Recommendations for diagnosis and treatment of methemoglobinemia.

Methemoglobinemia is a rare disorder associated with oxidization of divalent ferro-iron of hemoglobin (Hb) to ferri-iron of methemoglobin (MetHb). Methemoglobinemia can result from either inherited or acquired processes. Acquired forms are the most common, mainly due to the exposure to substances that cause oxidation of the Hb both directly or indirectly. Inherited forms are due either to autosomal recessive variants in the CYB5R3 gene or to autosomal dominant variants in the globin genes, collectively known as HbM disease. Our recommendations are based on a systematic literature search. A series of questions regarding the key signs and symptoms, the methods for diagnosis, the clinical management in neonatal/childhood/adulthood period, and the therapeutic approach of methemoglobinemia were formulated and the relative recommendations were produced. An agreement was obtained using a Delphi-like approach and the experts panel reached a final consensus >75% of agreement for all the questions.

Dapsone-induced hepatic complications: it's time to think beyond methemoglobinemia.

Drug-induced liver injury is an important cause of hepatotoxicity and poses a challenging clinical problem with respect to both diagnosis and management. Patients susceptible to hepatotoxicity on exposure to dapsone is constantly on the rise. Dapsone (4,4'-diaminodiphenylsulfone) is clinically used alone or in combination with rifampicin for the treatment of a variety of dermatological disorders such as acne, dermatitis herpetiformis, psoriasis, Toxoplasma gondii infections, leprosy and pneumocystis carinii pneumonia in AIDS patients. However, the clinical use of dapsone is limited because of dose-dependent adverse hematological reactions. The cholestatic injury caused by dapsone and its N- hydroxylated metabolites hinders bile flow and causes oxidative stress and hepatic necrosis, further, leading to hemolysis responsible for hepatitis due to iron overload in the liver. Hence, clinicians' awareness of the hepatotoxic potential of dapsone is highly warranted.

Whole bowel irrigation in dapsone intoxication with persistent methemoglobinemia.

Dapsone intoxication can be a life-threatening condition due its enterohepatic recirculation pharmacokinetics, and therefore, persistent methemoglobinemia development. We describe a case of a 17-year-old girl who was admitted 4 h after ingesting 5 g of dapsone. She presented methemoglobinemia (39%) and showed clinical signs of toxicity (cyanosis and altered mental status) despite mechanical ventilation. Multiple activated charcoal dosis and methylene blue infusions were performed. Notwithstanding initial improvement, a pattern of peaks and valleys was observed in serial methemoglobinemia measurements, with cyclic states of hypoxemia. On account of enterohepatic recirculation pharmacokinetics, clearance was enhanced by whole bowel irrigation. After 7 days of hospitalization, she was discharged in good general condition.

Neutropenia, Hypoxia, and the Complexities of Emergency Medicine: A Case of Dapsone-Induced Methemoglobinemia.

BACKGROUND: Methemoglobinemia is a rare dyshemoglobinemia that can be difficult to diagnose due to its nonspecific symptomatology and infrequent occurrence. A number of commonly used medications have been known to contribute to this disease process that results in acute hypoxemia. CASE REPORT: A 60-year-old man with history of acquired immunodeficiency syndrome presented to the Emergency Department (ED) with asymptomatic hypoxia. Supplemental oxygen proves to be ineffective in treating his low oxygen saturation. Numerous testing modalities are performed in the ED focused on an infectious versus pulmonary etiology prior to coming to the conclusion that the source is methemoglobinemia induced by dapsone therapy. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This article discusses the basic pathophysiology of the disease and the expected clinical findings. Patient outcome is correlated with prompt identification and discontinuation of the offending agents leading to the excessive accumulation of methemoglobin in the circulatory system. This makes it crucial that emergency providers know the symptomatology of the disease to facilitate appropriate treatment therapy.

Methemoglobinemia in a Case of Paint Thinner Intoxication, Treated Successfully with Vitamin C.

BACKGROUND: Methemoglobin (MetHb) is an oxidized form of hemoglobin. It is a poor transporter of oxygen and is unable to deliver oxygen to the tissue. Globally, drug & toxin induced methemoglobinemia is more common as compared with the congenital form. Methemoglobinemia caused by paint thinner intoxication is rare. Methylene blue is well established as the first-line therapy for severe methemoglobinemia. CASE REPORT: A 25-year old man was brought to the Emergency Department after accidental consumption of paint thinner. On clinical examination, he had cyanosis and there were discrepancies in his pulse oximetry and arterial blood gas (ABG) analysis results. With this clue and supporting laboratory investigations, the diagnosis of toxin-induced methemoglobinemia was made. Due to the unavailability of methylene blue, alternative treatment with high-dose vitamin C was attempted, to which the patient responded. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The role of vitamin C in the treatment of methemoglobinemia has not been well established, with only a few published case reports. This patient had severe methemoglobinemia, with MetHb of 46.4%, which responded dramatically to vitamin C therapy, with no side effects. This case shows that high-dose vitamin C is safe and has the potential to be an effective alternative for the treatment of severe methemoglobinemia. In the presence of cyanosis, mismatch of pulse-oximetry and ABG-analysis are the key for the physician to suspect methemoglobinemia.

Severe Heinz body anemia and methemoglobinemia in a kitten with chronic diarrhea.

INTRODUCTION: A 2-month-old kitten was referred for depression and partial anorexia since 3 days and chronic diarrhea lasting for over 3 weeks. General physical examination showed pale and cyanotic mucous membranes. Blood sample was of brownish appearance. Venous blood gas analysis and complete blood count showed 16% methemoglobin level and severe regenerative anemia with Heinz bodies in about 40% of the erythrocytes, respectively. The kitten was transfused with fresh whole blood and treated with supportive care, antimicrobial and antioxidant agents. The kitten totally recovered. To the authors' knowledge, this represents the first case report of severe Heinz body hemolytic anemia and methemoglobinemia with concurrent chronic diarrhea in a young kitten. Diarrhea resolution coincided with Heinz bodies and methemoglobin disappearance. The possibility that diarrhea might have stimulated an inflammatory state causing release of oxygen radicals and prolonged erythrocytes oxidative damage has been discussed.

An unusual complication after permanent pacemaker implantation: Methemoglobinemia.

Permanent pacemaker implantation (PPI) is usually a very safe procedure with a low complication risk. It is a relatively straightforward process carried out under local anesthetic. This case report presents an 80-year-old male patient who required a permanent pacemaker due to complete atrioventricular (AV) block, and who developed cyanosis and was diagnosed with methemoglobinemia after the pacemaker insertion procedure, in which the local anesthetic prilocaine was administered. To our knowledge, this is the first case in the literature to describe methemoglobinemia developing after PPI.

Methemoglobinemia in postchemotherapy stomatitis topical treatment: 2 pediatric cases.

Methemoglobinemia is a rare congenital or acquired disease of increased blood methemoglobin concentration. We documented 2 cases of children suffering from neuroblastoma whose postchemotherapy anemia, leucopenia, and stomatitis were complicated by methemoglobinemia after using a formulary oral gel (7.5% benzocaine, doxycycline, nystatin, glycerin). The complication resulted in hospital treatment. Percutaneous oxygen saturation remained at 85% and 87% despite administration of 100% oxygen through a nonrebreather mask. Arterial blood gas analysis showed an oxygen saturation of 98% and 97%, respectively. Spectroscopic measurement showed methemoglobin concentration of 42% and 35.5%, respectively. After red blood cell transfusion and oral ascorbic acid in case 1 and methylene blue in case 2, the patients' condition improved. Although the benzocaine gel is not in use in several medical systems, it should be considered as a possible reason for methemoglobinemia.

Dapsone-induced methemoglobinemia: a primer for clinicians.

OBJECTIVE: To present a comprehensive review of dapsone-induced methemoglobinemia and its management. DATA SOURCES: Literature retrieval was accessed through MEDLINE (1966-March 2011), Cochrane Library, and EMBASE, using the terms dapsone and methemoglobinemia. STUDY SELECTION AND DATA EXTRACTION: All case reports, small case series, and randomized controlled trials published in English were evaluated. Because of the absence of comprehensive updates on this topic since 1996, publications between 1997 and March 2011 were included in this review. DATA SYNTHESIS: Between 1997 and March 2011, the majority of publications describing methemoglobinemia associated with dapsone use reported this adverse effect at therapeutic doses. Excluding overdose situations, 18 described symptomatic dapsone-associated methemoglobinemia and clinical presentation ranging from cyanosis to dyspnea. In almost all of the accounts, patients had a concurrent event such as anemia or pneumonia, suggesting an interplay between these comorbidities and the onset of symptomatic methemoglobinemia. Delayed hemolytic anemia was seen in patients with high methemoglobin levels at presentation. Management in most cases consisted of administration of methylene blue. Overall, most reports described a successful outcome, and no mortality resulted from methemoglobinemia associated with therapeutic use. CONCLUSIONS: Clinicians should recognize methemoglobinemia as an adverse effect associated with dapsone use and the potential factors that precipitate it. They should also know how to promptly and effectively manage this event.

Methemoglobinemia: a systematic review of the pathophysiology, detection, and treatment.

Methemoglobin is the oxidized form of hemoglobin which does not bind to oxygen efficiently. An increased level of methemoglobin can be attributed to congenital enzymatic defects, alterations in the hemoglobin molecule, or as a result of medications and toxins. The main clinical characteristic of the disease include cyanosis which is unresponsive to oxygen therapy and blood that is chocolate color when drawn. Co-oximetry is the gold standard for diagnosis but arterial blood gas paired with pulse oximetry and serum methemoglobin levels can confirm the diagnosis clinically. Treatment is aimed at removal of the offending agent, if medication induced, and is directed at aggressive oxygen therapy and treatment with the antidote, methylene blue.

Infection and the risk of topical anesthetic induced clinically significant methemoglobinemia after transesophageal echocardiography.

BACKGROUND: Methemoglobinemia is a recognized complication of topical anesthesia with benzocaine during transesophageal echocardiography (TEE). Though several risk factors have been described, the importance of individual factors is not known. We performed a retrospective study to identify determinants of the risk of methemoglobinemia. MATERIALS AND METHODS: All patients who underwent TEE with benzocaine topical anesthesia between June 2005 and June 2007 were included in this retrospective study. RESULTS: Of the 886 patients who were included in the study, 140 had active infection (15.8%). The incidence of methemoglobinemia in this group was 2.9% (vs. 0%, P < 0.001). Compared to those without infection, patients in the active infection group were more likely to have a lower hemoglobin (P < 0.001), serum albumin level (P < 0.001), glomerular filtration rate less than 60 ml/min per 1.73 m(2) (P < 0.001), higher rates of dialysis (P < 0.001), a higher incidence of malignancy (P = 0.01), and increased use of acetaminophen and sulfa drugs (P < 0.001). However, multivariate logistic regression analysis did not identify any statistically significant covariates. CONCLUSION: In conclusion, patients with an active systemic infection who undergo TEE are at a higher risk of methemoglobinemia. However, none of the risk factors for methemoglobinemia including active infection reached statistical significance in the regression analysis which has to be interpreted with caution in view of the low event rate.

Methemoglobinemia in the Operating Room and Intensive Care Unit: Early Recognition, Pathophysiology, and Management.

The objectives of this review are to describe the acquired and hereditary causes of methemoglobinemia, to recommend the most sensitive diagnostic tests, and to enable critical care clinicians to rapidly detect and treat methemoglobinemia. To meet these objectives, Internet search engines were queried with the keywords to select articles for review that included case reports, case series, observational, longitudinal, and surveillance studies. The most common causes of methemoglobinemia include oxidizing reactions to cocaine-derived anesthetics, such as benzocaine and lidocaine, to antibiotics, such as dapsone and other sulfonamides, and to gases, such as nitric oxide. Additionally, CO-oximetry is superior to standard pulse oximetry in detecting methemoglobinemia. Finally, effective treatments for methemoglobinemia include intravenous administration of methylene blue, ascorbic acid, and riboflavin. In this manuscript we will discuss methemoglobinemia, how it occurs, and how to treat it.

Severe hemolysis and methemoglobinemia following fava beans ingestion in glucose-6-phosphatase dehydrogenase deficiency: case report and literature review.

INTRODUCTION: Reduced concentrations of glucose-6-phospate dehydrogenase (G6PD) render erythrocytes susceptible to hemolysis under conditions of oxidative stress. In favism, the ingestion of fava beans induces an oxidative stress to erythrocytes, leading to acute hemolysis. DISCUSSION: The simultaneous occurrence of methemoglobinemia has been reported only scarcely, despite the fact that both phenomena are the consequence of a common pathophysiologic mechanism. The presence of methemoglobinemia has important diagnostic and therapeutic consequences. We report a previously healthy boy who presented with combined severe hemolytic anemia and cyanosis due to methemoglobinemia, following the ingestion of fava beans. His condition was complicated by the development of transient acute renal failure. A G6PD-deficiency was diagnosed. We review the literature on the combination of acute hemolysis and methemoglobinemia in favism. Pathophysiologic, diagnostic, and therapeutic aspects of this disorder are discussed.

Methemoglobinemia: Infants at risk.

Methemoglobin is formed when the iron center in hemoglobin is oxidized from ferrous iron to ferric iron. The functional consequence of this change is that hemoglobin is transformed to methemoglobin and cannot oxygenate tissues adequately, causing hypoxia and cyanosis. Infants have unique physiology that increases their risk of developing methemoglobinemia. Infants drink more water per body weight compared to children and adults, have lower NADH cyb5r reductase activity that converts methemoglobin to hemoglobin, and have a higher percentage of fetal hemoglobin, which is easier to convert to methemoglobin. A well-studied exposure to a chemical that can cause methemoglobinemia in infants is nitrate in well water. For the first part specifically about methemoglobin in infants, articles that were recent (2015-now) were given preference over articles that were older. Search terms included: methemoglobin, methemoglobinemia, infant, acquired, congenital, and methylene blue. For the latter half of the paper on nitrate and methemoglobinemia, preference was given to articles that described regionally important cases. In addition, search terms were: Minnesota, methemoglobinemia, nitrate, well water, drinking water, and infant. Acquired methemoglobinemia is rare, yet can still be seen in medical settings, and when an infant is exposed to nitrate in well water above 10 mg/L. To prevent exposure, parents should have their water tested for nitrate before the baby comes home. Physicians should make it practice to ask what the source of drinking water is for newly pregnant women and urge them to test for nitrate and bacteria if using a well. Using bottled water to make formula is also an option, but the best option is still breastfeeding.

Application of topical analgesia in triage: a potential for harm.

To reduce the overall time spent in the ED, triage nurses are encouraged to treat patients with a topical anesthetic cream, eutectic mixture of local anesthetics (EMLA). We present a case in which a 28-day-old neonate who was treated with EMLA cream in triage developed severe methemoglobinemia 18 hours post admission to the pediatric ward. This case demonstrates that there may be some risks associated with this approach, and that protocols for the use of EMLA at triage should include not only the indications for its use, but also need to ensure that there is a process to have the EMLA removed before patient discharge or transfer.

Benzocaine-induced methemoglobinemia in two patients: interdisciplinary collaboration, management, and near misses.

Methemoglobin, a form of hemoglobin that does not bind oxygen, is produced when iron in red blood cells is oxidized from the ferrous state to the ferric state. Methemoglobinemia develops in the presence of oxidizing agents, such as benzocaine-containing topical anesthetic sprays, and it is characterized by cyanosis. If untreated, methemoglobinemia may prove lethal. We describe two patients who developed methemoglobinemia after they were administered benzocaine-containing topical anesthetic sprays. Using the Naranjo adverse drug reaction probability scale, the relationship between the administration of the benzocaine-containing spray and the development of methemoglobinemia was probable (score of 7) in both patients. Collaboration among health care providers is necessary to efficiently recognize, treat, and manage this condition.

Sulfhaemoglobinaemia caused by ferrous sulfate.

A 78-year-old man was referred from his primary care clinic to the emergency department due to bluish discolouration of his lips and decreased oxygen saturation on pulse oximetry. The patient was asymptomatic. Physical exam was normal except for lip cyanosis. A CT pulmonary angiogram was negative for pulmonary embolism. Arterial blood gas (ABG) analysis with co-oximetry showed low oxyhaemoglobin, normal partial pressure of oxygen and methaemoglobinaemia, but an unexplained 'gap' in total haemoglobin saturation. This gap was felt to be due to sulfhaemoglobinaemia. After a thorough review of his medications, ferrous sulfate was stopped which resulted in resolution in patient's cyanosis and normalisation of his ABG after 7 weeks.

Acquired Methemoglobinemia - A Sporadic Holi Disaster.

OBJECTIVE: To study clinical profile and outcome in patients with methemoglobinemia following exposure to toxic colors during Holi festival. METHODS: This retrospective study included 112 children (5 to 12 years) admitted with methemoglobinemia after playing Holi. Clinical and treatment details were reviewed. RESULTS: The common symptoms were giddiness, vomiting and headache. Treatment included thorough skin wash, intravenous fluid and methylene blue in 111 children. Age 7-9 and > 11 years, vomiting, giddiness, cyanosis, PaO2 < 80 mm Hg and oxygen saturation < 95% were associated with higher need for methylene blue. All children had a good outcome. CONCLUSION: Timely diagnosis and management of acquired methemoglobinemia can save lives.