TODD A. FLORIN
HISTORY OF PRESENT ILLNESS
The patient is a 7-week-old African-American boy who presents with a 2-day history of frequent vomiting. The vomiting is nonprojectile, nonbilious, and on one occasion, streaked with blood. Oral intake was poor. He had urinated once over an 18-hour period. On the day of admission he had profuse, watery diarrhea. No one in the family has had vomiting or diarrhea.
The patient was born at term weighing 3300 g. He was delivered via cesarean section due to arrested descent. Because of feeding difficulties in the nursery he was discharged home on a lactosefree formula. Since then his oral intake has been appropriate. He has not required previous hospitalization. He has received his first hepatitis B immunization.
T 38.1°C; RR 50/min; HR 170 bpm; BP 86/38 mmHg; SpO2 88% in room air
Weight 10th percentile (4.0 kg); Length 25th percentile; Head circumference 10th percentile
Examination revealed an infant who was crying but consolable (Figure 3-1). The anterior fontanelle was open and slightly sunken. The mucous membranes were moist and the sclerae were nonicteric. The lungs were clear to auscultation and the cardiac examination was normal without any murmurs. The abdomen was soft and mildly distended without hepatomegaly or splenomegaly. The extremities were cool. He had no rashes, good tone, and a symmetric neurologic examination.
FIGURE 3-1. Photograph of a slightly older child with similar findings to the case patient.
Laboratory evaluation revealed 24 500 white blood cells/mm3 with 9% band forms, 24% segmented neutrophils, 40% lymphocytes, 20% monocytes, and 5% atypical lymphocytes. The hemoglobin was 15.2 g/dL and the platelet count was 577 000 cells/mm3. Red blood cell morphology noted mild anisocytosis, poikilocytosis, and burr cells. Serum chemistries were significant for a CO2 of 10 mmol/L and cerebrospinal fluid cell counts, glucose and protein were normal; no bacteria were identified on Gram stain. His urine was dark yellow and turbid with a specific gravity of 1.038, a pH of 5.5, 3+ protein, and 5-10 granular casts without bacteria, nitrites, or white blood cells. On chest radiograph, the cardiac silhouette and lung fields were normal.
COURSE OF ILLNESS
The patient’s oxygen saturation on pulse oximeter increased to 93% when oxygen was administered by nasal cannula. Four extremity blood pressures were obtained as follows: right arm, 90/32 mmHg; left arm, 88/42 mmHg; right leg, 80/40 mmHg; left leg, 76/35 mmHg. On arterial blood gas (ABG), the pH was 7.01; PaCO2 18 mmHg; PaO2 232 mmHg; bicarbonate level, 4.7 mEq/L; and base deficit, 24.7. The patient received multiple normal saline boluses and bicarbonate in an attempt to correct his metabolic acidosis. The appearance of the patient (Figure 3-1) in conjunction with the ABG suggested a diagnosis.
DISCUSSION CASE 3-1
Vomiting in early infancy can be a very worrisome symptom. The most common cause of emesis in this age group is gastroesophageal reflux, which can be physiologic or due to overfeeding. Anatomic obstruction should always be considered. Obstructive lesions include malrotation with a volvulus, esophageal or intestinal atresia, pyloric stenosis, meconium ileus, congenital adhesions or bands, incarcerated hernia, intussusception, and Hirschsprung disease. The level of the obstruction will determine whether the vomitus is bilious or the abdomen is distended. Infectious causes include gastroenteritis, sepsis, urinary tract infection, meningitis, pneumonia, and pericarditis. Neurologic causes, such as subdural hematoma, hydrocephalus, and mass lesions, should also be considered. Bloody streaks in the emesis could be due to a milk protein allergy, gastroenteritis, necrotizing enterocolitis, or achalasia.
Metabolic and endocrine disorders must be considered in this child who presents with vomiting and a significant metabolic acidosis. These disorders include congenital adrenal hyperplasia (CAH), adrenal hypoplasia, inborn errors of metabolism, including both amino acid and organic acid disorders, and galactosemia.
The patient was cyanotic, a feature best visualized with the contrast of his lips to the white portion of the blanket (Figure 3-1). An arterial blood gas (ABG) with co-oximetry measurements revealed acidosis with a pH of 7.01; PaCO2, 18 mmHg; and PaO2, 232 mmHg. Co-oximetry readings revealed an oxyhemoglobin was 78.2%, methemoglobin 21.8%, and lactate level of 2.7 mmol/L confirming the diagnosis of methemoglobinemia.
INCIDENCE AND EPIDEMIOLOGY OF METHEMOGLOBINEMIA
Although methemoglobinemia is a relatively uncommon condition in pediatrics, it may cause significant cyanosis and even death. Methemoglobin is a derivative of normal hemoglobin in which the iron component has been oxidized from the ferrous (Fe2+) to the ferric (Fe3+) state. The oxidized iron (Fe3+) is unable to reversibly bind oxygen. Therefore, the oxidation of hemoglobin to methemoglobin produces a functional anemia by impairing the ability of the blood to transport oxygen. Methemoglobin occurs regularly in the body but rarely exceeds levels of 2% of the total hemoglobin because of antioxidant reactions in the body that reduce methemoglobin back to hemoglobin. The most important of these antioxidant reactions utilize either NADH-cytochrome b5 reductase or NADPH-methemoglobin reductase, although the latter system is largely inactive unless stimulated by the presence of methylene blue as a cofactor. NAPDH-methemoglobin reductase reduces methylene blue, an action that has important therapeutic implications as described in the treatment section below.
Methemoglobin levels increase when there is a disturbance in the balance between the oxidation and reduction of heme iron. Infants are at an increased risk of methemoglobinemia for two main reasons: (1) an immature NADH-dependent enzyme system (cytochrome b5 and cytochrome b5 reductase) resulting in lower levels of these enzymes and (2) fetal hemoglobin is more easily oxidized than adult hemoglobin. Both of these concerns are heightened in a state of metabolic acidosis. Methemoglobinemia can be caused by exposure to oxidant drugs and chemicals, development of enteritis and/or acidosis, or inherited conditions (Table 3-3). The most common oxidizing agents in acquired methemoglobinemia include sulfonamides, aniline dyes, chlorates, quinones, benzocaine, lidocaine, metoclopramide, dapsone, and phenytoin. In young babies, topical anesthetics, such as topical benzocaine and lidocaine, are common causes of methemoglobinemia as a result of their use as remedies for circumcision and tooth eruption pain. Ingestion of well water nitrates can also cause methemoglobinemia. Gastroenteritis results in an oxidant stress as nitric oxide is released in the enteric endothelium, and can cause methemoglobinemia in infants. Less common causes include inherited deficiencies of erythrocyte methemoglobin reductase or the presence of M hemoglobin (congenital methemoglobinemia).
TABLE 3-3. Agents typically implicated in methemoglobinemia
The clinical presentation of patients with methemoglobinemia depends on the concentrations of both hemoglobin and methemoglobin (Table 3-4). Increasing methemoglobin levels are associated with progressively more severe symptoms. Patients with lower hemoglobin percent concentrations are affected at lower percentage levels of methemoglobin. Patients with methemoglobin concentrations less than 10% rarely have symptoms unless they are already anemic. Most patients with concentrations between 10% and 25% will have cyanosis but few other symptoms. Levels from 30% to 50% are associated with confusion, dizziness, fatigue, headache, tachypnea, and tachycardia. Levels greater than 50% are associated with severe acidosis, arrhythmias, seizures, lethargy, and coma. Lethal levels occur at around 70%.
TABLE 3-4.Clinical symptoms of methemoglobinemia based on methemoglobin level.
Diagnosing a rare pediatric condition, such as methemoglobinemia, depends on having a high index of suspicion. Methemoglobinemia should be considered in cyanotic children without evidence of cardiac or pulmonary disease.
Bedside examination of blood. In a cyanotic patient, differentiating methemoglobin from deoxyhemoglobin is important. On white filter paper, blood containing a high level of methemoglobin turns chocolate brown, whereas blood containing deoxygenated hemoglobin appears dark red or purple initially but turns bright red on exposure to atmospheric oxygen.
Pulse oximetry. Oxygen saturation measured by pulse oximetry will be falsely elevated in the presence of high levels of methemoglobin. Most pulse oximeters use two wavelengths of light to determine “functional oxygen saturation,” which is the ratio of oxyhemoglobin to all hemoglobin capable of carrying oxygen. Normally, all hemoglobin present can potentially carry oxygen so that functional and trueoxygen saturation are equal. Because methemoglobin does not carry oxygen, it does not register as functional hemoglobin on the typical pulse oximeter. At normal methemoglobin levels (<2%), this exclusion is not important; however, at high methemoglobin levels (>10%) the functional and true oxygen saturations differ substantially resulting in unreliable pulse oximetry readings. Due to light absorption characteristics of methemoglobin, the pulse oximetry readings will not drop below 82% unless accompanied by an increased level of deoxyhemoglobin. Newer generation pulse oximeters are available that use eight wavelengths of light and are able to accurately measure methemoglobin and carboxyhemoglobin continuously.
Arterial blood gas. Methemoglobinemia should be strongly suspected when there is a “saturation gap” in a cyanotic patient: a normal or elevated arterial partial pressure of oxygen (PaO2) from an ABG with a low oxygen saturation on pulse oximetry.
Co-oximetry. Co-oximeters are spectrophotometers that measure light absorbance at different wavelengths, including the wavelengths for methemoglobin, oxyhemoglobin, deoxyhemoglobin, and carboxyhemoglobin. Co-oximeters accurately distinguish methemoglobin from oxyhemoglobin and provide a definitive diagnosis. Sulfhemoglobin and methylene blue (the treatment for methemoglobinemia) both produce erroneously elevated methemoglobin levels on routine co-oximetry. Therefore, co-oximetry generally should not be used to monitor response to methylene blue treatment. Newer generation co-oximeters are able to distinguish sulfhemoglobin and methemoglobin.
Potassium cyanide test. Elevated sulfhemoglobin levels can also cause a cyanotic appearance with a normal PaO2, and can be mistaken for methemoglobin on some co-oximeters. If a newer generation co-oximeter that accurately detects sulfhemoglobin and methemoglobin is not available, the potassium cyanide test can be used to distinguish between these two hemoglobins. Methemoglobin reacts with cyanide to form cyanomethemoglobin. The formation of cyanomethemoglobin turns the blood from chocolate brown to bright red. Sulfhemoglobin appears dark brown initially and does not change color after the addition of potassium cyanide.
Additional studies. Although methemoglobinemia does not directly cause hemolysis, many of the agents that provoke methemoglobinemia can trigger hemolysis. Tests that evaluate for hemolysis (e.g., complete blood count, reticulocyte count, haptoglobin, and lactate dehydrogenase) and end-organ damage (e.g., electrolytes, liver function, creatinine, glucose) should be considered.
Treatment depends on the methemoglobin level and the patient’s symptoms. In all cases, the causative agent or process should be identified and eliminated or treated, if possible. Generally, consider administering specific therapy in symptomatic patients with methemoglobin levels greater than 20% or asymptomatic patients with methemoglobin levels greater than 30%. Consider treating patients with concurrent problems that impair oxygen delivery, such as anemia, cardiac disease, or pulmonary disease even if their methemoglobin levels are low. Symptomatic patients should receive proper airway management and supplemental oxygen as necessary. Intravenous methylene blue, after reduction to leukomethylene blue by NADPH-methemoglobin reductase, aids in the reduction of methemoglobin back to hemoglobin. It is the treatment of choice and should reduce methemoglobin levels significantly within 1 hour of administration. Exchange transfusions or hyperbaric oxygen may be necessary for those patients with extremely high levels that do not respond to methylene blue therapy or those patients with severe disease in whom methylene blue therapy is contraindicated (e.g., severe G6PD deficiency).
G6PD is the first enzyme in the hexose mono-phosphate shunt, which is the sole source of NADPH in the red blood cell. Patients with G6PD may not produce sufficient NADPH to reduce methylene blue to leukomethylene blue. As a result, methylene blue therapy may not be effective and may induce hemolysis in patients with G6PD deficiency, and is thus generally contraindicated in these patients.
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