4.5. Methemoglobinemia and Carboxyhemoglobinemia in COVID-19 Patients: Consequences for Patient Monitoring and Treatment
Methemoglobinemia and carboxyhemoglobinemia seem to play a role in the pathophysiology of COVID-19, especially in more severe cases of the disease.
While the ability to determine MetHb and COHb levels is normally routinely available in clinical settings via blood gas analysis, there are only a few commercial monitoring devices that enable continuous non-invasive measurement of MetHb and COHb values, mainly the fingertip pulse CO-oximeters by Masimo and Nonin. These devices do not normally feature in standard clinical equipment. This is unfortunate since continuous monitoring of tHb, MetHb and COHb levels could be helpful in guiding the treatment and monitoring of COVID-19 disease progression.
From the reports discussed in Section 3.2 and Section 3.3 it is clear that the determination of MetHb and COHb is especially warranted when patients are treated with oxidizing drugs such as chloroquine and hydroxychloroquine. This is even more important when the patients have a confirmed G6PD deficiency.
For the interpretation of COHb values, the smoking status of the patient needs to be considered as smokers have a higher COHb concentration in the blood than non-smokers (2.7 ± 2.6% [80], 3.26 ± 2.2% [15], 5.12 ± 2.25% [81], 2.1 ± 1.02% [82]).
Knowledge of MetHb and COHb levels in the blood of COVID-19 patients is also relevant to prevent misinterpretations of arterial oxygen saturation values measured with fingertip pulse oximetry (SpO2). This is because MetHb and COHb interfere with the measurement of SpO2. An overestimation of the true arterial oxygenation (SaO2) can occur. In case of a decrease in SaO2 and an increase in MetHb or COHb, SpO2 will diverge more from SaO2 the higher the MetHb and COHb concentration (see Figure 4). For example, assuming a MetHb concentration of around 25% (corresponding to the upper end of the confidence interval of MetHb values in COVID-19 patients reported by Alamdari et al. [21]) and an assumed decrease of SaO2 to 75%, the SpO2 measurements would indicate a falsely too high SpO2 of about 88%. Measurement with pulse CO-oximetry instead of pulse oximetry would circumvent this problem since pulse CO-oximetry is able to non-invasively measure MetHb, COHb, tHb, and the correct SpO2. [83,84,85].
Methemoglobinemia and carboxyhemoglobinemia cause a shift in the Hb dissociation curve to the left, leading to a reduced ability of O2 to be released from Hb, which can result in hypoxia. Methemoglobinemia and carboxyhemoglobinemia need to be monitored and treated, therefore. Therapies of methemoglobinemia in COVID-19 patients have been performed with methylene blue and, in some cases, combined with blood transfusions [18,20,21].
The fact that COVID-19 patients could show hypoxemia without having dyspnea, i.e., silent hypoxia or so-called “happy” hypoxia [88,89,90], seems to be primarily due to (i) a blunted response of the respiratory control system to hypoxia which is prevalent in older subject and those with diabetes, (ii) changes in arterial CO2 levels, (iii) temperature-induced shifts in the O2 dissociation curve, and (iv) the inaccuracy of pulse oximeters at low SpO2 values, as highlighted by Tobin et al. [89,91].
For hospitals it might be also relevant to re-evaluate their water disinfection procedure since the use of a hydrogen peroxide/silver ion preparation for treating the water supplied in the hospital caused elevated levels of MetHb in the severely ill patients (treated with daily hemodialysis/hemodiafiltration) drinking this water [92]. When blood transfusions are given to COVID-19 patients, it should be also considered that the MetHb content of the banked blood increases over time [93] and that banked blood from smoking donors can have a relatively high COHb concentration [94], representing a possible risk for critically ill patients. It makes sense therefore to test the banked blood for MetHb and COHb concentration levels before administering it to patients, especially in case of COVID-19.