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- Dapsone oxygen saturation
Limited data regarding methemoglobinemia in pregnancy, particularly secondary to dapsone is available up to date. We report a case of dapsone-induced methemoglobinemia in a pregnant mother with multibacillary leprosy who presented with fever, productive cough and cyanosis of 2 days duration 2 weeks after multidrug therapy was commenced.
Dapsone was replaced by ofloxacin mg twice daily. There was a gradual increase in SpO 2 level. She delivered a healthy baby.
In conclusion, clinicians should be aware of the side effects of dapsone and know how to promptly manage any undesirable events. Ofloxacin is a safe and feasible alternative in replacement of dapsone in pregnancy. Leprosy remains a major public health concern in Malaysia despite the fact that it has achieved elimination since with the advent of multidrug therapy MDT [ 1 ].
However, the incidence has shown a resurgence over the years although prevalence remains static. This might be attributable to the roles of immigration and globalization.
Dapsone is associated with several side effects and methemoglobinemia is a rare serious adverse effect when patients present with unexplained cyanosis and hypoxemia. We report a case of dapsone-induced methemoglobinemia in a pregnant mother with multibacillary MB leprosy.
She was recently diagnosed as MB leprosy as evidenced by hypoaesthetic annular plaques on trunk and limbs Fig. Standard MB-MDT consisting of clofazimine, rifampicin and dapsone mg once daily was commenced 2 weeks prior to such complaints. She had no complaints of headache, chest pain, palpitation, dyspnea, altered consciousness, hemoptysis or syncope.
She denied any exposure to chemicals or unprescribed medications. On examination, she had central cyanosis and one spike of fever on admission.
Radial artery and venous blood was dark-colored. There was no laboratory evidence of hemolysis with normal hemoglobin, bilirubin and LDH. Leukocyte count was 7. Sputum workup for culture and acid-fast bacilli AFB as well as chest X-ray did not reveal any evidence of lung infection.
She was not G6PD deficient. Repeated ABG revealed almost similar values. Three pairs of intravenous IV parentrovite, which contained mg of ascorbic acid were given at the initial suspicion of methaemoglobinemia. As for MDT leprosy treatment, dapsone was replaced by ofloxacin mg twice daily and patient was closely monitored thereafter.
No cyanosis was evident, and there was a change in color of venous blood by this time. She delivered a healthy baby via spontaneous vaginal delivery 9 weeks later. The elimination of dapsone, particularly in pregnancy, is not completely understood.
It remains a great challenge to fully understand the pharmacokinetics of dapsone. One study demonstrated no correlation between dapsone level and methemoglobin in patients, but this did not include pregnant population [ 3 ]. The same study also reported that the dosage of dapsone used in leprosy treatment would not promote a significant methemoglobinemia. Dapsone is metabolized by the liver through the oxidation reactions of N-acetylation and N-hydroxylation.
Hydroxylated amine metabolites produced in the oxidation reactions are potent oxidants and are retained in the circulation for a long period as they undergo enterohepatic recirculation. They are taken up by the erythrocytes where they in particular, dapsone monohydroxylamine are primarily responsible for the hematologic adverse effects of methemoglobinemia and hemolysis [ 4 , 5 ]. The latter has higher oxygen affinity but a deceased oxygen binding capacity [ 6 ]. Clinicians should have high index of suspicion and be able to recognize methemoglobinemia as an adverse effect attributable to dapsone use as well as the potential factors that precipitate it, including other drugs, aniline dyes, nitrate-containing compounds and others.
Patients with cyanosis and hypoxemia of unclear etiology should be evaluated for methemoglobinemia, especially when there is presence of a saturation gap—the difference between oxygen saturation measured by pulse oximetry and ABG analysis. The presence of dark arterial blood in this case is attributable to the lack of physiologic hemoglobin—oxygen content due to elevated methemoglobin levels in blood [ 9 ]. Our patient showed improvement after cessation of dapsone.
This result is consistent with a study which demonstrated the resolution of dapsone-induced methemoglobinemia after the withdrawal of the offending agent [ 10 ]. Mild methemoglobinemia may spontaneously resolve with cessation of the concerned drug while severe cases would require other supportive therapy when patients are symptomatic.
In the setting of pregnancy, methemoglobinemia can pose a significant risk to both mother and fetus. Studies have shown that methylene blue has potential teratogenic effects in early pregnancy and unknown effects in late pregnancy. Pregnancy is a physiologic state of increased oxygen consumption and lower oxygen reserve, and maternal tolerance of methemoglobin levels is likely lower than that of a non-pregnant patient [ 11 ].
Therefore, the use of methylene blue in this case might be risky and the use of ascorbic acid could be appropriate. Vitamin C is an endogenous reducing agent within erythrocytes that has antioxidant effects on hemoglobin to prevent conversion to methemoglobin.
It is an effective alternative therapy in cases of methemoglobinemia as it increases glutathione production and prevents oxidative damage [ 12 ]. Therefore, the treatment should be continued during pregnancy unless there are other compelling reasons to stop it. This is in contrast to 12 months as suggested by WHO [ 3 ]. Ofloxacin was chosen in this case as it displayed powerful bactericidal activity against mycobacterium leprae and may be an important component of new multidrug regimens for the treatment of leprosy [ 14 ].
The rate of major birth defects after first-trimester exposure to fluoroquinolones was not increased compared to that for the non-exposed group, which is consistent with the findings of several publications [ 16 — 18 ]. In conclusion, clinicians should be aware of the side effects of dapsone therapy and know how to promptly and effectively manage any undesirable events.
No other persons have made substantial contributions to the article other than the authors. No ethical approval is required.
Each of the authors warrants that the enclosed article is original and does not infringe any copyright or violate any other right of any third parties, and the article has not been published elsewhere, has not been submitted for publication, and is not being considered for publication elsewhere in any form, except as explained to the Editor.
Ministry of Health Malaysia. Annual report. Ministry of Health Malaysia, Putrajaya. Model prescribing information: drugs used in leprosy. Methemoglobinemia and dapsone levels in patients with leprosy. Braz J Infect Dis ; 14 : 3.
Google Scholar. The recognition, physiology, and treatment of medication-induced methemoglobinemia: a case report. Anesth Prog ; 54 : — 7. An investigation of the role of metabolism in dapsone-induced methaemoglobinaemia using a two compartment in vitro test system. Br J Clin Pharmacol ; 30 : — Br J Dermatol ; : — Severe methemoglobinemia from topical anesthetic spray: case report, discussion and qualitative systematic review.
Mind the gap. J Emerg Med ; 33 : — 2. Philadelphia : Elsevier Saunders , , — Google Preview. Erstad BL.
Dapsone-induced methemoglobinemia and haemolytic anemia. Clin Pharm ; 11 : — 5. LoMauro A , Aliverti A. Respiratory physiology of pregnancy: physiology masterclass. Breathe Sheff ; 11 : — Methemoglobinemia: etiology, pharmacology, and clinical management. Ann Emerg Med ; 34 : — Chapter 2: Pengurusan Klinikal. Ministry of Health. Ji B , Grosset J. Ofloxacin for the treatment of leprosy.
Acta Leprol ; 7 : — 6. Clinical trial of ofloxacin alone and in combination with dapsone plus clofazimine for treatment of lepromatous leprosy. Antimircob Agents Chemother ; 38 : — 7. Observational cohort study of pregnancy outcome after first-trimester exposure to fluoroquinolones. Antimicrob Agents Chemother ; 58 : — 8.
A comparison of ciprofloxacin, norfloxacin, ofloxacin, azithromycin and cefixime examined by observational cohort studies. Br J Clin Pharmacol ; 41 : — The safety of quinolones—a meta-analysis of pregnancy outcomes. Eur J Obstet Reprod Biol ; : 75 — 8. Oxford University Press is a department of the University of Oxford.
It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Audiovestibular medicine. Cardiology and cardiovascular systems.
❾-50%}Dapsone oxygen saturation -
No ethical approval is required. Each of the authors warrants that the enclosed article is original and does not infringe any copyright or violate any other right of any third parties, and the article has not been published elsewhere, has not been submitted for publication, and is not being considered for publication elsewhere in any form, except as explained to the Editor.
Ministry of Health Malaysia. Annual report. Ministry of Health Malaysia, Putrajaya. Model prescribing information: drugs used in leprosy. Methemoglobinemia and dapsone levels in patients with leprosy. Braz J Infect Dis ; 14 : 3. Google Scholar. The recognition, physiology, and treatment of medication-induced methemoglobinemia: a case report. Anesth Prog ; 54 : — 7. An investigation of the role of metabolism in dapsone-induced methaemoglobinaemia using a two compartment in vitro test system.
Br J Clin Pharmacol ; 30 : — Br J Dermatol ; : — Severe methemoglobinemia from topical anesthetic spray: case report, discussion and qualitative systematic review. Mind the gap. J Emerg Med ; 33 : — 2. Philadelphia : Elsevier Saunders , , — Google Preview. Erstad BL. Dapsone-induced methemoglobinemia and haemolytic anemia. Clin Pharm ; 11 : — 5. LoMauro A , Aliverti A.
Respiratory physiology of pregnancy: physiology masterclass. Breathe Sheff ; 11 : — Methemoglobinemia: etiology, pharmacology, and clinical management.
Ann Emerg Med ; 34 : — Chapter 2: Pengurusan Klinikal. Ministry of Health. Ji B , Grosset J. Ofloxacin for the treatment of leprosy. Acta Leprol ; 7 : — 6. Clinical trial of ofloxacin alone and in combination with dapsone plus clofazimine for treatment of lepromatous leprosy.
Antimircob Agents Chemother ; 38 : — 7. Observational cohort study of pregnancy outcome after first-trimester exposure to fluoroquinolones. Antimicrob Agents Chemother ; 58 : — 8. A comparison of ciprofloxacin, norfloxacin, ofloxacin, azithromycin and cefixime examined by observational cohort studies.
Br J Clin Pharmacol ; 41 : — The safety of quinolones—a meta-analysis of pregnancy outcomes. Eur J Obstet Reprod Biol ; : 75 — 8. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Audiovestibular medicine. Cardiology and cardiovascular systems.
Critical care medicine. Emergency medicine. Endocrinology and metabolism. Gastroenterology and hepatology. Geriatrics and gerontology. Infectious diseases and tropical medicine. Medical ophthalmology. Medical disorders in pregnancy. Palliative medicine. Pharmacology and pharmacy. Radiology, nuclear medicine, and medical imaging. Respiratory disorders.
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Abstract Limited data regarding methemoglobinemia in pregnancy, particularly secondary to dapsone is available up to date. Surprisingly, blood gas analysis showed that the methaemoglobin MetHb level was After initial stabilisation and treatment, additional information about her medical history became clear. She was diagnosed with coeliac disease and was also suspected of dermatitis herpetiformis, for which the antibiotic dapsone was prescribed and dosage was increased from 50 to mg, once daily, four days prior to her visit to the Emergency Department.
Based on these results, the most likely diagnosis was thought to be symptomatic methaemoglobinaemia caused by dapsone.
Methylene blue was given intravenously, after which her MetHb level quickly declined figure 1 and shortly after infusion, she was extubated because of substantial clinical improvement, in particular, the normalisation of her blood oxygenation.
Dapsone was discontinued. Surprisingly, seven days after discharge and 12 days after discontinuing dapsone, the patient presented again with symptoms of progressive dyspnoea, which appeared to be based on a recurrent symptomatic methaemoglobinaemia. MetHb level was The patient was readmitted and again treated with methylene blue, and after two doses, her MetHb level stayed within normal ranges figure 1.
Toxicological analysis of a blood sample taken 12 days after discontinuation of dapsone showed a dapsone concentration of Unfortunately, no toxicological analysis was performed on blood samples taken during the first episode. Her pharmacy confirmed that she had turned in the remaining tablets after discharge from the previous admission; furthermore, she used no medication influencing pharmacokinetics of dapsone.
The toxicological analysis supports our theory that dapsone is the most likely agent for the relapse of the methaemoglobinaemia with a score of 7, as assessed by the Naranjo algorithm for assessment of adverse drug reactions.
Based on literature which will be reviewed later, cimetidine and ascorbic acid were added to the treatment to prevent a new relapse and to further diminish MetHb levels. Two days after readmission, the patient could be discharged from the hospital free of symptoms. Frequent outpatient clinic follow-up showed no increase of MetHb levels thereafter, and the concentration of dapsone decreased to 2.
Since then, there has been no more relapse of symptomatic methaemoglobinaemia figure 1. Methaemoglobinaemia by dapsone Dapsone is an antimicrobial agent registered for the treatment of leprosy and dermatitis herpetiformis. It can sometimes be used for other inflammatory conditions or as prophylaxis for pneumocystis jiroveci pneumonitis on an off-label basis.
Serious side effects are rare but include agranulocytosis, methaemoglobinaemia, and haemolysis, especially in patients with G6PD-deficiency. This reduction takes place by two pathways involving nonenzymatic antioxidants: the cytochrome b5 and NADPH reductase pathways figure 2.
Medication and toxins are the major cause of acquired methaemoglobinaemia. Dapsone, chloroquine, primaquine, and local anaesthetics such as benzocaine and lidocaine are most common; the latter, even if administered topically, can cause significant methaemoglobinaemia.
Chemicals known to cause methemoglobinemia are anilines, hydrogen peroxide, chlorates, and nitrates, ranging from polluted water and high-nitrate food to party drugs and medicinal nitrates. The oxygen dissociation curve shows a left shift and O 2 delivery to the tissues is decreased, leading to cellular hypoxia and cyanosis.
Symptoms vary based on MetHb concentration, ranging from asymptomatic cyanosis and headache to coma and severe hypoxic symptoms, as summarised in table 1. When blood is exposed to atmospheric oxygen, for example, in cases of MetHb, its appearance does not change in contrast to deoxyhaemoglobin, in which its colour changes to bright red.
This test is used in low resource settings to establish methaemoglobinaemia; it is also used to estimate the percentage of MetHb. However, some pulse oximeters use multiple wavelengths and can discriminate methaemoglobin, such as the Rad Pulse CO-Oximeter Masimo, Switzerland.
Blood gas analysis While pulse oximetry suffers from interference by MetHb and methylene blue, the spectrophotometry-based blood gas analysis by modern analysers is accurate. Unfortunately, there still are misunderstandings about the interference of methylene blue in the measurement of the MetHb concentration.
In AprilThe New York Times published an article about the importance of having a tiny fingertip device at home to assess oxygen saturation, which complained about the scarcity of the device at that time 2.
Due to the rise in the popularity of pulse oximeters, asymptomatic hypoxemia has become a common complaint of patients with leprosy under treatment during the pandemic. This drug is also commonly used in dermatology to treat inflammatory and immunobullous diseases, such as pemphigus, pemphigoids, and neutrophilic dermatoses 3.
This study primarily aimed to determine the adverse effects of dapsone on peripheral hypoxemia and its differential diagnosis with happy hypoxia encountered during the COVID pandemic. A descriptive observational case-series study was conducted involving 16 patients with leprosy who underwent multidrug therapy from a private clinic PC. In16 leprosy patients 8 males and 8 females, average age None of the patients had symptomatic anemia or a decrease in hemoglobin levels prior to dapsone use.
The mean SpO 2 was Only three patients presented with dyspnea, fatigue, and malaise, which improved when dapsone was replaced with ofloxacin. Unfortunately, testing for COVID infection was not performed in all patients, which is a limitation of our study. Thus, caution should be observed as the effects of oxidative stress due to dapsone are not yet fully understood, and the risk of this fake sign of hypoxemia needs to be highlighted in these COVID days.
Menu Mobile. Respir Res. Dapsone and sulfones in dermatology: overview and update. J Am Acad Dermatol. Pathophysiologic mechanisms, diagnosis, and management of dapsone-induced methemoglobinemia. J Am Osteopath Assoc. Delayed sulfhemoglobinemia after acute dapsone intoxication. J Toxicol Clin Toxicol. Consenso em paracoccidioidomicose.
Her initial oxygen saturation was 85% on room air prompting immediate placement of 2 L of oxygen via nasal cannula. Her oxygen saturation. Dapsone therapy is associated with methemoglobinemia. Pulse oximetry is used to indicate adequate oxygen saturations, and co-oximetry is. The oxygen saturation gap is measured as percentage. It is the difference between oxyhemoglobin concentration recorded by a pulse oximeter from. Dapsone therapy is associated with methemoglobinemia. Pulse oximetry is used to indicate adequate oxygen saturations, and co-oximetry is. His blood pressure was /69 mmHg, pulse rate was 85 beats per minute, oxygen saturation was recorded 85% on room air. Lung examination was clear with. Open in new tab Download slide. J Toxicol Clin Toxicol.The patient was experiencing progressive dyspnoea for a couple of days and had experienced multiple fainting spells. Because of her condition, the patient was immediately intubated and ventilated with pressure support. A CT scan ruled out pulmonary embolism and intraparenchymatous abnormalities explaining the low saturation.
Transthoracic ultrasound showed normal ventricular function and no signs of cardiac shunting. Surprisingly, blood gas analysis showed that the methaemoglobin MetHb level was After initial stabilisation and treatment, additional information about her medical history became clear.
She was diagnosed with coeliac disease and was also suspected of dermatitis herpetiformis, for which the antibiotic dapsone was prescribed and dosage was increased from 50 to mg, once daily, four days prior to her visit to the Emergency Department. Based on these results, the most likely diagnosis was thought to be symptomatic methaemoglobinaemia caused by dapsone. Methylene blue was given intravenously, after which her MetHb level quickly declined figure 1 and shortly after infusion, she was extubated because of substantial clinical improvement, in particular, the normalisation of her blood oxygenation.
Dapsone was discontinued. Surprisingly, seven days after discharge and 12 days after discontinuing dapsone, the patient presented again with symptoms of progressive dyspnoea, which appeared to be based on a recurrent symptomatic methaemoglobinaemia. MetHb level was The patient was readmitted and again treated with methylene blue, and after two doses, her MetHb level stayed within normal ranges figure 1.
Toxicological analysis of a blood sample taken 12 days after discontinuation of dapsone showed a dapsone concentration of Unfortunately, no toxicological analysis was performed on blood samples taken during the first episode. Her pharmacy confirmed that she had turned in the remaining tablets after discharge from the previous admission; furthermore, she used no medication influencing pharmacokinetics of dapsone. The toxicological analysis supports our theory that dapsone is the most likely agent for the relapse of the methaemoglobinaemia with a score of 7, as assessed by the Naranjo algorithm for assessment of adverse drug reactions.
Based on literature which will be reviewed later, cimetidine and ascorbic acid were added to the treatment to prevent a new relapse and to further diminish MetHb levels. Two days after readmission, the patient could be discharged from the hospital free of symptoms.
Frequent outpatient clinic follow-up showed no increase of MetHb levels thereafter, and the concentration of dapsone decreased to 2. Since then, there has been no more relapse of symptomatic methaemoglobinaemia figure 1. Methaemoglobinaemia by dapsone Dapsone is an antimicrobial agent registered for the treatment of leprosy and dermatitis herpetiformis. It can sometimes be used for other inflammatory conditions or as prophylaxis for pneumocystis jiroveci pneumonitis on an off-label basis. Serious side effects are rare but include agranulocytosis, methaemoglobinaemia, and haemolysis, especially in patients with G6PD-deficiency.
This reduction takes place by two pathways involving nonenzymatic antioxidants: the cytochrome b5 and NADPH reductase pathways figure 2. Medication and toxins are the major cause of acquired methaemoglobinaemia. Dapsone, chloroquine, primaquine, and local anaesthetics such as benzocaine and lidocaine are most common; the latter, even if administered topically, can cause significant methaemoglobinaemia.
Chemicals known to cause methemoglobinemia are anilines, hydrogen peroxide, chlorates, and nitrates, ranging from polluted water and high-nitrate food to party drugs and medicinal nitrates. The oxygen dissociation curve shows a left shift and O 2 delivery to the tissues is decreased, leading to cellular hypoxia and cyanosis. Symptoms vary based on MetHb concentration, ranging from asymptomatic cyanosis and headache to coma and severe hypoxic symptoms, as summarised in table 1.
When blood is exposed to atmospheric oxygen, for example, in cases of MetHb, its appearance does not change in contrast to deoxyhaemoglobin, in which its colour changes to bright red. This test is used in low resource settings to establish methaemoglobinaemia; it is also used to estimate the percentage of MetHb.
However, some pulse oximeters use multiple wavelengths and can discriminate methaemoglobin, such as the Rad Pulse CO-Oximeter Masimo, Switzerland. Blood gas analysis While pulse oximetry suffers from interference by MetHb and methylene blue, the spectrophotometry-based blood gas analysis by modern analysers is accurate.
Unfortunately, there still are misunderstandings about the interference of methylene blue in the measurement of the MetHb concentration. Unfortunately, various CO-oximetry methods using 4 or up to 17 wavelengths are reported to yield inaccurate MetHb measurements in the presence of methylene blue. Due to the large number of wavelengths used to determine the concentrations, the influence of interference is minimised.
The first reference to methylene blue as a treatment of methaemoglobinaemia is from the early s, 16 but no clinical trials were published. Methylene blue is a cofactor of the nicotinamide adenine dinucleotide phosphate hydrogen NADPH reductase pathway and forms leucomethylene blue, which acts as an electron donor and reduces MetHb to Hb figure 2.
The effect is expected in minutes to one hour. Methylene blue can induce G6PD-related haemolysis due to the formation of free radicals and direct oxidative stress, for which G6PD-deficient erythrocytes are more vulnerable. In cases of G6PD deficiency, ascorbic acid can be used at high doses up to four grams per day, which acts as a nonenzymatic MetHb-reducing agent. In addition, the hydrogen H 2 antagonist cimetidine can be added in a daily dose of mg once.
In extreme cases of methaemoglobinaemia, exchange transfusion must be considered, particularly in children. Second, G6PD deficiency was unlikely due to the significant drop in MetHb concentration after methylene blue administration. Third, to rule out delayed metabolism due to pharmacogenetic variants, the enzymatic pathways responsible for the metabolisation of dapsone were analysed through assessing genetic variants of the specific enzymes.
Dapsone is acetylated by N-acetyltransferase 2 NAT2 to the inactive metabolite monoacetyldapsone and will thereafter be deacetylated. Therefore, we excluded delayed metabolism of dapsone as cause of recurring methaemoglobinaemia. Furthermore, we found several theoretical explanations in earlier case reports also describing the recurrence of methaemoglobinaemia after the cessation of drug intake.
This recycling pathway may be responsible for the persistence of dapsone in the blood and thus the relapse of methaemoglobinaemia. However, the patient denied taking any additional dapsone after the first hospital admission and disposal of the remaining dosages was confirmed by her pharmacy. This case shows the importance of considering the possibility of a late rebound methaemoglobinaemia after discontinuation of dapsone and possible pathophysiological explanations for this phenomenon.
No funding or financial support was received. Toggle navigation. Jonkers , G. Cobanoglu , E. Blok , J. M van Hoof , A.
Tintu , C. Bethlehem , J. View abstract. Abstract Full text PDF.
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