Severe methemoglobinaemia due to benzocaine-containing - Burns

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burns at the Department of Plastic, Reconstruction Surgery and Burns, University Clinical Centre Ljubljana. In an adult methemoglobinaemia developed after ...
burns 37 (2011) e63–e66

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Case report

Severe methemoglobinaemia due to benzocaine-containing ‘burn cream’: Two case reports in an adult and in a child P. Poredos a,*, P. Gradisek a, C. Testen b, M. Derganc c a

Department of Anesthesia and Intensive Care, University Medical Centre Ljubljana, Ljubljana, Slovenia Department of Plastic Surgery and Burns, University Medical Centre Ljubljana, Ljubljana, Slovenia c Department of Pediatric Surgery and Intensive Care, University Medical Centre Ljubljana, Ljubljana, Slovenia b

article info Article history: Accepted 25 May 2011

Methemoglobinaemia (MetHb) is a life-threatening condition which is rarely considered and difficult to recognise. It is a consequence of extensive methemoglobin production or decreased reduction of methemoglobin in the body. Methemoglobin is a form of haemoglobin whereby the ferrous form of iron (Fe2+) is oxidised to the ferric state (Fe3+), making the haeme incapable of carrying oxygen. Furthermore, methemoglobin causes the shift of the oxyhemoglobin dissociation curve to the left, which makes oxygen unloading more difficult. The increased concentration of methemoglobin in the blood may cause functional anaemia, severe tissue hypoxia and even death. Acquired form of methemoglobinaemia develops after exposure to some drugs and chemicals (local anaesthetics, antimalarials, nitrites or nitrates, nitroprusside, sulfonamides, etc.), certain foods or food additives, significant smoke inhalation, or after serious illness such as gastrointestinal infections [1–3]. Known predisposing factors are sepsis, acidosis, anaemia [4,5], increased systemic absorption from compromised skin [6], the addition of occlusive dressing, simultaneous use of different oxidising drugs that could cause methemoglobinaemia and partial or severe deficiency of cytochrome-b5 reductase. The most common causes of acquired methemoglobinaemia are local anaesthetics, particularly benzocaine, used for transoesophageal cardiac ultrasound, endotracheal intubation, gastroscopy, bronchoscopy

and dental procedures. Very few cases of methemoglobinaemia have been published among patients with burns. In these patients, methemoglobinaemia developed after the use of topical antiseptic cream for burn wounds that contained cerious nitrate and sulphadiazine silver (Flammacerium1) [1]. Methemoglobinaemia appeared also after topical burn wound treatment with 0.5% silver nitrate [7]. After topical application of cream containing 3% benzocaine over burnt area [6] and, most recently, after application to scalds in an infant [8]. We describe two cases of moderate to severe methemoglobinaemia, a child and an adult, treated for deep dermal burns at the Department of Plastic, Reconstruction Surgery and Burns, University Clinical Centre Ljubljana. In an adult methemoglobinaemia developed after simultaneous use of 1.2% benzocaine cream and Flammacerium1, whereas in child it appeared after the use of 1.2% benzocaine containing cream alone.

1.

Case 1

‘Burn care cream’ containing 1.2% benzocaine was used in a 4.5-year-old boy with 44% of total body surface area deep dermal and subdermal flame burn. The course of early excision and grafting and several additional operative sessions were uneventful. On the 46th post-injury day, there were only some unhealed areas on the back left. In the late morning, he had a prolonged therapeutic shower after which the ‘burn care cream’ was applied over all burnt and donor areas. About 1 h later, he became very tired and seemed greyish. The consultant paediatrician was called who found that the boy was afebrile, greyish-cyanotic, agitated, tachycardic (150 min–1),

* Corresponding author at: Department of Anesthesiology, Reanimatology and Perioperative Intensive Care, University Clinical Centre Ljubljana, Zaloska 7, SI-1000 Ljubljana, Slovenia. Tel.: +386 41 252194. E-mail address: [email protected] (P. Poredos). 0305-4179/$36.00 # 2011 Elsevier Ltd and ISBI. All rights reserved. doi:10.1016/j.burns.2011.05.015

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tachypneic (35 min–1), blood pressure was 99/60 mmHg and SpO2 was 85% which did not improve with O2 application. Three boluses of saline (20 ml kg–1) were given and blood samples for lab analysis were taken. Partial pressure of oxygen in arterial blood ( paO2) was normal (10.7 kPa) as well as calculated saturation (90%). Chest X-ray and electrocardiogram (ECG) were normal. Blood was then sent to co-oxymetry. Due to technical problems (blood sample clotted), we only received the results 4 h later. MetHb concentration was 13% (10 times normal). As the boy’s clinical condition improved gradually and the repeated MetHb level 4 h later showed a decrease to 4.4%, the antidote methylene blue was not used. On the next morning, 0.2 g of benzocaine per litre was found in the urine, whereas the blood level of MetHb was 2.5%. The pharmacy confirmed that the burn cream contained 1.2% benzocaine. No abnormal Hb was found by Hb electrophoresis. As there was no history of another drug use that could cause methemoglobinaemia, benzocaine was identified as the only possible cause of methemoglobinaemia. He had mild anaemia (haemoglobin 103 g l–1), blood cultures remained negative. The boy was discharged 2 weeks later in excellent condition.

2.

Case 2

The second case was a 27-year-old patient who was injured in a boiler explosion and suffered a scald over 70% of body surface (a part was superficial, whereas in the lower parts of abdomen and in upper parts of thigh it was deep dermal burn). On admission, metabolic acidosis was seen, whereas cooxymetry was normal. Tracheotomy was performed and burn wound dressings using Flammacerium and ‘burn care cream’ was applied. Initial intensive care consisted of fluid resuscitation using the Parkland formula, analgesia with fentanyl and sedation with midazolam. Every day, burn wound dressing was changed, usually with the application of burn cream to healed areas and Flammacerium cream (containing cerious nitrate and silver sulphadiazine) to unhealed burnt areas. On the second day of hospitalisation, necrectomy (dermoepidermal excision) and grafting by autografts of 15% of burnt areas (lower abdomen and thighs) was performed. Arterial oxymetry values on the sixth day of hospitalisation were normal, haemodynamic and metabolic states were stable. On the 12th day of hospitalisation therapeutic shower was performed, burn wound dressing was replaced and ‘burn care cream’ reapplied. Thirty to 45 min after the application, cyanosis appeared with the decrease in pulse oxymetry saturation (SpO2) values (as low as 65%), which did not respond to oxygen supplement (100% O2). The patient became lethargic and appeared greyish. He became tachypnoic (25 min–1) and had tachycardia (125 min–1), but maintained normal blood pressure (140/70 mmHg). Arterial blood gas analysis revealed increased partial pressure of oxygen in arterial blood (66.9 kPa), arterial blood was chocolate coloured and the calculated saturation of 98%, which did not correlate to pulse oxymetry values. There was no acidosis (pH 7.48). Chest X-ray and transthoracic echocardiogram were normal. Acquired methemoglobinaemia was suspected, and a markedly elevated methemoglobin level (45%) confirmed the diagnosis. Wound dressing was immediately removed, the

skin was washed with saline and covered with sterile dressing. Intravenous methylene blue was infused at a dose of 1 mg kg–1 and the values of blood methemoglobin decreased almost to normal values within the next 3 h. Because of slightly supranormal values of methemoglobin in arterial blood (5.6%) and a possibility of continuous absorption of local anaesthetics, additional bolus of methylene blue was given. On the next day, the patient was fully recovered, without additional cyanosis or signs of neurological deficit. Patient was discharged 6 weeks later in excellent condition.

3.

Discussion

Benzocaine-induced methemoglobinaemia is a rare complication associated with topical anaesthesia and can be life threatening [9]. A total of 242 cases of local anaesthetic induced methemoglobinaemia have recently been described by Guay [10] 66% were due to benzocaine. Drug-induced methemoglobinaemia with significant cyanosis, hypoxaemia, and even fatalities was reported after exposure to benzocaine spray or lidocaine jelly during endotracheal intubation [11,12], flexible bronchoscopy [13–15], transoesophageal echocardiogram [4,16–18], direct laryngoscopy [19], upper-gastrointestinal (GI) endoscopy [20–22], topical anaesthetic teething preparations [23,24] and after topical treatment with 0.5% silver nitrate solution for necrotising fasciitis [7]. The highest blood levels of methemoglobin have been measured after the use of benzocaine [5]. There were few cases of methemoglobinaemia also in younger patients, including infants and newborns, after the use of topical lignocaine/prilocaine cream (EMLA; Astra Pharmaceuticals, North Ryde, New South Whales, Australia) for pain relief after circumcision in newborns [25,26]. In infants it has been shown that benzocaine can cause methemoglobinaemia when applied as an ointment [27], a rectal suppository [28], spray, lozenge [29] and a powder vaporised into the mouth [30]. However, there are just few reports of methemoglobinaemia after the use of topical antiseptic creams in treatment of burns [1,6,7]. Silver nitrate, silver sulphadiazine, cerium nitrate and combinations of them are the most commonly used [6]. At our burn centre, burn cream containing benzocaine has been topically administered to healed areas, whereas Flammacerium (a combination of cerium nitrate and silver sulphadiazine) is applied to burnt unhealed areas. The administration of both creams is performed according to instructions of the manufacturer (2–3-mm thickness at least once a day). Hundred grams of burn care cream contains 1.2 g of benzocaine, 1.1 g of hydrocortisone acetate, and 10.5 g of virgin olive oil, the rest is the vehicle that contains lanolin, white vaseline, paraffin and water. Burn wound dressing is replaced every day until healing or surgical procedure. Until now only one case of methemoglobinaemia after the application of benzocaine-containing cream to burn wounds has been published in peer-reviewed literature. However, burn wound cream contained much higher concentration of benzocaine than in our cases [31]. The only drug known to be associated with acquired methemoglobinaemia that was used in both presented patients was topically administered burn wound cream

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containing benzocaine. Benzocaine is the only ingredient of burn care cream that can be associated with methemoglobinaemia. In the child with burns, the additional risk factors were mild anaemia and dehydration after prolonged therapeutic bath. In our adult patient, burn wounds were treated also with Flammacerium, which contains 1% silver sulphadiazine and 2.2% cerium(III)nitrate hexahydrate. Both substances could cause methemoglobinaemia, but in our patient wound dressing with Flammacerium was performed almost 24 h before the occurrence of methemoglobinaemia. It is possible that Flammacerium increased methemoglobin production, but, below 10%, as our patient was without any clinical signs or symptoms before the methemoglobinaemia appeared. In a recent study, Kath et al. found that only 2% of patients who developed methemoglobinaemia after the application of Flammacerium had methemoglobin levels >10%, which were associated with clinical symptoms [32]. Moreover, the adult patient was given metoclopramide as prokinetic three times daily. Metoclopramide is one of the agents that can cause increased production of methemoglobin. In addition, patient was septic: he was febrile, inflammamarkers were markedly elevated (including tory procalcitonin) and his blood cultures were positive. Mild anaemia was also present. However, he had received metoclopramide for 11 days before methemoglobinaemia appeared and the oxymetry values were normal on the sixth day of hospitalisation (6 days before methemoglobinaemia broke out). The concomitant use of oxidising drugs that are possible causative agents for methemoglobinaemia, the abundant application of both creams, lost integrity of the skin, extensive body surface area burnt requiring the application of large quantities of benzocaine containing cream and Flammacerium, the frequency with which the dressings were changed led to toxic levels of methemoglobin in patient’s blood. After diagnosing methemoglobinaemia the possible causative agents were removed (the skin was washed with saline, dressing was replaced and metoclopramide was discontinued). Symptoms and signs of methemoglobinaemia in our patients appeared after 12 days of regular daily dressings in the adult and after 46 days in the child. It has been shown that methemoglobinaemia could appear as early as 3 days of therapy with causative agent for methemoglobinaemia or as late as 26 days of therapy [33,34]. The first finding in both patients was cyanosis. Besides, both patients were agitated, somnolent, tachycardic and tachypnoic. Symptoms and signs of methemoglobinaemia range from none to cyanosis, mental status changes, headache, fatigue, dizziness, syncope, arrhythmia, dyspnea, acidosis, seizures, coma and even death. They usually present 30–60 min after the application of causative topical agent [22]. Pulse-oxymetry recordings in our patients decreased according to their clinical deterioration and did not respond to oxygen supplement. Pulmonary (embolism, shunt) and cardiac causes for cyanosis were immediately ruled out (chest X-ray, echocardiography, ECG). Arterial blood gas analysis was performed which showed the discrepancy between calculated values of arterial oxygen saturation and pulse-oxymetry values, which is typical of methemoglobinaemia (the discrepancy between low pulseoxymetry and high calculated saturation values and also

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discrepancy between paO2 and saturation values) [35], the socalled oxygen ‘saturation gap’ [36]. Blood–gas analysers namely calculate the estimated O2 saturation from empirical equations using pH and paO2 values. These algorithms assume normal O2 affinity, normal 2,3-diphosphoglycerate concentrations, and no dyshaemoglobins or haemoglobinopathies. It was shown that in cases of increased methemoglobin fraction, pulse-oxymetry readings overestimate the actual oxygen saturation [37]. Therefore, in cases of suspected methemoglobinaemia, co-oxymetry is the method of choice. Recently, special oxymeters, using light of different wavelengths (Masimo Rad-57), have been manufacture, which make the direct diagnosis of methemoglobinaemia possible [38]. Methemoglobinaemia must be considered from the clinical findings. It must be considered whenever there is cyanosis after the use of burn cream (in the absence of other identifiable aetiology) that does not resolve despite oxygen supplementation. At the same time, values of paO2 in arterial blood are normal or increased and during blood sampling one can spot chocolate brownish blood colour. As pulse oxymetry is unreliable, laboratory oxymetry of arterial blood must be performed. In both patients, the presence of decreased cytochrome-b5 reductase activity could not be ruled out. Namely, it was not possible to assess the activity of this enzyme at our institution. After these cases, the use of burn cream containing benzocaine was forbidden at our hospital. Treatment of methemoglobinaemia includes the removal of causative agents, increase of inspired oxygen concentration and, in more severe cases, intravenous application of methylene blue in dosage of 1–2 mg kg–1 in 5 min. If increased values of blood methemoglobin still persist, the dose of methylene blue can be repeated. In life-threatening conditions (shock), haemodialysis, transfusion or exchange transfusion must be considered [39,40].

4.

Conclusions

Methemoglobinaemia must be considered in suddenly deteriorating, cyanotic patients after the treatment with different antiseptic and burn care creams containing local anaesthetic benzocaine. While antiseptic creams cannot be avoided, burn care creams with benzocaine must be banned – as recently suggested by Guay. With its acute onset and grave consequences, if not treated immediately, a prompt recognition and appropriate treatment of methemoglobinaemia are important. The diagnosis is mainly clinical, with chocolate-coloured blood, cyanosis unresponsive to oxygen therapy and oxygen saturation gap. The treatment includes oxygen supplement and application of methylene blue.

Acknowledgement Many thanks to Ognjen Cerovic, who was the attending physician at Burn Care Unit at the time of the methemoglobinaemia episode and took great care of the patient.

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