Anaesthesia, 1979, Volume 34, pages 18 1-1 82 CASE R E P O R T
Potential hazard of methylene blue
J.G. WHITWAM. A.R. TAYLOR
Methylene blue (methylthionium chloride) has many uses in clinical practice. Administered locally it may be used for the detection of urological fistulae, demonstrating the patency of fallopian tubes or for the recognition of ruptured amniotic membranes in obstetrics. Injected systemically in low concentration, its reducing action is utilised in the treatment of methaemoglobinaemia. * However, in high concentration it is an oxidising agent and converts the ferrous ion of haemoglobin to the ferric state (i.e. methaem~globin).~ Increasingly, it is administered systemically to assist the detection of endocrine tissue at operation, e.g. the parathyroid glands4e5 and pancreatic adenomata. This case report demonstrates that, when used for this purpose, at the recommended dose of 5 mg/kg body weight, methylene blue can cause methaemoglobinaemia.
Case report Mr HS, a 28-year-old research physicist, suffered from episodes of ureteric colic in May 1970, and sustained hypercalcaemia was demonstrated. Subsequently three enlarged parathyroid glands were removed and histological examination revealed nodular hyperplasia. Four years later he developed intermittent hypoglycaemic episodes which were shown to be caused by inappropriate insulin secretion. Selective pan-
AND
J.M. WHITE
Table 1. Methaemoglobin levels (%) following infusion of methylene blue
Time (min) after injection 0 30 60
90 I20 180 (postop.)
Methaemoglobin (%) 0.6 1.2 4.3 5.8 7.1 4.2
creatic angiography demonstrated two probable pathological circulations within the pancreas and an exploratory laparotomy was undertaken during which methylene blue (500 mg) was administered intravenously to aid the identification of the suspected tumours. Two adenomata were enucleated from the head and neck of the pancreas and its tail, which contained two more adenomata, was also removed. Routine general anaesthesia was used starting with premedication administered intramuscularly (papaveretum 20 mg, hyoscine 0.4 mg, droperido1 5 mg) and continued with a thiopentone (350 mg), pancuronium (total dose 13 mg) nitrous oxide (70”/;,) oxygen (30%) fentanyl (total dose 0.6 mg) sequence. The relaxant was reversed with neostigmine (5.0 mg) and atropine (1.2 mg) and the patient made an uneventful recovery. Venous blood samples were taken at intervals into heparinised tubes and methaemoglobin
J.G. Whitwam, PhD, MRCP, FFARCS, Reader in Clinical Anaesthesia, Honorary Consultant Anaesthetist, A.R.
Taylor, FRCS, Wellcome Research Fellow and Tutor in Surgery, Honorary Senior Surgical Registrar, Royal Postgraduate Medical School, Hammersmith Hospital, Ducane Road, London W12 OHS, and J.M.White, MD, MRC Path, Professor of Haematology, King’s College Hospital, Denmark Hill, London SES. 0003-2409/79/0200-0181S02.00 01979 Blackwell Scientific Publications 181
182
J.G. Whitwam, A.R. Taylor andJ.M. White
levels were measured by the method of Evelyn & Malloy as modified by Dacie & Lewis.’ The results are shown in Table 1. A peak methaemoglobin level of 7.1 % occurred 2 hours after the methylene blue injection. There were no problems referable to the administration of methylene blue and a change in skin colour did not occur. Histological and histochemical studies confirmed insulin-secreting pancreatic adenomata with surrounding multiple microadenomatosis.
the identification of insulin secreting pancreatic adenomata, during surgery in a patient with normal haemoglobin and red cells, was associated with an increase in the methaemoglobin concentration from 0.6% to 7.1 %. In patients with unstable haemoglobins or abnormalities of the hexose monophosphate pathway the administration of large amounts of methylene blue is potentially dangerous. Key words
Discussion
In vivo, methylene blue forms an oxidationreduction system. In low concentration methylene blue is a reducing agent and converts methaemoglobin to haemoglobin by a catalytic action on methaemoglobin reductase (Diaphorase 11) in conjunction with the first step of the aerobic hexose monophosphate shunt pathway.** However, in high concentration the reverse occurs. The peak methaemoglobin level (7.1 %)in this patient indicates that there was a severe oxidative stress within the patient’s red cells during the relevant period. The patient’s weight was 105 kg so that the dose of methylene blue (500 mg) was within the recommended amount.’S6 Blood was not transfused until 30 min after the peak level of methaemoglobin occurred. In the absence of any other known factors it must be concluded that the production of methaemoglobin was caused by the administration of met hylene blue. This patient did not have an unstable haemoglobin or any defect of the hexose monophosphate shunt pathway. However, it would seem advisable that screening for the above defects should be performed in all patients in whom methylene blue is to be infused, as in some patients a potentially dangerous clinical situation could occur. Summary The administration of methylene blue to assist
BLOOD; methaemoglobinaemia, methylene blue. COMPLICATIONS ; methaemoglobinaemia. Acknowledgment The authors wish to thank Professor R.B. Welbourn, Department of Surgery, Royal Postgraduate Medical School for permission to publish this case report. References 1. COWETT, R.M., HAKANSON, D.O., KOCON,R.W. &
2. 3.
4. 5.
6. 7.
OH, w.(1976) Untoward neonatal effect of intramniotic administration of methylene blue. Obstetrics and Gynecology, 48, 74s. GRUCHY,G.C. DE (1970) Clinical Haematology in Medical Practice, 3rd edn, p. 731. Blackwell Scientific Publications, Oxford. RIEDERS,F. (1971) Noxious gases and vapours. 1: carbon monoxide, cyanides, methemoglobin, and sulfhemoglobin. In: Drill’s Pharmacology in Medicine. 4th edn (Ed. J.R. Di Palma), p. 949. McGrawHill, New York. DUDLEY, N.E. (1971) Methylene blue for rapid identification of the parathyroids. British Medical Journal, 3, 600. GORDEN,D.L., AIRAN,M.C., THOMAS, W. & SEIDMAN, L.H. (1975) Parathyroid identification by methylene blue infusion. British Journal of Surgery, 62, 747. GORDON,D.L., AIRAN,M.C. & SUVANICH, S. (1974) Visual identification of an insulinoma using methylene blue. British Journal of Surgery, 61, 363. DACIE. J.V. & LEWIS,S.M. (1975) Practical Haematology, 5th ed, p. 196. Churchill Livingstone. Edinburgh.
Potential hazard of methylene blue
J.G. WHITWAM. A.R. TAYLOR
Methylene blue (methylthionium chloride) has many uses in clinical practice. Administered locally it may be used for the detection of urological fistulae, demonstrating the patency of fallopian tubes or for the recognition of ruptured amniotic membranes in obstetrics. Injected systemically in low concentration, its reducing action is utilised in the treatment of methaemoglobinaemia. * However, in high concentration it is an oxidising agent and converts the ferrous ion of haemoglobin to the ferric state (i.e. methaem~globin).~ Increasingly, it is administered systemically to assist the detection of endocrine tissue at operation, e.g. the parathyroid glands4e5 and pancreatic adenomata. This case report demonstrates that, when used for this purpose, at the recommended dose of 5 mg/kg body weight, methylene blue can cause methaemoglobinaemia.
Case report Mr HS, a 28-year-old research physicist, suffered from episodes of ureteric colic in May 1970, and sustained hypercalcaemia was demonstrated. Subsequently three enlarged parathyroid glands were removed and histological examination revealed nodular hyperplasia. Four years later he developed intermittent hypoglycaemic episodes which were shown to be caused by inappropriate insulin secretion. Selective pan-
AND
J.M. WHITE
Table 1. Methaemoglobin levels (%) following infusion of methylene blue
Time (min) after injection 0 30 60
90 I20 180 (postop.)
Methaemoglobin (%) 0.6 1.2 4.3 5.8 7.1 4.2
creatic angiography demonstrated two probable pathological circulations within the pancreas and an exploratory laparotomy was undertaken during which methylene blue (500 mg) was administered intravenously to aid the identification of the suspected tumours. Two adenomata were enucleated from the head and neck of the pancreas and its tail, which contained two more adenomata, was also removed. Routine general anaesthesia was used starting with premedication administered intramuscularly (papaveretum 20 mg, hyoscine 0.4 mg, droperido1 5 mg) and continued with a thiopentone (350 mg), pancuronium (total dose 13 mg) nitrous oxide (70”/;,) oxygen (30%) fentanyl (total dose 0.6 mg) sequence. The relaxant was reversed with neostigmine (5.0 mg) and atropine (1.2 mg) and the patient made an uneventful recovery. Venous blood samples were taken at intervals into heparinised tubes and methaemoglobin
J.G. Whitwam, PhD, MRCP, FFARCS, Reader in Clinical Anaesthesia, Honorary Consultant Anaesthetist, A.R.
Taylor, FRCS, Wellcome Research Fellow and Tutor in Surgery, Honorary Senior Surgical Registrar, Royal Postgraduate Medical School, Hammersmith Hospital, Ducane Road, London W12 OHS, and J.M.White, MD, MRC Path, Professor of Haematology, King’s College Hospital, Denmark Hill, London SES. 0003-2409/79/0200-0181S02.00 01979 Blackwell Scientific Publications 181
182
J.G. Whitwam, A.R. Taylor andJ.M. White
levels were measured by the method of Evelyn & Malloy as modified by Dacie & Lewis.’ The results are shown in Table 1. A peak methaemoglobin level of 7.1 % occurred 2 hours after the methylene blue injection. There were no problems referable to the administration of methylene blue and a change in skin colour did not occur. Histological and histochemical studies confirmed insulin-secreting pancreatic adenomata with surrounding multiple microadenomatosis.
the identification of insulin secreting pancreatic adenomata, during surgery in a patient with normal haemoglobin and red cells, was associated with an increase in the methaemoglobin concentration from 0.6% to 7.1 %. In patients with unstable haemoglobins or abnormalities of the hexose monophosphate pathway the administration of large amounts of methylene blue is potentially dangerous. Key words
Discussion
In vivo, methylene blue forms an oxidationreduction system. In low concentration methylene blue is a reducing agent and converts methaemoglobin to haemoglobin by a catalytic action on methaemoglobin reductase (Diaphorase 11) in conjunction with the first step of the aerobic hexose monophosphate shunt pathway.** However, in high concentration the reverse occurs. The peak methaemoglobin level (7.1 %)in this patient indicates that there was a severe oxidative stress within the patient’s red cells during the relevant period. The patient’s weight was 105 kg so that the dose of methylene blue (500 mg) was within the recommended amount.’S6 Blood was not transfused until 30 min after the peak level of methaemoglobin occurred. In the absence of any other known factors it must be concluded that the production of methaemoglobin was caused by the administration of met hylene blue. This patient did not have an unstable haemoglobin or any defect of the hexose monophosphate shunt pathway. However, it would seem advisable that screening for the above defects should be performed in all patients in whom methylene blue is to be infused, as in some patients a potentially dangerous clinical situation could occur. Summary The administration of methylene blue to assist
BLOOD; methaemoglobinaemia, methylene blue. COMPLICATIONS ; methaemoglobinaemia. Acknowledgment The authors wish to thank Professor R.B. Welbourn, Department of Surgery, Royal Postgraduate Medical School for permission to publish this case report. References 1. COWETT, R.M., HAKANSON, D.O., KOCON,R.W. &
2. 3.
4. 5.
6. 7.
OH, w.(1976) Untoward neonatal effect of intramniotic administration of methylene blue. Obstetrics and Gynecology, 48, 74s. GRUCHY,G.C. DE (1970) Clinical Haematology in Medical Practice, 3rd edn, p. 731. Blackwell Scientific Publications, Oxford. RIEDERS,F. (1971) Noxious gases and vapours. 1: carbon monoxide, cyanides, methemoglobin, and sulfhemoglobin. In: Drill’s Pharmacology in Medicine. 4th edn (Ed. J.R. Di Palma), p. 949. McGrawHill, New York. DUDLEY, N.E. (1971) Methylene blue for rapid identification of the parathyroids. British Medical Journal, 3, 600. GORDEN,D.L., AIRAN,M.C., THOMAS, W. & SEIDMAN, L.H. (1975) Parathyroid identification by methylene blue infusion. British Journal of Surgery, 62, 747. GORDON,D.L., AIRAN,M.C. & SUVANICH, S. (1974) Visual identification of an insulinoma using methylene blue. British Journal of Surgery, 61, 363. DACIE. J.V. & LEWIS,S.M. (1975) Practical Haematology, 5th ed, p. 196. Churchill Livingstone. Edinburgh.
