Acute methemoglobinemia during cardiopulmonary bypass caused by intravenous nitroglycerin infusion

Volume 90 Number 6 December; 1985

mammary artery is a simple and effective operation

applicable to many cases of coarctation of the aorta. REFERENCES

2

3

4

5

Vossschuite K: Surgical correction of coarctation of the aorta by an "isthrnusplastic" operation. Thorax 16:338345, 1961 Moor GF, Ionescu MI, Ross DN: Surgical repair of coarctation of the aorta by patch grafting. Ann Thorac Surg 14:626-630, 1972 Reul GJ, Kabbani SS, Sandiford FM, Wukasch DC, Cooley DA: Repair of coarctation of the thoracic aorta by patch aortoplasty. J THORAC CARDIOVASC SURG 68:696704, 1974 Sade RM, Taylor AB, Chariker EP: Aortoplasty compared with resection for coarctation of the aorta in young children. Ann Thorac Surg 28:346-353, 1979 Heming WH, Sarafian LB, Clark EB, Dooley KJ, Hofschire PJ, Hopeman AR, Ruckman RN, Mooring PK: Critical aortic coarctation. Patch aortoplasty in infants less than age 3 months. Am J Cardiol 44:687-690, 1979 Craaford C, Nylin G: Congenital coarctation of the aorta and its surgical treatment. J THORAC CARDIOVASC SURG 14:347-361, 1945 Gross RE: Treatment of certain aortic coarctations by homologous grafts. Report of 19 cases. Ann Surg 134:753768, 1951 Blalock A, Park EA: Surgical treatment of experimental coarctation (atresia) of aorta. Ann Surg 119:445-456, 1944 Clagett OT: Surgical treatment of coarctation of the aorta. Mayo Clin Proc 23:359-360, 1948 Waldhausen JA, Nahrwold DL: Repair of coarctation of the aorta with a subclavian flap. J THORAC CARDIOVASC SURG 51:532-533, 1966 Bergdahl L, Ljungqvist A: Long-term results after repair of coarctation of the aorta by patch grafting. J THORAC CARDIOVASC SURG 80: 177-181, 1980

Brief communications

93 I

became severely cyanotic because of methemoglobinemia after intravenous infusion of nitroglycerin. His condition responded promptly and favorably to the withdrawal of the offending agent and to administration of methylene blue.

Severe cyanosis of the arterial blood during cardiopulmonary bypass is an alarming event, which usually indicates serious inadequacy of the extracorporeal circuit, such as misdirected conduits, oxygenator malfunction, or mismatched gas cylinders. The following report concerns a case in which severe cyanosis developed in the course of cardiopulmonary bypass but was caused not by faulty perfusion but by acute methemoglobinemia resulting from intravenous nitroglycerin therapy. The patient responded well and immediately to appropriate pharmacologic treatment. To my knowledge this is the first such reported complication occurring during a cardiac operation or any other operative procedure.

The case of a patient is presented who was undergoing coronary bypass grafting and who, during cardiopulmonary bypass,

Case report. A 60-year-old retired businessman was admitted to the Charlotte Memorial Hospital and Medical Center in November, 1984, because of unstable angina pectoris. His past history did not include any blood dyscrasia or allergy to drugs or any other substances. On admission, his medications consisted of isosorbide dinitrate* 20 mg four times a day, metoprolol tartrate] 50 mg four times a day, nifedipine:j: 20 mgr three times a day, dipyridamole§ 75 mgr three times a day, and nitroglycerin O.4lng as needed. On physical examination the color of his skin and mucous membranes appeared to be normal. Laboratory findings were also essentially normal with a hemoglobin level of 12.7 gm/IOO ml. A coronary angiogram revealed severe two-vessel disease for which surgical intervention was thought to be indicated. The patient was taken to the operating theater on November 19 where he was anesthetized and intubated endotracheally. No lubricants or topical anesthetics were applied during intubation. Substances used during induction and in the course of anesthesia are shown in Fig. 1. The exposure and cannulation of the heart took about an hour. During this period the color of the patient's face and exposed tissues remained normal. Just before the beginning of cardiopulmonary bypass and core cooling to 26°C, intravenous infusion of 15 mg nitroglycerin in 250 ml of 5% glucose, 1.5 ml/min, was started because of elevated systemic circulatory resistance and ST segmental changes on the electrocardiogram. About 15 minutes after the initiation of the nitroglycerin infusion, the color of the blood entering the patient from the oxygenator was noted to be turning gradually darker and darker. Immediate check of the equipment did not reveal any malfunction and changing the oxygen source failed to alleviate the cyanosis. Oxygen tension of the arterial blood at that point was 400 torr. On the suspicion that the cyanosis was due to methemoglobinemia, all medication was discontinued, blood samples were

This research made possible by a grant from the Heineman Medical Research Center of Charlotte, N. C.

tLopressor, Geigy Pharmaceuticals, Ardsley, N. Y.

6 7

8

9 10

11

Acute methemoglobinemia during cardiopulmonary bypass caused by intravenous nitroglycerin infusion Francis Robicsek, M.D., Charlotte, N. C. From the Department of Thoracic and Cardiovascular Surgery and the Heineman Medical Research Laboratory, Charlotte Memorial Hospital and Medical Center, Charlotte, N. C.

Address for reprints: Heineman Medical Research Center, P.O. Box 35457, Charlotte, N. C. 28235.

"Sorbitratc. Stuart Pharmaceuticals, Wilmington, Del. :j:Procardia, Pfizer Laboratories, New York, N. Y. §Persantine, Boehringer-Ingelheim, Ltd., Richfield, Conn.

The Journal 01 Thoracic and Cardiovascular

9 3 2 Brief communications

Surgery

---- Ancel morphine scopolamine --{ Volium

PREMEDICATION

------IF entanyl

BOcc

LPavulon

15mgs.

-

5mgs

lr=

2

3

4

Valium

nitroglycerin 15 mgs. in 250cc 5% gl. 0.5cc.lmin.

~ Ethrane

0.5%

~

20cc

-

Fentanyl

methylprednisolone 2 gms.

- - - - 0< -

16.5%

BLUE

I

nitroglycerin

- - - K CI

1.7%

CARDIOPULMONARY BYPASS

0.9%1 TIME IN HOURS

- { Pavulon -

METHEMOGLOBIN LEVEL

15 mgs. in

250cc 5%gl. 1.5CC.lm. in.

Fentanyl DEGREE OF CYANOSIS DURING

5

2 gms. 5 mgs. 0.3 mgs. 10 mgs.

30 mEq 10 cc 5 mgs.

methylene blue 1% 10cc -

CaCI.

700mgs.

protormne

250 mgs

MEDICATION

Fig. 1. Substances used during induction and in the course of anesthesia. Ancef; Smith Kline & French Laboratories, Philadelphia, Pa. Valium; Roche Laboratories, Nutley, N. J. Fentanyl; Janssen Pharmaceutica, Piscataway, N. J. Pavulon; Organon Pharmaceuticals, West Orange, N. J. Ethrane; Ohio Medical Anesthetics. drawn for methemoglobin level determination, and 100 mg of methylene blue was injected into the oxygenator. In about 10 minutes the arterial blood gradually turned bright red and the operation was completed without further incident. The levels of methemoglobin in the blood before the injection of methylene blue, half an hour later, and the morning after the operation were reported as 16.5%, 1.77%, and 0.9%, respectively. Methemoglobin reductase leveldetermined I week after the operation was within normal limits. The patient made an uneventful recovery and was discharged 7 days after the operation.

Discussion Methemoglobin is a derivative of reduced hemoglobin, which is formed whenever the heme iron atom is oxidized from the ferrous (Fe!") to ferric (Fe"?") state. The polypeptide chains are not altered. Unlike the ferrous atom, the ferric iron is incapable of reversibly binding oxygen; thus, it is useless in the body's normal oxygen transport. Methemoglobin is continuously formed in the blood in minute amounts but is kept physiologically in check by different enzyme systems

within the ertythrocyte.' At least four pathways. exist by which this may occur. Besides these pathways there are so-called "reserve" systems that may be activated, such as ascorbic acid, reduced gluthothione, and NADH methemoglobin reductase, the latter of which functions only in the presence of either natural cofactors or an auto-oxidizable dye, such as methylene blue.' Under normal circumstances the amount of methemoglobin in the body does not exceed 1% of the total circulating hemoglobin. Pathological increase above this level (methemoglobinemia) may develop either because of inefficiency of the body to reduce the hemoglobin formed in normal amounts (primary or hereditary form) or to increased production (secondary or acquired form). Whereas the primary form may occur because of either inborn deficiency of the redox-enzyme system present in the erythrocytes or because of abnormal structure of the hemoglobin molecule itself, the secondary or acquired type is almost always caused by poisoning with chemi-

Volume 90 Number 6 December, 1985

cals or drugs, which may be classified as either direct oxidants, such as nitrites, or as indirect oxidants, such as benzocaine. The latter group does not form methemoglobin in vitro but is presumably metabolized within the body to active agents.' Some of these substances elicit methemoglobinemia in phenotypically aberrant patients in usual doses, but most of the time no defmite distinction can be drawn between idiosyncrasy resulting from inherited traits and true side effects of the drug.' The physiological effects of methemoglobinemia are multiple and are similar to those accompanying hypoxia from other causes.' Because the oxidized Fe"'" complexes will not participate in oxygen transport, the oxygen content of the blood will drop. Furthermore, the Fe'" iron in the hemoglobin tetramer in the presence of methemoglobin has a stronger than usual bind to oxygen and will therefore shift the oxyhemoglobin-to-dissociation curve to the left.S Both of these phenomena impair tissue oxygenation. This is usually well tolerated in chronic forms of the disease in otherwise healthy individuals," who may be described as "more blue than sick,"? but not in acute situations, especially not by patients with ischemic myocardium. Regarding the diagnosis of methemoglobinemia, a high index of suspicion should be maintained in any situation in which cyanosis occurs in the presence of adequate oxygenation. The diagnosis of methemoglobinemia may also be strongly supported by the peculiar color of the patient's blood, which is chocolate-brown rather than dark blue. Confirmation can naturally be obtained by laboratory tests, primarily spectrophotometry, specific to methemoglobin. Acute methemoglobinemia occurring in the course of anesthesia is a rare situation and the handful of reports published relate almost exclusively to topical anesthetics and lubricants and involve infants and small children. 3, 8-10 Methemoglobinemia in connection with benzocaine sprays used during endotracheal intubation.v" as well as after administration of lidocaine," has also been reported in adults. Because none of these substances was used in our patients, I have to suppose that the offending agent was nitroglycerin given in high-dose infusion. Nitrites and nitrates, nitroglycerin among them, are well-recognized causes of methemoglobinemia. Nitroglycerin has been reported to cause methemoglobinemia in animals' and after toxic peroral doses.":" The intravenous form of this drug has recently become available for general use and, because of its ease of administration and well-documented efficiency, it became a commonly used drug in cardiac anesthesia. Methemoglobinemia after administration of intravenous nitroglycerin in the

Brief communications 9 3 3

recovery" and coronary care units" was previously reported, and it is likely that our case represents a similar event occurring in the operating room. Because our patient had taken peroral nitroglycerin preoperatively without becoming cyanotic, it is most probable that the intraoperative acute methemoglobinemia represents a true dose-related toxic episode. Acute cases of suspected methemoglobinemia occurring in the course of a cardiac operation should be treated immediately and energetically. As a first step, the offending agent should be removed. Because the agent seldom can be identified with absolute certaintly, all drugs that may cause methemoglobinemia should be immediately discontinued. These include the following: amyl nitrate, benzocaine, chlorates, hydralazine, lidocaine, methylene blue, nitroglycerin, nitroprusside, phenoielin, phenozopyridine, prilocaine, silver nitrate, sodium nitrate, and sulfonal. Next, the probability of methemoglobinemia should be established by confirming that oxygen delivery to the patient is indeed adequate and the arterial oxygen tension is maintained high. If the arterial oxygen tension is high indeed and cyanosis persists, blood samples should be drawn for methemoglobin determination, but pharmacologic treatment should begin even before fmal confirmation of the diagnosis. The drug of choice in the management of acute methemoglobinemia is methylene blue, 1 to 3 mg/kg, administered in a 1% solution' It acts as an electrontransporting substance that induces a tenfold increase in erythrocyte oxygen consumption, and in the presence of glucose it converts methemoglobin rapidly to active hemoglobin. Response to methylene blue is usually dramatic and complete. Because of its relatively innocuous nature, its application in hypercute cases should not be delayed until laboratory diagnosis. However, one must be careful, because overdosage (>7 mg/kg) may worsen methemoglobinemia and cause toxic symptoms." In the rare instance in which the patient fails to respond to methylene blue, such as in the case of glucose-6-phosphate dehydrogenase deficiency, the treatment should consist of high doses of vitamin C and, in the most severe cases, exchange transfusion. REFERENCES Harris JC, Rumock BH, Peterson RG, McGuire BM: Methemoglobinemia resulting from absorption of nitrates. JAMA 242:2869-2872, 1979 2 Douglas DA, Henry JB: Hematology and coagulation, Todd-Sanford-Davidson Clinical Diagnosis and Management by Laboratory Methods, JB Henry, ed., Philadelphia, 1979, W. B. Saunders Company, p 869

9 3 4 Brief communications

3 Sherman 1M Jr, Smith K: Methemoglobinemia owing to rectal-probe lubrication. Am 1 Dis Child 133:439-440, 1979 4 Smith RP, Olson MV: Drug induced methemoglobinemia. Semin Hematol 10:253-268, 1973 5 Gibson GR, Hunter lB, Raabe DS lr, Manjoney DL, Litteman FP: Methemoglobinemia produced by high-dose intravenous nitroglycerin. Ann Intern Med 96:615-616, 1982 6 Fono R, Forbath P, Robicsek F: Congenitalis familiaris methemoglobinemia. Orvosi Hetlilap 22:67-72, 1953 7 laffe E, Hsieh HS: DPNH-methemoglobin reductase deficiency and hereditary methemoglobinemia. Semin HematoI8:417-425,1971 8 Kelleti PB, Copeland CS: Methemoglobinemia associated with benzocaine containing lubricant. Anesthesiology 59:75-76, 1983 9 Steinberg lB, Lepernick RG: Methemoglobinemia during anesthesia. 1 Pediatr 61:885-886, 1955 10 O'Donohue W1 lr, Moss LM, Angelillo VA: Acute methemoglobinemia induced by topical benzocaine and lidocaine. Arch Intern Med 140:1508-1509, 1980

The Journal 01 Thoracic and Cardiovascular Surgery

11 Douglas WW, Fairbanks VF: Methemoglobin inducedby a topical anesthetic spray (Cetacaine). Chest 71:587-591, 1977 12 Deas TC: Severe metheglobinemia following dental extractions under lidocaine anesthesia. Anesthesiology 17:204, 1956 13 Geffner ME, Powars DR, Choctaw WT: Acquired methemoglobinemia. West 1 Med 134:7-10, 1981 14 Marshall lB, Ecklund RE: Methemoglobinemia from overdose of nitroglycerin (letter). lAMA 244:330, 1980 15 Fibuch EE, Cech WT, Reed W A: Methemoglobinemia associated with organic nitrate therapy. Anesth Analg 58:521-523, 1970 16 Zurich AM, Wagner RH, Starr Nl, Lytle B, Estefanous FG: Intravenous nitroglycerin, methemoglobinemia and respiratory distress in a postoperative cardiac surgical patient. Anesthesiology 61:464-466, 1984 17 Cartwright GE: Methemoglobinemia and sulfhemoglobinemia, Harrison's Principles of Internal Medicine, ed 8. GW Thorn, et ai, eds., New York, 1977, McGraw-Hill Book Company, Inc., pp 1710-1713