Metoclopramide-Induced Methemoglobinemia

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364 PEDIATRICS Vol. 82 No. 3 September 1988

Metoclopramide-Induced

Methemoglobinemia

Gregory

L. Kearns,

PharmD,

and

Debra

H. Fiser,

MD

From the Departments of Pharmaceutics, Pediatrics, and Anesthesiology, University of Arkansas for Medical Sciences, and the Division of Critical Care Medicine, Arkansas Children’s Hospital, Little Rock

ABSTRACT. The case of a 3-week-old male infant is

described. After receiving an iatrogenic overdose of me-toclopramide (1.0 mg/kg every six hours) throughout a 36-hour period for the treatment of suspected gastro-esophageal reflux, he became cyanotic, lethargic, and irritable, he fed poorly, and he had diarrhea and

respira-tory distress. Methemoglobinemia (20.5%) and reduced oxyhemoglobin saturation (79%) were identified. The patient had an excellent clinical response following a single IV dose of methylene blue. Subsequently, methe-moglobin reductase activity was normal and there was no measurable hemoglobin M. The diagnosis of methemo-globinemia should be considered in any infant receiving large doses of metoclopramide who has clinical findings of cyanosis, ashen color, or a history of lethargy and/or motor restlessness. Pediatrics 1988;82;364-366;

metoclo-pramide, methemoglobinemia, methylene blue,

gastro-esophageal reflux.

Metoclopramide, a derivative of orthoprocain-amide,’ has pharmacologic effects that are believed to be consequent to dopamine receptor blockade2 and to possible modulation of acetylcholine re-lease.3 The therapeutic use of metoclopramide as an antiemetic and to enhance gastrointestinal mo-tility in adults has been reviewed.4’5 Metoclopram-ide has also been shown to improve symptoms associated with gastrointestinal reflux in

neo-nates,6’7 infants,’3 and children.’3’5 Commonly reported side effects include mild sedation, diar-rhea, extrapyramidal reactions, and dystonias.5”6

We describe a case of methemoglobinemia in an infant who received an tenfold accidental overdose of metoclopramide and review this side effect.

CASE REPORT

C.G. was a 3-week-old white boy seen at the emergency department with cyanosis, lethargy, and poor feeding of

Received for publication May 7, 1987; accepted June 26, 1987. Reprint requests to (G.L.K.) Slot 522, University of Arkansas for Medical Sciences, 4301 Markham, Little Rock, AR 72205. PEDIATRICS (ISSN 0031 4005). Copyright © 1988 by the American Academy of Pediatrics.

recent onset. Soon after discharge from the hospital following delivery, his mother noted that he began to have choking spells frequently associated with or just after feedings. Four days before hospital admission, he had a choking spell with resultant cyanosis. The diagnosis of gastroesophageal reflux was made on clinical criteria, and metoclopramide (0.1 mg/kg orally every six hours) was prescribed. On the following day, the mother noted more cyanosis that did not resolve and that was accom-panied by increasing respiratory distress, lethargy, irrit-ability, poor feeding, and mild diarrhea.

According to medical history, the patient’s prenatal and perinatal course had been normal. There was no family history of congenital heart disease or cyanosis. His diet consisted of breast milk only. Metoclopramide was the only medication that the infant had received, although consequent to a dosing error (use of a 5.0-mL syringe instead of a 1.0-mL syringe), the child had been receiving 1.0 mg/kg every six hours: a tenfold overdose. According to the infant’s mother, she had taken acet-aminophen with codeine and ampicillin during the first postpartum week. These medications had been discontin-ued for 13 days prior to the onset of illness in the patient.

At the time of physical examination, we saw a cyanotic infant in no acute distress with the following clinical findings: rectal temperature, 36#{176}C;heart rate, 120 beats per minute; respiratory rate, 48 breaths per minute; and systolic BP by Doppler, 75 mm Hg in all four extremities. The child was lethargic and slightly hypotonic but was arousable and had a vigorous suck. The lungs were clear to auscultation despite the presence of mild inspiratory stridor. Auscultation of the heart revealed a grade 1/6 systolic ejection murmur heard best at the lower left sternal border. His peripheral pulses were normal to palpation.

By chest radiograph, his heart size appeared to be at the upper limits of normal and his pulmonary vascularity to be slightly decreased. An ECG showed mild right ventricular hypertrophy and right axis deviation. An echocardiogram was obtained to rule out congenital heart disease, and a small apical ventricular septal defect was

seen. The pulmonic valve and pulmonary arteries ap-peared normal. By pulse oximetry with the baby breath-ing room air, the 02 saturation was 88% and when the Fi02 was increased to 0.40 the saturation increased to

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ARTICLES 365 92%. Results of an arterial blood gas obtained at an Fi02

of 0.3 were as follows: pH 7.42, Paco2 37.4 mm Hg, P02

152 mm Hg, Hco3 24.0 mEqjL, and base excess 0.4 mEqJ L. The measured oxyhemoglobin saturation was 79% (calculated value

=

99%) with a methemoglobin level of 20.5%. The patient’s hemoglobin (13.9 g/dL)

concentra-tion and WBC count and differential were normal for his age, as were the levels of serum electrolytes, calcium,

BUN, and creatinine.

When the diagnosis of methemoglobinemia had been established, the infant received a 3.0-mg IV dose of meth-ylene blue. Following drug administration, his color and

respiratory symptoms dramatically improved. After the patient was stabilized, a barium esophagram revealed

mild gastroesophageal reflux. Metoclopramide therapy was discontinued because it was a possible cause of the methemoglobinemia. Fluoroscopically, tracheomalacia was identified as the cause of the baby’s stridor. The infant was discharged from the hospital following three days of observation with conservative management of his gastrointestinal reflux.

At a follow-up visit 15 days after hospital discharge, the infant appeared to be healthy and had experienced a 520-g weight gain. The gastrointestinal reflux was symp-tomatically improved, and his only physical abnormality

was the murmur noted at the time of admission, and there were no residua of the methemoglobinemia. A met-hemoglobin reductase value of 2.73 units (normal range

2.2 to 3.8 units) was reported, as was the absence of hemoglobin M according to electrophoretic analysis.

DISCUSSION

Methemoglobin is hemoglobin in which the iron

has been oxidized. Methemoglobinemia results when any one or a combination of the following conditions is present: oxidative stress to RBC

ex-ceeds their reductive capacity, a congenital defi-ciency of nicotinamide adenine dinucleotide (NADH) diaphorase, and/or a sufficient

concentra-tion of hemoglobin M.’7 The absence of hemoglobin M and the presence of a normal activity of

methe-moglobin reductase in our patient suggested an

exogenous cause for methemoglobinemia.

There were several factors that prompted us to

suspect metoclopramide as the cause of

methemo-globinemia. The infant was not exposed to other medications or environmental agents known to pro-duce the condition.’8 Although acetaminophen has been associated with the development of methe-moglobinemia,’9 maternal drug treatment with an acetaminophen-containing compound had been dis-continued 13 days before administration of meto-clopramide, thereby making significant transport via breast milk unlikely. Additionally, the initial appearance of our patient (eg, restlessness progress-ing to cyanosis and lethargy) has been associated with extrapyramidal symptoms following

metoclo-pramide 2 and is consistent with

previous reports of metoclopramide toxicity in

in-fants both without2’ and with22 (Dr Anne Board, personal communication, Feb 17, 1987) associated methemoglobinemia.

There were also several physicochemical factors

in support of metoclopramide as the causative agent for the production of methemoglobinemia in our patient. Metoclopramide is structurally related to

the aniline dyes and to prilocaine, an amide local anesthetic known to produce methemoglobinemia in susceptible individuals.23’24 The drug is a weak

base (pK8 9.3) that contains a secondary nitrogen5 and, therefore, can exist as an uncharged secondary amine or as the positively charged ammonium

cation. Consequently, a substantial percentage of the drug would be expected to exist as the

unpro-tonated species at physiologic pH, a situation that would be accentuated with a tenfold overdose. Me-toclopramide and/or its metabolites25 would also be expected to accumulate following repeated dosing

in young infants consequent to developmental re-ductions in hepatic biotransformation and renal clearance,26 a potentially important consequence for metoclopramide in which 25% to 40% of total plasma clearance is attributable to renal clear-ance.25 A reduced plasma clearance of

metoclo-pramide in a 3-week-old full-term infant (t,12 23.0 hours) was recently reported,27 thereby lending sup-port to previous assertions of reduced metoclopram-ide clearance in infants.22’28

Young infants may also have reductions in the activity of nicotinamide adenine dinucleotide phos-phate (NADP)-dependent diaphorase, a condition that would render neonatal hemoglobin more sus-ceptible to a given oxidative stress. This is illus-trated by a report of three infants who experienced cyanosis with methemoglobinemia following three days of IM therapy.22 When these investigators incubated RBCs with 10 to 1,000 mg/mL of meto-clopramide, methemoglobin formation could not be

documented and NADH-dependent diaphorase

ac-tivity remained unchanged. After the IM adminis-tration of 1.0- to 2.0-mg/kg/d doses of metoclo-pramide to premature infants, full-term infants,

and adults, methemoglobin production was

ob-served in all infants who received the 2.0-mg/kg/d dose and in the premature infants who received the 1.0-mg/kg/d dose.22 These authors attributed the development of methemoglobinemia to a develop-mental reduction in NADH-dependent diaphorase activity, the presence of a metoclopramide metab-olite capable of producing oxidation of hemoglobin, and/or possible accumulation of the drug or its metabolite consequent to developmental renal in-sufficiency. In a subsequent investigation,28 these

investigators demonstrated that urine obtained

from patients treated with metoclopramide and

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366 METHEMOGLOBINEMIA

plasma obtained from premature infants given the drug produced a profound oxidizing effect on eryth-rocytes and no alteration in the activity of

NADH-dependent methemoglobin reductase. They then

postulated that a metabolite of metoclopramide was responsible for producing methemoglobinemia and

that premature infants were predisposed to this adverse effect. In addition to the previously pub-lished report of metoclopramide-associated methe-moglobinemia,22 two additional cases have been reported following iatrogenic overdoses (1.0 mg/kg/ dose) to infants (Dr Anne Board, personal com-munication, Feb 17, 1987). Both of the infants had

ashen color, lethargy, and documented methemo-globinemia after five to seven days of therapy that promptly resolved following discontinuation of me-toclopramide therapy.

SPECULATION AND RELEVANCE

Despite the fact that the pharmacodynamics’#{176} and pharmacokinetics27 of multiple-dose metoclo-pramide therapy in infants with gastrointestinal reflux has been evaluated in only two investigations and the fact that the drug is not approved for the treatment ofthe condition in infants, metoclopram-ide is frequently prescribed in both the ambulatory and inpatient setting. Based on our recent experi-ence, evidence that supports delayed metoclopram-ide clearance in young infants,27 and previously published reports,22’28 clinicians should suspect the presence of toxicity and/or methemoglobinemia in any infant receiving metoclopramide who has cy-anosis, ashen color, or a history of motor restless-ness and/or lethagy associated with drug treatment.

SUMMARY

Metoclopramide, especially in large (eg, >1.0 mg/

kg/d) doses, may produce methemoglobinemia in

neonates. When the drug is prescribed for the treat-ment of gastroesophageal reflux in infants, it should be initiated only on clear medical indication and

after conventional approaches to management have proven unsatisfactory. Metoclopramide treatment of gastroesophageal reflux should be initiated with low doses (eg, 0.1 to 0.15 mg/kg every six to eight hours) and the clinician must remain vigilant con-cerning all reported side effects of the drug, includ-ing the development of methemoglobinemia.

ACKNOWLEDGMENTS

We acknowledge the editorial assistance of Drs Helen L. Butler, Stephen F. Kemp, and Dan Lattin. We also thank Dorothy Nichols for secretarial assistance.

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1988;82;364

Pediatrics

Gregory L. Kearns and Debra H. Fiser