CHAPTER 126

Methemoglobin Inducers

Dennis P. Price

INTRODUCTION

Methemoglobin occurs when the iron atom in hemoglobin loses 1 electron to an oxidant, and the

ferrous (Fe2+) or oxidized state of iron is transformed into the ferric (Fe3+) state. Although

methemoglobin is always present at low concentrations in the body, methemoglobinemia is defined

herein as an abnormal elevation of the methemoglobin concentration above 1%.

The wide spread adoption of pulse oximetry has made it easier to recognize low oxygen saturation

consequently increasing our recognition of methemoglobinemia. The ubiquity of oxidants both in the

environment and in the hospital has increased the number of case reports associated with

methemoglobin. It is also evident that host factors play a crucial role in the development of

methemoglobinemia in many individuals.

Biological systems have protective cell membrane and intracellular mechanisms that are protective

with regard to oxidant stresses. Some are enzyme systems that involved electron transport mechanisms

whereas others are simple reducers such as ascorbic acid and reduced glutathione. When fully

functional these systems maintain methemoglobin concentration under 1% but with acute or chronic

stress may be overwhelmed allowing methemoglobin concentration to rise.

The cellular systems that protect the individual from oxidant stress involve cytochrome b reductase,

flavin, NADH methemoglobin reductase, NADPH methemoglobin reductase, reduced glutathione and

ascorbic acid are interrelated and incompletely understood. Depletion of the reducing power of these

systems leads to methemoglobinemia and other disorders of oxidant stress such as hemolysis.kkk[this

paragraph seems out of context in the intro]trying to lay out where im going and that oxidants also

produce other diseases

70? add 70 remove 25

25?, ,47, 57,74 3,17,58,71

Underlying illnesses, the treatment with xenobiotics for these illnesses and the

47,70
therapeutic and diagnostic modalities involved in patient care all predispose to

methemoglobinemia. Methemoglobinemia for many individuals is not caused by one oxidant stressor

but rather a series of stressors that makes methemoglobinemia clinically apparent and potentially

predictable.

Reduced hemoglobin functions reliably as an oxygen transporter because in its protected heme pocket

it shares an outer valence electron with the oxygen it transports. Normally reduced hemoglobin releases

this oxygen without giving up an electron, but occasionally this electron is lost to the departing oxygen

in the process of autooxidation. Oxidation is increased in the presence of some hereditary conditions

such as hemoglobin M disease. However, oxidizing xenobiotics may produce methemoglobin by direct

interaction with the Fe2+ moiety. These exogenous products are a major source of oxidant stress to the

individual and the most frequent cause of methemoglobinemia. Although typically not life threatening,

methemoglobinemia may produce symptoms of cellular hypoxia and should be considered in the
differential diagnosis of the cyanotic patient without an apparent cardiovascular cause. In the cases of

methemoglobinemia, cyanosis is not caused by deoxyhemoglobin but rather by the color imparted to

the skin as a result of oxidized hemoglobin.

HISTORY AND EPIDEMIOLOGY

Methemoglobin was first described by Felix Hoppe-Seyler in 1864. 29 Subsequently, in 1891, a case of

transient drug-induced methemoglobinemia was described. 65 In the late 1930s, methemoglobinemia

was recognized as a predictable adverse effect of sulfanilamide use, and methylene blue was

recommended for treatment of the ensuing cyanosis. 39 Some authors even recommended concurrent

use of methylene blue when sulfanilamides were utilized. 93 Methylene blue has been used

prophylactically during general surgery to treat an individual with congenital methemoglobinemia.6 In

1948, an enzyme defect was reported in twin brothers. The defect caused cyanosis in the absence of

cardiopulmonary disease, and responded to ascorbic acid. 31? or 32 31 is the reference

Methemoglobinemia can be hereditary or acquired. The hereditary types are rare, with only several

hundred cases reported. 40,89 While frequency with which xenobiotic-induced methemoglobinemia

occurs is unknown, the AAPCC annual TESS data show approximately one hundred uses of methylene

blue as an antidote. These data substantially underestimate the incidence of this poisoning because

Poison Control Centers are not notified in most cases. (Chapter 134)

Methemoglobinemia is relatively common and generally produces no clinical findings. Cooximetry

data collected at two teaching hospitals noted a significant number of elevated methemoglobin

concentrations. 4 Of a total of 5248 cooximetry tests over 28 months on 1267 patients, 660 tests
revealed methemoglobin concentrations >1.5% in 414 patients (some patients had more than one test).

Thus, 12.5% of all tests and 19.1% of all patients who had cooximetry performed had an abnormal

methemoglobin concentration. One hundred thirty-eight patients with peak methemoglobin

concentrations greater than 2% were identified. The mean peak methemoglobin concentration was

8.4% (range 2.1–60.1%), the ages of the patients ranged from 4 days to 86 years old.

Benzocaine spray accounted for the most seriously poisoned patients (5), with a mean peak

methemoglobin of 43.8% (range 19.1–60.1%). Dapsone accounted for the largest number of cases

(58), with a mean peak of 7.6% (range 2.1–34.1%). Thirty three of 35 patients who had elevated

methemoglobin concentrations, 8% had symptomatic methemoglobinemia and 12 received methylene

blue. There was one fatality and 3 near fatalities that were directly attributed to methemoglobinemia.

These data likely represent an underestimation of the true number of cases of methemoglobinemia at

these institutions because cooximetry was performed only upon physician orders for a suspected

dyshemoglobinemia, and one quarter of cases with concentrations >2% were found incidentally when

cooximetry was performed in the catheterization laboratory to provide data on oxyhemoglobin and

deoxyhemoglobin. Also, not all patients taking dapsone were tested. 4 Extrapolating this data

throughout the country would suggest under reporting and substantial under recognition of this entity

with its potential danger.

The incidence of induced methemoglobinemia in the workplace is poorly documented. A number of

reports, document several hundred such cases of methemoglobinia and several more workplace

exposures. 15,86,51? should be 61? reference is 61 Underreporting and underrecognition occur due to the limited

symptoms associated with low concentrations of methemoglobin in most cases.

HEMOGLOBIN PHYSIOLOGY

Hemoglobin consists of 4 polypeptide chains noncovalently attracted to one another. Each of these

subunits carries one heme molecule deep within the structure. The polypeptide chain protects the iron

moiety of the heme molecule from inappropriate oxidation (Figure 126–1).

The iron is held in position by six coordination bonds. Four of these bonds are between iron and the

nitrogen atoms of the protoporphyrin ring with the fifth and sixth bond sites lying above and below the

protoporphyrin plane. The fifth site is occupied by histidine of the polypeptide chain. A variety of

hemoglobin mutations are due to changes in the amino acid sequence of the polypeptide chain, as occur

in the hemoglobin M diseases. This influences this protective "pocket," allowing easier iron oxidation

(Figure 126–2), or hemoglobin autooxidation. The sixth coordination site is where most of the activity

within hemoglobin occurs. Oxygen transport occurs here, and this site is involved with the formation of

methemoglobin or carboxyhemoglobin (Figure 126–3). It is at this site that an electron is lost to oxidant

xenobiotics, transforming iron from its ferrous (Fe2⁺) to its ferric (Fe3+).

Hemoglobin transports an oxygen molecule only when its iron atom is in the reduced ferrous state

(Fe2+). During oxygen transport, the iron atom actually transfers an electron to oxygen, thus

transporting oxygen as a superoxide charged particle Fe3+O2-. When oxygen is released, the ferrous state

is restored, and hemoglobin is ready to accept another oxygen molecule. Interestingly, a small

percentage of oxygen is released from hemoglobin with its shared electron (forming superoxide O2),

leaving iron oxidized. (Fe3+) This sixth coordination site becomes occupied by a water molecule. This

abnormal unloading of oxygen contributes to the steady-state concentration of approximately 1%

methemoglobin found in normal individuals.

METHEMOGLOBIN PHYSIOLOGY AND KINETICS

Because of the spontaneous and xenobiotic-induced oxidation of iron, the erythrocyte has developed

multiple mechanisms to maintain a normal concentrtation of methemoglobin.12 All of these systems

donate an electron to the oxidized iron atom. Due to these effective reducing mechanisms, the half-life

of methemoglobin acutely formed as a result of exposure to oxidants is between 1 and 3 hours. 44,64 With

continuous exposure to the oxidant, the apparent half-life of methemoglobin is prolonged.

Quantitatively the most important reductive system requires nicotinamide adenine dinucleotide

(NADH), which is generated in the Embden-Meyerhof glycolytic pathway (Figure 126–4). NADH

serves as the donor of an electron donor, and along with the enzyme NADH methemoglobin reductase,

reduces Fe3+ to Fe2+. There are numerous cases of hereditary deficiencies of the enzyme NADH

methemoglobin reductase. 40 Individuals who are homozygotes for this enzyme deficiency usually have

methemoglobin concentrations of 10–50% under normal conditions without any clinical or xenobiotic

stressors. Individuals who are heterozygotes do not ordinarily demonstrate methemoglobinemia except

when they are subject to oxidant stress. Additionally, because this enzyme system lacks full activity

until approximately 4 months of age, even genetically normal infants are more susceptible than adults

to oxidant stress. 69,95

Oxidized iron can be reduced nonenzymatically using either ascorbic acid or reduced glutathione as

electron donors, but this method is slow and quantitatively less important under normal circumstances.

Within the red cell is another enzyme system for reducing oxidized iron that is dependent on the

nicotinamide adenine dinucleotide phosphate (NADPH) generated in the hexose monophosphate shunt

pathway (Figure 126–4). While it is generally accepted that this NADPH dependent system reduces
only a small percentage of methemoglobin under normal circumstance it may play a more prominent

role in maintaining oxidant balance in the cell. 53 Patients with a deficiency of NADPH methemoglobin

reductase do not exhibit methemoglobinemia under any circumstances,85 perhaps because of the

prominence of other cellular protective mechanisms.

However, when the NADPH methemoglobin reductase system is provided with an exogenous electron

carrier, such as methylene blue, this system is accelerated and can assist in the reduction of oxidized

hemoglobin.[Antidotes in Depth: Methylene Blue].

ETIOLOGIES

Nitrates and nitrites are powerful oxidizing agents that are two of the most common methemoglobin-

forming compounds. Sources of nitrates and nitrites include well water, food, industrial compounds,

and pharmaceuticals. Nitrogen-based fertilizers and nitrogenous waste from animal and human sources

may contaminate shallow rural wells. The contamination of drinking water occurs mainly with nitrates

because nitrites are easily oxidized to the highly soluble nitrates in the environment. Furthermore,

foods such as cauliflower, carrots, spinach, and broccoli have high nitrate content, as do preservatives

in meat products such as hot dogs and sausage.5 Dietary nitrates are generally converted by intestinal

bacteria to nitrates prior to absorption.28,40, 96 REMOVE THESE THREE REFERENCES

The reactions of nitrates that occur both in vivo and in vitro are complex and poorly understood.

Ingested nitrates are reduced to nitrites by bacteria in the gastrointestinal tract (especially in infants)

and then can be absorbed, ultimately leading to methemoglobin production. This conversion is not

essential, however, because nitrates themselves can oxidize hemoglobin. 27,38,88 some question whether

well water consumption alone can cause serious methemoglobinemia in the absence of comorbid
disease.24

In the past, nitrate contaminated well water were associated with infant fatalities due to

methemoglobinemia. 55,63 A number of reports from the midwest United States demonstrated the

problems of poorly constructed shallow wells that permit contamination by surface waters containing

chemicals, pesticides, fertilizers, and microorganisms. 66 In several South Dakota studies, 20–50% of

wells contained both coliform bacteria and water that exceeded the Environmental Protection Agency

(EPA) standards for permissible quantities of nitrogen as nitrates (10 ppm or 10 mg/L). 46? should be 45?

REFERENCE IS 46
In New York State, 419 wells from rural farms demonstrated elevated concentrations of

nitrogen compounds, and 15.7% were found to have well water nitrate concentrations >10 mg/L. 30

Nitroglycerin (glyceryl trinitrate) and organic nitrates are more effectively absorbed through mucous

membranes and intact skin than from the gastrointestinal (GI) tract. Their onset of action is more rapid,

and the total effect is much greater, when mucous membrane or cutaneous absorption occurs.

20,25,75
Aromatic amino and nitro compounds indirectly produce methemoglobin. 49 These xenobiotics do

not form methemoglobin in vitro; therefore, they are assumed to do so by in vivo metabolic chemical

conversion to some active intermediates.14,51

Elevated methemoglobin and carboxyhemoglobin concentrations are found in victims of fires and

automobile exhaust fume poisoning. 11,43? or 41?,48,59 REFERENCE IS 46 NOT 41 OR 43 Heat-induced hemoglobin

denaturation in burn patients and the inhalation of oxides of nitrogen from combustion are suggested to

be causative factors for methemoglobin formation.

Topical anesthetics are widely used to facilitate multiple procedures and are implicated in the most

serious of toxic methemoglobin cases. 1,36 Cetacaine spray (14% benzocaine, 2% tetracaine, 2%
butylaminobenzoate) and 20% benzocaine sprays commonly produce of methemoglobinemia. The

dosing recommendations are difficult to comprehend (eg, 0.5-second spray repeat once) and often are

ignored. One study showed that the dose is dependent on the residual volume in the canister and the

physical orientation of the canister as the spray is being applied.52

A review of fifty-two months of data from the FDA’s Adverse Event Reporting System demonstrated

132 cases of benzocaine-induced methemoglobinemia. Benzocaine spray was implicated in 107 severe

adverse events and 2 deaths. In 123 cases, the product was a spray. In 69 cases where the dose was

specified, 37 patients received a single spray.67

This FDA effort is exclusively based on self-reporting and probably greatly underestimates the extent

of the problem. 34?should be 36?REFERENCE IS 34 The FDA itself has estimated that approximately 10% of serious

events are reported and that some studies show ≤1% serious event reporting. 71? should be 67? REFERENCE IS 67

In one institution the incidence of benzocaine-induced methemoglobinemia occurring during

transesophogeal echocardiograms was determined in 28,478 patients over a 90 month period. The

incidence was low at 0.067% (one case per 1499 patient) with sepsis, anemia, and hospitalization

suggested as predisposing factors. 47 many cases not just one REMOVE PHRASE MANY CASES NOT

JUST ONE During a thirty-two months period at another institution an incidence of 0.115% (5/4336)

of benzocaine induced methemoglobinemia was observed. 70 There were no cases of

methemoglobinemia in a study of 154 patient receiving lidocaine for bronchoscopy at doses as high as

15 mg/kg. Lidocaine is a much weaker oxidant than benzocaine and a reasonable substitute in

susceptible individuals.

Nitric oxide delivered by inhalation is used to treat persistent pulmonary hypertension of the newborn
and other cardiopulmonary diseases associated with pulmonary hypertension because it is a potent

vasodilator. 82 Despite being a potent oxidant, if NO is used in doses of less than 40 ppm most patients

will maintain methemoglobin concentrations under 4%.41,92 Some cases of serious toxicity have

occurred because of intentional and unintentional overdoses.

Dapsone has been implicated as a cause of methemoglobinemia and is used in patients with AIDS.

Cases of prolonged methemoglobinemia from dapsone ingestion are related to the long half-life of

dapsone and the slow conversion to its methemoglobin-forming hydroxylamine metabolites. 23 Patients

receiving dapsone should be carefully monitored for methemoglobinemia. 94? did not see a ref 109? The bladder

anesthetic phenazopyridine is a commonly reported causes of methemoglobinemia. 19,26,30,68 For this

reason its use should be limited to short periods of time and at lowest dose to improve symptoms. This

approach is particularly pertinent in the presence of renal failure. Other causes of methemoglobinemia

are listed in Table 126–2.

Infants who are bottled-fed with well water may be exposed to nitrates and nitrites. Additionally,

infants have a relatively large body surface area, making dermal and mucosal absorption of oxidants

more of a threat to them than adults.

Methemoglobinemia of unknown origin is often reported in infants. 77,84,96 These patients are usually ill

for other reasons such as dehydration, acidosis, diarrhea.37 These infants can have methemoglobin

concentrations in the 20 to 67% range with severe consequences. 42 As noted above, young children are

relatively deficient in the enzyme glucose-6- phosphate dehydrogenase, accounting for their high

incidence of methemoglobinemia.

METHEMOGLOBINEMIA AND HEMOLYSIS

The enzyme defect responsible for most instances of oxidant-induced hemolysis is glucose-6-

phosphate dehydronase (G6PD) deficiency. A review of hemolysis addressed the confusion regarding

the relationship between hemolysis and methemoglobinemia.10,28

Both hemolysis and methemoglobinemia are caused by oxidant stress, and hemolysis can occur

following episodes of methemoglobinemia.10Certain protective mechanisms involving NADPH and

reduced glutathione nonspecifically reduce the oxidant burden and prevent the development of both

disorders. Another source of confusion concerning hemolysis and methemoglobinemia is that reduced

glutathione (GSH) is required to protect against both toxic manifestations. Erythrocytes are able to

withstand hemolytic oxidant damage as long as they can maintain adequate concentrations of reduced

glutathione, the principal cellular antioxidant. Glutathione is maintained in its reduced form by using

NADPH as its reducing agent. Cells with reduced capacity to produce NADPH (i.e., erythrocytes of

patients with G-6_PD deficiency or cells with depleted reduced glutathione/NADPH) are thus

susceptible to hemolysis. In the presence of methemoglobinemia, reduced glutathione plays a minor

role as a reducing agent, but NADPH is necessary for successful antidotal therapy with methylene blue.

This codependence on the reducing power of NADPH links the two disorders. Competition for

NADPH by oxidized glutathione and exogenously administered methylene blue is postulated to be the

cause of methylene blue-induced hemolysis, i.e., competitive inhibition of glutathione reduction.

Methylene blue itself is an oxidant, but in an assessment of the hemolytic potency of varied drugs,

methylene blue in doses of 390 to 780 mg proved to be only a moderate hemolytic agent. 50 The clinical

importance of this phenomenon is uncertain. It may be easier to consider hemolysis and

methemoglobin formation as subclasses of disorders of oxidant stress. They should be considered

separate clinical entities sharing limited characteristics.

However, oxidative damage to the erythrocyte occurs at different locations in the two disorders.

Hemolysis occurs when oxidants damage the hemoglobin chain acting directly as electron acceptors or

through the formation of hydrogen peroxide or other oxidizing free radicals. This results in Oxidants

forming irreversible bonds with sulfhydryl group of hemoglobin cause denaturation and precipitation of

the globin protein to form Heinz bodies within the erythrocyte. Cells with large numbers of Heinz

bodies are removed by the reticuloendothelial system, producing hemolysis. Alternatively, a limited

number ofoxidants can destroy the erythrocyte membrane directly, causing non-Heinz body hemolysis.

Methemoglobinemia does not necessarily progress to hemolysis, even if untreated.

Numerous cases describe the occurrence of hemolysis following methemoglobinemia. The combined

occurrence is reported with dapsone, 23 phenazopyridine, 19,26,32,68 amyl nitrite, 16? should this be 15?REFERENCE IS 16

and aniline. 46,49? or should be 51? REFERENCE IS 49 These instances of combined syndromes may represent the

incidental toxicity of an oxidizing agent at both locations or it may represent the depletion of all

cellular defenses against oxidants. Currently it is not possible to predict when hemolysis will follow

methemoglobinemia with any level of certainty.

CLINICAL MANIFESTATIONS

The clinical manifestations of methemoglobinemia are related to impaired oxygen carrying capacity

and delivery to the tissue. The clinical manifestations of acquired methemoglobinemia usually are more

severe than those produced by a corresponding degree of anemia. This discordance occurs because

methemoglobin not only decreases the available oxygen-carrying capacity but also increases the

affinity of the unaltered hemoglobin for oxygen. This shifts the oxygen hemoglobin dissociation curve

to the left, which further impairs oxygen delivery.22 (see chapter 21) This effect is attributed to the

formation of heme compounds intermediate between normal reduced hemoglobin (all four iron atoms
are ferrous) and methemoglobin, in which one or more of the iron moieties are in the ferric state.22 The

degree to which this high oxygen affinity hemoglobin reduces oxygen delivery to the tissue from

arterial blood is unclear, but is clinically significant.18

Because the symptoms associated with methemoglobinemia are related to impaired oxygen delivery to

the tissues, concurrent diseases such as anemia, congestive heart failure, chronic obstructive pulmonary

disease, and pneumonia may greatly increase the clinical effects of methemoglobinemia (see Fig. 126–

6). Predictions of symptoms and recommendations for therapy are based on methemoglobin percentage

in previously healthy individuals with normal total hemoglobin concentrations.

Cyanosis is a consistent physical finding in patients with substantial methemoglobinemia and is due to

the deeply pigmented color of methemoglobin. Cyanosis typically occurs when just 1.5 g/dL of

methemoglobin is present. This represents only 10% conversion of hemoglobin to methemoglobin if

the baseline hemoglobin is 15 g/dL. In contrast, 5 g/dL of deoxyhemoglobin (which represents 33% of

hemoglobin) is needed to produce the same degree of cyanosis from hypoxia.

In previously healthy individuals, methemoglobin concentrations of 10-20% usually result in cyanosis

without apparent adverse clinical manifestations. At 20-50% methemoglobin levels, dizziness, fatigue,

headache, and exertional dyspnea may develop. At about 50% methemoglobin, lethargy and stupor

usually appear. The lethal percent probably is greater than 70% (Table 126–3).

The cyanosis associated with methemoglobinemia is both peripheral and central. Patients often appear

in less distress or less ill than patients with cyanosis secondary to cardiopulmonary causes.

The symptoms of methemoglobinemia are determined not only by the absolute percent of

methemoglobin but also by its rates of formation and elimination. A percentage of methemoglobin that
may be clinically benign when caused by hereditary defects or maintained chronically, likely will

produce more severe signs when acutely acquired. Healthy subjects lack the compensatory mechanisms

that develop over a lifetime in individuals with hereditary compromise, such as erythrocytosis and

increased 2,3-diphosphoglyceric acid.

DIAGNOSTIC TESTING

For an individual in whom methemoglobinemia is suspected, a source for the oxidant stress should be

sought. Arterial blood gas sampling may reveal blood with a characteristic chocolate brown color.

However, in patients who are clinically stable and not in need of an arterial puncture, a venous blood

gas will be accurate in demonstrating the methemoglobin concentration. The arterial PO2 should be

normal, reflecting the adequacy of pulmonary function to deliver dissolved oxygen to the blood.

However, arterial PO2 does not directly measure the hemoglobin oxygen saturation (SaO2) or oxygen

content of the blood. When the partial pressure of oxygen is known and oxyhemoglobin and

deoxyhemoglobin are the only species of hemoglobin, oxygen saturation can be calculated accurately

from the arterial blood gas. If, however, other hemoglobins are present, such as methemoglobin,

sulfhemoglobin, or carboxyhemoglobin, then the fractional saturation of the different hemoglobin

species must be determined by cooximetry.

The cooximeter is a spectrophotometer that identifies the absorptive characteristics of several

hemoglobin species at different wavelengths. Because oxyhemoglobin, deoxyhemoglobin,

methemoglobin, and carboxyhemoglobin all have different absorptions at the different measuring

points of the co-oximeter, their proportions and concentrations can be determined. Some newer

cooximeters have an expanded spectrum at which they read and are also able to read fetal hemoglobin
and sulfhemoglobin.97

The pulse oximeter applied to a patient’s finger at the bedside was developed to estimate oxygen

saturation trends in critically ill patients. The device takes advantage of the unique absorptive

characteristics of oxyhemoglobin and deoxyhemoglobin and the different concentrations of these two

hemoglobin species during different phases of the pulse. Each manufacturer has calibrated its oximeter

using volunteers breathing progressively increasingly hypoxic gas mixtures in the absence of a

dyshemoglobinemia.78,87,91? should these be 79,89,96? REFERENCE IS 78,87,91In other words, the oxygen

saturation values displayed on the pulse oximeter are derived independently by each manufacturer, who

develops a formula using their own hardware and sensor. The manufacturer then compares this value to

a set of validation data derived from an experimental population.

Most pulse oximeters in use today use two different wavelengths to determine O₂ saturation and the

manufactures do not provide validation data for situation where any dyshemoglobin is present. These

manufactures disclaim accuracy under such circumstances. Like cooximetry, the dual wavelength pulse

oximeter reads absorbance of light at wavelengths of 660 and 940 nm, which are selected to efficiently

separate oxyhemoglobin and deoxyhemoglobin. However, methemoglobin absorption at these

wavelengths is greater than that of either oxyhemoglobin or deoxyhemoglobin.8,72 Therefore, when

methemoglobin is present, the readings become inaccurate. The degree of inaccuracy is unique for each

brand of instrument and may be influenced by signal quality, skin temperature, refractive error induced

by blood cells and other factors, such as finger thickness and perfusion, etc.80

In the dog model, the pulse oximeter oxygen saturation (SpO2) values drop with increasing

methemoglobin levels. This fall in SpO2 is not exactly proportional to the percentage of

methemoglobin. However, as the pulse oximeter overestimates the level of actual oxygen saturation.
For example, in a case where the methemoglobin level measured in the blood using a cooximeter was

20%, the pulse oximeter indicated an SpO2 of 90%.8,90 However, as the methemoglobin concentration

approached 30%, the pulse oximeter saturation values decreased to about 85% and then leveled off,

regardless of how much higher the methemoglobin level became.8,90

From our experience and that of others, 35,79 in humans much lower levels of oxygen saturation (SpO2)

than 85% can occur by pulse oximetry when methemoglobin levels rise above 30%.45 These

differences result from variations in the way different model pulse oximeters deal with methemoglobin

interference. 78,78? should be 79? REFERENCE IS 78 AND 79 The clinician, therefore, must understand how

the particular pulse oximeter measures oxygen saturation when methemoglobin levels are elevated and

(2) recognize that cooximetry determination is needed when methemoglobinemia is suspected.

Although the pulse oximeter reading in patients with methemoglobinemia may not be as accurate as

desired, it may be helpful when it is compared with that of the arterial blood gas: if there is a difference

between the measured oxyhemoglobin saturation of the pulse oximeter (SaO2) and the calculated

oxyhemoglobin saturation of the arterial blood gas (SpO2 )then a "saturation gap" exists. The

calculated SaO2 of the blood gas will be greater than the measured SpO2 if methemoglobin is present

(Table 126–4).

Recently, a pulse oximeter has been developed that reads at eight different wave lengths. This pulse

oximeter displays methemoglobin and carboxyhemoglogin. Validation experiments were performed

using volunteers with varying degrees of methemoglobinemia.7

MANAGEMENT

For most patients with mild methemoglobinemia of approximately 10%, no therapy is necessary other
than withdrawal of the offending xenobiotic, as reduction of the methemoglobin will occur by normal

re-conversion mechanisms (NADH methemoglobin reductase). However in some patients even small

elevations of methemoglobin should be considered problematic because they suggest the individual is

at a point where further oxidant stress may cause methemoglobin levels to rise. An individual receiving

dapsone with a small elevation of methemoglobin level may be more susceptible to clinically

significant methemoglobinemia if challenged with a benzocaine containing anesthetic or an increase in

dapsone dose. In the clinical setting, continued absorption, prolonged half-life, and toxic intermediate

metabolites may prolong methemoglobinemia. Patients should be examined carefully for signs of

physiologic stress related to decreased oxygen delivery to the tissue (Figure 126–6). Obviously,

changes in mental status or ischemic chest pain necessitate immediate treatment, but subtle changes in

behavior or inattentiveness may be signs of global hypoxia and should be treated. Abnormal vital signs

tachycardia and tachypnea or lactic acidosis thought to be caused by tissue hypoxia or the functional

anemia of methemoglobinemia should be treated aggressively. An elevated methemoglobin

concentration alone generally is not an adequate indication of need for therapy.

The most widely accepted treatment of methemoglobinemia is administration of methylene blue 1–2

mg/kg body weight infused intravenously over 5 minutes. This is 0.1–0.2 mL/kg of 1% solution. The

use of a slow 5-minute infusion helps prevent painful local responses from rapid infusion. When a

painful reaction occurs, it can be minimized by flushing the IV rapidly with at least 15 to 30 mL of

fluid following the infusion. Clinical improvement should be noted within 1 hour of methylene blue

administration. If cyanosis has not disappeared within one hour of the infusion, a second dose should

be given and other factors considered (Fig. 126-6). Methylene blue causes a transient decrease in the

pulse oximetry reading because its blue color has excellent absorbance at 660 mm.54,60
The use of methylene blue in patients with G6PD deficiency is controversial. Deficiency of this

enzyme is an estimated 200 million people worldwide. Its incidence in the United States is highest

among African Americans (11%) 9 among whom the disease has different levels of severity. For this

reason, G-6-PD-deficient patients have been excluded from most treatment protocols because

methylene blue is a mild oxidant and case reports have suggested methylene blue’s toxicity. However,

because of the lack of immediate availability of G-6-PD testing, most patients who need treatment

receive methylene blue therapy before their G-6-PD status is known. Although many patients with G-6-

PD deficiency undoubtedly have been treated unknowingly, few case reports of toxicity are described.

Even the authors of the review most frequently cited as a rationale for withholding methylene blue

treatment were unsure whether the methylene blue given to their G-6-PD-deficient patient produced

hemolysis; 83 the dose of methylene blue given to the patient under study was small, and the patient had

taken other xenobiotics capable of producing hemolysis. Patients with G-6-PD deficiency have variable

activity of the enzyme and manifest different levels of disease in response to oxidant stress. For all of

these reasons, the judicious use of methylene blue is warranted in most patients with G-6-PD

deficiency and symptomatic methemoglobinemia.

If methylene blue treatment fails to significantly relieve the methemoglobinemia, a number of

possibilities should be considered. The cause of the oxidant stress may not have been identified and

adequately removed, allowing for continuing oxidation. In such situations, decontamination of the gut

and skin cleansing must be assured. Additional doses of methylene blue are also indicated. Patients

who have sulfhemoglobinemia, or are deficient in NADPH methemoglobin reductase, or have severe

G6PD deficiency, may not improve following methylene blue therapy (see Antidotes in Depth).

Theoretically, exchange transfusion or hyperbaric oxygen may be beneficial when methylene blue is
ineffective. Both interventions are time consuming and costly, but hyperbaric oxygen allows the

dissolved oxygen time to protect the patient while endogenous methemoglobin reduction occurs.

Ascorbic acid is not indicated in the management of acquired methemoglobinemia if methylene blue is

available because the rate at which ascorbic acid reduces methemoglobin is considerably slower than

the rate of normal intrinsic mechanisms.13 Methylene blue has no therapeutic benefit in the presence of

sulfhemoglobinemia.76

Treatment of dapsone deserves special consideration because of its tendency to produce prolonged

methemoglobinemia. N-hydroxylation of dapsone to its hydroxylamine metabolite by a cytochrome

P450-mediated reaction is partly responsible for methemoglobin formation in both therapeutic and

overdose situations. Both parent compound and its metabolites are oxidants with long half-lives.

Cimetidine is competitive inhibitor in the cytochrome p450 metabolic pathway and reduces

methemoglobin concentrations during therapeutic dosing because less dapsone will be metabolized by

the route.81 In overdose situations, cimetidine may exert some protective effects and should be used

with methylene blue. When dapsone is therapeutically indicated but low levels of methemoglobin are

found, cimetidine should be considered as a method for reducing oxidant stress.

SULFHEMOGLOBIN

Sulfhemoglobin is a hemoglobin variant in which a sulfur atom is incorporated into the heme molecule,

but is not attached to iron. The exact location of the sulfur atom in the porphyrin ring is unclear.

Sulfhemoglobin is a darker pigment than methemoglobin, producing cyanosis when only 0.5 g/dL of

blood is affected. The cyanosis produced is similar to that produced by methemoglobinemia.

Sulfhemoglobin also reduces the oxygen saturation determined by the pulse oximeter and 2,73 is
characterized in the laboratory by its spectrophotometric appearance and its lack of reaction when

cyanide is added to the mixture. Cyanide does not react with sulfhemoglobin but does react with

methemoglobin forming cyanomethemoglobin which has no adsorption at the spectrums tested. In

contrast, the methemoglobin absorption peak will no longer be present after the addition of cyanide.

Using conventional cooximetery, sulfhemoglobin is misidentified as methemoglobin. However, the addition

of cyanide to the blood sample eliminates the methemoglobin peak (through conversion to

cyanomethemoglobin) but not the methemoglobin peak due to sulfhemoglobin.This technique is not

routinely done in the clinical laboratory, and the diagnosis often is made based upon the patient’s

failure to improve with methylenblue.2,56,62,73 In the laboratory, isoelectric focusing techniques further

define sulfhemoglobin.

Sulfhemoglobin is an extremely stable compound that is eliminated only when red blood cells are

removed naturally from circulation. Although the oxygen-carrying capacity of hemoglobin is reduced

by sulfhemoglobinemia, unlike methemoglobinemia there is a decreased affinity for oxygen in the

remaining "unaltered" hemoglobin. The oxyhemoglobin dissociation curve is shifted to the right (see

Fig. 21–2). This makes oxygen more available to the tissues. This phenomenon reduces the clinical

effect of sulfhemoglobin at the tissue level.

Sulfhemoglobin can be produced experimentally in vitro by the action of hydrogen sulfide on

hemoglobin and was produced in dogs fed elemental sulfur. 76 A number of xenobiotics induce

sulfhemoglobin in humans, including acetanilid, phenacetin, nitrates, trinitrotoluene and sulfur

compounds. Most of the xenobiotics that produce methemoglobinemia have been reported in various

degrees to produce sulfhemoglobinemia. Sulfhemoglobinemia is also recognized in individuals with

chronic constipation and in those who abuse laxatives76 Table 126–5 lists some differences between
methemoglobin and sulfhemoglobin.

Sulfhemoglobinemia usually requires no therapy other than withdrawal of the offending xenobiotic. It

appears that patients come to the attention of clinicians earlier because sulfhemoglobinemia produces

more cyanosis than does methemoglobinemia. There is no antidote for sulfhemoglobinemia because it

results from an irreversible chemical bond that occurs within the hemoglobin molecule. Exchange

transfusion would lowers sulfhemoglobin concentration, but this approach usually is unnecessary.

SUMMARY

Oxidation of hemoglobin is a less common but rapidly treatable etiology of cyanosis. In the absence of

findings of cardiopulmonary disease, methemoglobinemia is likely the cause of cyanosis from. The

diagnosis is confirmed by evaluation of blood by cooximetry. When treatment is clinically indicated,

methylene blue is the treatment of choice. The source of oxidant stress should be sought and

eliminated. Patients with low methemoglobin percentages should be considered to be under oxidant

stress and at risk for more serious methemoglobinemia if oxidant stressors persist on increase in their

environment. Methemoglobinemia should be considered to be a disease state caused sometimes by an

acute overwhelming oxidant protective mechanisms of the host by an oxidant or more commonly and

importantly as a final clinical manifestation of multiple oxidant stressors.

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Figure 126–1. Hemoglobin molecule symbolically represented with its heme center surrounded by the
globin portion of the molecule. his = histidine
Figure 126–2. Hemoglobin M occurs when histidine is replaced by tyrosine in the amino acid sequence
of the polypeptide chain. Hemoglobin M is more easily autooxidized (as shown) to methemoglobin.
Figure 126–3. Heme molecule depicted with its bonding sites. Oxyhemoglobin, carboxyhemoglobin,
and methemoglobin all involve the sixth coordination bonding site of iron.
Figure 126–4. Role of glycolysis in the Embden-Meyerhof pathway and the role of methylene blue in
the reduction of methemoglobin.
Figure 126–5. Clinical manifestations of methemoglobinemia depend on the level of methemoglobin
and on host factors such as preexisting disease, anemia, and hypoxemia. Five examples of arterial
blood gas and cooximeter analyses are presented. A. Blood gas from a normal individual with 14 g/dL
of hemoglobin. Almost all hemoglobin is saturated with oxygen. B. Blood gas from a patient with
cardiopulmonary disease producing cyanosis in which only 9 g/dL of hemoglobin is capable of oxygen
transport. C. Methemoglobin level of 28% in an otherwise normal individual will reduce hemoglobin
available for oxygen transport to <9 g/dL (approximately 4 g/dL of methemoglobin and 1.3 g/dL of
high-oxygen-affinity hemoglobin because of the left shift of the oxyhemoglobin dissociation curve). D.
Same degree of methemoglobin as in C but in a patient with a hemoglobin of 10 g/dL. Only 6 g/dL of
hemoglobin would be capable of oxygen transport. E. Methemoglobinemia and anemia to the same
degree as D but in a hypoxic patient.
Figure 126-6. Toxicologic assessment of the cyanotic patient.
TABLE 126-1. Factors that may Predispose an Individual to Methemoglobinemia
Acidosis 92,105 new 84,96
Advanced Age 76 new 70

Age less than thirty six months 21,74,104 new 21,69,95

Anemia 50 new 47

Concomitant oxidant use 3,77,61 new 3,58,71

Diarrhea 39, 85 new 37,77
Hospitalization50,76 new 47,70
We Malnutrition
Renal insufficiency 9new 33

Sepsis, 50,60,76,81 new 47,57,70,74

TABLE 126–2. Common Etiologies of Methemoglobinemia

Hereditary

Hemoglobin M

Cytochrome b5 reductase deficiency

(homozygote and heterozygote)

Acquired

A. Medications

Amyl nitrite

Benzocaine

Dapsone

Lidocaine

Nitric oxide

Nitroglycerin

Nitroprusside

Phenazopyridine

Prilocaine

Quinones (chloroquine, primaquine)

Sulfonamides (sulfanilamide, sulfathiazide, sulfapyridine, sulfamethoxazole)

B. Other xenobiotics

Aniline dye derivatives (shoe dyes, marking inks)

Chlorobenzene

Fires (heat-induced denaturation)

Organic nitrites (e.g., Isobutyl nitrite, butyl nitrite)

Naphthalene

Nitrates (e.g., well water)

Nitrites (e.g., foods)

Nitrophenol
 Nitrous gases (seen in arc welders)

Silver nitrate

Trinitrotoluene

Pediatric

Reduced NADH methemoglobin reductase activity in infants (<4 months)

Associated with low birth weight, prematurity, dehydration, acidosis, diarrhea, and
hyperchloremia

TABLE 126–3. Signs and Symptoms Typically Associated with Methemoglobin Percentages in
Healthy Patients with Normal Hemoglobin Concentrations

Methemoglobin Concentration (%) Signs and Symptoms

1–<3 (Normal) None

3–15 Possibly none

Slate gray cutaneous coloration

Pulse oximeter will read low SaO2

15–20 Cyanosis

Chocolate brown blood

20–50 Dyspnea

Exercise intolerance

Headache

Fatigue

Dizziness, syncope

Weakness

50–70 Tachypnea

Metabolic acidosis

Dysrhythmias

Seizures

CNS depression

Coma
>70 Grave hypoxic symptoms

Death
TABLE 126–4. Hemoglobin Oxygenation Analysis

Measuring Source What is How Are Benefits Pitfalls Insight

Device Measured? Data
Expressed?

Blood gas Blood Partial PO2 Also gives Calculates An

analyzer pressure informati SaO2 abnormal
of on about from the Hb form
dissolved pH and partial may exist
oxygen PCO2 pressure if gap
in whole of exists
blood oxygen between
in ABG and
plasma; pulse
inaccurat oximeter
e if forms
of Hb
other
than
OxyHb
and
DeoxyHb
are
present

Cooximeter Blood Directly SaO2 Measures provides Most

measures %MethH hemoglo data on accurate
absorptiv b, bin hemoglo method to
e %CoHb, species bin only; determine
characteri %OxyHb directly most oxygen
stics of , instrume content of
oxyhemo %Deoxy nts will blood
globin, Hb not
deoxyhe measure
moglobin sulfhemo
, globin,
methemo HbM,
globin, and some
carboxyh other
emoglobi forms of
n at Hb
different
waveleng
th bands
in whole
blood

Pulse Monitor Absorptive SpO2 Moment-to- Inaccurate Maximum

oximeter Sensor characteri moment data, if depressio
on stics of bedside interferin n 75–
patient oxyhemo data g 85%,
globin in substance regardles
pulsatile s are s of how
blood present: much
assuming methemo methemo
the globin, globin is
presence sulfhemo present
of only globin,
OxyHb carboxyh
and emoglobi
DeoxyHb n,
in vivo methylen
e blue

New not inserted —27,38,88??

This would be a good figure. Most people do not know what a Heinz body looks like. (Agree- Should I draw it myself or
use someone elses?)