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Intraoperative cyanosis: a case of dapsone-induced Warren Mayo ran FRC~, Kenneth Leighton rub FRCPC, Barbara Robertson biD FRCPC, John Ruedy raI~ FRCPC methaemoglobinaemia

Intraoperatlve cyanosls is most commonly caused by hypoxae- cigarette smoking. Allergies and the ingestion of any drug mia. The anaesthetist is required w perform a rapid series of prior to admission were denied by the patient and his diagnostic manoeuvres and take remedial action. Occasionally father. methaemogtobin, sulfhoemoglobin, or haemoglobin M, an. Physical exam revealed a well hydrated 15-year-old detec~ted preoperatieeiy, is the cause of the eyanosis. We report boy whose skin appeared somewhat grey, with a BP of a ease ofmethaemoglobinclemir secondary to dopsone ingestion 180/70, a pulse of 96 and a temperature of 38.0~ that was diagnosed intraoperatively. Dapsone, a sulfone, is used Abdominal examination was consistent with a diagnosis therapeutieally to treat leprosy and dermatitis herpetiforrnis. of acute appendicitis. The respiratory and cardiovascular The differential diagnosis of cyanosis, and the origin and fate systems werc normal. Thc laboratory data were Hb of methaemoglobin are discussed. In addition the diagnostic 15.0g.dl -~, WBC 15.2• 103/all, polymorphonuclear steps and the laboratory investigalions required to make the leukocytes 13.9 • 103/dl with the serum electrolytes, diagnosis are listed. BUN and creatinine all within normal limits. The patient was brought to the operating room and prior to induction he received d-tubocurare 3 mg and fenlanyl Cyanosig it a sign for which the anaesthetist must be alert. 100 txg~ A rapid-sequence induction technique was t~sed. Intraoperative eyanosis requires rapid and definitive Foltowing pro-oxygenation he was given thiopentone diagnostic manoeuvres to rule out hypoxaemia prior to 250mg and succinylcholine 100mg. Anaesthesia was considering more exotic causes. The following case maintained with isoflurane one per cent, nitrous oxide 66 illustrates the course of such an investigation. per cent, oxygen 33 per cent, and fentanyl 150 ~g. At the time of intubation there was an increase in BP to 185/90 Case report and pulse to 125 but these soon became steady at BP A 15-year-old boy from France, while attending an 130/80 pulse 80. The ventilator settings were: tidal international church conference, developed periumbilieal volume 800ml, rate nine per minute, with a peak pain. After 48 hours the pain localized to the right lower inspiratory pressure of 14 cm H20. quadrant and he was taken late at night to the emergency Following incision of the skin the surgeon commented department. A diagnosis of appendicitis was made. that the blood was "blue." The patient was then ventilated Intravenous fluids were started and he was given metroni- manually. The FtO~ was increased to 1.0. The chest was dazole 5(~0 rag, tobmmycin 60 rag, meperidine 50 mg and ausculated and its movement observed. The correct dimenhydrinate 50 rag. position of the tube in the larynx was confirmed visually. The patient gave a history of essential hypertension and The oxygen analyzer confirmed that 100 per cent oxygen was being delivered. The BP and pulse were unchanged. Arterial blood drawn for gas analysis was chocolate brown, with pH 7.39, PaCOz 37mmHg and PaO2 Key words 438 mmHg. A tentative clinical diagnosis of methaemo- COMPLICATIONS: cyanosis; BLOOD: methaemo- globinaemia was made. The appendectomy continued globinaemia; ANAESTHETICTECHNIQUES: general; uneventfully, with an FIO~ of 0.5. Mcthylene blue was PHARMACOLOGY: dapsone. not given because the BP and pulse were stable and the pH was normal. From the Department of Anaesthesia, Health Sciences Centre, The patient had an unremarkable postoperative course. University of British Columbia, and the Department of Blood sent intraoperatively revealed metbaemoglobin Medicine, St. Paul's Hospital, Vancouver, British Columbia. levels of 2.34 g.dl -I, confirming the clinical diagnosis. Address correspondence to: Dr. Warren Mayo, Department Two days later the methaemoglobin level had fallen to of Medicine, St. Paul's Hospital, 1081 Burrard Street, 0.32g'dl -~. As the methaemoglobin disappeared so did Vancouver, British Columbia V6Z IY6. the patient's grey complexion.

CAN J ANAESTH 1987 I 34: i / pp79-82 80 CANADIAN JOURNAL OF ANAESTHESIA

Investigations undertaken postoperatively to determine TABLE 11 Causesof hypoxaemiaduring anaesthesia the cause of the methaemoglobinaemia were: a G6PD Red,teed I"A 02 screening test, an oxygen dissociation curve, 2,3-DPG decreasedFI02 levels and NADH reduetase levels, all of whicla were decreasedalveolar walilation normal. Also no Hb M nor other abnormal haemoglobins were detected by haemoglobin electrophoresis. All three Normal P ,~ 02 of the patient's siblings had normal methaemoglobin diffusiondefect - rare anatomicshunt levels. ventilatioa-perfusiortinequalities A supplementary history was taken from the patient and increased'venous desataration - e.g., decreasedcardiac outpt.t, malig- his father. There had been no previous episodes of nant hyperthermia cyanosis or greyncss but eventually the father admitted that the boy had ingested approximately ten "pep pills" (French proprietary medicine containing belladonna) and neither a sensitive nor a reliable sign~'3 of hypoxaemia two 100 mg dapsone tablets the evening prior to admis- does not lessen the anaesthetist's responsibility to deter- sion to hospit~d. The dapsone had been supplied by a mine as rapidly as possible that he is delivering adequate European physician who worked in Africa with the church amounts of oxygen to the patient. Very quickly the groups. She had exhausted her supply of sulfa drugs flowmeters, oxygen monitor and integrity of the circuit which she normally used to treat diarrhoea and abdominal can be checked when eyanosis is recognized. The patient pain, and had substituted dapsone to treat the young man. should be taken off the ventilator and ventilated manually The patient made a satisfactory recovery and was while checking the spirometer, inspiratory pressures, and discharged seven days postoperatively. observing and aucultating the chest bilaterally. The endotracheal tube's correct position must also be verified.

Discussion The blood pressure, pulse and tempcrature of the patient Cyanosis may be peripheral or central. Peripheral cyano- should be measured. If all of the preceding investigations sis is due to reduced flow in the extremities, with are normal, only ventilation-peffusion inequalities, ana- subsequent desaturation. It is characteristically seen in the tomic shunts and diffusion defects remain as possible nailbeds and the nose. The arterial blood will be red. causes of hypoxaemia. The next step in the investigation Central cyanosis is observed in the mucous membranes of is direct measurement of the arterial Pad z. the mouth, the lips and the eonjuctiva. The arterial blood There are two other causes of deoxyhaemoglobin in will not he red. In the preceding case cyanosis was clearly excess of 5g-dl -t. The first, polycythaemia, can be seen in the operative field in the abdomen. determined with reference to the patient's preoperative The differential diagnosis of cyanosis is given in Table haemoglnhin. The second, and much rarer cause, is a low I. The most common cause of inU'aoperative cyanosis is affinity haemoglobin. These haemoglobin mutants have hypoxaemia. Causes of hypoxaemia during anaesthesia oxygen dissociation curves shifted to the right, e.g., Hb are listed in Table II. Kansas has a P3o of 70. This form of cyanosis should be It is generally accepted that cyanosis is apparent in the noticeable preoperatively.4 skin and mucous membranes when there is 5g.dl -t of Methaemoglobin is the haemoglobin molecule with the deoxyhaemoglobin present. I The fact that cyanosis is haeme moiety in the oxidized or ferric state. Normally less than 0.15 g.dl -t of haemoglobin is in this form and TABLE I Dilterenlialdiagnosis of cyanosis when methaemoglobin levels rise to 1.5 to 2.0g.dl -~ cyanosis can be detected clinically. Patients are often Deexyhaemoglobin hypoxaemia described as having a greyish hue and the aderial blood is polycythaemia chocolate brown in colour. 4 Symptoms do not usually Hb with increasedP~o occur until levels are above 4g'dl -I. To prevent accumulation of spontaneously occurring Methaemogtobinaemta methaemoglobin there are two enzymatic systems in vivo Congenital enzyme deficiency which are capable of reducing the methaemoglobin to - cytochromebz deficiency haemoglobin: - haemaglcbinM 1 NADH-methaemoglobin reduetase. This enzyme trans- Acquired fers an electron from NADH to the haeme using - toxic cytochrome bs as an electron carrier (Figure (A)). 2 NADPH-methaemoglobin reductase. This enzyme trans- Sulfltaemogtobmaemm fers an electron fl'om NADPH to the haeme but in vivo Mayo etal.: INTRAOPERATIVECYANOSIS: A CASE OF DAPSONE-INDUCEDMETHAEMOGLOBINAEMIA

accumulation of spontaneously occurring methaemoglo- | bin or the recently described 7 deficiency of cytochrome b5 which cripples the NADH-reductase system by not NADH \/CYTOCHROMEb5~ ,#Hb(Fe**) providing an electron cartier. These patients are described y (OXIDIZED) as being more blue than sick. 4's Acquired methaemoglobinaemia is the common form. MetHb-REDUCTASE Many chemical compounds and therapeutic agents are / known to directly or indirectly oxidize the haeme moiety. NAD ACYTOCHROMEb5 MetHb(Fe*§ An abbreviated list of the common problem agents is (REDUCED) given in Table III. The therapeutic agents commonly incriminated and encountered in anaesthetic practice are prilocaine, benzocaine, amyl nitrite, nitroglycerine, phe- | nacetin and sulfonamides. 6'9 Dapsone, which appears to have been the cause of the NADPHIMETHYLENEBLUE~Hb(Fe +*) methaemoglobinaemia in this case, is a sulfone used to treat leprosy and dermatitis herpetiformis and is well known to produce a dose related methaemoglobinaemia. The dose administered (200 mg) is well above the dose MetHb-REDUCTASE~. j~ which would produce methaemoglobinaemia, lo-13 Sulfhaemoglobinaemia is the final cause of cyanosis. It is a green pigmented molecule with a sulfur atom NADPP "LEUKOMETHYLENEz ' MetHb (Fe § incorporated in the porphyrin ring. It results from irre- BLUE versible oxidation of haemoglobin by drugs or chemicals. Many of the agents listed in Table III have this potential. It FIGURE Enzymaticsystems for the reductionof methaemoglobin is not understood why reversible methaemoglobin is to haemoglobin.(A) NADH-methaemoglobinreductase pathway- this pathway is the primary in vivo route for the reductionof methaemo- formed in some instances and irreversible sulfhaemo- globin. (B) NADPH-methaemoglobinreductase pathway - thispathway requiresan exogenouselectron carder such as methyleneblue. TABLE 111 Agentsimplicated in acquired methaemoglobinaemia

has no electron cartier. If methylene blue is added to the Direct oxidants system it acts as an electron carrier and the methaemo- globin is rapidly reduced (Figure (B)). Therapeutic agents Domestic and industrial agents Amyl nitrite Well waterhigh in nitrogen Patients who are symptomatic with methaemoglobi- Ethyl nitrite Food high in nitrates naemia can be treated with intravenous methylene blue. Sodiumnitrite Nitrousgases (arc welders,silo fillers) The initial dose should be 1 mg.kg- i over five minutes. If Ammoniumnitrate Coming extract no effect is seen in 30 to 60 minutes a repeat dose of Silver nitrate Potassiumchlorate 2mg.kg -t may be given. NADPH is required as an Bismuthsubnitrate electron donor for methylene blue to be converted to Nitroglycerine Quinones leukomethylene blue and in turn reduce the methaemoglo- bin (Figure (B)). Therefore methaemoglobinaemia pa- lndireetagents tients who have a deficiency of glucose-6-phosphate Sulfonamides Miscellaneous compounds dehydrogenase (G6PD) are unaffected by methylene Sulfamethazone Acetanilid blue. In addition methylene blue may initiate a haemolytic Sulfanilamide Aminobenzenes episode in G6PD-deficient individuals further embaras- Sulfapyridine Aminophenol sing their oxygen carrying capacity. ~4 Sulfathiazole Benzocaine Methaemoglobinaemia causing cyanosis can be either Prontosil Nitrobenzenes Nitrotoluenes congenital or acquired. Congenital methaemoglobinae- Aniline Dyes Phenacetin mia, which is rare, can be of three forms. A haemoglobin- Diaper markingink Phenazopyridine (pyridium) opathy in which an amino acid substitution in the Dyed blankets Phenylenediamine haemoglobin molecule creates an environment in which Laundry markings Prilocaine the haeme molecule is preferentially oxidized. The Freshlydyed shoes Resorcin Red wax crayons Toluenediamine modified haemoglobin is called haemoglobin M. A Triuitrotoluene deficiency of the NADH-reductase enzyme allowing the 82 CANADIAN JOURNAL OF ANA'ESTHtCSIA globin in others. Patients with sulfhaemoglobinaemia can attunes, 1. Methaemoglobinaemia, haemolysis and heinz be profoundly cyanosed but have minimal dyspnoea. body formation induced by 4,4-diaminodiphenylsulphone, This is because eyanosis can be detected at a blood level of Biochemical Pharmacology. 1965; 14:1119-28. 0.5 g.dl- L, lower than methaemoglobin (1.5-2.0 g.dl- ~) 12 Elonen E, Neuvonen P J, Halmekoski J, Malrila MJ. Acute or deoxyhaemoglobin (5.0g.dl-l), a and in addition, dapsone intoxication: a case with prolongezt symptoms. sulNaemoglobin moves the P50 of the oxygen-disoccia- Clinical Toxicology. 1979; 14: 79-85, tion curve to the right, enhancing oxygen delivery to the 13 Cooke TJL. Dapsone poisoning. Med J Australia. 1979; tissues) 5 The arterial blood is described as having a 1158-9. mauve or lavender hue. 4 14 Rosen PJ, Johnson C, McGehee W, Beutler E. Failure of When cyanozis is diagnosed intraoperatively the anaes- methylene blue treatment in toxic methemoglobinemia. Ann thetist must act quickly and decisively, A rapid set of Intern Mcd 1971; 75: 83-6. manoeuvres must be performed to rule out hypoxaemia. A 15 Park CM, Nagel RL. Sulfhemeglobiuemia-----cliniealand clear understanding of the differential diagnosis of cyano- molecular aspects. N Engl J Med. 1984; 310: 1579-84. sis in conjunction with several laboratory tests should then reveal the more exotic causes such as methaemoglobi- R~sum6 naemia. La cyanose intraop~ratoire est l~ plus soavent provoqude par l'hypox~mie. L'anesthOsiste est demand~ d'accomplir rapide- Acknowledgements meat nne sdrie de manoeuvres diagnostiques afin d'y rem~dier. The authors wish to thank the Haematology Department Occaxionnellement la mdth~moglobine, fa sulflldmoglobine ou of Vancouver General Hospital for performing the unusu- l' h~moglobine M, non ddtectg en pdriode prdopdratoire est ta al haematological tests and Dr. A. Mangal for his advice cause de cyanose. On rapporte le cos d' one mdthgmoglobiu~mie and assistance. Also we are greateful for the secretarial secondaire d l' ingestion de dapsone ayant dt~ diagnostiquge en help of Ruth Minchington. pdriode op~ratoire. Le dapsone, un suifone, est utilis~ ofin de traiter la ldpre et la dermatite herpdtiforme. Le diagnostic diffgrentiel de la cyanose ainsf que l' origine et le sort de la References mOthgmoglobine soot discords, En pl~ les manoeuvres diagnos- 1 Lundsgaard C, Van Slyke DD. Cyanosis. Medicine. 1923; tiques el I'inoestigation du laboratoire requis pour eonfirmer le 2: 1-76, diagnostic soot dnumlrdes. 2 ComroeJH. Bothelo S. The unreliability ofcyanosis in the recognition of arterial anoxernia. Am J Med Sciences. 1947; 47: 1-6, 3 Kelman GR. NnnnJF. Clinical recognition of hypoxaemi~ under fluorescent lamps. Lancet, 1966; 1: 1400-3, 4 Wintrobe MM. Clinical Hematology, 8th edition. Phila- delphia: Lea and Febiger, 198l: 1011-20. 5 Jaffe ER. Methemoglobincmia. Clinics in Hematology. 1981; 10: 99-122. 6 SmithRP. OlsonMW. Drug induced methemeglobinemia. Seminars in Hematology. 1973; 10: 253-68. 7 Hegcsh E. Hegesh ,1, Kaftory A. Congenital methemoglo- binemia with a deficiency ofcytochrome bs. N Engl J Med. 1986; 314: 757-61. 8 Gabel RA, Bunn HF. Hereditary methemoglobinemia as a cause of cyano~is during anesthesia. Anesthesiology. 1974; 40; 516-8. 9 Schmirter CR. Sulfhemoglobinemia and methemoglo- binemia - uncommon cause of eyanosis. Anesthesiology. 1975; 43: 586 7, 10 Manfredi G, De Panfilis G, Zampeoi M. Allegro F. Studies on dapsone induced haemolytie anaemia. Br J Derm, 1979; 100: 427-32. 11 Hjelm M, De Verdict CH. Biochemical effects of aromatic