglobin). However, some laboratories report SaO2 based on total hemoglobin (e.g., equivalent to FHbO2) as was true in the ABG values given previously. SpO2 from the pulse oximeter is the ratio of the pulse added absorbance at the two wavelengths (660 and 940 nm) that is used to create an estimate of the arterial oxygen saturation.3

Our patient was recommended to discontinue dapsone and switch to trimethoprim-sulfamethoxazole after adequate desensitization.

PEARLS

  1. Acquired methemoglobinemia should be suspected in the setting of cyanosis, low pulse oximetric readings, and chocolate-brown blood on arterial blood gas sampling with normal arterial PaO2 values.

  2. Co-oximetry should be performed when the PaO2 is significantly lower or higher than expected based on the SpO2.

  3. Methemoglobin is a form of hemoglobin which does not bind oxygen, and elevated levels result in a shift of the oxyhemoglobin dissociation curve to the left leading to functional anemia and decreased oxygen delivery to tissues.

  4. Symptoms of methemoglobinemia worsen as the levels increase and can be potentially life threatening above 40%.

  5. Treatment includes stopping the offending agent and use of methylene blue or ascorbic acid in more severe cases.

DISCLOSURE STATEMENT

This was not an industry supported study. The authors have indicated no financial conflicts of interest.

CITATION

Spoon KC; Ramar K. Unexplained hypoxemia. J Clin Sleep Med 2011;7(6):679-680.

ACKNOWLEDGMENTS

Institution at which work was performed: Center for Sleep Medicine, Mayo Clinic, Rochester, MN

REFERENCES

1 

Gregg XT, Prchal JT, authors; Hoffman R, Benz E, Sanford S, et al., editors. Red blood cell enzymopathies. Hematology: basic principles and practice. 2008. 5th edition. Philadelphia: Churchill Livingstone Elsevier. chapter 45.

2 

Ash-Bernal R, Wise R, Wright S, authors. Acquired methemoglobinemia: a retrospective series of 138 cases at 2 teaching hospitals. Medicine. 2004;83:265–73. [PubMed]

3 

Barker S, Tremper KK, Hyatt J, authors. Effects of Methemoglobinemia on pulse oximetry and mixed venous oximetry. Anesthesiology. 1989;70:112–17. [PubMed]