Case Discussion < Presentation of Case > 　　A 36-year-old man was sent to the Emergency Department (ED) at this hospital because of gradual onset of nausea, decreased urine output, dyspnea, and consciousness disturbance for 3 days. At ED, high blood pressure (192/110 mmHg) was noted along with azotemia, oliguria and hyperkalemia that were refractory to medical treatment (see laboratory results). Hypertensive emergency or uremia was impressed and he was immediately admitted to the intensive care unit (ICU) for emergent hemodialysis and blood pressure control. 　　 He had been diagnosed as having type 1 diabetes mellitus 22 years earlier before this evaluation, but with poor adherence to medications prescribed. His average glycated hemoglobin (HbA1c) was around 70 mmol/ml (approximately equivalent to DCCT [The Diabetes Control and Complications Trial)- HbA1c 8.5%] when he was followed as an outpatient at this hospital, and retinopathy and impaired renal function had been noted since 7 years earlier (see laboratory results). 　　 During the ICU stay, the hemodialysis was performed for 3 consecutive days, followed by thrice a week. The hemodialysis session was uneventful and dyspnea caused by metabolic acidosis resolved gradually. After the 4th session of hemodialysis, he was found to have cyanosis and desaturation (SaO2: 85 to 87% while he was breathing ambient air) but he did not report worsening dyspnea. An arterial blood gas analysis while he was breathing 40% supplemental oxygen revealed PaO2 of 110 mmHg with an oxygen saturation of 96%. His hemoglobin level at that time was 11 g/dl (see laboratory results). 　　 The physical examination revealed a well-developed man (body mass index, 25 kg/m2) with ill-looking. The heart rate was 78 beats per minute, the temperature was 36.8°C, and the blood pressure was 148/84 mmHg. Conjunctiva was pick and sclera was anicteric. Remarkable cyanosis of the lips and fingers was noted. There was no palpable lymph nodes at the neck or axilliary region. The heart beat was regular without murmur. Auscultation of the lung fields revealed mild crackles at the bibasilar regions of the lungs. Abdomen examination was unremarkable. Leg edema in resolution was noted. < Laboratory and Image Study > 1. CBC and differential count Day after admission WBC K/μL Hgb g/dL MCV fL MCHC % Hct % Plt K/μL Band % Seg % Lym % OPD (7 years earlier) 7.62 13.5 91 35 39.9 350 N/A N/A N/A ED 7.62 7.5 90 34 24.8 250 0 78 3 Development of cyanosis 7.62 11 91 32 33.6 330 N/A N/A N/A Post methylene blue treatment 7.68 11.2 92 33 33.8 320 N/A N/A N/A N/A: not applicable 2. Biochemistry Day after admission BUN mg/dl Cre mg/dl Na mmol/l K mmol/l Ca mg/dl P mg/dl GOT U/l GPT U/l Sugar mg/dl HbA1C % Albumin g/dl OPD (7 years earlier) 34 2.5 137 4.2 10.5 3.8 35 34 140 8.7 3.8 ED 108 11.2 130 6.4 9.8 5.6 30 32 220 8.4 3.5 Development of cyanosis 60 7.2 137 4.6 N/A N/A N/A N/A 120 N/A N/A Post methylene blue treatment 63 7.1 136 4.6 10.4 4.8 N/A N/A 138 N/A N/A 3. Urinalysis Date Appearance Specific gravity pH Protein (mg/dl) Glucose Ketone Occult blood OPD (7 years earlier) yellow, clear 1.01 6.5 30 mg/dl + -- -- ED yellow, mildly turbid 1.012 6.5 100 mg/dl + + 1+ Date Urobilinogen Bilirubin RBC WBC Epithelial cells Cast Crystal OPD (7 years earlier) 0.1 -- <5 <5 <5 -- -- ED 0.1 -- 5-10 5-10 <5 waxy cast -- 4. Arterial blood gas analysis Date PH paO2(mmHg) paCO2(mmHg) HCO3-(mEq/L) ED 7.12 120 (40% O2) 29 17 Development of cyanosis 7.37 110 (40% O2) 39 23 Post methylene blue treatment 7.37 110 (40% O2) 37 24 5. Renal sonography: Both kidneys are mildly enlarged (right/left: 13.5/13.8 cm in the long axis) without cystic lesion or mass, or hydronephrosis of both kidneys; and hyper-echogenecity of the renal cortex was noted. Those findings are consistent with parenchymal renal disease. < Course and Treatment > 　　Because of the findings of maintained O2 saturation, arterial O2 pressure, and adequate Hb level and lack of the respiratory distress in the presence of cyanosis, methemoglobinemia was suspected. The diagnosis was confirmed by elevated blood methemoglobin level, 7.8% of hemoglobin (normal 0-3% of hemoglobin). He was treated with methylene blue 1 mg/kg administered by parenteral route and a repeat methemoglobin level 30 minutes after treatment was 2.1% of hemoglobin. After further review of his family history and medication history, no predisposing factor was noted. Since the chloramine that may remains in the water system was occasionally reported to be the cause of methemoglobinemia, we measured methemoglobin levels before and after hemodialysis session, which was 5.6% and 3.3%, respectively. The finding suggested that chloramine remaining in the water supply for hemodialysis was causative for methemoglobinemia in this patient. After new carbon adsorption columns were used, the methemoglobinemia level in this patient was in the normal range before and after each session during his stay in the ICU. < Analysis > 　　紅血球有4個hemoglobin，每個hemoglobin又帶有4個heme。正常情況下，每個heme以Fe2+(ferrous state)的形式存在，但當hemoglobin攜帶的鐵離子因某些原因使Fe2+被氧化成Fe3+(ferric state)時，此時的hemoglobin稱之為methemoglobin(變性血紅素)。由於methemoglobin無法與氧氣結合，所以methemoglobinemia的病患會出現組織氧氣供應不足的症狀，尤其是高需氧的系統如心血管及中樞神經系統，會最早受到影響。依據血中methemoglobin比例不同可出現如頭痛、呼吸困難、疲倦、頭暈、嗜睡、意識狀態改變甚至死亡。 　　 由於紅血球對抗氧化的機制(NADH system)在孩童並不成熟，因此臨床上methemoglobinemia多好發於孩童，尤其小於四個月大的嬰幼兒又是其中的高好發群。Methemoglobinemia可分為先天性(如NADH methemoglobin reductase (diaphorase I) deficiency、pyruvate kinase deficiency及Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency，蠶豆症)等)或後天性，而後天性多由藥物造成(Table 1)或化學物質(如aniline、nitrite、nitrate與nitrobenzene等)。由於臨床上常見之致命者多為後天性，因此，在此將只討論後天性之methemoglobinemia。基本上，臨床症狀與methemoglobin濃度有關，但正常人血中還是可檢驗出methemoglobin，約為1% (0-3%)。一般而言，當血中methemoglobin佔全部hemoglobin的3-15%時，皮膚顏色會改變，可為藍色或灰色。通常皮膚顏色改變是最起初被注意到的表現。當methemoglobin比例為15-20%時，病患通常仍無症狀，但會開始出現cyanosis。與deoxygenated hemoglobin造成的cyanosis相比，deoxygenated hemoglobin要高達5 g/dL才會出現cyanosis，但methemoglobin血中濃度只要約1.5 g/dL時即可出現。當methemoglobin比例為25-50%時，則會出現虛弱無力、頭暈、嗜睡、胸悶及昏厥(syncope)等症狀；50-70%時可出現心律不整、意識狀態改變、瞻妄、癲癇及至昏迷。而當methemoglobin比例大於70%以上，則可能死亡。但是要是病患本身有其他心血管及中樞神經系統疾病，即使methemoglobin的濃度較低，仍可提早出現症狀甚至造成死亡。 　　 臨床上一旦已排除其他心肺疾病導致的cyanosis，且懷疑methemoglobinemia時，第一步是先停止可疑的藥物(Table 1)及視情況進行dermal decontamination或GI decontamination，接者給予病患氧氣，試著提升組織供氧，並抽血檢驗arterial blood gas及血中methemoglobin的濃度。在單純無其它併發症methemoglobinemia病患，以傳統的pulse oximetry測量methemoglobinemia病患的O2 saturation，在低濃度的methemoglobinemia時，pulse oximetry會低估病患的O2saturation；但在高濃度的methemoglobinemia時，pulse oximetry反而會高估病患的O2 saturation。而在arterial blood gas中，PaO2是正常的，但若組織缺氧嚴重，則還可能見到metabolic acidosis。所以，臨床上若病患出現cyanosis，但無明顯呼吸窘迫；O2saturation下降，但arterial oxygen tension正常時，就一定要高度懷疑methemoglobinemia。一般正常人血中methemoglobin濃度約為1% (0-3%)，只要臨床懷疑加上血中methemoglobin濃度上升，就可診斷為methemoglobinemia了。 　　 治療方面主要是依症狀決定，除了視情況進行dermal decontamination或GI decontamination，並給予病患氧氣外，在健康無末端器官受損(end-organ damage)之病患，只需觀察即可。但若病患本身已有心血管疾病或肺部疾病、或已有末端器官受損，即使methemoglobin濃度仍低，也要考慮直接給予治療。Hemoglobin在釋放氧氣時，可能同時失去電子，形成methemoglobin，但因還原酵素NADH-cytochrome b5 reductase的存在，使體內之methemoglobin，可維持在1%以下，但此反應十分緩慢。另外可利用第一線用藥，methylene blue(甲烯藍)，以加速NADPH-methemoglobin reductase之還原作用，進而減少methemoglobin。Methylene blue初始劑量為1-2 mg/kg，以葡萄糖溶液稀釋後緩慢靜脈注射(大於5 min)，療效約在20分鐘到1小時內出現，必要時可重覆給予。若病患接受高劑量的methylene blue注射，反而可能加重methemoglobinemia (所謂的paradoxical methemoglobinemia)，這也是使用methylene blue最主要的副作用。當病患有禁忌症而無法使用methylene blue，或因使用methylene blue而產生副作用時，則可考慮替代性療法如高壓氧或換血，至於vitamin C則並未被證明具有療效。Methylene blue使用的禁忌症包括G6PD deficiency、重度腎功能障礙、已知NADPH-methemoglobin reductase enzymatic pathway酵素缺陷及正在使用MAO (monoamine oxidase)-A inhibitor的病患，因為有報告指出methylene blue與MAO-A inhibitor交互作用可造成serotonin syndrome。 　　 此病患可能是因為活性碳管柱故障或效能下降，導致水中的chloramine在體內蓄積引起methemoglobinemia，經更換管柱及methylene blue治療後已完全恢復。 < References > Am J Kidney Dis. 2002;39:1307-1309. Kidney International. 2010;78:327–328. 臨床醫學 2006; 57: 105-11. Medscape reference (http://emedicine.medscape.com) 繼續教育考題 1. (C) 關於methemoglobinemia的描述，何者不正確？ A 可為遺傳性 B 因hemoglobin攜帶的Fe2+被氧化成Fe3+ C 與hemoglobin相比具較強的氧氣結合力 D 較好發生於孩童 2. (A) 關於methemoglobinemia的描述，何者不正確？ A 健康正常人血中都驗不出methemoglobin (0%) B 好發於孩童是因紅血球對抗氧化的機制(NADH system)在孩童並不成熟 C 臨床上常見之致命者多為後天性 D 臨床症狀與methemoglobin濃度有關 3. (D) 關於methemoglobinemia臨床症狀的說明，何者不正確？ A 臨床症狀與methemoglobin濃度有關 B 皮膚顏色改變是最起初被注意到的表現 C 有心血管及中樞神經系統疾病的病患，在較低的濃度methemoglobin時，就可能提早出現症狀 D 在無心血管及中樞神經系統疾病的病患，因methemoglobin濃度升高而出現cyanosis時，都會伴隨明顯的呼吸窘迫 4. (B) 臨床上關於何時需懷疑methemoglobinemia的說明，何者不正確？ A 有家族史 B 腎功能嚴重異常易導致methemoglobinemia C 病患出現cyanosis，但無明顯呼吸窘迫；O2 saturation下降，但arterial oxygen tension正常 D 門診病患主訴使用dapsone後皮膚顏色改變，但無自覺呼吸症狀 5. (A) methemoglobinemia治療的說明，何者不正確？ A 治療方面主要是依methemoglobin濃度決定 B 第一步是先停止可疑的藥物、視情況進行decontamination及給予氧氣 C 第一線用藥為methylene blue，替代性性療法如高壓氧或換血 D 使用methylene blue治療前需詢問家族病史，尤其在台灣需注意G6PD deficiency 6. (D) 何謂paradoxical methemoglobinemia？ A 病患無症狀但血中methemoglobin比例超過30% B 病患有症狀但血中methemoglobin比例低於15% C 腎功能異常導致的methemoglobin檢驗誤差 D 病患若接受高劑量的methylene blue注射，反而加重methemoglobinemia 答案解說 ( C ) 當hemoglobin攜帶的鐵離子因某些原因使Fe2+被氧化成Fe3+(ferric state)時，此時的hemoglobin稱之為methemoglobin(變性血紅素)。由於methemoglobin無法與氧氣結合，所以methemoglobinemia的病患會出現組織氧氣供應不足的症狀，尤其是高需氧的系統如心血管及中樞神經系統，會最早受到影響。依據血中methemoglobin比例不同可出現如頭痛、呼吸困難、疲倦、頭暈、嗜睡、意識狀態改變甚至死亡。由於紅血球對抗氧化的機制(NADH system)在孩童並不成熟，因此臨床上methemoglobinemia多好發於孩童，尤其小於四個月大的嬰幼兒又是其中的高好發群。Methemoglobinemia可分為先天性(如NADH methemoglobin reductase (diaphorase I) deficiency、pyruvate kinase deficiency及G6PD deficiency [蠶豆症]等)或後天性，而後天性多由藥物造成(Table 1)或化學物質(如aniline、nitrite、nitrate與nitrobenzene等)。 ( A ) 由於紅血球對抗氧化的機制(NADH system)在孩童並不成熟，因此臨床上methemoglobinemia多好發於孩童，尤其小於四個月大的嬰幼兒又是其中的高好發群。Methemoglobinemia可分為先天性(如NADH methemoglobin reductase (diaphorase I) deficiency、pyruvate kinase deficiency及G6PD deficiency等)或後天性，而後天性多由藥物造成(Table 1)或化學物質(如aniline、nitrite、nitrate與nitrobenzene等)。臨床上常見之致命者多為後天性。基本上，臨床症狀與methemoglobin濃度有關，但正常人血中還是可檢驗出methemoglobin，約為1% (0-3%)。 ( D ) 基本上，臨床症狀與methemoglobin濃度有關。一般而言，當血中methemoglobin佔全部hemoglobin的3-15%時，皮膚顏色會改變，可為藍色或灰色。通常皮膚顏色改變是最起初被注意到的表現。當methemoglobin比例為15-20%時，病患通常仍無症狀，但會開始出現cyanosis；當methemoglobin比例為25-50%時，則會出現虛弱無力、頭暈、嗜睡、胸悶及昏厥(syncope)等症狀；50-70%時可出現心律不整、意識狀態改變、瞻妄、癲癇及至昏迷。而當methemoglobin比例大於70%以上，則可能死亡。但是要是病患本身有其他心血管及中樞神經系統疾病，即使methemoglobin的濃度較低，仍可提早出現症狀甚至造成死亡。在無心血管及中樞神經系統疾病的病患，因methemoglobin濃度升高而出現cyanosis時，多不會伴隨明顯的呼吸窘迫。 ( B ) Methemoglobinemia可分為先天性(如NADH methemoglobin reductase (diaphorase I) deficiency、pyruvate kinase deficiency及G6PD deficiency等)或後天性，而後天性多由藥物造成(Table 1)或化學物質(如aniline、nitrite、nitrate與nitrobenzene等)。臨床上若病患出現cyanosis，但無明顯呼吸窘迫；O2 saturation下降，但arterial oxygen tension正常時，就一定要高度懷疑methemoglobinemia。一般正常人血中methemoglobin濃度約為1% (0-3%)，只要臨床懷疑加上血中methemoglobin濃度上升，就可診斷為methemoglobinemia了。腎功能與methemoglobin無關。由於dapsone是可能造成methemoglobinemia的藥物之一，因此病患皮膚顏色改變，但無自覺呼吸症狀時也須考慮methemoglobinemia此診斷。 ( A ) 治療方面主要是依症狀決定而非濃度，除了視情況進行dermal decontamination或GI decontamination，並給予病患氧氣外，在健康無末端器官受損(end-organ damage)之病患，只需觀察即可。但若病患本身已有心血管疾病或肺部疾病、或已有末端器官受損，即使methemoglobin濃度仍低，也要考慮直接給予治療。第一線治療用藥為methylene blue(甲烯藍)，初始劑量為1-2 mg/kg，以葡萄糖溶液稀釋後緩慢靜脈注射(大於5 min)，療效約在20分鐘到1小時內出現，必要時可重覆給予。若病患有禁忌症而無法使用methylene blue，或因使用methylene blue而產生副作用時，則可考慮替代性療法如高壓氧或換血，至於vitamin C並未證明具有療效。Methylene blue使用的禁忌症包括G6PD deficiency、重度腎功能障礙、已知NADPH-methemoglobin reductase enzymatic pathway酵素缺陷及正在使用MAO-A inhibitor的病患，因為有報告指出methylene blue與MAO-A inhibitor交互作用可造成serotonin syndrome。 ( D ) 若病患接受高劑量的methylene blue 注射，反而可能加重methemoglobinemia (所謂的paradoxical methemoglobinemia)，這也是使用methylene blue最主要的副作用。