Anesthetic management of a patient with methemoglobinemia.

Clinicians, especially those who are involved in anesthesia, surgery, and critical care, devote a significant proportion of their time to worrying about oxygen delivery in their patients. This is a simple function of cardiac output, hemoglobin concentration, and saturation. Most consideration is given to optimizing cardiac output and oxygenation, because saturated hemoglobin "always" carries 1.34 ml [O.sub.2/g]. The article by Groeper et al (1) on page 504 of this issue of Southern Medical Journal serves as an important reminder that all may not be what it seems. The presence of methemoglobin or a similar dysfunctional hemoglobin species may render simple clinical assumptions invalid. (2) Hereditary hemoglobinopathies include abnormal hemoglobins: sickling disorders, unstable hemoglobins, abnormal oxygen affinities, and methemoglobins (hemoglobins M), disorders of hemoglobin chain production ([alpha] and [beta] thalassemias), and methemoglobinemias due to nicotinamide adenine dinucleotide diaphorase deficienc y. (3) Acquired hemoglobinopathies are those due to sulfhemoglobinemia, methemoglobinemia, and carboxyhemoglobinemia. (3)

As admirably presented by Groeper, Katcher and Tobias, (1) methemoglobinemia can further complicate what would otherwise be the administration of a routine high-risk anesthetic. The particular cause of methemoglobinemia that they describe--namely, after dapsone therapy--will become increasingly common because dapsone is also used for the prophylaxis of Pneumocystis carinii pneumonia in immunocompromised patients such as those receiving chemotherapy for cancer or, increasingly, patients who are being treated for human immunodeficiency virus infection. (4)

Even when recognized and treated appropriately, methemoglobinemia may be lethal. A few years ago, at another center where I worked, two cases of methemoglobinemia were seen within a few weeks of each other. Both anesthetics followed awake intubation facilitated by the liberal use of 20% benzocaine spray. Despite early therapy with methylene blue, one of the two patients had a permanent cerebrovascular accident. Methylene blue itself is not innocuous, because it may cause significant reactions, including anaphylaxis.

Pulse oximetry is inaccurate in the presence of methemoglobinemia. Because the absorbance of methemoglobin is similar at 660 and 940 nm, it diminishes the difference between the alternating signal at both wavelengths, and the computed ratio, "R" tends toward unity, which corresponds to oxygen saturation for hemoglobin of 85%. This is in spite of the fact that the true saturation may be much less. On the other hand the pulse oximeter is probably the most useful early indicator of a problem despite its inaccuracy. The patient in Groeper et al's (1) article and both of the cases mentioned above were diagnosed by a clinically inappropriate pulse oxygen saturation (Sp[O.sub.2]), which was then appropriately investigated with arterial blood gas analysis when the usual maneuvers did not help.

Awareness of the potential for drug-induced methemoglobinemia is probably the most important lesson to take from this discussion. Many drugs have been implicated in this process, including local anesthetics; vasodilators, including nitroglycerin and nitroprusside infusions; analgesics, such as phenacetin and acetaminophen; and antimicrobials, such as sulfanilamide, chloroquine, and dapsone. (4) Arguably, the drugs most commonly implicated as causing methemoglobinemia are the two local anesthetics prilocaine and benzocaine. Prilocaine was introduced into obstetric analgesia as a safe alternative to lidocaine but was discovered to cause cyanosis as a result of methemoglobinemia. (5) Several clinical studies followed, (6,7) and injectable prilocaine has mostly disappeared from clinical anesthesia. It is still used, however, in dental anesthesia (8) and is a component of EMLA (lidocaine-prilocaine topical; AstraZeneca, Wilmington, DE). Benzocaine is currently used as a major component of topical analgesic agents , sprays, and teething gels. (9) After the two cases at my former hospital, the use of benzocaine was abandoned, as it was after another incident reported by Kuschner et al. (10)

Two worrying aspects to the methemoglobin formation induced by topical benzocaine and injectable prilocaine are, first, the delay between the use of the drug and the appearance of sentinel cyanosis and, second, the propensity of benzocaine-induced methemoglobinemia to return many hours later. Dinneen et al (11) described the development of cyanosis in a patient 55 minutes after esophagoduodenoscopy facilitated by 20% benzocaine spray. Dinneen et al also described complete resolution in another patient who required vitamin C therapy 12 hours after exposure. (11) Another case report described cyanosis and methemoglobinemia that developed 30 minutes after awake intubation, requiring repeat treatment 3 hours and again 20 hours after the administration of topical benzocaine.

These reports and others like them demonstrate the delayed and continued risk that the administration of topical benzocaine represents. Perhaps this benzocaine and dental prilocaine complication maybe significantly underrecognized and underreported because the patient has either left the outpatient facility by the time cyanosis develops or the patient was initially so critical that the delayed development of cyanosis is ascribed to worsening of the primary disease process. Interestingly, several authors (12-14) have quoted a 1 in 7,000 incidence of the development of methemoglobinemia on the basis of just one case report by Douglas and Fairbanks (15) in 1977 after 7,000 previous, apparently uneventful topical uses. This case report and series was published at least 7 years before the introduction of the pulse oximeter. Hence, the true incidence of cyanosis and methemoglobinemia after the administration of topical benzocaine may be much higher than previously assumed. In my institution, lidocaine spray and fl avored oral solution have almost completely replaced benzocaine when the Department of Anesthesiology is performing with endoscopy. This is due more to better conditions for endoscopy than to a perceived need to avoid the possible development of methemoglobinemia.

Methemoglobin, in either the congenital or the acquired form, presents an often unrecognized and potentially life-threatening challenge for the patient. Because even recognition and prompt treatment of methemoglobinemia may not prevent an unfortunate outcome, any center that currently administers topical benzocaine as needed must carefully consider monitors and protocols with the goal of preventing unfortunate outcomes.

Accepted February 10, 2003.

References

(1.) Groeper K, Katcher K, Tobias JD. Anesthetic management of a patient with methemoglobinemia. South Med J 2003;96:504-509.

(2.) Motulsky AG, Stamatoyannopoulos G. Drugs, anesthesia and abnormal hemoglobins. Ann N Y Acad Sci 1968;151:807-821.

(3.) Beutler E. Disorders of hemoglobin, in Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Martin JB, Kasper DL, et al (eds): Harrison's Principles of Internal Medicine. New York, McGraw-Hill, 1998, vol 1, ed 14, pp 645-652.

(4.) Sprung J, Bourke DL, Mackenzie CF, Thomas P. Chronic methemoglobinemia: Improving hemoglobin saturation monitoring during anesthesia. J Clin Monit 1994;10:267-269.

(5.) Onji Y, Tyuma I. Methemoglobin formation by a local anesthetic and some related compounds. Acta Anaaesthesiol Scand Suppl 1965;16:151-159.

(6.) Spoerel WE, Admason DH, Eberhard RS. The significance of methaemoglobinaemia induced by prilocaine (Citanest). Can Anaesth Soc J 1967;14:1-10.

(7.) Arens JF, Carrera AE. Methemoglobin levels following peridural anesthesia with prilocaine for vaginal deliveries. Anesth Analg 1970;49:219-222.

(8.) Wilburn-Goo D, Lloyd LM. When patients become cyanotic: Acquired methemoglobinemia. J Am Dent Assoc 1999;130:826-831.

(9.) Rodriguez LF, Smolik LM, Zbehlik AJ. Benzocaine-induced methemoglobinemia: Report of a severe reaction and review of the literature. Ann Pharmacother 1994;28:643-649.

(10.) Kuschner WG, Chitkara RK, Canfield J Jr, Poblete-Coleman LM, Cunningham BA, Sarinas PS. Benzocaine.associated methemoglobinemia following bronchoscopy in a healthy research participant. Respir Care 2000;45:953-956.

(11.) Dinneen SF, Mohr DN, Fairbanks VF. Methemoglobinemia from topically applied anesthetic spray. Mayo Clin Proc 1994;69:886-888.

(12.) Wurdeman RL, Mohiuddin SM, Holmberg MJ, Shalaby A. Benzocaine-induced methemoglobinemia during an outpatient procedure. Pharmacotherapy 2000;20:735-738.

(13.) Cooper HA. Methemoglobinemia caused by benzocaine topical spray. South Med J 1997;90:946-948.

(14.) Khan NA, Kruse JA. Methemoglobinemia induced by topical anesthesia: A case report and review. Am J Med Sci 1999;318:415-418.

(15.) Douglas WW, Fairbanks VF. Methemoglobinemia induced by a topical anesthetic spray (cetacaine). Chest 1977;71:587-591.

From the Division of Anesthesiology, Critical and Palliative Care, Department of Anesthesiology, M.D. Anderson Cancer Center, Houston, TX.

Reprint requests to Peter H. Norman, MD, Division of Anesthesiology, Critical and Palliative Care, Department of Anesthesiology, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 42, Houston, TX 770302956. Email: [e-mail]

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