A Case Report and Review of Sulfhemoglobinemia

ARTICLE Pseudomethemoglobinemia A Case Report and Review of Sulfhemoglobinemia

Howard C. Lu, MD; Richard D. Shih, MD; Steven Marcus, MD; Bruce Ruck, PharmD; Thelma Jennis

Objectives: To see if methemoglobin could poten- Results: Diagnosis of sulfhemoglobinemia achieved with tially be misdiagnosed and the limitation of present co- final confirmation made with gas chromatography. Pa- oximeters. tient steadily improved with supportive care.

Patient: A 17-year-old girl who overingested a combi- Conclusions: There is a potential for the diagnosis of nation of cimetidine, acetaminophen, ibuprofen, and methemoglobin with some of the limitations of present naproxen in a suicide attempt. co-oximeters. The laboratory diagnosis of sulfhemoglobinemia can be difficult to make. Method: Use of pulse co-oximeters to aid in the diagnosis of suspected sulfhemoglobinemia. Arch Pediatr Adolesc Med. 1998;152:803-805

blood pressure, 138/84 mm Hg; heart rate, Editor’s Note: Here’s one to keep in the back of your mind– 112/min; respirations, 16/min; and pulse behind the blue curtain. oxygen, 99%. Findings from her physical Catherine DeAngelis, MD examination revealed tachycardia and fre- quent vomiting but otherwise were unremarkable. Laboratory test values were note- worthy for acetaminophen (4 hours after ULFHEMOGLOBIN (SulfHb) is ingestion), 1959 µmol/L, and potassium, 3.4 a green-pigmented molecule mEq/L. Results of her other tests for elec- with a greatly reduced oxy- trolyte levels, liver function, coagulation gen affinity.1 This particular studies, and salicylate and alcohol levels cause of “cyanosis” has been were all within normal limits. The electro- associatedS with many drugs, exposure to cardiogram was unremarkable. She was ad- sulfur compounds, and constipation. How- mitted with the initial impression of acet- ever, it is not completely understood why aminophen toxicity. sulfhemoglobinemia develops. More- The patient received a “loading dose” over, it can be a readily missed diagnosis of oral N-acetylcysteine, 140 mg/kg, but due to the similarity clinically and spec- the dose was promptly vomited. During trophotometrically of SulfHb and to met- the next 24 hours, she had repeated epi- hemoglobin (MetHb).2,3 sodes of emesis associated with adminis- tration of N-acetylcysteine (70 mg/kg ev- REPORT OF A CASE ery 4 hours). In an attempt to alleviate her gastrointestinal tract symptoms, the pa- From the Department of A 17 year-old girl presented to the emer- tient was administered metoclopramide Emergency Medicine, gency department complaining of nausea, (100 mg intravenously [IV]). Because of Morristown Memorial Hospital, vomiting, and abdominal pain 2 hours continued nausea and vomiting, she re- Morristown, NJ (Drs Lu and after an intentional overdose of cimeti- ceived ondansetron (16 mg IV) and meto- Shih); and the New Jersey dine, acetaminophen, ibuprofen, and clopramide (100 mg IV per dose; total Poison Information and naproxen. Her medical history was note- dose, 500 mg) over 48 hours. By hospital Education System (Drs Shih, Marcus, and Ruck and worthy for depression, suicide attempts, and day 2, the patient’s gastrointestinal tract Ms Jennis) and the Department use of tobacco, but she denied the use of symptoms resolved and the N-acetylcys- of Pediatrics (Dr Marcus), alcohol or other drugs. On presentation, she teine was administered without any prob- Newark Beth Israel Medical was alert and oriented. Her vital signs were lems. She completed a total of 18 doses of Center, Newark, NJ. as follows: temperature, 37.2°C; arterial N-acetylcysteine by the next day.

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 On hospital day 3, the patient experienced several MetHb is, with methylene blue, and has no effective an- dystonic reactions, developed discoloration of her lips, tidote. Although transfusions may be useful in some cases, face, and nailbeds, and complained of severe headaches. SulfHb is only eliminated after the red blood cells’ life Her vital signs at this time were as follows: blood pres- span is naturally concluded (after Ϸ 120 days). sure, 130/90 mm Hg; heart rate, 90/min; respirations, The production of SulfHb requires a compound with 20/min; and pulse oxygen, 88%. Findings from physical oxidative properties and a source of sulfur. This has been examination were unremarkable except for a blue-gray demonstrated in the laboratory where an oxidant, phen- general appearance. Results of her liver function tests acetin, given with precipitated sulfur produced SulfHb, and coagulation studies remained within normal limits. whereas the oxidative agent given alone caused MetHb.4 An arterial blood gas test was performed using a Dow However, in the human model, the origin of sulfhemo- Corning 2500 Co-oximeter (Dow Corning, Ambridge, globinemia is less clear because in some cases the sulfur Pa) that revealed a MetHb level of 0.26 (normal, 0.01- source is not clearly evident. A number of drugs have been 0.02). The patient was treated with a total of 3 doses of associated with sulfhemoglobinemia. These include ac- methylene blue (1 mg/kg IV) without improvement of etanilid, phenacetin, nitrates, trinitroluene, and sulfur her cyanosis. Suspecting sulfhemoglobinemia, another compounds. However, theoretically, any oxidative agent arterial blood gas test was performed using a co- that causes methemoglobinemia can be a possible pre- oximeter capable of evaluating SulfHb levels, the Dow cipitant of sulfhemoglobinemia. The origin of sulfur, in Corning 270 Co-oximeter. A SulfHb level of greater cases where it is not overtly apparent, has been theo- than 0.015 and a MetHb level of 0.001 were found. rized to come from hydrogen sulfide released by intes- Final confirmation of sulfhemoglobinemia was achieved tinal organisms (particularly in patients with constipa- with gas chromatography. tion) and/or glutathione. Specifically, our case is perplexing because of the RESULTS drugs that were associated with the sulfhemoglobinemia. Metoclopramide is a drug with mild oxidant activ- After a definitive diagnosis was made, the patient steadily ity that has been associated with rare reports of sulfhe- improved with supportive care. Complete recovery moglobinemia after long-term use.5 It is structurally related occurred over the next several months with no adverse to the aniline dyes and to prilocaine which are known sequelae. to produce methemoglobinemia.6 N-acetylcysteine is a biochemical precursor of glutathione7 and a source of hy- COMMENT drogen sulfide. These two drugs may have acted to- gether in this patient to produce the sulfhemoglobine- Most presentations of cyanosis are secondary to difficul- mia. Curiously, N-acetylcysteine is a commonly prescribed ties with the respiratory or the cardiac system. How- therapy for acetaminophen overdose and is frequently ever, hemoglobinopathies, such as methemoglobinemia used along with metoclopramide, yet few documented and sulfhemoglobinemia, can present in this manner and cases of sulfhemoglobinemia exist.7 Perhaps, the very large are often not considered. dose of metoclopramide in this case was essential for the This case of sulfhemoglobinemia presents several is- production of sulfhemoglobinemia. sues that have been poorly delineated in the medical lit- Many commonly used co-oximeters are not capable erature: (1) differentiating SulfHb from MetHb and (2) of detecting SulfHb. Co-oximeters use spectrophotomet- difficulties in diagnosing sulfhemoglobinemia. ric techniques to measure different types of hemo- Methemoglobin is hemoglobin where the heme has globins. Typically, the most commonly used machines been oxidized from the normal ferrous (Fe2+) to the fer- differentiate only 4 types of hemoglobin: oxygenated- ric state (Fe3+) making it incapable of oxygen transport. hemoglobin, deoxygenated-hemoglobin, MetHb, and car- This leads to a decreased oxygen-carrying capacity and boxyhemoglobin. Therefore, when other types of hemoglo- a leftward shift of the oxy-deoxygenated dissociation bin are present, such as SulfHb and fetal hemoglobin, these curve. Oxygen unloading in the tissues is diminished, pre- hemoglobins are either undetected or falsely measured as disposing to tissue hypoxia. Treatment with methylene one of the other types of hemoglobin. Fetal hemoglobin is blue is successful in most cases. the most studied interfering hemoglobin and has been Sulfhemoglobin, also in the ferric state, addition- shown to have a positive linear correlation with carboxy- ally has a sulfur atom incorporated in the hemoglobin. hemoglobin.8,9 Little data, however, are available regard- This abnormal hemoglobin is also rendered incapable of ing the effects of interfering substances on MetHb measure- oxygen transport. However, counteracting this, tissue oxy- ments. Moreover, different co-oximeters vary among each gen delivery is somewhat protected by a rightward shift other and can be quite different from gas chromatography, of the oxygen dissociation curve by decreasing the oxy- which is considered the “criterion” standard.10,11 The dis- gen affinity of the unaffected hemoglobin. The right- advantage with gas chromatography is the need for special- ward shift allows for easier oxygen unloading in tissues. ized equipment, time, and expertise. Presently, co-oximeters Although patients may have a similar percentage of he- are the most commonly used instruments for assessing moglobin effected as patients with methemoglobin- MetHb, with SulfHb known as a possible cause for errone- emia, patients with sulfhemoglobinemia have less se- ously elevated levels of methemoglobin, a phenomenon that vere clinical symptoms because of the difference in their can be pseudo-methemoglobinemia. effects on the oxygen dissociation curve. Sulfhemoglo- The cause for this interference has long been known. bin cannot be reconverted to normal hemoglobin, as Sulfhemoglobin has an absorption band very similar to

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 that of MetHb, about 620 µm. 4,12 Several techniques have Corresponding author: Richard D. Shih, MD, Morris- been used to differentiate SulfHb from MetHb spectro- town Memorial Hospital, Department of Emergency Medi- photometrically. One method uses the addition of cya- cine, 100 Madison Ave, Morristown, NJ 07962-1956 (e- nide to eliminate the MetHb absorption band peak (cya- mail: [email protected]). nide does not affect the SulfHb absorption band). Carbon monoxide can also be used for its ability to bind to SulfHb REFERENCES and not to MetHb. Finally, newer generation co-

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