Impact of a digital manual for guidance on malignant hyperthermia: patient education.

BACKGROUND: Malignant hyperthermia (MH) is a rare, hereditary disease with a hypermetabolic response to volatile anesthetics/succinylcholine. Susceptible patients face difficulties due to a lack of knowledge about MH. As informational materials could increase knowledge and adherence to prevention/therapy, digital information about rare diseases validated for patients is needed. Our objective was to evaluate the following: (1) the impact of digital manuals on the knowledge/quality of life of MH patients and (2) access to MH services. MATERIALS AND METHODS: Fifty MH-susceptible patients filled out a virtual questionnaire twice (demographic/economic/clinical data, MH knowledge and impact on daily life, and SF-36 quality of life). Test groups 1 (n = 17) and 2 (n = 16) were evaluated 30 and 180 days after receiving a digital manual, and the control group (n = 17; without manual) was evaluated after 180 days. We collected the MH service data about the number of contacts. RESULTS: Twenty-four (48%) patients reported problems in personal/professional life, sports, clinical/surgical/dental treatments, and military service, in addition to concerns about emergency care and complaints of sequelae. The percentage of correct answers in the second MH knowledge questionnaire increased for test group 2 (62% vs. 74.1%; unpaired t test, p < 0.01), was significantly greater in test groups 1 (68.1%) and 2 (74.1%) than in the control group (56.5%; Kruskal-Wallis, p < 0.05), and correlated with more time studying the manual and reports of MH-related problems (multiple regression, p < 0.05). CONCLUSIONS: The digital manual improved patients' MH knowledge. Online contacts with the MH service increased, allowing greater information dissemination. As informational materials could increase knowledge/adherence to prevention/therapy, digital information about MH validated for patients should be implemented.

Caso de hipertermia maligna en paciente intervenida de apendicectomía laparoscópica / Malignant Hyperthermia after a laparoscopic appendicectomy: Case report

Malignant hyperthermia is an hypermetabolic syndrome in which the intracellular calcium receptors are altered. Patients who present compatible symptoms with this symdrome are genetically predisposed. Many of the cases have been described in the surgical area, due to the use of anesthesic drugs and neuromuscular blockers. However, there are some cases with an unknown trigger. The prevalence of the syndrome is very difficult to estimate. The diagnosis and early treatment are pronostic factors predicting the evolution of the syndrome.

La hipertermia maligna es conocida como un síndrome de estimulación masiva del metabolismo, debido a la alteración en la liberación de calcio intracelular. Muchos pacientes que presentan clínica compatible con este síndrome están genéticamente predispuestos. La mayoría de los casos se describen en el ámbito quirúrgico, con el empleo de fármacos anestésicos y determinados relajantes neuromusculares, aunque también existen casos en los que no se halla desencadenante. De prevalencia difícil de estimar, la sospecha diagnóstica y el tratamiento precoz marcan el pronóstico evolutivo de estos pacientes.

Síndrome de hipertermia maligna: una patología infrecuente / Malignant hyperthermia syndrome: A rare entity

Resumen Introducción: El síndrome de hipertermia maligna es un trastorno farmacogenético del músculo esquelético de carácter hereditario, que se caracteriza por un estado hipermetabólico relacionado con la exposición a anestésicos inhalatorios o relajantes musculares despolarizantes. Se trata de una afección infrecuente en individuos genéticamente predispuestos, con una incidencia muy baja en pediatría (1 de cada 10,000-15,000 procedimientos anestésicos). Caso clínico: Se presenta un caso de hipertermia maligna relacionado con la exposición a sevoflurano durante una cirugía de adenoidectomía en un paciente de sexo femenino de 6 años de edad. La paciente presentó taquicardia, hipercapnia e hipertermia, que precisaron la administración de dos dosis sucesivas de dantroleno sódico. La evolución posterior fue buena. Conclusiones: El síndrome de hipertermia maligna es un cuadro poco frecuente en la edad pediátrica. Se debe sospechar de forma precoz, ya que es fundamental su detección temprana para iniciar el tratamiento.

Abstract Background: Malignant hyperthermia syndrome is a hereditary pharmacogenetic disorder of skeletal muscle characterized by hypermetabolic state related to the exposure of volatile anesthetic gases or depolarizing muscle relaxants. It is an infrequent entity that occurs in genetically predisposed individuals, with a very low incidence in pediatrics (1 in 10,000-15,000 anesthetic procedures). Case report: We report a case of malignant hyperthermia related to exposure to sevoflurane during adenoidectomy surgery in a 6-year-old female. The patient presented with tachycardia, hypercapnia, and hyperthermia, requiring two successive doses of dantrolene sodium administration, with an adequate response to the treatment. Conclusions: Malignant hyperthermia syndrome is a rare condition in pediatric patients that should be detected in early stages since it is essential to initiate the treatment as soon as possible.

Malignant hyperthermia syndrome: A rare entity.

Background: Malignant hyperthermia syndrome is a hereditary pharmacogenetic disorder of skeletal muscle characterized by hypermetabolic state related to the exposure of volatile anesthetic gases or depolarizing muscle relaxants. It is an infrequent entity that occurs in genetically predisposed individuals, with a very low incidence in pediatrics (1 in 10,000-15,000 anesthetic procedures). Case report: We report a case of malignant hyperthermia related to exposure to sevoflurane during adenoidectomy surgery in a 6-year-old female. The patient presented with tachycardia, hypercapnia, and hyperthermia, requiring two successive doses of dantrolene sodium administration, with an adequate response to the treatment. Conclusions: Malignant hyperthermia syndrome is a rare condition in pediatric patients that should be detected in early stages since it is essential to initiate the treatment as soon as possible.

Background: Introducción">El síndrome de hipertermia maligna es un trastorno farmacogenético del músculo esquelético de carácter hereditario, que se caracteriza por un estado hipermetabólico relacionado con la exposición a anestésicos inhalatorios o relajantes musculares despolarizantes. Se trata de una afección infrecuente en individuos genéticamente predispuestos, con una incidencia muy baja en pediatría (1 de cada 10,000-15,000 procedimientos anestésicos). Caso clínico: Se presenta un caso de hipertermia maligna relacionado con la exposición a sevoflurano durante una cirugía de adenoidectomía en un paciente de sexo femenino de 6 años de edad. La paciente presentó taquicardia, hipercapnia e hipertermia, que precisaron la administración de dos dosis sucesivas de dantroleno sódico. La evolución posterior fue buena. Conclusiones: El síndrome de hipertermia maligna es un cuadro poco frecuente en la edad pediátrica. Se debe sospechar de forma precoz, ya que es fundamental su detección temprana para iniciar el tratamiento.

MALIGNANT HYPERTHERMIA IN A CHILD AFTER MAGNETIC RESONANCE IMAGING: A CASE REPORT.

OBJECTIVE: To report on a case of malignant hyperthermia in a child after a magnetic resonance imaging of the skull was performed using sevoflurane anesthesia. CASE DESCRIPTION: A 3-year-old boy admitted to the pediatric intensive care unit after presenting clinical and laboratory findings consistent with unspecified viral meningoencephalitis. While the patient was sedated, a magnetic resonance imaging of the skul was performed using propofol followed by the administration of sevoflurane through a laryngeal mask in order to continue anesthesia. Approximately three hours after the start of the procedure, the patient presented persistent tachycardia, tachypnea, generalized muscular stiffness and hyperthermia. With a diagnostic hypothesis of malignant hyperthermia, dantrolene was then administered, which immediately induced muscle stiffness, tachycardia, tachypnea and reduced body temperature. COMMENTS: Malignant hyperthermia is a rare pharmacogenetic syndrome characterized by a severe hypermetabolic reaction after the administration of halogenated inhalational anesthetics or depolarizing muscle relaxants such as succinylcholine, or both. Although it is a potentially fatal disease, the rapid administration of continued doses dantrolene has drastically reduced the morbidity and mortality of the disease.

Malignant hyperthermia in a child after magnetic resonance imaging: a case report / Hipertermia maligna em criança após exame de ressonância magnética: relato de caso

ABSTRACT Objective: To report on a case of malignant hyperthermia in a child after a magnetic resonance imaging of the skull was performed using sevoflurane anesthesia. Case description: A 3-year-old boy admitted to the pediatric intensive care unit after presenting clinical and laboratory findings consistent with unspecified viral meningoencephalitis. While the patient was sedated, a magnetic resonance imaging of the skul was performed using propofol followed by the administration of sevoflurane through a laryngeal mask in order to continue anesthesia. Approximately three hours after the start of the procedure, the patient presented persistent tachycardia, tachypnea, generalized muscular stiffness and hyperthermia. With a diagnostic hypothesis of malignant hyperthermia, dantrolene was then administered, which immediately induced muscle stiffness, tachycardia, tachypnea and reduced body temperature. Comments: Malignant hyperthermia is a rare pharmacogenetic syndrome characterized by a severe hypermetabolic reaction after the administration of halogenated inhalational anesthetics or depolarizing muscle relaxants such as succinylcholine, or both. Although it is a potentially fatal disease, the rapid administration of continued doses dantrolene has drastically reduced the morbidity and mortality of the disease.

RESUMO Objetivo: Relatar um caso de hipertermia maligna em criança após exame de ressonância magnética de crânio realizada sob efeito anestésico de sevoflurano. Descrição do caso: Menino de três anos de idade, admitido na Unidade de Terapia Intensiva Pediátrica (UTIP) após apresentar quadros clínico e laboratorial compatíveis com meningoencefalite viral não especificada. Foi realizado um exame de ressonância magnética de crânio com sedação utilizando, na indução anestésica, o propofol seguido pela administração de sevoflurano por meio de máscara laríngea para manutenção anestésica. Aproximadamente três horas após o início do procedimento, o paciente apresentou taquicardia, taquipneia, rigidez muscular generalizada e hipertermia persistentes. Com hipótese diagnóstica de hipertermia maligna, foi então administrado dantrolene, que fez ceder de forma imediata a rigidez muscular, a taquicardia, a taquipneia e reduziu a temperatura corporal. Comentários: A hipertermia maligna é uma síndrome farmacogenética rara, que se caracteriza por reação hipermetabólica grave após administração de anestésicos inalatórios halogenados e/ou relaxantes musculares despolarizantes, como a succinilcolina. Apesar de ser uma doença potencialmente fatal, a rápida administração de dantrolene, junto às doses de manutenção, tem reduzido drasticamente a morbimortalidade da doença.

Implementation of a new dantrolene formulation across a multifacility health system.

PURPOSE: An initiative to optimize the treatment of malignant hyperthermia in surgical patients through a dantrolene product conversion program is described. SUMMARY: A large health system's formulary evaluation of a new dantrolene sodium product indicated that despite a higher cost per treatment course, the product could offer key advantages over older formulations of dantrolene in terms of preparation and administration time, product content, and storage requirements. A work group, consisting of pharmacy personnel, an anesthesiologist, a nurse anesthetist, and a representative of the health system's group purchasing organization, determined that a switch to the new dantrolene product would offer both patient care benefits and process benefits. With the approval of the health system's pharmacy and therapeutics committee, the new product was added to the formulary as the preferred dosage form of dantrolene, and existing dantrolene product stock was converted to the new formulation. Key implementation steps included (1) concurrent replacement of dantrolene stock on all "malignant hyperthermia carts" across the 15-hospital health system, (2) development of educational materials to raise awareness of the conversion and revised product preparation procedures, (3) anesthesiology provider and pharmacy staff education, (4) revision of dantrolene listings in each hospital's computerized prescriber-order-entry system, and (5) redistribution of returned dantrolene product stock. The dantrolene product conversion occurred over a four-month period. CONCLUSION: A multifacility health system was successful in converting an existing stock of dantrolene to a newly available formulation.

Hipertermia maligna: reporte de un caso clínico / Malignant hyperthermia: report of a clinical case

La Hipertermia Maligna (HM), es un síndrome clínico que ocurre en pacientes susceptibles tras la exposición a un agente anestésico desencadenante. La mortalidad desciende con tratamiento específico, por lo que es fundamental su diagnóstico y tratamiento precoz. Se presenta el caso clínico de una niña de 3 años y 10 meses, en estudio por hemiparesia derecha de 3 meses de evolución. Se plantea probable enfermedad desmielinizante. Se le realizaron dos resonancias magnéticas (RNM) previas con anestesia sin incidentes. Por mala evolución de su enfermedad, se realiza nueva RNM con anestesia. A las 5 horas presenta episodio de distonías, acidosis, CPK elevada. Se interpreta como HM, se inicia tratamiento para la misma con mejoría del cuadro clínico. Presentamos este caso con el objetivo de exponer un enfoque diagnóstico y terapéutico de esta patología.

Intravenous administration of azumolene to reverse malignant hyperthermia in swine.

BACKGROUND: The efficacy of intravenous (IV) administration of azumolene (Az), an analogue 30-fold more soluble than dantrolene, on pigs susceptible to malignant hyperthermia (MH) is incompletely understood. OBJECTIVE: To evaluate efficacy of Az on MH crisis in pigs. ANIMALS: Eight normal (MHN) and 7 susceptible to MH (MHS) pigs (Landrace × Large White × Pietran). METHODS: Prospective, laboratory trial. Hypermetabolic crisis was observed in MHS pigs, but not in MHN pigs, after a combined administration of inhaled halothane (1.5%) and IV injection of succinylcholine (SCh; 2.5 mg/kg). Susceptibility was confirmed using a caffeine and halothane contracture test. Az was administered 15 minutes after administration of SCh. RESULTS: Respiratory acidosis (pH 7.16 ± 0.02; Pco(2) , 46.2 ± 9.1 mmHg, HCO(3) , 22.5 ± 2.3 mmol/L), fever (38.2 ± 1.1°C), cardiac arrhythmias, and muscle contracture were observed in MHS pigs. MHS pigs (n = 5) treated with Az (2 mg/kg IV) survived the crisis with attenuation of signs (pH 7.30 ± 0.10; Pco(2) , 36.3 ± 4.5 mmHg; HCO(3) , 22.9 ± 2.3 mmol/L) and recovery of normal muscle tone and cardiac rhythm. CONCLUSIONS AND CLINICAL IMPORTANCE: Az represents a possible substitute for dantrolene to reverse MH crisis in susceptible pigs.

Effects of azumolene on normal and malignant hyperthermia-susceptible skeletal muscle.

Malignant hyperthermia is a pharmacogenetic disease of skeletal muscle in which a life-threatening, hypermetabolic syndrome is induced by exposure of susceptible patients to halogenated general anaesthetics and/or succinylcholine. Dantrolene sodium, the only drug effective for treatment of malignant hyperthermia, has low water solubility that makes its clinical use difficult. The aim of this study was to investigate the potency of azumolene, a 30-fold more water-soluble analogue, in comparison to the prototype dantrolene sodium, on mammalian and human skeletal muscles. The twitches of extensor digitorum longus and soleus muscles from mice were inhibited by azumolene with IC(50) of 2.8 +/- 0.8 and 2.4 +/- 0.6 microM, respectively. The IC(50) of dantrolene sodium in these muscles was 1.6 +/- 0.4 and 3.5 +/- 1.2 microM, respectively, with no difference in comparison to azumolene. Previous in vitro exposure of mouse soleus muscle to azumolene and dantrolene sodium (10 microM) significantly inhibited 8 mM caffeine-induced contractures. Azumolene was just effective as dantrolene sodium in relaxing caffeine-induced contractures of mouse soleus muscle. Intravenous injection caused dose-dependent decreases in twitches of guinea pig gastrocnemius muscle with IC(50) of 1.2 +/- 0.1 and 1.5 +/- 0.2 mg/kg for azumolene and dantrolene sodium, respectively. Azumolene, 10 microM, was effective in blocking and reversing caffeine-induced contracture of human malignant hyperthermia susceptible skeletal muscle in vitro. These studies provide evidence that azumolene is equipotent to dantrolene sodium in blocking pharmacologic-induced muscle contractures and that azumolene should be efficacious for treatment/prevention of malignant hyperthermia.

Malignant hyperthermia in a liver transplant patient: a case report.

Malignant hyperthermia is an autosomal dominant disorder with incomplete penetrance and variable expression. This syndrome is characterized by a hypermetabolic response to all commonly used inhalational anesthetics and depolarizing muscle relaxants. It can happen during or after the anesthesia. We describe a case of malignant hyperthermia during orthotopic liver transplantation. Our patient was a 48-year-old man, born in Brazil but with European ascendance, who developed malignant hyperthermia associated with the use of isoflurane. He was treated with dantrolene, which caused hepatic graft dysfunction. It is important that transplant teams be able to recognize and treat this complication.

Farmacología y aplicaciones clínicas del dantrolene / Dantrolene: pharmacology and clinical uses

El dantrolene (DNL) es el fármaco de elección para prevenir y revertir los síntomas de la hipertermia maligna (HM); es un derivado liposoluble de la hidantoína que relaja y paraliza totalmente al músculo esquelético. La HM es un síndrome que produce estragos fisiológicos. La identificación de los pacientes sensibles a hipertermia maligna (SHM) puede prevenir el desencadenamiento de este síndrome evitando el uso de agentes anestésicos y relajantes que lo inducen. El dantrolene ejerce su efecto miorrelajante disminuyendo la frecuencia de reapertura de los canales de calcio del retículo sarcoplásmico a través del receptor de ryanodina (RYI), disminuyendo el calcio en el sarcoplasma y de este modo la exitación-contracción, con un efecto agonista dopaminérgico. El dantrolene se metaboliza en el hígado y aunque atraviesa la barrera placentaria, no se han reportado efectos adversos en neonatos. La mortalidad de la HM, sin la administración del dantrolene era del 95 por ciento y solo se podía hacer un tratamiento sintomático. La aplicación de este medicamento, sumado a un diagnóstico precoz y un tratamiento específico, ha reducido la mortalidad a un 3 por ciento. El síndrome de hipertermia maligna (SHM) se presenta con: taquicardia, aumento de CO2, taquipnea, rigidez muscular, arritmias cardíacas, acidosis respiratoria y metabólica, aumento de la temperatura corporal, tensión arterial inestable, cianosis, mioglobinuria, oliguria y rigidez del músculo masetero (RMM). También puede ocurrir como un síndrome serotoninérgico, o ser causado por intoxicación por IMAO, anfetaminas, cocaína o CO. Se adjuntan tres casos clínicos donde se utilizó con éxito el DNL.

Dantrolene (DNL) is the medication of choice to prevent and to revert the symptoms of the malignant hyperthermia(HM), it is a liposoluble derivative of the hydantoine that relaxes and paraIyzes totally the skeletal muscle. HM is a syndrome that produces physiological devastations. The identification of the sensitive patients to hyperthermia malignant (SHM) can anticipate the triggering of these cases avoiding the use of anaesthesic and relaxing agents who induce it. The miorelaxing effect diminishes the frequency of reopening of the calcium channels of the reticulum sarcoplasmatic across the ryanodine receptor (RYI), diminishing the calcium in the sarcoplasma and hereby it reduce the excitation-contraction, resulting in agonist dopaminergic effect. DNL is metabolized in the liver. It crosses the placental barrier; nevertheless adverse effects have not been reported in neonates. The mortality in the HM without the specific drug was 95 percent, it was possible to do only symptomatic treatment. The application of this medicine, added to an early diagnosis and a specific treatment, has reduced the mortality to 3 percent. The syndrome of hyperthermia malignant (SHM) appears with: tachycardia, increase of CO2, taquipnea, muscular inflexibility, cardiac arrhythmias, respiratory and metabolic acidosis, increase of the corporal temperature, arterial unstable tension, cyanosis, mioglobinuria, oliguria and inflexibility of the masseter muscle (RMM). Also it can happen as a serotoninergic syndrome, poisoning for IMAO, anfetamines, cocaine and poisoning from CO. Three clinical cases are included where the DNL was in use successfully.

O dantrolene (DNL)‚ é o fármaco de escolha para a prevençao e reversao dos sintomas da hipertermia maligna (HM); e um derivado lipossolúvel da hidantoína que relaxa e paralisa totalmente o músculo esquelético. A HM é uma síndrome que causa enormes danos fisiológicos; a identificaçao dos pacientes sensíveis à hipertermia maligna (SHM) pode prevenir o desencadeamento dessa síndrome evitando o uso de agentes anestésicos e relaxantes que a induzem. O daxtrolene exerce seu efeito miorrelaxante diminuindo a freqüência de reabertura dos canais de cálcio do reticulo sarcoplásmico através do receptor da ryanodina (RYI) e reduzindo o cálcio no sarcoplasma, e, conseqüentemente, também a excitaçao-contraçao, com efeito agonista dopaminérgico. E metabolizado pelo fígado, e apesar de atravessar a barreira placentária, nao se informaram efeitos adversos em neonatos. A mortalidade da HM sem a administraçao de dantrolene era de 95 por cento, e apenas era possivel o tratamento sintomático. A aplicaçao deste medicamento, junto a um diagnóstico precoce e tratamento específico, tem diminuída a mortalidade a 3 por cento. A síndrome de hipertermia maligna (SHM) associa-se a: taquicardia, aumento do CO2, taquipnéia, rigidez muscular, arritmias cardíacas, acidose respiratória e metabólica, aumento da temperatura corporal, tensao arterial instável, cianose, mioglobinúria, oligúria e rigidez do músculo masseter (RMM). Também pode-se apresentar como síndrome serotoninérgica, intoxicaçao por IMAO, anfetaminas, cocaína e intoxicaçao por CO. Sao informados três casos clínicos nos quais se utilizou o DNL.

Hipertermia maligna: adelantándose a las complicaciones / Malignant hyperthermia: moving forward before the complications

La hipertermia maligna (HTM) es una enfermedad fármaco-genética de carácter autosómico dominante de baja incidencia pero potencialmente mortal, caracterizada por un síndrome hipermetabólico del músculo estriado esquelético, que puede desencadenar la destrucción completa de éste, resultando en aumento de la temperatura corporal, alto consumo de oxígeno, hiperpotasemia, falla renal y arritmias. A continuación se da a conocer el caso de un paciente de 6 años portador de una distrofia muscular de Duchenne con antecedentes familiares de hipertermia maligna y que se sometió a cirugía adenoamigdaliana en la cual se tomaron las medidas anestésicas para prevenir la aparición de una crisis.

Hipertermia maligna / Malignant hyperthermia

La hipertermia maligna es un desorden hipermetabólico de los músculos esqueléticos, caracterizado por hipercalcemia intracelular y consumo rápido de adenosín trifosfato; esta condición se desencadena por la exposición a 1 o más agentes anestésicos precipitantes incluidos halotano, enflurano, isoflurano, desflurano, sevoflurano y el succinilcolina. Los síntomas de esta afección pueden presentarse en el quirófano o en la Unidad de Cuidados Posanestésicos y se caracteriza por aparición súbita de taquicardia, taquipnea, hipertensión, hipercapnia, hipertermia, acidosis y rigidez musculoesquelética. El dantroleno atenúa la elevación del calcio intracelular y puede ser administrado de forma profiláctica o inmediatamente que se sospeche el diagnóstico. Con el objetivo de conocer las bases fisiopatológicas de este síndrome y las pautas de tratamiento más empleadas se realizó una exhaustiva revisión bibliográfica(AU)

Hipertermia maligna / Malignant hyperthermia

La hipertermia maligna es un desorden hipermetabólico de los músculos esqueléticos, caracterizado por hipercalcemia intracelular y consumo rápido de adenosín trifosfato; esta condición se desencadena por la exposición a 1 o más agentes anestésicos precipitantes incluidos halotano, enflurano, isoflurano, desflurano, sevoflurano y el succinilcolina. Los síntomas de esta afección pueden presentarse en el quirófano o en la Unidad de Cuidados Posanestésicos y se caracteriza por aparición súbita de taquicardia, taquipnea, hipertensión, hipercapnia, hipertermia, acidosis y rigidez musculoesquelética. El dantroleno atenúa la elevación del calcio intracelular y puede ser administrado de forma profiláctica o inmediatamente que se sospeche el diagnóstico. Con el objetivo de conocer las bases fisiopatológicas de este síndrome y las pautas de tratamiento más empleadas se realizó una exhaustiva revisión bibliográfica(AU)

Malignant hyperthermia is a hypermetabolic disorder of the skeletal muscles, characterized by intracellular hypercalcemia and rapid consumption of adenosine triphosphate. This condition appears as a result of the exposure to 1 or more precipitating anesthetic agents, including halothane, enflurane, isoflurane, desflurane, sevoflurane and succinylcholine. The symptoms of this affection may be present in the operating room or in the Unit of Postanesthetic Care and it is characterized by the sudden appearance of thachycardia, tachypnea, hypertensiion, hypercapnia, hyperthermia, acidosis and muscoloskeletal rigidity. Dantrolene attenuates the elevation of intracellular calcium and may be prophylactically administered or as soon as the diagnosis is suspected. In order to know the physiopathological basis of this syndrome and the most used treatment patterns, an exhaustive bibliographic review was made(AU)