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.

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.

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.

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.

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.

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.

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.

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.

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.

Clinical manifestations of food protein-induced enterocolitis syndrome.

PURPOSE OF REVIEW: To raise awareness among healthcare providers about the clinical and laboratory findings in acute and chronic food protein-induced enterocolitis syndrome (FPIES). RECENT FINDINGS: FPIES can be caused by trivial exposure or rare foods. SUMMARY: FPIES is a non-IgE-mediated reaction that usually presents with acute severe repetitive vomiting and diarrhea associated with lethargy, pallor, dehydration, and even hypovolemic shock. Manifestations resolve usually within 24-48 h of elimination of the causative food. In chronic cases, symptoms may include persistent diarrhea, poor weight gain, failure to thrive, and improvement may take several days after the food elimination. In the acute cases, laboratory evaluation may reveal thrombocytosis and neutrophilia, peaking about 6 h postingestion. Depending on the severity, metabolic acidosis and methemoglobinemia may occur. In chronic cases, anemia, hypoalbuminemia and eosinophilia may be seen. Radiologic evaluation or other procedures, such as endoscopy and gastric juice analysis may show nonspecific abnormal findings. The diagnosis is based on clinical manifestations. Further studies looking at the phenotypes of FPIES are needed to identify clinical subtypes, and to understand the predisposing factors for developing FPIES compared with immediate-type, IgE-mediated gastroenteropathies.

Neurometabolic disorder with microcephaly, dystonia, and central cyanosis masquerading as cerebral palsy.

Many neurodegenerative diseases can be misdiagnosed as cerebral palsy. The correct diagnosis is reached when the condition recurs in families or when there are specific clinical signs. The clinical and imaging features of 3 children, from 2 unrelated families, presenting with global developmental delay and dystonia are described, in whom the presence of cyanosis and methemoglobinemia confirmed the diagnosis of recessive hereditary methemoglobinemia type 2. Magnetic resonance imaging showed significant cerebellar atrophy in 2 of the 3 babies. In dark-skinned children, this condition is underdiagnosed, as mild cyanosis is difficult to detect. Screening for methemoglobinemia in children with dystonia, microcephaly, and progressive cerebellar atrophy can be helpful in identifying more cases. As there is no curative treatment for this autosomal recessive condition, the exact diagnosis offers the best chance for prenatal screening, by detecting deficient NADH--cytochrome b5 reductase enzyme activity or by identifying the specific mutation in cultured amniotic fluid cells.

A case of severe methemoglobinemia caused by hair dye poisoning.

CONTEXT: Hair dyes are widely used and very popular xenobiotics. Most of these products contain paraphenylenediamine (PPD) that can cause methemoglobinemia. We here report a case of severe methemoglobinemia that we treated using large amounts of methylene blue. CASE DETAILS: A 30-year-old man visited a regional hospital with cyanosis. He was congenitally blind and had autism. For several weeks, he had mistaken hair dye for toothpaste. When he arrived at a regional hospital, he was drowsy with cyanosis and his initial serum methemoglobin (MetHb) level was 59.5%. After being treated with 2 mg/kg methylene blue (1 mg/kg × 2 administrations), he was transferred to a tertiary university hospital. Upon presentation at the Emergency Department in the tertiary hospital, his MetHb level was found to be 49.4% and his oxygen saturation was 80%. He was then admitted to the intensive care unit. After treatment with 4 mg/kg methylene blue (1 mg/kg × 4 administrations), he successfully recovered. DISCUSSION: Because PPD can result in serious methemoglobinemia, clinicians should test it in cyanotic patients who have been exposed to hair dye for an extended period.

[Mechanisms of changes of microcirculation in rats under acute methemoglobinemia].

It was investigated the features of microcirculation and mechanisms it's conditioned, under acute administration of sodium nitrite in 5 mg of dry substance per 100 g of body weight. It was shown that acute administration of sodium nitrite leads to the development of methemoglobinemia, arterial and venous hypoxemia, and severe tissue hypoxia. Increase in the diffusion path O2 at methemoglobinemia is caused due to significant hyperhydratation of lung air-blood barrier and its individual layers, and is accompanied by a decrease in both components of the diffusion capacity of the lungs for oxygen: its membrane and blood components. It was revealed that the administration of sodium nitrite has a double effect, leading to inactivation of hemoglobin, as well as to microcirculatory disturbances associated primarily with changes in the regulation of vascular tone. In this initial perfusion per unit volume of tissue per time unit intrinsic for the organism defines a set of mechanisms which are responsible for changes in tissue blood flow under methemoglobinemia.