Hereditary methemoglobinemia, toxic methemoglobinemia and the reduction of methemoglobin.
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Erythrocytes↗
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Methemoglobinemia in infancy; two case reports, one of the congenital and one of the acquired variety of methemoglobinemia.
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Child↗
Benzocaine-induced methemoglobinemia in an adult: accuracy of pulse oximetry with methemoglobinemia.
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Anesthesia, Local↗
Acquired methemoglobinemia: a retrospective series of 138 cases at 2 teaching hospitals.
Methemoglobin is a form of hemoglobin that does not bind oxygen. When its concentration is elevated in red blood cells, functional anemia and tissue hypoxia may occur. We performed a retrospective case series to describe the cases of acquired methemoglobinemia (methemoglobin level >2%) detected and the clinical circumstances under which they occurred at 2 tertiary care hospitals and affiliated outpatient clinics over 28 months. We surveyed co-oximetry laboratory data to identify patients with methemoglobinemia. We reviewed these patients' medical records to extract the clinical information and context. One hundred thirty-eight cases of acquired methemoglobinemia were detected over the 28 months. There was no gender predisposition, and the condition occurred over a wide range of ages (patients aged 4 days to 86 years). Cases occurred in many areas of the hospital, including outpatient clinics. One fatality and 3 near-fatalities were directly attributable to methemoglobinemia. Dapsone was the most common etiology of acquired methemoglobinemia, accounting for 42% of all cases. The mean peak methemoglobin level among these individuals was 7.6%. In 5 of the patients with the most severely elevated levels, 20% benzocaine spray (Hurricaine Topical Anesthetic spray, Beutlich Pharmaceuticals, Waukegan, IL) was the etiology, associated with a mean peak methemoglobin level of 43.8%. Eleven pediatric patients developed methemoglobinemia either from exogenous exposure, such as drugs, or due to serious illness, such as gastrointestinal infections with dehydration. Almost all (94%) patients with methemoglobinemia were anemic. Drugs that cause acquired methemoglobinemia are ubiquitous in both the hospital and the outpatient setting. Acquired methemoglobinemia is a treatable condition that causes significant morbidity and even mortality. We hope that a heightened awareness of methemoglobinemia will result in improved recognition and treatment. Primary prevention efforts have the potential to reduce the morbidity and mortality associated with this condition.
Adolescent↗
Anesthetic management of a patient with methemoglobinemia.
Methemoglobinemia results from the oxidation of the ferrous iron in hemoglobin to the ferric iron state. Methemoglobin is incapable of carrying O2, and high levels may impact on O2 delivery to the tissues. Methemoglobinemia may result from congenital deficiencies of enzymes that normally convert methemoglobin to hemoglobin, alterations in the hemoglobin molecule itself or, most commonly, from the ingestion of medications or toxins that oxidize the ferrous iron of hemoglobin. Several issues must be considered when anesthetizing patients with methemoglobinemia, including the potential for decreased O2 delivery, which may be exacerbated by intraoperative blood loss and anemia, interference with normal intraoperative monitoring devices, and the potential for medications to cause or exacerbate methemoglobinemia. We describe a patient with acquired methemoglobinemia from dapsone therapy who required anesthetic care for shoulder arthroscopy. The patient's drug-induced methemoglobinemia was diagnosed intraoperatively during previous anesthesia on the basis of discrepancy between the O2 saturation noted by pulse oximetry and that obtained from arterial blood gas analysis. Anesthetic care for patients with methemoglobinemia is discussed and a review of methemoglobinemia presented.
Anesthesia↗
Influence of the halogen-substituent pattern of fluoronitrobenzenes on their biotransformation and capacity to induce methemoglobinemia.
In the present study both the biotransformation patterns and the capacity to induce methemoglobinemia of a series of fluoronitrobenzenes were investigated. This was done to investigate to what extent variation in the number and position of the halogen substituents influence the metabolic fate of the fluoronitrobenzenes, thereby influencing their capacity to induce methemoglobinemia. The results obtained were compared to the effect of the fluorine substituent patterns on the calculated electronic characteristics and, thus, on the chemical reactivity of the fluoronitrobenzenes. Analysis of the in vivo metabolic profiles demonstrates a dependence of the extent of nitroreduction, of glutathione conjugation, and of aromatic hydroxylation with the pattern of halogen substitution. With an increasing number of fluorine substituents at electrophilic carbon centers, 24-hr urine recovery values decreased and fluoride anion elimination increased, due to increased reactivity of the fluoronitrobenzenes with cellular nucleophiles. In vitro studies even demonstrated a clear correlation between calculated parameters for the electrophilicity of the fluoronitrobenzenes and the natural logarithm of their rate of reaction with glutathione or with bovine serum albumin, taken as a model for cellular nucleophiles (r = 0.97 and r = 0.98, respectively). Increased possibilities for the conjugation of the fluoronitrobenzenes to cellular nucleophiles were accompanied by decreased contributions of nitroreduction and aromatic hydroxylation to the overall in vivo metabolite patterns, as well as by a decreased capacity of the fluoronitrobenzenes to induce methemoglobinemia. In vitro studies on the rates of nitroreduction of the various fluoronitrobenzenes by cecal microflora and rat liver microsomes revealed that the changes in the capacity of the fluoronitrobenzenes to induce methemoglobinemia were not due to differences in their intrinsic reactivity in the pathway of nitroreduction, leading to methemoglobinemia-inducing metabolites. Thus, the results of the present study clearly demonstrate that the number and position of fluorine substituents in the fluoronitrobenzenes influence the capacity of the fluoronitrobenzenes to induce methemoglobinemia, not because their intrinsic chemical reactivity for entering the nitroreduction pathway is influenced. The different methemoglobinemic capacity must rather result from differences in the inherent direct methemoglobinemic capacity and/or reactivity of the various toxic metabolites and/or from the fact that the halogen substituent pattern influences the electrophilic reactivity, thereby changing the possibilities for reactions of the nitrobenzenes with glutathione and, especially, other cellular nucleophiles. When the number of fluorine substituents increases, the electrophilicity of the fluoronitrobenzenes can become so high that glutathione conjugation is no longer able to compete efficiently with covalent binding of the fluoronitrobenzenes to cellular macromolecules. As a consequence, it can be suggested that with an increasing number of fluorine substituents at electrophilic carbon centers in a nitrobenzene derivative, a toxic end point of the nitrobenzene other than formation of methemoglobinemia can be foreseen.
Acetylcysteine↗
Combined effects of inhaled nitric oxide (iNO) and oxidant agents on the production of methemoglobinemia in newborn piglets.
OBJECTIVE: To investigate the effects of the association of inhaled nitric oxide (iNO) and oxidant drugs (acetaminophen, phytomenadione, and EMLA cream) on methemoglobinemia during the neonatal period. DESIGN: Prospective, randomized, experimental study. SETTING: University Experimental Pharmacology laboratory. SUBJECTS: Sixty newborn piglets weighing 1.5-2.0 Kg. INTERVENTIONS: Twelve groups of five piglets were anaesthetized, mechanically ventilated, and studied for 3 hrs. Eight groups received iNO (40 ppm or 80 ppm) alone or in association with a single intravenous dose of acetaminophen (120 mg/kg propacetamol), phytomenadione (5 mg vitamin K1) or EMLA cream (2.5 g) applied to the ventral lower abdomen for 3 hrs. Three other groups received, respectively, acetaminophen, phytomenadione, or EMLA cream without iNO. The last group (control group) received neither drugs nor iNO. MEASUREMENTS AND MAIN RESULTS: Methemoglobinemia was measured before the beginning of each experiment, 30 mins later, and every hour for 3 hrs. There was no significant difference in methemoglobinemia at any time between groups receiving acetaminophen (0.90%+/-0.12%), phytomenadione (0.88%+/-0.11%), or EMLA cream alone (0.97%+/-0.11%) and the control group (0.92%+/-0.12%). At 3 hrs, methemoglobinemia was slightly but significantly increased in group receiving iNO alone (1.04%+/-0.17% at 40 ppm iNO and 1.14%+/-0.16% at 80 ppm iNO; p < .05). Conversely, methemoglobinemia increased as a function of time in groups in which iNO was associated to drug administration and was significantly greater than the control group at 3 hrs (80 ppm iNO + acetaminophen, 2.80%+/-0.47%; 80 ppm iNO + phytomenadione, 2.38%+/-0.45%; 80 ppm iNO + EMLA cream, 2.33%+/-046%; p < .001). CONCLUSIONS: These results demonstrate that if oxidant drugs (acetaminophen, phytomenadione, or EMLA cream) did not increase blood methemoglobinemia in neonatal piglets, their association with iNO caused an increase in methemoglobin. Special care should be taken to monitor methemoglobinemia when iNO is combined to such drugs in newborn infants.
Acetaminophen↗
Endogenous methemoglobinemia associated with diarrheal disease in infancy.
Infantile diarrhea is sometimes associated with methemoglobinemia. To determine the significance of intestinal bacterial infection or overgrowth and other predisposing factors in this entity, we evaluated prospectively 45 consecutive patients who were admitted for gastroenteritis and methemoglobinemia between March 1980 and September 1992. All the patients were younger than 3 months of age. In 95% of them, methemoglobinemia occurred between the ages of 15 days to 2 months. The peak mean methemoglobin concentration was 9.4% (range, 2.4-57%). Although stool cultures were positive in only 22% of the infants, the epidemiologic data strongly suggested a bacterial or viral etiology in our study population: for 12 years, there was a significant decrease in the annual incidence of methemoglobinemia associated with diarrhea in parallel to the decrease in infantile diarrhea due to known pathogens throughout the country in the same period. There was also a marked seasonal variation in the incidence of the disease, with two peaks in January and the summer months when viral and bacterial infections, respectively, are prevalent. Failure to thrive and low admission-weight percentiles were associated with methemoglobinemia in most of the patients and diarrhea lasting > or = 7 days in 22 (49%) patients. The blood pH and the degree of acidosis did not correlate with the severity of methemoglobinemia. All the patients were formula fed. In the etiology of methemoglobinemia in infants with enteritis, viral and bacterial pathogens appear to play an important role by altering intestinal flora. Breast feeding appears to protect against this entity.
Acidosis↗
Dapsone- and primaquine-induced methemoglobinemia in HIV-infected individuals.
Clinically significant methemoglobinemia can develop as a result of medications. Although dapsone and primaquine are known to produce methemoglobinemia in susceptible individuals, methemoglobinemia has been reported only rarely in the human immunodeficiency virus (HIV) population. We describe five cases of methemoglobinemia caused by either primaquine or dapsone alone or in combination. The initial methemoglobin level ranged from 15.3% in the patient whose methemoglobinemia was caused by primaquine alone to 33.1%. Five patients developed symptomatic methemoglobinemia requiring hospitalization for 1 to 12 days. Two cases resulted from intentional overdoses of dapsone, and three developed within several days of commencing primaquine while dapsone remained present in the bloodstream. The four severe cases required intravenous methylene blue, supplemental oxygen, plus erythrocyte transfusions, whereas the mild case responded to oxygen therapy plus discontinuation of the precipitating drugs. Blood gases and pulse oximetry do not aid in the diagnosis, which requires cooximetry. Our study indicates that dapsone and primaquine alone or in combination can produce clinically significant methemoglobinemia in HIV-infected individuals, either in the setting of an overdose or when primaquine is instituted before dapsone has been cleared from the bloodstream.
AIDS-Related Opportunistic Infections↗
Methemoglobinemia and hemolytic anemia associated with Campylobacter jejuni enteritis.
A 7-week-old infant with methemoglobinemia, hemolytic anemia, and inadequate weight gain was found to have a Campylobacter jejuni gastrointestinal tract infection. Known etiologies of methemoglobinemia such as oxidative drug exposure, deficiency of NADH-methemoglobin reductase, and hemoglobin M disorder were excluded. The patient had a twin brother (probably identical) who had neither methemoglobinemia nor stool cultures positive for C. jejuni. The twin essentially served as an experimental control, making other environmental or genetic causes of methemoglobinemia unlikely in the patient. Both the methemoglobinemia and the C. jejuni infection responded to adequate treatment with erythromycin. The association of a C. jejuni infection with methemoglobinemia is discussed in light of previous associations of enteritis and methemoglobinemia in infants.
Anemia, Hemolytic↗
Benzocaine-induced methemoglobinemia: report of a severe reaction and review of the literature.
OBJECTIVE: To report a case of benzocaine-induced inethemoglobinemia and present a review of the related literature. CASE REPORT: An 83-year-old man received benzocaine topical anesthesia 600 mg prior to intubation for resection of a thyroid adenoma. The patient became severely cyanotic after induction of anesthesia. After a negative workup for common causes of cyanosis. blood co-oximetry analysis revealed a methemoglobin concentration of 54.1 percent. Intravenous methylene blue reversed the methemoglobinemia, although delayed recurrence 20 h later necessitated readministration of intravenous methylene blue. The patient developed cardiovascular instability and severe neurologic depression requiring prolonged ventilatory support. DISCUSSION: Methemoglobinemia can result from exposure to a number of drugs including benzocaine. Cyanosis, neurological and cardiac dysfunction may result when methemoglobin concentrations exceed 30 percent. Clinical diagnosis is made on the presentation of cyanosis unresponsive to oxygen administration and a distinctive arterial blood brown color; laboratory confirmation is by cooximetry. Treatment of symptomatic methemoglobinemia is by intravenous methylene blue (1-2 mg/kg) administration. Fifty-four cases of benzocaine-induced methemoglobinemia have been reported in the literature. Intubation, endoscopy/bronchoscopy, and ingestion were the most common procedures in which benzocaine administration produced methemoglobinemia. Infants and the elderly were more likely to develop toxic methemoglobinemia after benzocaine exposure. Other risk factors included genetic reductase deficiencies, exposure to high doses of anesthetic, and presence of denuded skin and mucous membranes. CONCLUSIONS: Because of the potential for severe complications, methemoglobinemia should be corrected promptly in compromised patients and those with toxic benzocaine concentrations. The possibility of masking symptoms during general anesthesia carries special risk of use of this agent in the preanesthesia setting.
Administration, Topical↗
Celecoxib-induced methemoglobinemia.
OBJECTIVE: To report a case of acute methemoglobinemia in a patient treated with celecoxib for osteoarthritis. CASE SUMMARY: A 72-year-old African American man developed an acute confusional state (ACS) one month after receiving celecoxib for osteoarthritis of his knee joints. There was no other identifiable cause of ACS such as any recognized cause of metabolic encephalopathy, meningoencephalitis, cerebrovascular accident, or drug intoxication. He was found to have severe methemoglobinemia (serum methemoglobin fraction 9%; reference range 0-0.2). His symptoms improved substantially, and serum methemoglobin levels decreased to 0.7% after the initiation of methylene blue therapy. He was discharged on oral riboflavin and ascorbic acid and was advised not to restart celecoxib therapy. He had not shown any recurrence of the symptoms at a follow-up visit 2 months after the withdrawal of celecoxib. DISCUSSION: Celecoxib is a nonsteroidal antiinflammatory drug that selectively inhibits cyclooxygenase-2. Acute methemoglobinemia can present as a syndrome of nonspecific symptoms such as headache, nausea, fatigue, dyspnea, and lethargy; these may progress to respiratory depression, coma, shock, seizures, and death. Although acute methemoglobinemia has been reported with the use of several drugs, including sulfonamides, as of August 13, 2004, this is the first case report of severe methemoglobinemia manifesting as ACS with celecoxib therapy. Use of the Naranjo probability scale indicated a probable relationship between the clinical manifestations of methemoglobinemia and celecoxib therapy in this patient. CONCLUSIONS: Celecoxib can be associated with acute methemoglobinemia. Prompt diagnosis of this condition, withdrawal of celecoxib, and treatment with the antagonists (methylene blue, ascorbic acid, riboflavin) can reverse this potentially serious condition.
Aged↗
Acquired methemoglobinemia. The relationship of cause to course of illness.
To better characterize methemoglobinemia in children, we reviewed the charts of 17 patients who were admitted to a children's hospital over the last 10 years. Two distinct groups were identified: (1) The endogenous group (n = 9) included patients with methemoglobinemia associated with an intercurrent illness. (2) The exogenous group (n = 8) included patients with methemoglobinemia secondary to drug exposure. Despite similar initial methemoglobin levels in the endogenous (mean, 29%) and exogenous (mean, 28%) groups, children in the endogenous group had more acidosis (serum bicarbonate levels of 5.9 vs 19.1 mmol/L and arterial pH of 7.01 vs 7.35). All the children in the exogenous group with methemoglobinemia secondary to an accidental ingestion stayed only 1 day in the hospital, while children in the endogenous group were admitted for an average of 19 days. Children with methemoglobinemia secondary to a drug exposure have a more benign illness with a shorter duration than children with methemoglobinemia associated with an intercurrent illness. It appears that the absolute level of methemoglobin is not as important as the underlying cause in determining both the course and severity of illness.
Bicarbonates↗
Methemoglobinemia in children with acute lymphoblastic leukemia (ALL) receiving dapsone for pneumocystis carinii pneumonia (PCP) prophylaxis: a correlation with cytochrome b5 reductase (Cb5R) enzyme levels.
BACKGROUND: Dapsone is commonly used for pneumocystis carinii pneumonia (PCP) prophylaxis in immunocompromised patients. Methemoglobinemia is a known complication of dapsone, but its true frequency and pathogenesis in childhood cancer patients are unknown. Additionally, practice guidelines for evaluation and management of dapsone-induced methemoglobinemia are not available. PROCEDURE: We studied 15 children with acute lymphoblastic leukemia (ALL) receiving dapsone for PCP prophylaxis to determine the frequency of methemoglobinemia, and correlate its occurrence with cytochrome b5 reductase (Cb5R) enzyme levels. Ten children with ALL receiving trimethoprim-sulfamethaxazole (TMP-SMX) were studied as controls. All patients underwent physical examination, pulse oximetry, and methemoglobin (metHb) estimation. Commercially available assay was used to measure Cb5R levels. RESULTS: Three (20%) patients receiving dapsone developed symptomatic methemoglobinemia. Average duration of dapsone prophylaxis prior to diagnosis was 6.6 weeks (range 3.5-10 weeks). Mean metHb level in symptomatic patients was 11.67%; 95% confidence interval (CI) 0-25.79 (range 7-18%), and 1.37%; 95% CI 0.6-2.14 (range 0.02-3%) in asymptomatic patients (P = 0.09), whereas the mean metHb level in the control group was 0.54%; 95% CI 0.35-0.73 (range 0.1-0.8%) (asymptomatic vs control P < 0.0001). Mean Cb5R level in symptomatic patients was 8.6 IU/g Hb; 95% CI 3.4-13.7 (range 6.9-10.9) compared to 12.5 IU/g Hb; 95% CI 11.1-13.9 (range 10.8-14.6) in asymptomatic patients (P = 0.06). Two symptomatic patients had Cb5R levels at or below 50% of normal, consistent with heterozygosity. Parental studies for Cb5R levels were suggestive of a carrier state in one of each patient's parents. CONCLUSIONS: Heterozygosity for Cb5R deficiency may pre-dispose to methemoglobinemia even on a thrice-weekly regimen of dapsone. Such individuals should avoid subsequent exposure to oxidant agents, if possible. Children with ALL tend to be symptomatic at low levels of metHb and may have delayed detection of methemoglobinemia. Hence, frequent monitoring of patients receiving dapsone is recommended. Monitoring guidelines for dapsone prophylaxis are proposed.
Anti-Infective Agents↗
Incidence of subclinical methemoglobinemia in infants with diarrhea.
STUDY HYPOTHESIS: Infants with diarrhea are at a greater-than-recognized risk of developing methemoglobinemia. DESIGN: Prospective clinical study. SETTING: A university hospital pediatric emergency department. PARTICIPANTS: Consecutive infants under 6 months of age with a history of diarrhea of more than 24 hours' duration not associated with vomiting. INTERVENTIONS: Blood samples were obtained for methemoglobin (MHgb) assay (normal, 0.4% to 1.5%) and electrolytes. Treatment interventions were performed as clinically indicated. Patients with elevated MHgb levels subsequently underwent hemoglobin electrophoresis to exclude congenital methemoglobinemia. RESULTS: Forty-three patients were studied; 27 (64%) had elevated MHgb levels and 13 were cyanotic. Five patients received infusions of methylene blue for methemoglobinemia. All patients recovered without sequelae. There was a strong correlation between weight at or below the tenth percentile for age and the development of methemoglobinemia. Contrary to previous studies, there was no correlation between incidence or severity of methemoglobinemia and acidosis, hyperchloremia, or positive microbiologic studies. CONCLUSION: In ill infants with diarrhea, particularly those who are small for age, consideration should be given to screening for methemoglobinemia.
Blood Protein Electrophoresis↗
Acquired methemoglobinemia and hemolytic anemia after usual doses of phenazopyridine.
Two patients developed symptomatic methemoglobinemia and hemolytic anemia after treatment with phenazopyridine. Methemoglobinemia appears to be a rare occurrence after commonly used doses of phenazopyridine; phenazopyridine-associated hemolytic anemia has been reported both after overdose and after usual doses. The presentation of methemoglobinemia in the first patient and the response to treatment with methylene blue in the second patient were unusual, suggesting that the patients had a red cell defect or were exposed to other oxidizing substances. One of the major metabolites of phenazopyridine is aniline, a known cause of methemoglobinemia. Aniline-induced methemoglobinemia is less responsive to treatment with methylene blue than nitrate- or nitrite-induced methemoglobinemia. This may explain, in part, the poor response to methylene blue by one of our patients.
Aged↗
[Methemoglobinemia in children as a differential diagnosis of cyanosis].
Methemoglobinemia is characterized by cyanosis with various degrees of severity. Symptoms range from asymptomatic to unconsciousness and death. Although cyanosis caused by methemoglobinemia is well-documented in the literature, it is rare and the consequences can be fatal. The cause of methemoglobinemia can be environmental, acquired, congenital or a combination of the above. Among the potential sources for methemoglobinemia are local anaesthetics that are in common use in hospitals and clinics, some of which can be purchased without prescription. Although these drugs are considered to be safe, they can still induce methemoglobinemia and can be life-threatening. In this review we describe patients admitted to the Pediatric Intensive Care Unit during the year 2000 suffering from cyanosis and diagnosed as having methemoglobinemia.
Child↗
Protracted methemoglobinemia after phenazopyridine overdose in an infant.
Acquired methemoglobinemia may be produced by the ingestion or absorption of certain chemicals and xenobiotics. A case of methemoglobinemia in an 8.5-month old infant who ingested approximately 227 mg/kg of phenazopyridine is presented. Although this adverse event is often reversed with a single dose of methylene blue, this patient required three doses of methylene blue (1 mg/kg) over a 25-hour period. It is suggested that the need for repeated doses of methylene blue in this case was not only related to the large dose of phenazopyridine, but also its metabolites (i.e., aniline), which have the potential to produce methemoglobinemia. This case illustrates the need for close observation and serial monitoring of methemoglobin levels in patients who are at increased risk for the development of protracted methemoglobinemia. Integration of knowledge of developmental pharmacology, drug metabolism, and pharmacodynamic properties are critical determinants in the evaluation and treatment of patients with drug-induced methemoglobinemia.
Adolescent↗