Symptoms - of the Disease

Fact Explanation
Introduction Methaemoglobinaemia is the presence of methaemoglobin more than 1% of the total haemoglobin concentration. This could be either congenital or acquired. The usual haemoglobin contains Ferous (Fe 2-) ion. In methaemoblobinaemia Ferric (Fe 3+) ion is present in one heme site. This heme with ferric ion has less binding capacity to oxygen and increases the affinity of oxygen on other 3 heme sites of the haemoglobin molecule. There by it reduces the release of oxygen at tissue site which leads tissue hypoxia. This leads the discoloration of the blood into blue or chocolate brown. when the methaemoglobin level reaches around 30%, cardiac and cerebral insufficiency occurs. If levels are >70% it is usually fetal. The sole pathophysiology of the disease is due to the increased oxidative stress in the haemoglobin molecule, which causes oxydation of ferus ion in to ferric. Under normal conditions the methaemoglobin is maintained below 1% by 2 important mechanisms. The first is hexose-monophosphate shunt pathway within the red cell. The other more important pathway has two enzyme systems named diaphorase I and diaphorase II, which in collaboration with NADH and NADPH reduce the methaemoglobin to the normal state. The diaporase I system with NADH is the major pathway in reducing methaemoglobin. The enzyme Cytochrome b5 reductase is involved in 90-95% for the process in that pathway playing a pivotal role. Diaphorase II system plays a minor role with NADPH by glutathione production and glucose-6-phosphate dehydrogenase (G6PD) to reduce the methaemoglobin. There for the alterations in those pathways either congenital or acquired could lead to accumulation of methaemoglobin. Congenital methaemoglobinaemia is rare and most cases are ith cytochrome b5 reductase defficiency. Acquired cases are mostly due to the exposure to certain drug and toxins mentioned below. Children below 4 months are specially susceptible to the disease due to primarily active NADH dependent pathway. Most congenital causes are autosomal recessive. Acquired cases may show slight male predominance due to X-linked pattern of G6PD deficiency [1][2][3]
Bluish discoloration (Cyanosis) Diffuse and persistent bluish discoloration is obvious since birth in congenital instances. Patient doesn't have features of cardiopulmonary diseases and otherwise healthy. Even 100% oxygen is unable to correct the cyanosis and it is very suggestive of the disease. In acquired acute methaemoglobinaemia also levels less than 15% will show only the discoloration without other symptoms. when the concentration increases it cause various symptoms due to lack of tissue perfusion to end organs. [1][2][4]
References
  1. REHMAN HU. Methemoglobinemia West J Med [online] 2001 Sep, 175(3):193-196 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1071541
  2. SACHDEVA R, PUGEDA JG, CASALE LR, MEIZLISH JL, ZARICH SW. Benzocaine-Induced Methemoglobinemia: A Potentially Fatal Complication of Transesophageal Echocardiography Tex Heart Inst J [online] 2003, 30(4):308-310 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC307717
  3. AVERY AA. Infantile methemoglobinemia: reexamining the role of drinking water nitrates. Environ Health Perspect [online] 1999 Jul, 107(7):583-586 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1566680
  4. BURKE P, JAHANGIR K, KOLBER MR. Dapsone-induced methemoglobinemia: Case of the blue lady Can Fam Physician [online] 2013 Sep, 59(9):958-961 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771723

Symptoms - of Complications

Fact Explanation
Palpitation, chest pain and syncope when the methaemoglobin level is around 50-70% significant cardiac insufficiency can happen which lead to severe arrhythmia and myocardial ischaemia due to the inadequate release of oxygen at myocardial level. [1][2][3][4][5]
Confusion and altered sensorium This happens when the methaemoglobin is around 50% due to the reduced oxygenation at brain level. [6][7]
Seizures and Coma when the methaemoglobin level further rises it causes further oxygen insufficiency and patients can present with seizures. when the culprit is persistent and the methaemoglobinaemia is persistent it could lead to comatose state. [6][7][8][9]
Features of metabolic acidosis Patient may complain confusion, shortness of breath, smelly breathing. This occurs due to the generalized hypoxic status. [3][9][10]
Death when the methaemoglobin levels are more than 70% death causes due to generalized hypoxia and above mentioned severe complications. [3][11][12]
References
  1. HAMIRANI YS, FRANKLIN W, GRIFKA RG, STAINBACK RF. Methemoglobinemia in a Young Man Tex Heart Inst J [online] 2008, 35(1):76-77 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2322912
  2. SU YF, LU LH, HSU TH, CHANG SL, LIN RT. Successful treatment of methemoglobinemia in an elderly couple with severe cyanosis: two case reports J Med Case Rep [online] :290 [viewed 29 December 2014] Available from: doi:10.1186/1752-1947-6-290
  3. REHMAN HU. Methemoglobinemia West J Med [online] 2001 Sep, 175(3):193-196 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC107154
  4. SACHDEVA R, PUGEDA JG, CASALE LR, MEIZLISH JL, ZARICH SW. Benzocaine-Induced Methemoglobinemia: A Potentially Fatal Complication of Transesophageal Echocardiography Tex Heart Inst J [online] 2003, 30(4):308-310 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC307717
  5. BURKE P, JAHANGIR K, KOLBER MR. Dapsone-induced methemoglobinemia: Case of the blue lady Can Fam Physician [online] 2013 Sep, 59(9):958-961 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771723
  6. AFZAL A, COLLAZO R, FENVES AZ, SCHWARTZ J. Methemoglobinemia precipitated by benzocaine used during intubation Proc (Bayl Univ Med Cent) [online] 2014 Apr, 27(2):133-135 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954671
  7. PATNAIK S, NATARAJAN MM, JAMES EJ, EBENEZER K. Methylene blue unresponsive methemoglobinemia Indian J Crit Care Med [online] 2014 Apr, 18(4):253-255 [viewed 29 December 2014] Available from: doi:10.4103/0972-5229.130582
  8. LARSON A, STIDHAM T, BANERJI S, KAUFMAN J. Seizures and methemoglobinemia in an infant after excessive EMLA application. Pediatr Emerg Care [online] 2013 Mar, 29(3):377-9 [viewed 29 December 2014] Available from: doi:10.1097/PEC.0b013e3182854790
  9. MIRAKBARI SM. Methylene blue unresponsive methemoglobinemia Indian J Crit Care Med [online] 2014 Jul, 18(7):483-484 [viewed 29 December 2014] Available from: doi:10.4103/0972-5229.136087
  10. TEJESH C, SHIVANNA S, MANJUNATH A, PRATHIMA P. ICU management of Methemoglobinemia due to unknown compound poisoning J Anaesthesiol Clin Pharmacol [online] 2013, 29(1):139-140 [viewed 29 December 2014] Available from: doi:10.4103/0970-9185.105835
  11. GOWANS WJ. Fatal methaemoglobinaemia in a dental nurse. A case of sodium nitrite poisoning. Br J Gen Pract [online] 1990 Nov, 40(340):470-471 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1371420
  12. HUNTER L, GORDGE L, DARGAN PI, WOOD DM. Methaemoglobinaemia associated with the use of cocaine and volatile nitrites as recreational drugs: a review Br J Clin Pharmacol [online] 2011 Jul, 72(1):18-26 [viewed 29 December 2014] Available from: doi:10.1111/j.1365-2125.2011.03950.x

Risk Factors

Fact Explanation
Family history Though the congenital methaemoglobinaemia is rare history of similar occurrence has to be explored. Other than that family history of G6PD deficiency has to be explored. G6PD deficiency is associated with methaemoglobinaemia due to the impaired funtion in diaphorase II pathway of ferric reduction. [1][2][3]
History of prematurity Premature infants and infants less than four months are more susceptible to the illness due to several factors. Their haemoglobin is easy to be oxidized, low level of NADH and bacterial infection associated acidity. [1][4]
History of exposure to a toxic substance or a drug The commonest aetiology for methaemoglobinaemia is exposure to a toxic agent which may impair one of the to pathways of ferric ion reduction. Exposure to such agent may cause gastro intestinal symptoms such as nausea, vomiting and diarrhoea. [1][2]
History of exposure to organic and inorganic nitrates or nitrites These include cardiac drug including GTN, ISMN and ISDN. Other than that drinking water which is contaminated with fertilizers and prepackaged food may also contain them and can lead to methaemoglobinaemia. So a such history has to be elicited. [1][5][6]
History of exposure to chlorates These chlorates are present in fungicides and explosive agents. [1][7]
History of exposure to local anaesthetic agents Local anaesthetics such as benzocaine, lignocaine has been reported to cause the illness especially when there is an underlying methaemoglobin reductase enzyme deficiency. Therefore history of invasive procedures such as gastro intestinal endoscopies, bronchoscopy, trans-oesophageal echo and surgeries under local anesthesia have to be asked from the patient. [8][9]
History of exposure to Dapsone Dapsone which is used to treat leprosy and and Pneumocystis jiroveci pneumonia also could lead to methaemoglobinaemia. Therefore a history of such illness or treating agent has to be asked. This drug has to be avoided in patients with G6PD deficiency. [1][10][11]
History of liver cirrhosis In patients with liver cirrhosis especially hen there is a bleeding there is a tendency to have methaemoglobinaemia due to the oxidative stress. [12]
Ingestion of partially cooked vegetables Inadequately cooked vegetables may contain bacteria and gives evidence of causing methaemogloginaemia. [13][14]
History of exposure to other culprit drug Following drug also could lead to methaemoglobinaemia. Anti-malarials, antibiotics (Sulfonamides, nitrofurans), Analgesics and antipyretics (paracetamol, celocoxib). [1][15][16]
References
  1. REHMAN HU. Methemoglobinemia West J Med [online] 2001 Sep, 175(3):193-196 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1071541
  2. TURNER MD, KARLIS V, GLICKMAN RS. The Recognition, Physiology, and Treatment of Medication-Induced Methemoglobinemia: A Case Report Anesth Prog [online] 2007, 54(3):115-117 [viewed 29 December 2014] Available from: doi:10.2344/0003-3006(2007)54[115:TRPATO]2.0.CO;2
  3. HASSAN KS, AL-RIYAMI AZ, AL-HUNEINI M, AL-FARSI K, AL-KHABORI M. Methemoglobinemia in an Elderly Patient with Glucose-6-Phosphate Dehydrogenase Deficiency: A Case Report Oman Med J [online] 2014 Mar, 29(2):135-137 [viewed 29 December 2014] Available from: doi:10.5001/omj.2014.33
  4. ORGERON JD, MARTIN JD, CARAWAY CT, MARTINE RM, HAUSER GH. Methemoglobinemia from eating meat with high nitrite content Public Health Rep [online] 1957 Mar, 72(3):189-193 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2031154
  5. AVERY AA. Cause of methemoglobinemia: illness versus nitrate exposure. Environ Health Perspect [online] 2001 Jan, 109(1):A12-A14 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1242065
  6. EDWARDS RJ, UJMA J. Extreme methaemoglobinaemia secondary to recreational use of amyl nitrite. J Accid Emerg Med [online] 1995 Jun, 12(2):138-142 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1342554
  7. BRADBERRY S, AW T, WILLIAMS N, VALE J. OCCUPATIONAL METHAEMOGLOBINAEMIA Occup Environ Med [online] 2001 Sep, 58(9):611-616 [viewed 29 December 2014] Available from: doi:10.1136/oem.58.9.611
  8. SACHDEVA R, PUGEDA JG, CASALE LR, MEIZLISH JL, ZARICH SW. Benzocaine-Induced Methemoglobinemia: A Potentially Fatal Complication of Transesophageal Echocardiography Tex Heart Inst J [online] 2003, 30(4):308-310 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC307717
  9. HEGEDUS F, HERB K. Benzocaine-induced Methemoglobinemia Anesth Prog [online] 2005, 52(4):136-139 [viewed 29 December 2014] Available from: doi:10.2344/0003-3006(2005)52[136:BM]2.0.CO;2
  10. BURKE P, JAHANGIR K, KOLBER MR. Dapsone-induced methemoglobinemia: Case of the blue lady Can Fam Physician [online] 2013 Sep, 59(9):958-961 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771723
  11. SINGH S, SETHI N, PANDITH S, RAMESH GS. Dapsone-induced methemoglobinemia: “Saturation gap”—The key to diagnosis J Anaesthesiol Clin Pharmacol [online] 2014, 30(1):86-88 [viewed 29 December 2014] Available from: doi:10.4103/0970-9185.125710
  12. GINIMUGE PR, JYOTHI SD. Methylene Blue: Revisited J Anaesthesiol Clin Pharmacol [online] 2010, 26(4):517-520 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3087269
  13. MANASSARAM DM, BACKER LC, MESSING R, FLEMING LE, LUKE B, MONTEILH CP. Nitrates in drinking water and methemoglobin levels in pregnancy: a longitudinal study Environ Health [online] :60 [viewed 29 December 2014] Available from: doi:10.1186/1476-069X-9-60
  14. SIMUNANIEMI AM, ANDERSSON A, NYDAHL M. Fruit and vegetable consumption close to recommendations. A partly web-based nationwide dietary survey in Swedish adults Food Nutr Res [online] :10.3402/fnr.v53i0.2023 [viewed 29 December 2014] Available from: doi:10.3402/fnr.v53i0.2023
  15. GHARAHBAGHIAN L, MASSOUDIAN B, DIMASSA G. Methemoglobinemia and Sulfhemoglobinemia in Two Pediatric Patients after Ingestion of Hydroxylamine Sulfate West J Emerg Med [online] 2009 Aug, 10(3):197-201 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2729224
  16. LIU H, DING Y, WALKER LA, DOERKSEN RJ. Effect of antimalarial drug primaquine and its derivatives on the ionization potential of hemoglobin: A QM/MM study Medchemcomm [online] 2013 Aug 1, 4(8):1145-1147 [viewed 29 December 2014] Available from: doi:10.1039/C3MD00045A

Signs - of the Disease

Fact Explanation
Discoloration of the skin and mucosa Due to the higher concentration of methaemoglobin in blood the colour of the skin and mucosa may be bluish or chocolate brown. This would be the distinguishing feature for diagnosis. when the methaemoglobin concentration is more than 1.5 g/dl it may manifest as cyanosis. when the patient is having anaemia the discoloration may not be obvious. Therefore the color of conjunctiva has to be checked at the same time for pallor. Cyanosis may be obvious in mucosa and nose, cheeks, fingers, toes. The patient may not be clinically in relation to the level of cyanosis. As a hallmark in methaemoglobinaemia in the absence of cardiopulmonary disease the cyanosis can't be corrected by oxygen replacement in compared to deoxygenated haemoglobin causing cyanosis. [1][2]
Evidence of congenital malformation Congenital methaemoglobinaemia is known to be associated with skeletal deformities and mental retardation, therefore the mental examination and thorough skeletal examination has to be done. [1][3]
Eye examination During eye examination cyanosis and pallor may be obvious. Other than that there may be conjunctival epitheliopathy which is also known to associate with congenital methaemoglobinaemia. [4]
References
  1. REHMAN HU. Methemoglobinemia West J Med [online] 2001 Sep, 175(3):193-196 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1071541
  2. TURNER MD, KARLIS V, GLICKMAN RS. The Recognition, Physiology, and Treatment of Medication-Induced Methemoglobinemia: A Case Report Anesth Prog [online] 2007, 54(3):115-117 [viewed 29 December 2014] Available from: doi:10.2344/0003-3006(2007)54[115:TRPATO]2.0.CO;2
  3. KATSUBE T, SAKAMOTO N, KOBAYASHI Y, SEKI R, HIRANO M, TANISHIMA K, TOMODA A, TAKAZAKURA E, YUBISUI T, TAKESHITA M, SAKAKI Y, FUKUMAKI Y. Exonic point mutations in NADH-cytochrome B5 reductase genes of homozygotes for hereditary methemoglobinemia, types I and III: Putative mechanisms of tissue-dependent enzyme deficiency Am J Hum Genet [online] 1991 Apr, 48(4):799-808 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1682939
  4. CHAURASIA S, RAMAPPA M, BHARGAVA A. Corneal epitheliopathy in congenital methemoglobinemia. Cornea [online] 2014 Apr, 33(4):422-4 [viewed 29 December 2014] Available from: doi:10.1097/ICO.0000000000000076

Signs - of Complications

Fact Explanation
Initially vital parameters has to assess Due to the high concentration of methaemoglobin patient may be having compromised cardiac, respiratory or neurology. GCS, pulse rate, pulse regularity, blood pressure, conscious level, saturation and pattern of breathing with smell of the breath (acidosis can be present) have to be assessed at the emergency department. [1]
Thorough cardiovascular examination There may be arrhythmias and myocardial ischaemia due to myocardial hypoxia. The pulse examination with the rate, regularity and character has to assess. Blood pressure has to see. Evidence of heart failure; increased JVP, basal crepitation, tender hepatomegaly, pedal edema has to be elicited. Precordial examination should be done to any murmurs and cardiac anomaly. Congenital heart diseases can be associated with congenital methaemoglobinaemia. [1][2][3]
Respiratory examination Respiratory pattern, respiratory rate, lung examination has to be carried out. when the acidosis is associated due to severe hypoxia patient may have acidotic smell with acidotic pattern of breathing. Asthma may be a differential diagnosis. [1][2][4]
Neurological examination The patient may be comatose, may be impaired conscious or confuse. The level of consciousness has to be assessed. Patient may have a seizure, type has to be differentiated. Patient may have injuries following a seizure such as tongue bite. Full neurology examination of cranial nerves, cerebellar signs, upper and lower limb examination has to be carried out to elicit any focal deficiency of neurology. These neurological events are due to the cerebral hypoxia which is due to the high concentration of methaemoglobin. [1][5]
References
  1. REHMAN HU. Methemoglobinemia West J Med [online] 2001 Sep, 175(3):193-196 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1071541
  2. AWASTHY N, KHAN N, RADHAKRISHNAN S. Methemoglobinemia: Arterial blood gas as a diagnostic tool Indian Heart J [online] 2014 May, 66(3):394-395 [viewed 29 December 2014] Available from: doi:10.1016/j.ihj.2014.03.019
  3. HAMIRANI YS, FRANKLIN W, GRIFKA RG, STAINBACK RF. Methemoglobinemia in a Young Man Tex Heart Inst J [online] 2008, 35(1):76-77 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2322912
  4. TASCI C, NEVRUZ O, CANDIR N, BILGIC H. A methemoglobinemia case who was previously diagnosed and treated as asthma Respir Med Case Rep [online] :11-12 [viewed 29 December 2014] Available from: doi:10.1016/j.rmcr.2012.08.002
  5. HUNTER L, GORDGE L, DARGAN PI, WOOD DM. Methaemoglobinaemia associated with the use of cocaine and volatile nitrites as recreational drugs: a review Br J Clin Pharmacol [online] 2011 Jul, 72(1):18-26 [viewed 29 December 2014] Available from: doi:10.1111/j.1365-2125.2011.03950.x

Differential Diagnoses

Fact Explanation
Cardio-respiratory diseases causing cyanosis Diseases such as cyanotic congenital heart diseases, right to left shunts, pulmonary hypoxia may cause cyanosis with deoxygenated haemoglobin more than 5g/dl. In Methaemoglobinaemia hallmark is the unresponsive cyanosis even for the high flow of oxygen in the absence of any cardio-pulmonary aetiology for cyanosis. In respiratory diseases cyanosis is usually corrected by oxygen. But in cases of large right to left shunt the cyanosis may persist even with oxygen. Further investigations may be necessary in doubtful cases as discussed in next section. [1][2]
Sulfhaemoglobinaemia This also could lead to bluish discoloration of the skin and mucosa which is not responding to oxygen therapy. The exposure to sulfa containing agents and further investigations may differentiate the to condition. [2][3]
Ingestion of blue/ash colour dyes ; eg: Methylene blue Ingestion of colour containing dyes such as methylene blue also give a cyanotic appearance which is resistant to oxygen therapy. The history may give the idea of such diagnosis. [4]
Anaemia Symptomatic anaemia also causes features such as dizziness, headache, myocardial ischaemia, stroke according to the severity. Clinically the patient may be pale and may find a obvious cause for anaemia in history and examination. Full blood count ill diagnose the anaemia and blood picture with further investigation may arrive to a diagnosis. [2][5]
Heart failure Patients with heart failure also will present with similar symptoms. Patient may have had previous events or history of ischaemic heart disease. On examination JVP may be elevated with basal crepitation, pedal oedema and tender hepato megaly. Xray finding with 2D echocardiogram, BNP will conclude the diagnosis. [2][6]
Acute asthma Acute asthma may also present with cyanosis and breathing difficulty with evidence of hypoxia. The patient with asthma may give a similar exacerbation history with improvement to the bronchodilators. On examination rhonchi may be auscultated. Cyanosis in acute severe asthma may improve with the treatment with bronchodilators and oxygen. [7]
Pulmonary embolism Patient may give a history suggestive of deep vein thrombosis with provocating factors and sudden onset shortness of breath. Similar history may be present with cyanosis in severe cases. ECG may or not show the typical features. D-Dimer levels support the diagnosis, venous duplex with CTPA conclude the diagnosis.[3][6]
References
  1. STEINHORN RH. Evaluation and management of the cyanotic neonate Clin Pediatr Emerg Med [online] 2008 Sep, 9(3):169-175 [viewed 29 December 2014] Available from: doi:10.1016/j.cpem.2008.06.006
  2. REHMAN HU. Methemoglobinemia West J Med [online] 2001 Sep, 175(3):193-196 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1071541
  3. GHARAHBAGHIAN L, MASSOUDIAN B, DIMASSA G. Methemoglobinemia and Sulfhemoglobinemia in Two Pediatric Patients after Ingestion of Hydroxylamine Sulfate West J Emerg Med [online] 2009 Aug, 10(3):197-201 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2729224
  4. GINIMUGE PR, JYOTHI SD. Methylene Blue: Revisited J Anaesthesiol Clin Pharmacol [online] 2010, 26(4):517-520 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3087269
  5. MALKARNEKAR SB, ANJANAPPA R, NAVEEN L, KIRAN BG. Acute methemoglobinemia with hemolytic anemia following bio-organic plant nutrient compound exposure: Two case reports Indian J Crit Care Med [online] 2014 Feb, 18(2):115-117 [viewed 29 December 2014] Available from: doi:10.4103/0972-5229.126089
  6. SACHDEVA R, PUGEDA JG, CASALE LR, MEIZLISH JL, ZARICH SW. Benzocaine-Induced Methemoglobinemia: A Potentially Fatal Complication of Transesophageal Echocardiography Tex Heart Inst J [online] 2003, 30(4):308-310 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC307717
  7. HEATH TS, BURROUGHS Z, THOMPSON AJ, TECKLENBURG FW. Acute Intoxication Caused by a Synthetic Cannabinoid in Two Adolescents J Pediatr Pharmacol Ther [online] 2012, 17(2):177-181 [viewed 30 December 2014] Available from: doi:10.5863/1551-6776-17.2.177

Investigations - for Diagnosis

Fact Explanation
Bed side test When exposed to air the colour of the normal venous blood will improve from black to red. In contrast with methaemoglobinaemia colour will not change and remain chocolate brown. Kronenberg’s “red-brown” test uses this phenomenon a drop of patient's blood on a filter paper and comparing its color change with a drop of normal venous blood while exposed to air. This test is simple and carried out as a bedside test, but it's subjective [1]
Arterial blood gas The calculated saturation of the blood through the arterial blood gas may be falsely normal in methaemoglobinaemia. This is called "saturation gap" [2][3][4]
Co-oximetry This is the method of spectrophotometry which is the key to diagnose methaemoglobianemia. It can differentiate, methaemoglobinaemia, carboxy-haemoglobin, deoxy-haemoglobin and even sulfhaemoglobin. This is based of the relative absorbance of different ave lengths of light. [5][6]
Pulse oxymetry This can be used to see the approximate saturation of blood. But in case of methaemoglobinaemia the saturation may be falsely lo in pulse oximeter. The patient may not be significantly ill in relation to the saturation. In cardiac and respiratory diseases the patient is clinically ill related to the saturation. [7][8]
Specific enzyme assay Specific enzyme assays such as NADH dependent reductase, cytochrome b5 reductase can be performed. [9][10]
To exclude haemolysis Full blood count, blood picture, billirubin level, LDH level can be performed to see any ongoing haemolysis in the patient. [11][12]
Serum levels of offending drug and toxins The serum levels of possible culprit drug and toxins can be performed even though not essential for the diagnosis [13]
Potassium cyanide test Methaemoglobin reacts with cyanohaemoglobin and causes change in the colour. But sulfhaemoglobin doesn't react with it and doesn't lead to a colour change. [5][14]
ECG, Chest Xray and 2D echocardiogram These tests are better done even in uncomplicated cases just to exclude cardio-respiratory causes of cyanosis. [6][14][15]
References
  1. CANNING J, LEVINE M. Case Files of the Medical Toxicology Fellowship at Banner Good Samaritan Medical Center in Phoenix, AZ: Methemoglobinemia Following Dapsone Exposure J Med Toxicol [online] 2011 Jun, 7(2):139-146 [viewed 30 December 2014] Available from: doi:10.1007/s13181-011-0151-9
  2. AWASTHY N, KHAN N, RADHAKRISHNAN S. Methemoglobinemia: Arterial blood gas as a diagnostic tool Indian Heart J [online] 2014 May, 66(3):394-395 [viewed 29 December 2014] Available from: doi:10.1016/j.ihj.2014.03.019
  3. TEJESH C, SHIVANNA S, MANJUNATH A, PRATHIMA P. ICU management of Methemoglobinemia due to unknown compound poisoning J Anaesthesiol Clin Pharmacol [online] 2013, 29(1):139-140 [viewed 29 December 2014] Available from: doi:10.4103/0970-9185.105835
  4. SINGH S, SETHI N, PANDITH S, RAMESH GS. Dapsone-induced methemoglobinemia: “Saturation gap”—The key to diagnosis J Anaesthesiol Clin Pharmacol [online] 2014, 30(1):86-88 [viewed 29 December 2014] Available from: doi:10.4103/0970-9185.125710
  5. GHARAHBAGHIAN L, MASSOUDIAN B, DIMASSA G. Methemoglobinemia and Sulfhemoglobinemia in Two Pediatric Patients after Ingestion of Hydroxylamine Sulfate West J Emerg Med [online] 2009 Aug, 10(3):197-201 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2729224
  6. SACHDEVA R, PUGEDA JG, CASALE LR, MEIZLISH JL, ZARICH SW. Benzocaine-Induced Methemoglobinemia: A Potentially Fatal Complication of Transesophageal Echocardiography Tex Heart Inst J [online] 2003, 30(4):308-310 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC307717
  7. JUBRAN A. Pulse oximetry Crit Care [online] 1999, 3(2):R11-R17 [viewed 29 December 2014] Available from: doi:10.1186/cc341
  8. HAMIRANI YS, FRANKLIN W, GRIFKA RG, STAINBACK RF. Methemoglobinemia in a Young Man Tex Heart Inst J [online] 2008, 35(1):76-77 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2322912
  9. KATSUBE T, SAKAMOTO N, KOBAYASHI Y, SEKI R, HIRANO M, TANISHIMA K, TOMODA A, TAKAZAKURA E, YUBISUI T, TAKESHITA M, SAKAKI Y, FUKUMAKI Y. Exonic point mutations in NADH-cytochrome B5 reductase genes of homozygotes for hereditary methemoglobinemia, types I and III: Putative mechanisms of tissue-dependent enzyme deficiency Am J Hum Genet [online] 1991 Apr, 48(4):799-808 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1682939
  10. BORGESE N, PIETRINI G, GAETANI S. Concentration of NADH-cytochrome b5 reductase in erythrocytes of normal and methemoglobinemic individuals measured with a quantitative radioimmunoblotting assay. J Clin Invest [online] 1987 Nov, 80(5):1296-1302 [viewed 29 December 2014] Available from: doi:10.1172/JCI113205
  11. AU WY, NGAI CW, CHAN WM, LEUNG RY, CHAN SC. Hemolysis and methemoglobinemia due to hepatitis E virus infection in patient with G6PD deficiency Ann Hematol [online] 2011 Oct, 90(10):1237-1238 [viewed 29 December 2014] Available from: doi:10.1007/s00277-011-1167-6
  12. HASSAN KS, AL-RIYAMI AZ, AL-HUNEINI M, AL-FARSI K, AL-KHABORI M. Methemoglobinemia in an Elderly Patient with Glucose-6-Phosphate Dehydrogenase Deficiency: A Case Report Oman Med J [online] 2014 Mar, 29(2):135-137 [viewed 29 December 2014] Available from: doi:10.5001/omj.2014.33
  13. MANASSARAM DM, BACKER LC, MOLL DM. A Review of Nitrates in Drinking Water: Maternal Exposure and Adverse Reproductive and Developmental Outcomes Environ Health Perspect [online] 2006 Mar, 114(3):320-327 [viewed 29 December 2014] Available from: doi:10.1289/ehp.8407
  14. REHMAN HU. Methemoglobinemia West J Med [online] 2001 Sep, 175(3):193-196 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1071541
  15. SAXENA H, PRAKASH SAXENA A. Acute methaemoglobinaemia due to ingestion of nitrobenzene (paint solvent) Indian J Anaesth [online] 2010, 54(2):160-162 [viewed 29 December 2014] Available from: doi:10.4103/0019-5049.63635

Investigations - for Management

Fact Explanation
Full blood count and blood picture As mentioned above it ill give the idea about three cell lines including anaemia and haemolysis. In cyanotic cardiorespiratory diseases there will be a polycythaemia. [1][2]
ECG Arrhythmias and myocardial ischaemia may occur due to impaired oxygen delivery to the myocardium, which ill show the ischaemic changes and evidence of arrythmia. [3]
Arterial blood gas analysis (ABG) In emergency situation ABG has to perform to see the saturation as well as the acidosis which has to be corrected if significant. [4]
Serum electrolytes and renal function Serum creatine levels with electrolytes has to be assessed to see background renal status and also to see the evidence of end organ damage. [1]
Chest xray and 2D echocardiogram This is to see any cardio-respiratory causes leading to the presentation and also to see the complications due to methaemoglobinaemia [3]
Brain imaging Patients with cerebral complications may present with seizures or strokes. In that situations cerebral imaging with CT and MRI has to be carried out.[5]
References
  1. REHMAN HU. Methemoglobinemia West J Med [online] 2001 Sep, 175(3):193-196 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1071541
  2. MALKARNEKAR SB, ANJANAPPA R, NAVEEN L, KIRAN BG. Acute methemoglobinemia with hemolytic anemia following bio-organic plant nutrient compound exposure: Two case reports Indian J Crit Care Med [online] 2014 Feb, 18(2):115-117 [viewed 29 December 2014] Available from: doi:10.4103/0972-5229.126089
  3. SAXENA H, PRAKASH SAXENA A. Acute methaemoglobinaemia due to ingestion of nitrobenzene (paint solvent) Indian J Anaesth [online] 2010, 54(2):160-162 [viewed 29 December 2014] Available from: doi:10.4103/0019-5049.63635
  4. AWASTHY N, KHAN N, RADHAKRISHNAN S. Methemoglobinemia: Arterial blood gas as a diagnostic tool Indian Heart J [online] 2014 May, 66(3):394-395 [viewed 29 December 2014] Available from: doi:10.1016/j.ihj.2014.03.019
  5. HUNTER L, GORDGE L, DARGAN PI, WOOD DM. Methaemoglobinaemia associated with the use of cocaine and volatile nitrites as recreational drugs: a review Br J Clin Pharmacol [online] 2011 Jul, 72(1):18-26 [viewed 29 December 2014] Available from: doi:10.1111/j.1365-2125.2011.03950.x

Management - General Measures

Fact Explanation
Emergency management Patients may come to the emergency department with methaemoglobinaemia. The initial suspicion and the diagnosis is the paramount importance. Investigations with FBC, ECG, ABG has to be carried out. In the emergency department the most important management is oxygen supplementation and avoiding causative toxic agents. If a history of ingestion of a such toxic agent is present activated charcoal therapy, gastric lavarge may be needed. Any arhythmia has to be treated promptly with trying to correct the aetiology. Severe acidosis has to be treated ith IV sodium bicarbonate. Asymptomatic patients who are having chronic exacerbation can be discharged following observation provided that there is know complication or end organ damage. [1][2]
Health education The patient should be educated about the illness with specific consideration on possible toxic drug and other agents. Patients with G6PD deficiency has to have and special consideration on those as they are more prone to have the illness due to culprit agents. Patient also should be educated about the reason of extensive investigations to exclude other diagnosis. Patients should be thoroughly emphasized on the lethal complications of the disease such as arrhythmias, myocardial infarctions, seizures and strokes. [1][3][4]
Avoidance of culprit agents The avoidance of culprit agents will be drug such as nitrates, dapsone, benzocaine, lignocaine. On day to day living patient should be explained about exacerbation of the diseases due to ingestion of water polluted with fertilizers and ingestion of some partially cooked vegetables. [1][5][6][7]
References
  1. REHMAN HU. Methemoglobinemia West J Med [online] 2001 Sep, 175(3):193-196 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1071541
  2. SACHDEVA R, PUGEDA JG, CASALE LR, MEIZLISH JL, ZARICH SW. Benzocaine-Induced Methemoglobinemia: A Potentially Fatal Complication of Transesophageal Echocardiography Tex Heart Inst J [online] 2003, 30(4):308-310 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC307717
  3. HASSAN KS, AL-RIYAMI AZ, AL-HUNEINI M, AL-FARSI K, AL-KHABORI M. Methemoglobinemia in an Elderly Patient with Glucose-6-Phosphate Dehydrogenase Deficiency: A Case Report Oman Med J [online] 2014 Mar, 29(2):135-137 [viewed 29 December 2014] Available from: doi:10.5001/omj.2014.33
  4. GHATAK T, PODDAR B, BARONIA AK. Dapsone Induced Methemoglobinemia and Hemolysis in a G6PD Deficient Girl, Possibly Aggravated by Aggressive Methylene Blue Therapy Indian J Dermatol [online] 2013, 58(5):410 [viewed 29 December 2014] Available from: doi:10.4103/0019-5154.117360
  5. KWOK S, FISCHER JL, ROGERS JD. Benzocaine and lidocaine induced methemoglobinemia after bronchoscopy: a case report J Med Case Reports [online] :16 [viewed 29 December 2014] Available from: doi:10.1186/1752-1947-2-16
  6. FEWTRELL L. Drinking-Water Nitrate, Methemoglobinemia, and Global Burden of Disease: A Discussion Environ Health Perspect [online] 2004 Oct, 112(14):1371-1374 [viewed 29 December 2014] Available from: doi:10.1289/ehp.7216
  7. BURKE P, JAHANGIR K, KOLBER MR. Dapsone-induced methemoglobinemia: Case of the blue lady Can Fam Physician [online] 2013 Sep, 59(9):958-961 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771723

Management - Specific Treatments

Fact Explanation
Intravenous methylene blue injection This is the first line treatment in symptomatic ill patients with the illness. Dose can be repeated as needed to control the symptoms not exceeding the maximum dose. Methylene blue it self is an oxidant and have to be administered with caution. It is best avoided in patients with G6PD deficiency. [1][2][3]
Exchange transfusion In patients refractory to Methylene blue injection or in patients with G6PD deficiency exchange transfusion is a second line option. This will remove the methaemoglobin. [3][4][5]
Hyperbaric oxygen treatment This is also used as a second line treatment modality in resistant cases and in patients with G6PD deficiency. This permits the transport of oxygen to the end organs in dissolved states in the plasma rather than through haemoglobin. [6][7]
IV hydration with 5% Dextrose Patients with deficient NADPH pathway may be benefited with dextrose.[8]
Oral methylene blue, ascorbic acid, riboflavin and cimetidine Patients with mild methaemoglobinaemia due to enzyme deficiency may be benefited from long term oral therapy with such medications. Cimetidine will reduce the metobolites of dapsone and thereby the tendency to have methaemoglobinaemia. [4][9][10]
References
  1. SACHDEVA R, PUGEDA JG, CASALE LR, MEIZLISH JL, ZARICH SW. Benzocaine-Induced Methemoglobinemia: A Potentially Fatal Complication of Transesophageal Echocardiography Tex Heart Inst J [online] 2003, 30(4):308-310 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC307717
  2. GINIMUGE PR, JYOTHI SD. Methylene Blue: Revisited J Anaesthesiol Clin Pharmacol [online] 2010, 26(4):517-520 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3087269
  3. MIRAKBARI SM. Methylene blue unresponsive methemoglobinemia Indian J Crit Care Med [online] 2014 Jul, 18(7):483-484 [viewed 29 December 2014] Available from: doi:10.4103/0972-5229.136087
  4. REHMAN HU. Methemoglobinemia West J Med [online] 2001 Sep, 175(3):193-196 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1071541
  5. GEORGE T, SHAIKH AI, THOMAS L, KUNDAVARAM AP. Severe methemoglobinemia due to insecticide poisoning Indian J Crit Care Med [online] 2014 Feb, 18(2):113-114 [viewed 29 December 2014] Available from: doi:10.4103/0972-5229.126087
  6. SAIDI H, SHOKRANEH F, GHAFOURI HB, SHOJAIE S. Effects of hyperbaric oxygenation on survival time of aluminum phosphide intoxicated rats J Res Med Sci [online] 2011 Oct, 16(10):1306-1312 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3430020
  7. PATNAIK S, NATARAJAN MM, JAMES EJ, EBENEZER K. Methylene blue unresponsive methemoglobinemia Indian J Crit Care Med [online] 2014 Apr, 18(4):253-255 [viewed 29 December 2014] Available from: doi:10.4103/0972-5229.130582
  8. SAXENA H, PRAKASH SAXENA A. Acute methaemoglobinaemia due to ingestion of nitrobenzene (paint solvent) Indian J Anaesth [online] 2010, 54(2):160-162 [viewed 29 December 2014] Available from: doi:10.4103/0019-5049.63635
  9. GEORGE T, SHAIKH AI, THOMAS L, KUNDAVARAM AP. Severe methemoglobinemia due to insecticide poisoning Indian J Crit Care Med [online] 2014 Feb, 18(2):113-114 [viewed 29 December 2014] Available from: doi:10.4103/0972-5229.126087
  10. COLEMAN MD, RHODES LE, SCOTT AK, VERBOV JL, FRIEDMANN PS, BRECKENRIDGE AM, PARK BK. The use of cimetidine to reduce dapsone-dependent methaemoglobinaemia in dermatitis herpetiformis patients. Br J Clin Pharmacol [online] 1992 Sep, 34(3):244-249 [viewed 29 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1381395