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Methemoglobinemia by cerium nitrate poisoning
Burns 32 (2006) 1060–1061 www.elsevier.com/locate/burns
Case report
Methemoglobinemia by cerium nitrate poisoning Attof Rachid *, Magnin Christophe, Bertin-Maghit Marc, Olivier Laure, Tissot Sylvie, Petit Paul Centre de traitement des bruˆles, pavillon I, hoˆpital Edouard Herriot, 69437, France Accepted 7 April 2006
Abstract Cerium nitrate is a topical antiseptic used with silver sulfadiazine (Flammacerium1) for the treatment of serious burns. This topical agent can induce methemoglobinemia, but no cases have been reported in the recent literature. In this article, we present the case of a 16-year old girl, with third-degree burns over 95% of her body. After daily dressings of Flammacerium1, on the sixth day she developed a bluish skin coloring. When tested for methemoglobinemia, levels of 31.8% were found. These returned to normal after classic treatment with Methylene blue. # 2006 Elsevier Ltd and ISBI. All rights reserved. Keywords: Methemoglobinemia; Cerium nitrate; Flammacerium
1. Introduction Methemoglobin is formed when the iron atom that is in the ferrous state (Fe2+) in the heme, loses an electron and changes to the ferric state (Fe3+). The iron can then no longer fix O2, leading to cyanosis, anoxia and even death, depending on the levels of methemoglobin. In the present case, cerium nitrate would seem to be cause of this oxidation and the formation of methemoglobin. Cerium nitrate is a topical antiseptic used in the treatment of extensive burns, in association with silver sulfadiazine (Flammacerium1) [1]. No case of cerium nitrate poisoning has been reported in the recent literature and only one case before 1976 [2]. It therefore seemed worthwhile to describe this clinical case.
2. Clinical case A 16-year-old girl was admitted to intensive care in the serious burns unit following immolation. There were no previous histories of allergies or treatment. Initial treatment * Corresponding author. Tel.: +33 668207598. E-mail address: [email protected] (A. Rachid). 0305-4179/$30.00 # 2006 Elsevier Ltd and ISBI. All rights reserved. doi:10.1016/j.burns.2006.04.005
consisted of standard intensive care together with a first series of discharge incisions on the upper and lower limbs. On admission at the referral center (H +4h), 95% of the body surface was covered with deep third-degree burns. Distal ischemia of the four limbs was still present, so the surgeon performed complementary escharotomy incisions (upper limbs, neck, thorax and lower limbs). Flammacerium1 dressings were then applied. Initial intensive care consisted of fluid resuscitation using the Parkland formula, sedation with midazolam and analgesia with sufentanil. Arterial gases were normal at the start. The first intervention was carried out on D2, consisting of a dermo-epidermal excision on the hands and a tangential excision down to the fat layer in the area of the thorax. Flammacerium1 dressings were applied every day. The haemodynamic and metabolic states were stable. With regards to breathing, multiple episodes of de-saturation were noted on D4 and D5 (92% SaO2/1 FiO2). On D6, bluish skin coloring was observed in the healthy areas (feet) of the face and hands. SaO2 levels were now at 94%, not correlated to arterial gases (SaO2 measured 98.2%, PaO2 12.2 kPa, FiO2 0.3). No other anomalies were noted and the hemodynamic parameters were stable. The hypothesis of methemoglobinemia was then considered. Methemoglobin levels of 31.8% were found (usual levels are 0–1.5%).
A. Rachid et al. / Burns 32 (2006) 1060–1061
Subsequent treatment was then as follows: - Oxygen therapy: FiO2 100%. - Methylene blue: 1.5 mg/kg (i.e.100 mg) for 15 min. - Dressing replacement: complete removal of Flammacerium1, replacing it with Flammazine1 dressing. These anomalies were quickly corrected, with the methemoglobinemia down to 3.5% when checked 1 h after treatment. Arterial gasometry also returned to normal (pH 7.39, PCO2 6.5 kPa, PO2 57.9 kPa under FiO2 0.8, SaO2 99.7%), as did the skin coloration. Checks of methemoglobinemia gave readings of 3.3% on D7 and 0.9% on D8. There was no recurrence after the Flammacerium1 was removed. The outcome was nonetheless catastrophic and the patient died on D33 from multiple organ failure.
3. Discussion Physiologically, hemoglobin can be oxidized in red blood cells, though oxidation remains below 1.5%. There are chemical and enzymatic mechanisms that can reduce ferric iron and therefore restore the capacity of hemoglobin to fix oxygen. However, when these mechanisms are bypassed, the level of methemoglobinemia rises and becomes toxic [3]. The two main causes of methemoglobinemia are: - Hereditary methemoglobinemia, which is the result of a severe deficit of NADH-cytochrome b5 reductase, resulting in a permanent methemoglobinemia of 15–50%. - The acquired form, which manifests itself after intoxication by an oxidizing substance. Cerium nitrate was the cause in the present case. Clinical symptoms vary depending on the level of methemoglobinemia: - cyanosis above 10% - signs of anoxia above 30% - neurological after-effects above 60% - fatal coma above 70%. Neurological signs linked to anoxia are therefore predominant. However, in a deeply sedated patient, this diagnosis
1061
can be problematic, and only cyanosis can be an early indicator of methemoglobinemia. Later on, one can observe secondary signs of hypoxia: tachycardia, polypnoea. In the present case, several factors were probably involved, all linked to the high levels of resorption of the poison: - Extensive body surface area burnt (95%), requiring the application of large quantities of Flammacerium1. - Large number of incisions and aponeurotomies, putting the Flammacerium1 directly into contact with muscular aponeuroses and subcutaneous cell tissues. - Frequency with which the dressings were changed. The classic treatment with methylene blue at a posology of 1–2 mg/kg, resulted in a very quick drop in methemoglobinemia levels. This treatment should be repeated in the absence of improvement, without exceeding a dose of 7 mg/ kg, to avoid the risk of paradoxical methemoglobinemia. It is also possible to use ascorbic acid (Vitamin C) at a posology of 600 mg/d in 2 or 3 slow intravenous perfusions, to be repeated if necessary [4].
4. Conclusion Although rare, methemoglobinemia is no less serious due to the potential after-effects that can result. In addition, in the treatment of serious burns, caregivers should be aware of this complication due to the large quantities of topical antiseptic needed.
References [1] Garner JP, Heppell PSJ. Cerium nitrate in the management of burns. Burns 2005;31:539–47. [2] Monafo WW, Tandon SN, Ayvazian VH, Tuchsmidt J, Skinner AM, Deitz F. Cerium nitrate: a new topical antiseptic for extensive burns. Surgery 1976;80(4):465–73. [3] Faivre-Fiorina B, Caron A, Labrude P, Vigneron C. Erythrocyte, plasma and substitute hemoglobins facing physiological oxidizing and reducing agents. Ann Biol Clin (Paris) 1998;56(September–October (5)):545–56. [4] Wolak E, Byerly FL, Mason T, Cairns BA. Methemoglobinemia in critically ill burned patients. Am J Crit Care 2005;14(March (2)):104–8.
Case report
Methemoglobinemia by cerium nitrate poisoning Attof Rachid *, Magnin Christophe, Bertin-Maghit Marc, Olivier Laure, Tissot Sylvie, Petit Paul Centre de traitement des bruˆles, pavillon I, hoˆpital Edouard Herriot, 69437, France Accepted 7 April 2006
Abstract Cerium nitrate is a topical antiseptic used with silver sulfadiazine (Flammacerium1) for the treatment of serious burns. This topical agent can induce methemoglobinemia, but no cases have been reported in the recent literature. In this article, we present the case of a 16-year old girl, with third-degree burns over 95% of her body. After daily dressings of Flammacerium1, on the sixth day she developed a bluish skin coloring. When tested for methemoglobinemia, levels of 31.8% were found. These returned to normal after classic treatment with Methylene blue. # 2006 Elsevier Ltd and ISBI. All rights reserved. Keywords: Methemoglobinemia; Cerium nitrate; Flammacerium
1. Introduction Methemoglobin is formed when the iron atom that is in the ferrous state (Fe2+) in the heme, loses an electron and changes to the ferric state (Fe3+). The iron can then no longer fix O2, leading to cyanosis, anoxia and even death, depending on the levels of methemoglobin. In the present case, cerium nitrate would seem to be cause of this oxidation and the formation of methemoglobin. Cerium nitrate is a topical antiseptic used in the treatment of extensive burns, in association with silver sulfadiazine (Flammacerium1) [1]. No case of cerium nitrate poisoning has been reported in the recent literature and only one case before 1976 [2]. It therefore seemed worthwhile to describe this clinical case.
2. Clinical case A 16-year-old girl was admitted to intensive care in the serious burns unit following immolation. There were no previous histories of allergies or treatment. Initial treatment * Corresponding author. Tel.: +33 668207598. E-mail address: [email protected] (A. Rachid). 0305-4179/$30.00 # 2006 Elsevier Ltd and ISBI. All rights reserved. doi:10.1016/j.burns.2006.04.005
consisted of standard intensive care together with a first series of discharge incisions on the upper and lower limbs. On admission at the referral center (H +4h), 95% of the body surface was covered with deep third-degree burns. Distal ischemia of the four limbs was still present, so the surgeon performed complementary escharotomy incisions (upper limbs, neck, thorax and lower limbs). Flammacerium1 dressings were then applied. Initial intensive care consisted of fluid resuscitation using the Parkland formula, sedation with midazolam and analgesia with sufentanil. Arterial gases were normal at the start. The first intervention was carried out on D2, consisting of a dermo-epidermal excision on the hands and a tangential excision down to the fat layer in the area of the thorax. Flammacerium1 dressings were applied every day. The haemodynamic and metabolic states were stable. With regards to breathing, multiple episodes of de-saturation were noted on D4 and D5 (92% SaO2/1 FiO2). On D6, bluish skin coloring was observed in the healthy areas (feet) of the face and hands. SaO2 levels were now at 94%, not correlated to arterial gases (SaO2 measured 98.2%, PaO2 12.2 kPa, FiO2 0.3). No other anomalies were noted and the hemodynamic parameters were stable. The hypothesis of methemoglobinemia was then considered. Methemoglobin levels of 31.8% were found (usual levels are 0–1.5%).
A. Rachid et al. / Burns 32 (2006) 1060–1061
Subsequent treatment was then as follows: - Oxygen therapy: FiO2 100%. - Methylene blue: 1.5 mg/kg (i.e.100 mg) for 15 min. - Dressing replacement: complete removal of Flammacerium1, replacing it with Flammazine1 dressing. These anomalies were quickly corrected, with the methemoglobinemia down to 3.5% when checked 1 h after treatment. Arterial gasometry also returned to normal (pH 7.39, PCO2 6.5 kPa, PO2 57.9 kPa under FiO2 0.8, SaO2 99.7%), as did the skin coloration. Checks of methemoglobinemia gave readings of 3.3% on D7 and 0.9% on D8. There was no recurrence after the Flammacerium1 was removed. The outcome was nonetheless catastrophic and the patient died on D33 from multiple organ failure.
3. Discussion Physiologically, hemoglobin can be oxidized in red blood cells, though oxidation remains below 1.5%. There are chemical and enzymatic mechanisms that can reduce ferric iron and therefore restore the capacity of hemoglobin to fix oxygen. However, when these mechanisms are bypassed, the level of methemoglobinemia rises and becomes toxic [3]. The two main causes of methemoglobinemia are: - Hereditary methemoglobinemia, which is the result of a severe deficit of NADH-cytochrome b5 reductase, resulting in a permanent methemoglobinemia of 15–50%. - The acquired form, which manifests itself after intoxication by an oxidizing substance. Cerium nitrate was the cause in the present case. Clinical symptoms vary depending on the level of methemoglobinemia: - cyanosis above 10% - signs of anoxia above 30% - neurological after-effects above 60% - fatal coma above 70%. Neurological signs linked to anoxia are therefore predominant. However, in a deeply sedated patient, this diagnosis
1061
can be problematic, and only cyanosis can be an early indicator of methemoglobinemia. Later on, one can observe secondary signs of hypoxia: tachycardia, polypnoea. In the present case, several factors were probably involved, all linked to the high levels of resorption of the poison: - Extensive body surface area burnt (95%), requiring the application of large quantities of Flammacerium1. - Large number of incisions and aponeurotomies, putting the Flammacerium1 directly into contact with muscular aponeuroses and subcutaneous cell tissues. - Frequency with which the dressings were changed. The classic treatment with methylene blue at a posology of 1–2 mg/kg, resulted in a very quick drop in methemoglobinemia levels. This treatment should be repeated in the absence of improvement, without exceeding a dose of 7 mg/ kg, to avoid the risk of paradoxical methemoglobinemia. It is also possible to use ascorbic acid (Vitamin C) at a posology of 600 mg/d in 2 or 3 slow intravenous perfusions, to be repeated if necessary [4].
4. Conclusion Although rare, methemoglobinemia is no less serious due to the potential after-effects that can result. In addition, in the treatment of serious burns, caregivers should be aware of this complication due to the large quantities of topical antiseptic needed.
References [1] Garner JP, Heppell PSJ. Cerium nitrate in the management of burns. Burns 2005;31:539–47. [2] Monafo WW, Tandon SN, Ayvazian VH, Tuchsmidt J, Skinner AM, Deitz F. Cerium nitrate: a new topical antiseptic for extensive burns. Surgery 1976;80(4):465–73. [3] Faivre-Fiorina B, Caron A, Labrude P, Vigneron C. Erythrocyte, plasma and substitute hemoglobins facing physiological oxidizing and reducing agents. Ann Biol Clin (Paris) 1998;56(September–October (5)):545–56. [4] Wolak E, Byerly FL, Mason T, Cairns BA. Methemoglobinemia in critically ill burned patients. Am J Crit Care 2005;14(March (2)):104–8.