Chapter 126 Corrected

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? Underlying illnesses,

add 70 remove 25 25?, ,47, 57,74

the treatment with xenobiotics for these illnesses

therapeutic and diagnostic modalities involved

47,70

3,17,58,71

and the

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 methemoglobinforming 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-6phosphate 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-6PD 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 Device

What is How Are Benefits Measured? Data Expressed?

Blood gas analyzer

Partial PO2 pressure of dissolved oxygen in whole blood

Blood

Pitfalls

Insight

Also gives Calculates An informati SaO2 abnormal on about from the Hb form pH and partial may exist PCO2 pressure if gap of exists 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

Absorptive SpO2

Monitor

Moment-to- Inaccurate Maximum

oximeter

Sensor on patient

characteri stics of oxyhemo globin in pulsatile blood assuming the presence of only OxyHb and DeoxyHb in vivo

moment bedside data

data, if interferin g substance s are present: methemo globin, sulfhemo globin, carboxyh emoglobi n, methylen e blue

depressio n 75– 85%, regardles s of how much methemo globin is present

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?)