October 2017

When hypoxia is not hypoxia?


Colin Brueggemeir, Jamie Traynor, Louise McElwee, Jonathan Fox, Colin Geddes

Glasgow Renal and Transplant Unit, Queen Elizabeth University Hospital, Govan Road, Glasgow 


The case:

A 25-year-old female was admitted to the renal ward with vague symptoms of general malaise, and shortness of breath on exertion. The symptoms had progressively worsened over the preceding two weeks.

She had presented with heavy proteinuria and been diagnosed with dense deposit disease associated with C3 nephritic factor and mesangiocapillary pattern glomerulonephritis 8 years previously. Six year later and two years before the present admission this had progressed to nephrotic syndrome with deterioration in renal function.  At that time a decision had been made to try rituximab (1g intravenously on 2 occasions 14 days apart) and a short course of high dose Prednisolone. To reduce the risks of pneumocystic jirovecii infection and thrombo-embolic events she started co-trimoxazole 480mg daily and warfarin respectively. Three weeks later she developed a widespread maculopapular rash thought to be an allergic reaction to co-trimoxazole and this was stopped. Dapsone 100mg daily was started instead of co-trimoxazole after ensuring that glucose-6-phosphate dehydrogenase genotype was normal.  Following this, nephrotic syndrome entered sustained partial remission (urine protein:creatinine ratio <300mg/mmol and serum albumin >30g/L) starting 3 months after the first dose of rituximab, and renal function improved to baseline eGFR of approximately 50mL/min/1.73m2. Dapsone was discontinued after 3 months as planned. Throughout this period hypertension and proteinuria were treated with lisinopril, amlodipine and furosemide.

She remained well for a further 15 months but then nephrotic syndrome relapsed.  Two months before the current admission a decision was made to treat with Rituximab and a short course of high dose Prednisolone as before and to give dapsone as pneumocystis prophylaxis again. 

She had no other significant past medical history.

At the time of this admission her medication was:

  • Prednisolone 30mg daily
  • Dapsone 100mg daily
  • Lisinopril 10mg twice daily
  • Furosemide 160mg twice daily
  • Amlodipine 10mg daily
  • Simvastatin 20mg daily
  • Sodium Bicarbonate 1g twice daily
  • Warfarin
  • Ferrous sulphate 200mg three times per day
  • Folic acid 5mg once daily
  •  Darbepoetin 30 micrograms every 4 weeks


On admission, the only examination findings of note were resting sinus tachycardia (92 beats per minute), oxygen saturation (SpO2) of 90% on air measured by pulse oximetry and mild abdominal swelling felt to represent fluid retention. Her lung fields were clinically clear, she was apyrexial and had no peripheral oedema.


Peripheral blood (normal ranges in parenthesis):

Haemoglobin: 101 g/L (115 - 165 g/L),

White cell count: 17x10^9/L (4.0 - 11.0 x10^9/L)

Serum creatinine: 257micromol/L (40-130 micromol/L),

eGFR: 20mL/min/1.73m2 (>60 mL/min/1.73m2)

Serum albumin: 18 g/L (35 - 50 g/L)

D-Dimer: 192 ng/ml (0 - 230 ng/ml)

C-reactive protein: < 1 mg/L (0 - 10 mg/L).

Urine protein:creatinine ratio: 1739 mg/mmol

ECG: Sinus rhythm, 92/min, normal axis. No ischaemic changes.

Chest X-ray: Normal sized heart with clear lung fields. 


The symptoms were initially attributed to extracellular fluid overload related to nephrotic syndrome but it was noted that the lack of peripheral oedema and lack of pulmonary oedema on chest X-ray were not consistent with this. She was treated with oxygen and intravenous diuretic but hypoxia (as assessed by pulse oximetry) persisted. Opportunistic infection was also considered but this seemed unlikely due to the lack of localising signs or symptoms, fever or raised CRP and no pathogens were detected on blood, sputum, throat gargle or urine samples.

After several days, an arterial blood gas sample was taken and revealed: pO2 of 10.6 kPa, pCO2 4.7kPa, SpO2 96,6%, methaemoglobin 17.9%.  Methaemoglobinaemia secondary to dapsone was diagnosed.   Dapsone was discontinued and within three days she felt dramatically better, SpO2 by pulse oximetry was consistently >95% off supplemental oxygen and methaemoblobin level in arterial blood sample was 1.6%. She was able to go home and two months later nephrotic syndrome has improved but at the time of writing has not yet reached partial remission.  


Methaemoglobinaemia is a rare disorder, presenting with vague symptoms of functional anaemia. In this case the symptoms were initially ascribed to excess fluid. In methaemoglobin, the iron of the haemoglobin is oxidised to ferric form (Fe3+). In this oxidised state, the haemoglobin is unable to bind oxygen. The oxygen affinity of remaining ferrous (Fe2+) haem increases resulting in a further fall in oxygen delivery to the tissues. The result is functional anaemia even though absolute haemoglobin levels are usually normally.

Pulse oximetry shows a falsely low level of oxygen saturation in patients with methaemoglobinaemia, as the methaemoglobin absorbs light at the pulse oximetry’s two wave lengths, leading to errors in estimating both the percentage of reduced and oxyhaemoglobin (1).  A rise of methaemoglobin from 2 to 30-35% typically shows a reduction of oxygen saturation as measured by pulse oximetry from 98% to 85% (2). A rise above 35% does not result in a further drop in the measured oxygen saturation, meaning that the pulse oximetry gives a falsely optimistic impression of tissue oxygenation in severe methaemoglobinaemia.

A discrepancy between SpO2 measured by pulse oximetry and an arterial blood gas sample should alert to the possibility of methaemoglobinaemia. This discrepancy results from the way blood gas machines analyse blood samples. The partial pressure of oxygen in the blood (pO2) is a measurement of the total oxygen that is dissolved in the plasma not just that bound to haemoglobin. Diffusion of oxygen from the alveoli of the lungs to blood plasma is the main determinant of pO2 and is not impaired by methemoglobinemia, so that despite what might be severe cyanosis, pO2 remains normal in those with methemoglobinemia. The oxygen saturation is then calculated from the falsely normal pO2. Fortunately, most modern arterial blood gas analysers have an incorporated co-oximeter and provide a read-out of methaemoglobin concentration routinely. 

Methaemoglobinaemia can be congenital or acquired. Most cases are acquired (3). Whilst there is an extensive list of medicines and toxins that have been linked to methaemoglobinaemia, the most common precipitants are dapsone and topical anaesthetics agents such as lidocaine, benzocaine and prilocaine (4).

In a review of 138 patients with acquired methaemoglobinaemia, dapsone accounted for 42% of cases, usually with moderate methaemoglobin concentrations between 2 -34% (median 7.6%) (4). Dapsone is absorbed through the gut and metabolised through oxidation reactions in the liver.  Hydroxylated amine metabolites and potent oxidants are produced in these reactions that have been hypothesized to cause dapsone's hematologic adverse effects, including hemolytic anemia and methemoglobinemia (5).

More severe cases of methaemogloninaemia have been linked to the use of 20% benzocaine spray, with median levels of 32%, though this occurs very rarely. A study in 28,478 patients, measuring methaemoglobin levels after use of benzocaine spray for a trans-oesophageal cardiac echo, reported an incidence of methaemogloninaemia of 0.07 % (19/28,478) (6). Underlying risk factors for the development of acquired methaemoglobinaemia are the asymptomatic heterozygous state for cytochrome b5R deficiency, infancy (as the erythrocyte cytochrome b5 reductase activity is normally 50 to 60 percent of adult activity) and G6PD deficiency. It is therefore advisable to screen for G6PD deficiency prior to initiating therapy with dapsone.

Symptoms in patients with acquired methemoglobinemia result from an acute impairment in oxygen delivery to tissues and worsen with the concentration of the oxidised haemoglobin, as shown in the following table (3):

High levels of methaemoglobin cause the blood to turn a chocolatey/brownish colour, that does not change after being exposed to oxygen (7). Any patient presenting with acute onset of hypoxia after starting treatment with a new drug with oxidative potential should be checked for methemoglobinemia. The standard way to diagnose methaemoglobinaemia is a blood test, using a co-oximeter. The machine analyses the absorption spectrum of the blood sample, with methaemoglobin having a peak absorbance at 631 nm. This test is not very specific, as the presence of other pigments with peak absorbance at that wave length, such as methylene blue, will result in false positives. A positive initial testing should therefore be confirmed by the specific Evelyn-Malloy method (8,9).


In asymptomatic or mildly symptomatic patients with mild/moderate degrees of methaemoglobin (<20%), no other therapy than discontinuation of the causative drug may be required. Patients with severe levels of methaemoglobinaemia should be managed in the intensive care unit for cardiopulmonary support.

There are two main drugs available to treat severe methaemoglobinaemia: methylene blue (MB) and ascorbic acid (vitamin C). While there are no randomized trials comparing these two agents, it is generally agreed, that MB is quicker and more effective at lowering levels of methaemoglobin and should therefore be used as first line therapy if available and not contraindicated (10,11).

MB works as an artificial donor of electrons for the reduction of methaemoglobin through the NADPH-related pathway. It is administered intravenously, at a dose of 1-2 mg/kg, over 5 minutes. Usually, the response is rapid, and a single dose is sufficient in reducing levels below toxicity. If one hour after treatment the methaemoglobin level is still > 20 %, the dose can be repeated (12,13). It is important to remember that the co-oximeter measurements are no longer accurate in the presence of MB, showing falsely high levels of methaemoglobin. It is important to be aware of possible side effects of MB, such as acute haemolysis.

MB is contraindicated in patients with G6PD deficiency, as the reduction of the methaemoglobin through MB is dependent on the NADPH generated through G6PD. MB is therefore not only ineffective in G6PD deficiency, but potentially dangerous since its oxidation potential can induce acute haemolysis in patients already suffering from functional anaemia (14). MB is also a potent reversible inhibitor of monoamine oxidase A, an enzyme responsible for breaking down serotonin in the brain. It should therefore not be given to patients on seretonergic psychiatric drugs, as it can induce the potentially fatal serotonin syndrome (15).

As a potential alternative to methylene blue, vitamin C has been used successfully in the treatment of methaemoglobinaemia. It usually requires multiple doses and takes a much longer time than MB, making it an inferior alternative in emergency cases (10). It can be used in patients with G6PD deficiency, albeit at a reduced dose, as high doses of vitamin C can also induce haemolysis in that particular group of patients (16).

Refractory cases of methaemoglobinaemia have been successfully treated with blood or exchange transfusion. This treatment may be particularly helpful in anaemic patients, or patients who are in shock. There has also been some anecdotal success of hyperbaric oxygen treatment in severe cases of methaemoglobinaemia (17,18).


Learning points:

  • Methaemoglobinaemia is a potentially life-threatening condition, most commonly induced through exogenous agents, such as dapsone.
  • Most cases show only mild to moderate degrees of methaemoglobinaemia, often requiring no further treatment than withdrawing the responsible agent.
  • In our patient, the symptoms of methaemoglobinaemia were exacerbated by anaemia and fluid overload, as the level of methaemoglobin seen in this case would usually be asymptomatic.
  • The diagnosis was made more difficult as our patient had previously tolerated treatment with dapsone, and her G6PD level had been normal.
  • It is possible that she developed a similar level of methaemoglobinaemia during her first treatment with dapsone, but remained asymptomatic as she was not suffering from exacerbating factors such as anaemia or fluid overloaded at the time.
  • An important clue was the normal oxygen saturation in her aBGA, whilst pulse oximetry showed hypoxia.   



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