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Acquired methemoglobinemia in infants / Sut cocuklarinda edinsel methemoglobinemi.

Abstract

Objective: This study aimed to determine the etiologic factors of acquired methemoglobinemia in infants younger than three months in our region.

Material and Methods: This study was carried out retrospectively in infants with methemoglobinemia admitted to Karadeniz Technical University, Pediatric Clinic, during the period 2000-2009. Infants with methemoglobinemia were identified according to the medical records or ICD-10 code.

Results: Nine infants with acquired methemoglobinemia (8 male, 1 female) were included in the study. Seven cases were associated with the use of prilocaine for circumcision, one case with the use of prilocaine-lidocaine for local pain therapy, and one case with neonatal sepsis caused by Staphylococcus aureus.

Conclusion: Prilocaine should not be used in infants less than three months of age because of the risk of methemoglobinemia. Ascorbic acid is an effective therapy if methylene blue is not obtained. It should not be forgotten that sepsis caused by S. aureus may cause methemoglobinemia in infants. (Turk J Hematol 2011; 28: 131-4)

Key words: Methemoglobinemia, infant, local anesthetics, sepsis

Received: April 8, 2010

Accepted: May 11, 2010

Ozet

Amac: Bolgemizde uc aydan kucuk bebeklerde meydana gelen akkiz methemoglobinemilerin etiyolo-jisini arastirmak.

Yontem ve Gerecler: Bu cahsma, 2000-2009 yillari arasmda pediatri klinigine baruran ve ICD-10 koduna veya hasta kart defterine gore akkiz methemoglobinemi tanisi alan hastalarin kartlannin retrospektif incelenmesi ile gerceklestirildi.

Bulgular: Sekizi erkek olmak uzere, dokuz akkiz methemoglobinemili infant cahsmaya ahindi. Yedi vaka; sunnet icin prilokain kullannm ile iliskili iken, bir vaka; lokal anestezi icin kullamlan prilokain-lidokain ile ye diger vaka ise; Staphylococcus aureus sepsisi ile iliskili idi.

Sonuc: Uc aydan kucuk infantlarda prilokain methemoglobinemi riski nedeniyle kullamlmamandir ve metilen mavisi elde edilemedigi durumlarda vitamin C effektif bir tedavi seklidir. Staphylococcus aureus'a bath sepsisin infantlarda methemoglobinemiye neden olabilecegi unutulmamahdir. (Turk J Hematol 2011; 28: 131-4)

Anahtar kelimeler: Methemoglobinemi, infant, lokal anestezikler, sepsis

Gelis tarihi: 8 Nisan 2010

Kabul tarihi: 11 Mayis 2010

Introduction

Methemoglobinemia is an uncommon cause of cyanosis. It should be suspected in an infant with cyanosis who has no respiratory distress or cyanotic congenital heart disease. Cyanosis is recognized in patients with methemoglobin (MetHb) concentrations higher than 1.5 g/dl (1), (2). It develops due to both acquired and congenital factors. Congenital causes of methemoglobinemia are NADH-cytochrome b5 reductase and NADPH-MetHb reductase deficiencies or presence of abnormal Hb such as Hb M (2). Acquired methemoglobinemia is caused by some drugs such as local anesthetics, some foods or water containing high levels of nitrate, gastrointestinal infection, and sepsis (2-4). Most of the acquired methemo-globinemia cases in clinical practice are due to local anesthetics. In this report, nine infants with methe-moglobinemia are presented and the etiologic factors are discussed.

Materials and Methods

This study was carried out retrospectively in infants with methemoglobinemia admitted to Karadeniz Technical University, Pediatric Clinic, during the period 2000-2009. Infants with methemoglobinemia were identified according to the medical records or ICD-10 code. Medical charts of all infants with methemoglo-binemia were reviewed for birth weight (g), gender, postnatal age, Hb levels, presenting symptoms, etiologic causes, type of feeding, MetHb levels, treatment, recovery time of methemoglobinemia, and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Blood MetHb levels were measured by using a Rapidlab[R] 1200 Blood Gas Analyzer (Siemens Healthcare Diagnostics) with spectrophotometric method. Blood MetHb levels were measured at four-hour intervals. Sepsis was considered in infants having two or more of the following criteria associated with positive blood culture: (a) fever or hypothermia, (b) tachycardia, (c) tachypnea or apnea, and (d) abnormal white blood cells or increase in band/total neutrophils. Written informed consent was obtained from the patients' family.

Results

Nine infants with methemoglobinemia (8 male, 1 female) were included in the study. Mean birth weight and postnatal age were 3655[+ or -]270 (3300-4100) g and 33.7[+ or -]16.6 d (5-60) days, respectively. Cyanosis was present in all infants, fever in three (33%), and hypotonia and refusal to breast-feed in two (22%). Mean percentage of MetHb levels of the infants was 28.8[+ or -]9.8 (14.7-44%). Seven cases were associated with the use of a local anesthetic agent (prilocaine; Citanest[R] 0.5%) for circumcision. The applied prilocaine doses were not determined. One case was associated with the use of prilocaine-lido-caine (EMLA[R], 5%, Astra Zeneca) for local pain therapy after scalding to 3% of the body surface, and three cases were associated with neonatal sepsis. No phenol disinfectant was used for floor cleaning in the hospital during this period.

Staphylococcus hominis was grown in blood cultures of two infants (Case 3 and Case 5) associated with the use of prilocaine. Staphylococcus aureus was grown in the blood culture of Case 6. Acute phase reactants (procalcitonin and C-reactive protein [CRP]) were positive in these neonates, and they met sepsis criteria. They were treated with vancomycin. All of the neonates were receiving only breast milk. Their mothers denied the use of any medications and consumption of any foods containing a high nitrate level.

Two neonates were treated with methylene blue (1-2 mg/kg) intravenously, and the others were treated with vitamin C (300 mg) intravenously because methylene blue was not obtained. Repeated doses were not necessary. Mean recovery time was 10.2[+ or -]3.5 (4-16) hours. The plasma G6PD levels were normal in all neonates. Cytochrome b5 reductase activity could not be measured in the neonates because of the lack of technical facilities. Demographic, clinic and laboratory characteristics of the neonates associated with methemoglobinemia are shown in Table 1.
Table 1. Demographic, clinic and laboratory characteristics of
the patients with methemoglobinemia

       Birth  Postnatal  Gender  Complaints        Hb  MetHb
      Weight  age (day)                       (gr/dL)    (%)
         (g)

Case    4000         45  Male    Cyanosis        10.9   24.1
1

Case    3700         60  Male    Cyanosis        11.2   39.9
2

Case    4100          5  Male    Cyanosis,       14.7   14.7
3                                hypotonia,
                                 fever,
                                 refusal to
                                 breast-feed

Case    3300         22  Male    Cyanosis         8.8   33.7
4

Case    3600         35  Male    Cyanosis,       13.5   19.0
5                                fever,
                                 refusal to
                                 breast-feed

Case    3300         17  Female  Fever,          13.5   20.9
6                                hypotonia,
                                 cyanosis

Case    3600         45  Male    Cyanosis        10.5     44
7

Case    3700         37  Male    Cyanosis        11.5   30.4
8

Case    3600         48  Male    Cyanosis        11.8   26.8
9

      Etiologic             Treatment        Recovery  G6PD
      causes                                 time (h)  level
                                               (MetHb
                                                 <5%)

Case  Prilocaine             300 mg C vit           8  Normal
1

Case  Prilocaine             300 mg C vit          12  Normal
2

Case  Prilocaine Sepsis      300 mg C vit         4 1  Normal
3                            +Antibiotics

      caused by S. hominis?                         1

Case  Prilocaine             300 mg C vit          12  Normal
4

Case  Prilocaine-lidocaine   300 mg C vit           8  Normal
5     Sepsis caused by S.    +Antibiotics
      hominis??

Case  Sepsis caused by S.    300 mg C vit           8  Normal
6     aureus                 +Antibiotics

Case  Prilocaine             Methylene blue        16  Normal
7                            (1 mg/kg)

Case  Prilocaine             300 mg C vit          12  Normal
8

Case  Prilocaine             Methylene blue        12  Normal
9                            (1 mg/kg)

G6PD: Glucose-6-phosphate dehydrogenase, Hb: Hemoglobin,
MetHb: Methernoglobin


Discussion

Methemoglobinemia is characterized by oxidation of the iron in Hb from a ferrous (Fe + +) to a ferric (Fe + + +) form. Methemoglobinemia occurs in healthy persons but the intraerythrocytic MetHb-reducing system maintains its concentration at less than 1% of the total Hb (5). There are two MetHb-reducing systems (NADH-cytochrome b5 reductase and NADPH-MetHb reductase) in erythrocytes. Under physiological conditions, NADH-cytochrome b5 reductase is responsible for the removal of 95-99% of the MetHb (5). NADPH-MetHb reductase usually plays only a minor role in the removal of MetHb. This enzyme system utilizes NADPH, which is produced by G6PD. NADPH-MetHb reductase has a more important role in MetHb regulation in infants with cytochrome b5 reductase deficiency. MetHb has an increased affinity for oxygen, and causes a leftward shift in the oxygen dissociation curve, and hypoxemia and lactic acidosis develop (1), (2), (6). If MetHb level is higher than 10%, cyanosis Occurs, and a MetHb level of 70% is lethal. Cyanosis was observed in all of our infants and all of them improved after the appropriate treatments.

Prilocaine is widely used in children and adults as a local anesthetic agent, and its metabolite o-toluidine can cause methemoglobinemia. The dose of prilocaine and the age of the infant are the most important predictive factors for higher MetHb formation (7). Infants are more vulnerable to methemoglobinemia because they have higher gastric pH than that in older children, and this causes greater bacterial proliferation of the intestinal flora that can convert the ingested nitrate to nitrite (6). Fetal Hb is the predominant form of Hb in infants, bin and is oxidized more readily to MetHb by nitrite (6). The cytochrome b5 MetHb reductase activity is reduced 50% in infants compared with older children and adults (6), (8). Guay (9) suggested that prilocaine should not be used in children younger than six months and the doses should not exceed 2.5 mg/kg in children older than six months. In this study, MetHb in seven neonates was associated with the use of prilocaine for circumcision, and all of them were younger than two months.

Symptomatic methemoglobinemia may develop due to the application of EMLA[R] on the injured skin (10). Methemoglobinemia was observed in Case 5 due to the application of EMLA[R] for local pain therapy.

Blood MetHb levels may be increased in patients with sepsis (3), (4). Large amounts of nitric oxide (NO) are released in sepsis and septic shock (11), (12). NO interacts with Hb, and leads to methe-moglobinemia (13). S. aureus has a respiratory type of nitrate reductase enzyme system. This enzyme system may convert nitrate to nitrite, and methemo-globinemia may develop (14). Vancomycin-related methemoglobinemia has not been reported in the literature. We believe that methemoglobinemia was related with sepsis rather than vancomycin (15); nevertheless, methemoglobinemia related with vancomycin could not be completely ruled out. As far as we know, S. hominis does not have this enzyme system. Therefore, we believe that prilocaine was responsible for the methemoglobinemia in the neonates (Case 3-Case 5).

Methylene blue accelerates the NADPH-dependent MetHb reduction pathway (16). Methylene blue was given (1-2 mg/kg) in only two infants because it was not obtained for the others. Ascorbic acid directly reduces MetHb and it is effective when used alone (17). Intravenous 300 mg ascorbic acid was used in seven cases, and all cases recovered between 8-16 hours.

Prilocaine should not be used in infants less than three months of age because of the risk of methemoglobinemia. Ascorbic acid is an effective therapy if methylene blue is not obtained. It should not be forgotten that S. aureus may cause methemoglobinemia in infants.

Conflict of interest statement

The authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included.

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(10.) Book A, Fehlandt C, Krija M, Radke M, Pappert D. Methemoglobin intoxication by prilocaine in EMLA. Accidental intoxication of an infant with scald injuries. Anaesthesist 2009;58:370-4.

(11.) Ochoa JB, Udekwu AO, Billiar TR, Curran RD, Cerra FB, Simmons RL, Peitzman AB. Nitrogen oxide levels in patients after trauma and during sepsis. Ann Surg 1991;214:621-6.

(12.) Lorente JA, Delgado MA, Landin L. Septic shock and nitric oxide. Enferm Infecc Microbiol Clin 1997;3:14-9.

(13.) Wennmalm A, Benthin G, Petersson AS. Dependence of the metabolism of nitric oxide (NO) in healthy human whole blood on the oxygenation of its red cell haemo-globin. Br J Pharmacol 1992;106:507-8.

(14.) Burke ICA, Lascelles J. Nitrate reductase activity in heme-deficient mutants of Staphylococcus aureus. J Bacteriol 1976;126:225-31.

(15.) Mutlu M, Erduran E, AksoyA, Asian Y. Methemoglobinemia associated with Staphylococcus aureus sepsis in a newborn. JNPM 2010;3:63-5.

(16.) Hoffman R, Benz E, Shattil S, Furie B, Cohen H. Hematology Basic Principles and Practice. New York: Churchill Livingstone, 2005;650-7.

(17.) Gibson QH. The reduction of methemoglobin by ascorbic acid. Biochem J 1943;37:615-8.

Mehmet Mutlu, Erol Erduran, Yakup Aslan

Department of Pediatrics, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey

Address for Correspondence: Asst. Prof. Mehmet Mutlu, Department of Pediatrics, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey Phone: +90 462 377 55 68 E-mail: drmehmetmutlu38@hotmail.com

doi:10.5152/tjh.2011.29
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Title Annotation:Research Article
Author:Mutlu, Mehmet; Erduran, Erol; Aslan, Yakup
Publication:Turkish Journal of Hematology
Date:Jun 1, 2011
Words:2223
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