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Methemoglobinemia is an uncommon cause of cyanosis; however, rapid diagnosis is critical to avoid potentially fatal consequences. Several local anesthetics can precipitate methemoglobinemia in susceptible patients. This case report of acute methemoglobinemia occurred during fiberoptic intubation in an awake patient without a past medical history of adverse reactions to local anesthetics.
Over the last 25 years, significant advances have been made in supportive care of the immunocompromised patient. One significant advance is the use of trimethoprim-sulfamethoxazole (TMP-SMZ) in the prevention of Pneumocystic carinii pneumonia (PCP). Although TMP-SMZ remains the drug of choice for PCP prophylaxis, children who develop or have a history of adverse reactions must be prescribed an alternative treatment. In these instances, medications such as dapsone, aerosolized pentamidine, or atovaquone are prescribed. This report discusses four children with sulfa allergy who were prescribed dapsone and later developed methemoglobinemia. Although methemoglobinemia is associated with dapsone, there was no reference found regarding this link in the pediatric oncology literature. The purpose of these clinical examples is to alert the pediatric nurse and advanced practitioner to the association of dapsone and methemoglobinemia.
Oxygen transport, the major function of hemoglobin, is dependent upon reduced heme iron. In the red cell, the heme iron is maintained in the reduced form by the methemoglobin reduction system. When the balance between oxidation and reduction of heme iron is perturbed due to the presence of excessive oxidants, decreased reducing capacity or the presence of abnormal hemoglobin, methemoglobinemia ensues. In most cases methemoglobinemia is transitory and of no major clinical consequence. Occasionally, however, it can be life threatening and must be rapidly diagnosed and treated. When methemoglobinemia is of hereditary nature, either due to deficiency of red cell NADH-methemoglobin reductase or due to the presence of M hemoglobin, it is a lifelong problem. Since most of these patients do not have major disabling symptoms, the treatment is aimed at correction of cyanosis.
The objectives of this study were to examine the reported accuracy of cooximetry in determination of methemoglobin levels, to report the apparent discrepant values of "measured" methemoglobin and carboxyhemoglobin, and to discuss the effect that methemoglobinemia has on pulse oximetry readings. Secondly, relative oxygen saturations measured by pulse oximetry and calculated from arterial blood gas samples were compared. A retrospective analysis was performed in an academic medical center with two patients who were diagnosed with acute methemoglobinemia after taking sulfa-containing medications. Serial pulse oximetry, arterial blood gas, and cooximeter analysis were performed for two patients. Cooximetry was performed using an IL-482 oximeter, arterial blood gas analysis was performed using a BLE 1400 oximeter, and pulse oximetry was performed using Ohmeda Biox S740, Hewlett Packard SPO2, or Marquette SPO2 models. Methemoglobin levels ranged from 6% to 48%, however, summation of methemoglobin and oxyhemoglobin were as high as 120%. As a result, negative values of carboxyhemoglobin were recorded by the cooximeter, generating a total sum of 100%. Comparison of pulse oximetry and arterial blood gas oxygen saturation (measured and calculated values, respectively) revealed significant discrepancies; methemoglobin was > 9%, whereas oxygen saturation uniformly was lower with pulse oximetry. Therefore, we recommend that when methemoglobin levels exceed 10%, cooximetry be used as a screen for methemoglobinemia and that serial cooximeter measurements be used to guide therapy and reliance on noninvasive pulse oximetry.
Topical anesthetic drugs are widely used by clinicians during hospital and outpatient procedures and are also available to the public in a variety of over-the-counter preparations. Although generally safe, they may cause potentially life-threatening methemoglobinemia. We describe a patient who developed repeated episodes of severe methemoglobinemia after administration of topical Cetacaine spray (a proprietary mixture of benzocaine, tetracaine, and butamben) employed for pharyngeal anesthesia before endotracheal intubation, and briefly review the etiology and pathophysiology of this disorder. Cautious interpretation of oxyhemoglobin saturation values obtained by pulse oximetry or estimated from arterial blood gas analysis is crucial lest the diagnosis of severe methemoglobinemia and the resulting hypoxemia are overlooked. If necessary, the condition is usually readily corrected by intravenous administration of methylene blue.
This report describes a case of methemoglobinemia in association with dapsone therapy. The patient, an immunocompromised child with chronic immune thrombocytopenic purpura, presented with fever, cough, perioral cyanosis, bilateral lower lobe rales, and low O2 saturation by pulse oximetry (89%). His medications included prednisone and rituximab for chronic immune thrombocytopenic purpura, and dapsone for Pneumocystis carinii pneumonia prophylaxis. Because of his lack of dyspnea and tachypnea, and the temporal association of his perioral cyanosis with the initiation of dapsone therapy, a methemoglobin (MetHb) level was obtained and found to be elevated at 9.6%. The authors discuss the mechanism and treatment of methemoglobinemia secondary to dapsone. They also stress the importance of monitoring for signs and symptoms of methemoglobinemia in immunocompromised patients on dapsone therapy for P. carinii pneumonia prophylaxis.
Methylene blue is used to check tubal patency during laparoscopy. A case of methemoglobinemia which was induced by methylene blue is presented. Methemoglobinemia is usually treated with methylene blue; however, in patients with glucose-6-phosphate dehydrogenase deficiency, methylene blue can induce methemoglobinemia.
OBJECTIVES: To determine whether sodium thiosulfate (STS) produces a clinically significant decline in sodium nitrite-induced methemoglobinemia in an in-vitro model. METHODS: This was an in-vitro, controlled study where methemoglobinemia was induced by the addition of sodium nitrite (0.4 mg/mL) to 35-mL aliquots of blood obtained from ten healthy volunteers. Methemoglobin (MetHb) concentrations were measured at 5-minute intervals for 30 minutes by co-oximetry, and each aliquot was then subdivided into six 5-mL samples (time zero). Sample 1 served as control. The remaining samples received serial dilutions of STS (0.125 mg, 1.25 mg, 12.5 mg, 125 mg, 1,250 mg). MetHb concentrations were measured by co-oximetry at baseline, 0, 15, 30, 45, and 60 minutes. Areas under the MetHb concentration-time curve (AUC) between time zero and 60 minutes were compared using the Kruskal-Wallis test. RESULTS: Methemoglobin concentrations increased from 0.07 g/dL (+/-0.06) at baseline to 8.42 g/dL (+/-0.69) at time 0 (the addition of STS). No significant difference was detected between baseline and time 0 hemoglobin concentrations (15.8 +/- 0.5 vs. 16.1 +/- 0.6 g/dL). There was no detectable difference found between the AUCs (measured in g min/dL) of any of the STS serial dilutions or control groups (0.125 mg STS = 576.01 +/- 42.53; 1.25 mg STS = 573.47 +/- 40.82; 12.5 mg STS = 583.68 +/- 42.29; 125 mg STS = 554.75 +/- 42.68; 1,250 mg STS = 566.95 +/- 38.08; p = 0.81). CONCLUSIONS: Sodium thiosulfate was not found to be an effective reducing agent for the acute treatment of methemoglobinemia.
A biologically based mathematical model was created to characterize time and dose-dependent relationships between exposure to nitrite and induction of methemoglobinemia. The model includes mass action equations for processes known to occur: oral absorption of nitrite, elimination from the plasma, partitioning between plasma and erythrocytes, binding of nitrite to hemoglobin and methemoglobin, and the free radical chain reaction for hemoglobin oxidation. The model also includes Michaelis-Menten kinetics for methemoglobin reductase-catalyzed regeneration of hemoglobin. Body weight-scaled rate constants for absorption (k(a)) and elimination (k(e)), the effective erythrocyte/plasma partition coefficient (P), and the apparent K(m) for methemoglobin reductase were the only parameters estimated by formal optimization to reproduce the observed time course data. Time courses of plasma nitrite concentrations and blood levels of hemoglobin and methemoglobin in male and female rats that had received single intravenous or oral doses of sodium nitrite were measured. Peak plasma levels of nitrite were achieved in both sexes approximately 30 min after oral exposure, and peak methemoglobin levels were achieved after 100 min. The model predicts that 10% of the hemoglobin is oxidized to the ferric form after oral doses of 15.9 mg/kg in male rats and 11.0 mg/kg in female rats and after intravenous doses of 8.9 and 7.1 mg/kg in male and female rats, respectively. The t(1/2) for recovery from methemoglobinemia was 60 to 120 min depending on dose and route of administration. A sensitivity analysis of the model was performed to identify to which parameters the predictions of the model were most sensitive and guide attempts to simplify the model. Replacement of the V(max) of methemoglobin reductase with a value representative of humans predicted a 10% methemoglobinemia following an intravenous dose of 5.8 mg/kg, in close agreement with an observed value of 5.7 mg/kg for humans.
Oral pretreatment with diethyldithiocarbamate (DTC) and carbon disulfide (CS2) prevented mice from methemoglobinemia induced by phenacetin. This treatment resulted in marked elevation of plasma p-phenetidine concentrations, prolongation of phenacetin levels, and lowering of N-acetyl-p-aminophenol and p-aminophenol levels. Both DTC and CS2 also suppressed p-phenetidine-induced methemoglobinemia with a delay in plasma p-phenetidine disappearance. In vitro, methemoglobin formation by p-phenetidine was decreased in liver microsomes isolated from DTC- or CS2-treated mice. The liver microsomal phenacetin and p-phenetidine O-deethylation activities and p-phenetidine N-hydroxylation activity decreased 1 h after administration of DTC or CS2, whereas deacetylation of phenacetin and N-acetyl-p-aminophenol by microsomes and acetylation of p-phenetidine by a soluble fraction from a liver homogenate were scarcely affected. The suppression of methemoglobinemia by DTC and CS2 may result from an inhibition of metabolic conversion of p-phenetidine to methemoglobin-forming substances such as N-hydroxy-p-phenetidine which is of most importance, p-aminophenol and 2-hydroxy-p-phenetidine by the microsomal cytochrome P-450-containing monooxygenase system in the liver.
OBJECTIVE: To determine whether the nonsteroidal antiandrogenic drug flutamide is a clinically relevant inducer of methemoglobinemia in patients with prostatic cancer. METHODS: Fifty consecutive outpatients with prostatic cancer stage D2 entered the study (age 71.1 +/- 7.3 y). Five patients were lost to follow-up; the remaining 45 patients received the recommended oral dose of flutamide 250 mg three times daily. Total hemoglobin (Hb) and methemoglobin (Met-Hb) concentrations were measured on varying days using an ultraviolet/visible-spectrophotometric method with an intra- and interday variability < 8%. In 12 patients, Met-Hb was analyzed before initiating flutamide therapy and after therapy was begun. RESULTS: On average, 2.6 venous blood samples per patient were analyzed with a mean Met-Hb concentration of 1.9% of total Hb. Mean concentrations of > or = 3% were detected in only six patients (13%). The data from 12 patients evaluated before and after initiating flutamide therapy were without significantly different changes. During the study period, no clinical signs of methemoglobinemia were reported or observed. CONCLUSIONS: This study found no clinically relevant increase of Met-Hb concentrations in elderly patients with prostatic cancer during chronic treatment with flutamide. However, clinicians should be aware of the very rare possibility of flutamide-induced methemoglobinemia.
This report describes erythrocyte biochemical findings in an adult Spanish mustang mare that exhibited persistent methemoglobinemia, eccentrocytosis, and pyknocytosis that were not related to the consumption or administration of an exogenous oxidant. The methemoglobinemia was attributed to a deficiency in cytochrome-b5 reductase (Cb5R) activity, and the eccentrocytes and pyknocytes were attributed to a marked deficiency in reduced nicotinamide adenine dinucleotide phosphate-dependent glutathione reductase (GR) activity that resulted in decreased reduced glutathione concentration within erythrocytes. The GR activity increased to a near-normal value after addition of flavin adenine dinucleotide (FAD) to the enzyme assay, indicating a deficiency of FAD in erythrocytes. The methemoglobinemia, eccentrocytosis, and pyknocytosis were attributed to deficiency of FAD in erythrocytes because the GR and Cb5R enzymes use FAD as a cofactor. This deficiency in FAD results from a defect in erythrocyte riboflavin metabolism, which has not been documented previously in animals.
In twenty five patients who presented the cutaneous form of loxoscelism, serum haptoglobin and lactic dehydrogenase, erythrocyte glucose-6-phosphate dehydrogenase, glutathione reductase, glutathione peroxidase, methemoglobin, bilirubin and reticulocytes were investigated after bite. No hemolysis was detected but an increase in methemoglobin was found in 54% of the cases; in 7% it was between 1.1% and 2%, in 27% it ranged from 2.1% to 4%, and in 20% from 4.1% to 8%. Blood samples of a normal, blood group 0 individual and of a patient who exhibited methemoglobinemia after Loxosceles bite were incubated separately with antisera against Loxosceles gaucho, Crotalus terrificus, Bothrops jararaca, with Loxosceles gaucho venom and 0.3% phenol. No methemoglobin was found after 1, 4, 8 and 15 days in both sets of samples. At the 25th day all the samples, including the controls, exhibited similar methemoglobin reductase decrease. The data suggest that the methemoglobinemia which occurs in 50% of the patients probably arises from in vivo venom metabolism, inasmuch as the crude venom does not induce methemoglobinemia.
Two workers from the same factory presented to the same emergency department within six weeks of one another with moderate (Case 1) and severe (Case 2) methemoglobinemia. Subsequent investigation revealed that the factory produces phenylpropanolamine and that both patients, shortly before becoming ill, were inadvertently exposed to methyl nitrite, a critical reagent in this production. Although other nitrites induce methemoglobinemia, exposure to methyl nitrite during phenylpropanolamine production appears to be a new cause of occupational methemoglobinemia.
Recessive congenital methemoglobinemia due to nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase (b5R) deficiency is classified into 2 clinical types: type 1 (erythrocyte type) and type 2 (generalized type). We found a Chinese family with type 1 recessive congenital methemoglobinemia, the patients from which were diagnosed according to clinical symptoms and b5R enzyme activity in the blood cells. To learn the molecular basis of type 1 recessive congenital methemoglobinemia in this Chinese family, we isolated total RNA from the peripheral leukocytes of the propositus and b5R complementary DNA (cDNA) by reverse transcription- polymerase chain reaction (RT-PCR). The coding region of the b5R cDNA was analyzed by sequencing the cloned PCR products. The results showed that the propositus was homozygous for a G-->A transition at codon 203 in exon 7, changing a cysteine to a tyrosine (Cys203Tyr). To characterize the mutant enzyme, both glutathione S-transferase (GST)-fused wild-type b5R and GST-fused mutant Cys203Tyr b5R were expressed in Escherichia coli and affinity purified. The results showed that the catalytic activity of the enzyme was not much affected by this amino acid substitution, but the mutant enzyme exhibited decreased heat stability and increased susceptibility to trypsin. These properties of the mutant enzyme would account for the restricted b5R deficiency and mild clinical manifestations of these type 1 patients. The finding of this novel mutation makes codon 203 the only position within the b5R gene at which more than 1 mutation has been found.
We experienced an anesthetic case, in which interference in oxygen saturation values by patent blue was mistaken for nitroglycerin-induced methemoglobinemia. A 40-year-old woman underwent mastectomy for breast cancer under general anesthesia. Nitroglycerin was infused to produce hypotensive anesthesia. Patent blue was locally injected around the cancer by a surgeon and surgery was started. A few minutes later, oxygen saturation by finger pulse oximeter suddenly decreased from 100% to 90%. And then, blood gas analysis was performed to confirm this change. The decrease of oxygen saturation and the increase of methemoglobin were also observed in the finding of blood gas analysis. At first, we judged these changes as methemoglobinemia by nitroglycerin infusion. Finally, however, we concluded that all these changes were attributable to the interference by patent blue on oxygen saturation value because we found that there had been some inconsistent findings as methemoglobinemia. The fact seems that nothing happened to the patient during the episode. This case showed us that anesthesiologists should understand the principle of hematological monitors and the meaning of the data obtained by monitors.
Aluminium phosphide (AlP) a grain fumigant is the leading cause of intentional poisoning in North India. The mechanisms involved in toxicity are not known and there is no antidote till date. The present study was carried out to investigate the oxygen free radical generation, methemoglobinemia and effect of methylene blue treatment on survival time in rat model of AlP poisoning. AlP (50 mg/kg, intragastric) was administered in one group and the other group received AlP + Methylene Blue (MB) (0.1%, 1 mg/kg/5 min, i.v.). Malonyldialdehyde (MDA) and methemoglobin (MeHb) levels were measured at 10 and 30 min intervals. Blood MDA levels increased at 10 and 30 min after AlP exposure with simultaneous rise in MeHb levels suggesting methemoglobinemia could be due to increased oxygen free radical generation. Methylene blue caused a significant fall in both the parameters with prolongation of survival time. It is concluded that AlP causes methemoglobinemia responding to methylene blue treatment.
Methylene blue is utilized as the main treatment of methemoglobinemia conventionally, but it may be ineffective in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. We report a G6PD-deficient patient who suffered from aniline-induced methemoglobinemia with initial good response Heinz body but hemolytic anemia appeared later 3 d after methylene blue therapy. G6PD deficiency was identified. He recovered uneventfully with hydration, packed blood transfusion and adjuvant luvela-N(dl-alpha-tocopheryl nicotinate) medication. Caution should be taken in using methylene blue as antidote of acute methemoglobinemia, especially when a history of G6PD deficiency is obscure.