Compilación sobre feocromocitoma

TABLA DE CONTENIDOS REVISIÓN/COMPILACIÓN REALIZADA A PROPÓSITO DE PACIENTE CON ESTUDIO DE HIPERTENSIÓN SECUNDARIA EN QUIEN SE CONSIDERÓ EL DIAGNÓSTICO. Tumores suprarrenales*: Presentación de 8 pacientes con estudios bioquímicos e histopatológicos ................................................................................... 2 Tratamento cirúrgico da hipertensão arterial secundária com origem na glândula supra-renal...............................................................................23 Preparação do paciente para a operação ................................................27 CARCINOMA RENAL Y FEOCROMOCITOMA IPSILATERAL. .............................35 Pheochromocytoma and perioperative management ...................................38 [Anesthetic management with propofol during pheochromocytoma resection under bispectral index monitoring] ........................................................60 Regitine Medicamento vital no disponible en Colombia según decreto 481 de 2004 ....................................................................................................60 Clinical features of pheochromocytoma and perioperative anesthetic management .........................................................................................72 Importance of preoperative hypertension control by administration of vasodilators and restoration of blood volume ..........................................76 [Perioperative anesthetic management for the excision of phaeochromocytoma complicated with catecholamine cardiomyopathy] ......................................77 [Clinical features of pheochromocytoma and anesthetic management during perioperative period] ..............................................................................84 Factors Associated with Perioperative Morbidity and Mortality in Patients with Pheochromocytoma: Analysis of 165 Operations at a Single Center1 .............88 Table 4. Perioperative features in operations without and with complications .........................................................................................................96 Surgery and anesthesia for pheochromocytoma--a series of 40 operations. . 102 [Repeated postoperative hypoglycemia in a woman with multiple pheochromocytomas] ........................................................................... 104 The preoperative management of phaeochromocytoma. ........................... 106 [Anesthetic management in pheochromocytoma] ..................................... 109 [Current problems in adrenal surgery] .................................................... 121

Gaceta Médica de Caracas ISSN 0367-4762 versão impressa

http://www.scielo.org.ve/scielo.php?script=sci_arttext&pid=S036747622003000100005&lng=pt&nrm=iso Gac Méd Caracas v.111 n.1 Caracas jan. 2003 LOPEZ, José Enrique, MARCANO TORRES, Myriam, SUKERMAN, Efraín et al. Tumores suprarrenales: Presentación de 8 pacientes con estudios bioquímicos e histopatológicos. Gac Méd Caracas, jan. 2003, vol.111, no.1, p.30-45. ISSN 0367-4762.

LOPEZ, José Enrique, MARCANO TORRES, Myriam, SUKERMAN, Efraín et al. Tumores suprarrenales: Presentación de 8 pacientes con estudios bioquímicos e histopatológicos. Gac Méd Caracas. [online]. jan. 2003, vol.111, no.1 [citado 24 Abril 2008], p.30-45. Disponível na World Wide Web: <http://www.scielo.org.ve/scielo.php?script=sci_arttext&pid=S0367-47622003000100005&lng=pt&nrm=iso>. ISSN 0367-4762.

Tumores suprarrenales*: Presentación de 8 pacientes con estudios bioquímicos e histopatológicos Drs. José Enrique López**, Myriam Marcano Torres***, Efraín Sukerman****, José Enrique López Salazar****, Yolanda López Salazar****, Hermaliz Urbaneja****, Humberto Fasanella**** Academia Nacional de Medicina *Trabajo presentado en la Academia Nacional de Medicina el 10-04-2003. **Individuo de Número, Sillón XVII, Academia Nacional de Medicina. ***Miembro Correspondiente, Puesto Nº 15, Academia Nacional de Medicina. ****Médicos Internistas.

RESUMEN Se estudiaron 8 pacientes con tumores de la glándula suprarrenal, 4 de ellos afectos de feocromocitoma. Una paciente consultó por hipertensión arterial sistémica, hiperglicemia intensa y sintomatología cardíaca interpretada al inicio como infarto agudo del miocardio y luego como miocarditis por catecolaminas aumentadas; el ecocardiograma de la paciente fue normal, las cifras de catecolaminas, ácido vanililmandélico y metanefrinas urinarias estuvieron muy elevadas, los estudios imagenológicos (ecosonograma abdominal, y la aortografía) revelaron tumor de la glándula suprarrenal derecha. Fue sometida a intervención quirúrgica, resecándose la tumoración que medía 10 x 8 x 7 cm.

Los valores de catecolaminas, ácido vanililmandélico, metanefrinas y la glicemia alcanzaron valores normales a la 72 horas del posoperatorio; 1 paciente con hipertensión arterial refractaria; 2 presentaron shock con dolor abdominal intenso, confundiéndose con abdomen agudo quirúrgico.

Los pacientes fallecieron en la sala de emergencia y la autopsia reveló que uno de los pacientes tenía un feocromocitoma de la glándula suprarrenal derecha y el otro era de la suprarrenal izquierda.

Estos pacientes se consideran como secretores de epinefrina en cantidad mucho mayor que la norepinefrina; 2 pacientes presentaron adenoma de una suprarrenal, uno de ellos se presentó con pérdida de la fuerza muscular en los 4 miembros, hipertensión arterial, hipernatremia e hipokalemia importantes, con alcalosis metabólica, ya que el ascenso del bicarbonato sérico es el resultado de la pérdida del ión hidrogenión y migración del potasio al interior de las células, con disminución del potasio sérico, también el magnesio estuvo disminuido. Se interpretó al inicio como enfermedad de Conn, sin embargo, los valores de aldosterona se encontraron dentro de los valores normales. No fue realizada la determinación de renina, la histopatología fue de un adenoma de la glándula suprarrenal derecha. La otra paciente se presentó con hipertensión arterial pos eclampsia, el estudio bioquímico para feocromocitoma estuvo dentro de límites normales y el estudio microscópico de la resección suprarrenal izquierda reveló adenoma no cromafínico. La 7ª historia clínica fue de un paciente con sintomatología y signología, característico del síndrome de Cushing, siendo posteriormente demostrado por el estudio hormonal, imagenológico e histopatológico, la resección del adenoma de la glándula suprarrenal izquierda, condujo a la remisión de la sintomatología. La 8ª historia clínica fue de una paciente con carcinoma suprarrenal funcionante con síndrome de virilización, el tumor infiltró la cara inferior del hígado y la compresión con obstrucción de la vena cava inferior explicó el edema de miembros inferiores; la proteinuria de 24 horas fue normal, lo cual demostró que los edemas no fueron por síndrome nefrótico paraneoplásico. Los exámenes de laboratorio demostraron un incremento de androstenediona, y de testosterona total y libre, que explicaban el síndrome de virilización que presentaba la paciente. Se decidió la intervención quirúrgica, demostrándose la friabilidad del tumor que sangraba al mínimo contacto lo cual impidió su extirpación. Se tomó biopsia para estudio histopatológico, el cual reveló carcinoma funcionante de la glándula suprarrenal.

INTRODUCCIÓN Las dos glándulas suprarrenales se encuentran en situación retroperitoneal, por dentro de la cápsula adiposa renal (fascia de Gerota), inmediatamente por encima y en contacto con el polo superior del riñón. En condiciones normales el peso aproximado de cada una de ellas es de 3 a 5 gramos, midiendo entre 3 y 5 cm de largo, x 2 a 3 cm de ancho, aunque sólo tiene un espesor de 4 a 8 mm.

Su forma triangular es característica a modo de gorro frigio, más típica en el lado derecho que en el izquierdo. La glándula se relaciona en el lado derecho con el hígado y la vena cava inferior mientras que en el lado izquierdo lo hace con el riñón, la aorta y la grasa perirrenal. La irrigación arterial es muy rica a partir de múltiples ramas de la aorta abdominal, de las arterias renales y de la arteria frénica; en contraste con ello el drenaje venoso está constituido por una sola vena, drenando la glándula derecha directamente en la vena cava inferior y la izquierda directamente en la vena renal.

La corteza suprarrenal empieza a aparecer en la cuarta-quinta semana del desarrollo embrionario a partir del blastema mesonéfrico próximo a la raíz del mesenterio, desarrollándose en forma de células acidófilas que posteriormente van a ser rodeadas por otras más pequeñas y basófilas. Las primeras forman la llamada corteza fetal y las basófilas la definitiva. La médula suprarrenal y el sistema nervioso simpático se forman al mismo tiempo hacia la 5ª semana, cuando aparecen células de la cresta neural ectodérmica que emigran invadiendo la corteza fetal y que suponen el esbozo de la zona medular de las glándulas suprarrenales. Al mismo tiempo, otras de esas células llamadas simpatogonias, se situarán a ambos lados de la médula espinal constituyendo los ganglios simpáticos primitivos. El desarrollo completo tanto de la zona medular como la cortical se alcanza después del nacimiento, cuando otros tejidos del mismo origen involucionan de forma fisiológica viniendo a constituir los órganos para aórticos de Zuckerkandt. El conocimiento de estas ectopias de tejido medular hiperfuncionante tiene por tanto una importante relevancia clínica, toda vez que puede haber tejido cromafín ectópico distante, en la vejiga, mediastino, cuello.

La corteza suprarrenal elabora, a partir de un precursor común, el colesterol, glucocorticoides, mineralocorticoides, y hormonas esteroideas sexuales. Los glucocorticoides tienen su principal

representante en el cortisol, mientras que el mineralocorticoide más importante es la aldosterona. La citada producción hormonal se inicia en las mitocondrias y en el retículo endoplasmático de las células corticales a partir del colesterol y el ritmo secretorio sigue el circadiano, por lo que en las determinaciones en sangre será necesario conocer exactamente la hora de la extracción. Los niveles de la hormona adrenocorticotrópica (ACTH) influyen igualmente en la función cortical que ajusta su ritmo de secreción a aquellos niveles. El cortisol plasmático inhibe la producción de la hormona ACTH a través de un feedback negativo con lo que regula la función de la corteza suprarrenal. En el caso de la secreción de aldosterona existe una interrelación con la ACTH, aunque menor, pues por otro lado el sistema renina-angiotensina, así como los niveles de sodio y volumen plasmático, entre otros, actuarán regulando la producción de mineralocorticoides. El potasio por sí solo, cuando está aumentado puede estimular de forma directa la secreción de mineralocorticoides. El catabolismo de las hormonas corticales se efectúa en el hígado donde son conjugadas con el ácido glucorónico, antes de su eliminación por vía urinaria.

La biosíntesis de las catecolaminas en las células cromafines se inicia a partir de la tirosina, que puede ser aportada a través de la dieta o sintetizada en el hígado a partir de la fenilalanina. La dopamina y la noradrenalina que son neurotransmisores, originarán la adrenalina mediante interacción enzimática medular. Las catecolaminas se almacenan en gránulos específicos que ante determinados estímulos salen de las células por exocitosis y son drenadas a la vena en una proporción aproximada de 80 % de epinefrina y un 20 % de norepinefrina, con un efecto biológico extremadamente rápido pero de vida corta.

El uso médico frecuente de los recursos diagnósticos imagenológicos tanto ecosonográficos como tomográficos para las afecciones abdominales ha conducido al descubrimiento casual de algunas tumoraciones suprarrenales. El reto para el clínico es determinar si es o no funcionante, si es benigno o maligno, si debe resecarse o no, y así poder evitar que se realicen pruebas innecesarias o intervenciones quirúrgicas no requeridas por su afección no funcionante y benigna.

Prinz y col. (1) han denominado a los tumores suprarrenales diagnosticados de manera casual, al utilizar un método imagenológico como "incidentalomas". Su frecuencia es elevada ya que varía de 0,3 % a 5 % de todos los pacientes que se someten a estudios imagenológicos abdominales (2). Si se excluyen los pacientes que tienen lesiones malignas primarias extra adrenales concurrentes, la hemorragia suprarrenal, las lesiones adrenales inflamatorias como la tuberculosis y las micosis, la frecuencia de estos incidentalomas verdaderos varían entre 0,6 % y 1,4 %, lo cual concuerda con los resultados de estudios de necropsia que demuestran que adenomas suprarrenales no diagnosticados en vida del paciente se encuentran en el 1,9 % (3).

La valoración y el tratamiento apropiados de los adenomas incidentales son motivo de controversias, a pesar de que siempre se realicen exhaustivos estudios bioquímicos e imagenológicos antes de considerar la necesidad de realizar una intervención quirúrgica. Los criterios más razonables para resolver esta situación serían: 1. Los adenomas adrenocorticales benignos y clínicamente inactivos son descubrimientos frecuentes en la autopsia.

2. Los carcinomas adrenocorticales son raros en extremo y su frecuencia anual se ha estimado entre 0,06 a 0,17 por cada 100 000 habitantes (4,5).

3. Las glándulas suprarrenales son sitios frecuentes de metástasis (6).

El diagnóstico diferencial de una tumoración suprarrenal descubierta de manera incidental en un adulto, abarca: 1. Adenoma cortical, 2. Carcinoma adrenocortical, 3. Feocromocitoma, 4.

Hemorragia o fibroma organizado, 5. Mielolipoma: tumor producido por tejido adiposo adulto, bien diferenciado, mezclado con elementos hematopoyéticos de las 3 series (7), 6. Adenolipoma, 7.

Metástasis.

El propósito de este trabajo será comentar las historias clínicas de 8 pacientes afectos de tumores suprarrenales: 4 feocromocitomas, 2 adenomas, 1 síndrome de Cushing y 1 carcinoma suprarrenal,

y realizar consideraciones sobre la sintomatología, el diagnóstico bioquímico, imagenológico e histopatológico.

Historías clínicas 1ª Historia Clínica. Paciente femenina, de 49 años conocida diabética e hipertensa arterial desde 7 años antes de su ingreso, en tratamiento con insulina NPH 25 U diarias más insulina cristalina y como antihipertensivo Nadolor 160 mg diarios e hidroclorotiazida 25 mg día, consulta en emergencia por presentar en horas de la noche un intenso dolor epigástrico, sin irradiación, acompañado de náuseas, sudoración profusa, malestar general y escalofríos. Su examen físico reveló malas condiciones generales, diaforesis acentuada, sudoración fría copiosa, palidez y somnolencia, Pulso de 140 x m y presión arterial de 160/120 mmHg, los ruidos cardíacos eran rítmicos y se encontraron estertores húmedos en bases pulmonares; el electrocardiograma reveló ausencia de progresión de la onda "R" desde V1 hasta V6, acompañado de un desnivel positivo del segmento ST, la creatinfosfoquinasa MB fue de 34 U (valor de referencia 0-10 U) y el lactato deshidrogenasa fue de 5 780 U (valor de referencia 160-320 U). La paciente fue ingresada con el diagnóstico de infarto agudo del miocardio de la pared anterior y se indica tratamiento en ese sentido. Doce horas después de su admisión la enferma presenta severa hipotensión arterial (presión arterial de 50/30 mmHg), empeoramiento de su estado general, sudoración intensa que empapa el lecho, taquicardia, frialdad de los tegumentos, por lo que recibe infusión parenteral con dopamina, a pesar de lo cual la hipotensión arterial se mantiene durante cuarenta y ocho horas, constatándose para ese momento valores de CK total de 265 U, CKMB de 30 U, lactato deshidrogenasa de 1 640 U y aspartato aminotransferasa de 111 U. Los electrocardiogramas sucesivos muestran descenso progresivo del segmento ST hasta su normalización en 36 horas, con reaparición de las ondas R en las precordiales y sin evidencia de ondas Q ni trastornos de la repolarización ventricular (Figura 1). Se indicó clonidina parenteral con resultados poco satisfactorios. Simultáneamente se aprecia ascenso de la glicemia de 598 mg/dL resistente al tratamiento con elevadas dosis de insulina; se hace el diagnóstico clínico de probable feocromocitoma.

Figura 1. Derivación V2 del electrocardiograma de un paciente con feocromocitoma simulando infarto del miocardio: a. V2 normal 1 semana antes de la crisis. b. y c. V2 muestra elevación del segmento ST en presencia de epigastralgia y diaforesis intensas con presión arterial de 160/120. d. descenso importante del segmento ST. e. 36 horas después del ingreso hay normalización del electrocardiograma y de los niveles séricos de las enzimas.

Estudios bioquímicos: a. ácido vanililmandélico (Orina) 18 mg/24 horas (valor de referencia 0 a 1 mg/24 horas); b. catecolaminas urinarias 213 µg 24 horas (valor de referencia 30 a 100 µg/24 horas); c. metanefrinas urinarias 12,3 mg/24 horas (valor de referencia 0 a 1 mg/24 horas).

Ecocardiograma: normal Urografía de eliminación: se aprecian riñones aumentados de tamaño y una imagen compatible con masa tumoral extrarenal superior derecha que distorsiona parcialmente el grupo calicial superior.

Ecosonograma abdominal: en el hipocondrio derecho, entre el riñón y el lóbulo hepático derecho se observa una masa mixta, predominantemente sólida con áreas anecoicas y áreas hiperecoicas, bien delimitadas, con sombra posterior, de bordes regulares, la cual mide 114 x 92 x 71 mm. El riñón derecho es de forma normal y se encuentra desplazado inferiormente.

Aortograma y angiografía renal: se confirma la presencia de una masa suprarrenal derecha, grande, que debe corresponder a una variante de feocromocitoma quístico, ya que no hay tinción ni revascularización y el llenado venoso es precoz (Figura 2).

Figura 2. Aortografía y angiograma renal. Puede observarse en el lado derecho la arteria renal alongada y de calibre normal. Riñón derecho descendido y desplazado hacia la línea media y una arteria capsular inferior derecha cuyas ramas circunscriben una masa de 9 x 9 cm, en la cual no se aprecia tinción ni vasos neoformados, correspondiente a un feocromocitoma quístico de la glándula suprarrenal derecha.

Con el diagnóstico de feocromocitoma de la glándula suprarrenal derecha es intervenida quirúrgicamente, constatándose durante el acto operatorio la existencia de una masa tumoral, bien encapsulada, de aproximadamente 10 cm de diámetro, de color rojizo, muy vascularizada y de consistencia firme y en cuyo corte se observaron numerosos quistes de pequeño tamaño (Figura 3).

Figura 3. Aspecto macroscópico de un feocromocitoma de la glándula suprarrenal derecha de 10 x 8 x 7 cm. Al corte se observa su color rojo parduzco y numerosos pequeños quistes en su interior.

El estudio histopatológico reveló que el tumor estaba constituido por células poliédricas, irregulares, dispuestas en una sola hilera, con citoplasma granuloso que se tiñe positivamente con la coloración de ácido peryódico de Shift (PAS) (Figura 4). La coloración para reticulina mostró que el estroma del tumor contiene escasas fibras de reticulina y las coloraciones con cromo tiñeron selectivamente el tejido correspondiendo a un feocromocitoma de la glándula suprarrenal derecha.

Figura 4. Corte histopatológico de la glándula suprarrenal (Hematoxilina eosina 250 X). Se observa la existencia de un tumor constituido por células poliédricas, irregulares, generalmente dispuestas en una sola hilera, con citoplasma ligeramente granuloso, correspondiente a su feocromocitoma.

Después de la intervención quirúrgica la paciente mejoró rápidamente tanto desde el punto de vista clínico en relación con su hipertensión arterial, normalización de su glicemia lo mismo que desde el punto de vista de las cifras urinarias de catecolaminas, vanililmandélico y metanefrinas (Cuadro 1).1 Cuadro 1 Valores de catecolaminas pre y posoperatorias en un paciente con feocrocitoma Antes cirugía Catecolaminas orina de 24 horas

en 213 µg

Ácido vanililmandélico orina de 24

18 mg

de 72 horas de 5º día de Valores posoperatorio posoperatorio normales 107 ,4 µg

83, 1 µg

30 a 100 µg

7, 2 mg

4, 0 mg

0,7 a 6,8 mg

1, 1 mg

0, 7 mg

0 a 1,0 mg

en

Metanefrinas en orina 12, 3 mg de 24 horas

2ª Historia clínica. Paciente masculino, de 40 años, con hipertensión arterial sostenida refractaria a tratamiento médico y acompañada de insuficiencia cardíaca y renal. Consultó numerosas veces por cifras tensionales elevadas 260/160 mmHg. Tratamiento con nifedipina, inhibidores de la enzima convertidora de la angiotensina. Progresivamente fue entrando en insuficiencia cardíaca, agregándose a la terapéutica diuréticos del asa tipo furosemida al inicio oral 40 mg b.i.d. y luego endovenosa. Posteriormente los valores de creatinina sérica ascendieron a 3 mg/dL. Las cifras de ácido vanilil mandélico, catecolaminas y metanefrinas en orina de 24 horas estuvieron por encima de los valores normales (10 mg, 150 µg y 8,0 mg) (con valores de referencia 0,7 a 6,8 mg; 30 a 100 µg; 0 a 1 mg respectivamente). El paciente rechazó las pruebas imagenológicas, exigió el alta voluntaria y fallece en su domicilio. El diagnóstico clínico y bioquímico fue de feocromocitoma.

3ª Historia clínica. Paciente femenino, de 24 años, consulta por vómitos y dolor abdominal. Su enfermedad comienza 4 días antes del ingreso con cefalea intensa, vómitos incoercibles, sudoración fría, profusa y crisis de angustia que llega al pánico. Recibe tratamiento antihipertensivo sin mejoría de su cuadro clínico, ingresando al hospital por exacerbación de su sintomatología, acompañada de palidez e intenso dolor abdominal. Pulso de 130 x m, T.A 220/110 mmHg. Midriasis con escasa respuesta a la luz. Ruidos cardíacos normales, taquicardia. Abdomen difusamente doloroso, con defensa pero sin contractura. Hb 17,4 g/dL. Hematocrito 58 %. Leucocitos 22 500 con 85 % de neutrófilos. Electrocardiograma: ritmo sinusal. Frecuencia 130 x m; AP +75º, AQRS +30º ondas P altas y acuminadas en D2, D3; AVF, ondas T invertidas y simétricas en V4, V5 y aplanadas en D1 y AVL (Figura 5), se hace diagnóstico de feocromocitoma y se aplica 1 ampolla de fentolamina (Regitina Ciba de 5 mg) debido a la presión arterial de 260/160, a los 5 minutos la tensión fue de 0 x 0 mmHg, recuperándose luego a 130/60. A la hora sube a 270/160 acompañándose de rubicundez facial, intensa midriasis y piloerección y sin medicación alguna antihipertensiva la paciente incrementa su dolor abdominal y la paciente entra en shock con TA 0 x 0 y fallece. Se hace el diagnóstico de abdomen agudo quirúrgico.

Se requiere de control de parámetros de VMA, catecolaminas, metanefrinas, HVA (ácido homovanílico) en orina de 24 horas después de la cirugía.

1

Figura 5. Electrocardiograma: pueden observarse ondas P altas y acuminadas en DI, DIII y AVF con ondas T invertidas y simétricas en V4, V5 y aplanadas en DI y V6.

Autopsia. Examen macroscópico: peso del corazón 380 g, hipertrofia moderada del ventrículo izquierdo. Suprarrenal derecha de tamaño y peso normal. En la suprarrenal izquierda se aprecia tumor blando, bien encapsulado, de color rosado, muy hemorrágico.

Examen microscópico: tumor de células cromafínicas, bien diferenciado correspondiente a un feocromocitoma (Figura 6).

Figura 6. Examen histopatológico de médula suprarrenal: tumor rico de células cromafínicas, bien diferenciadas, características de un feocromocitoma.

Historia clínica 4. Paciente J.R.P.; 35 años, masculino; historia: 30.718; quien ingresa por dolor abdominal, vómitos y cianosis. Su enfermedad se inicia de manera súbita con vómitos alimentarios y dolor abdominal difuso, luego de la ingestión de una bebida gaseosa; consulta a un facultativo quien constató pulso de 140 p.m. y tensión arterial de 180/140 mmHg, por lo cual el paciente fue medicado con 1 ampolla de clonidina IV diluida y meperidina IM previo a su admisión en el hospital. A su ingreso refirió intensa sudoración, sensación de angustia e inquietud, cefaleas

intensas y frecuentes, palpitaciones y un cuadro similar 5 años antes de su ingreso, que cedió espontáneamente.

Examen físico: paciente en malas condiciones generales, obnubilado. Pulso: 160 l.p.m. T.A.: 0 x 0 mmHg. Temp.: 36º C. Resp.: 22 p.m. Cianosis periférica; retardo del llenado capilar. Midriasis que no responde a la luz. Ruidos cardíacos rítmicos; taquicárdicos, dolor a la palpación de región umbilical e hipocondrio derecho, con defensa pero sin contractura. Se procede a cateterismo vesical, constatándose oliguria extrema.

Electrocardiograma: ritmo sinusal; frecuencia 136 p.m.; eje del QRS: +90º, ondas T aplanadas en todas las derivaciones. Rx de tórax: imagen cardiopulmonar normal. Rx de abdomen: no hay imágenes de niveles líquidos ni neumoperitoneo. Evolución: el paciente recibió tratamiento a base de soluciones hidroelectrolíticas, hidrocortisona; meperidina por el intenso dolor abdominal y oxígeno húmedo, sin obtener mejoría del cuadro clínico. A las 24 horas de su ingreso presenta hiperpirexia de 42º C y fallece. Se hace el diagnóstico de abdomen agudo quirúrgico.

Necropsia: A-495/71. Macroscópico: peso del corazón 370 g, ligera hipertrofia del ventrículo izquierdo, suprarrenal izquierda con peso de 16 g; suprarrenal derecha con peso de 200 g, con un tumor bien encapsulado, blando de color grisáceo.

Estudio microscópico: en la médula suprarrenal derecha se observan abundantes células con pigmento cromafínico, típicas de un feocromocitoma muy diferenciado, con ligera necrosis.

Miocardio con pequeñas cicatrices periarteriales. (Figura 7).

Figura 7. Histopatología de médula suprarrenal. Feocromocitoma bien diferenciado, muy rico en células pequeñas de núcleos redondeados. Observamos el corte de dos venas.

5º Historia clínica. Paciente femenina, de 35 años de edad, quien empieza a presentar hipertensión arterial intensa después de un embarazo complicado con eclampsia grave, lo cual condujo a la interrupción del embarazo. Posteriormente se le encuentran cifras de presión arterial de 240/140 mmHg. En algunas ocasiones sensación de angustia que lleva al pánico, sensación de muerte inminente, taquicardia y sudoración profusa, por lo cual se establece el diagnóstico clínico provisional de feocromocitoma. En el examen físico destacan las alteraciones del fondo de ojo con angioespasmo, pérdida de la relación arteriovenoso, signo de Gunn Salus, arterias en hilo de cobre.

En la auscultación cardíaca se aprecia reforzamiento del 2º ruido en área aórtica y SS ++/4 en área mitral.

Las exploraciones complementarias revelaron: Hb. 9 g/dL, Hto. 27% leucocitos 8 300 x mm3 con fórmula normal. Plaquetas normales; glicemia 83 mg/dL, creatinina 0,9 mg/dL, hierro sérico 11,5 µg (V.N. 60-160 µg/dL). Proteinograma electroforético normal; T3, T4 y TSH normales.

Catecolaminas urinarias 96,3 (V.N: 30 a 100 µg); ácido vanililmandélico 7,1 mg (V.N. 0,7 a 6,9 mg); metanefrinas 1,1 mg (V.N. 0 a 1 mg); cortisol 200 µg (V.N. 170-210 µg); 17- cetoesteroides

urinarios 13,6 mg (V.N. 3 a 15 mg). Estos resultados no son concluyentes para feocromocitoma.

Anemia crónica ferropénica. Electrocardiograma: hipertrofia ventricular izquierda con sobrecarga sistólica. Ecocardiograma: severa hipertrofia concéntrica del ventrículo izquierdo con predominio septal con masa ventricular izquierda de 380 g (V.N. 94 a 276 g); regurgitación discreta mitral.

(Figura 8) Ecosonograma abdominal: neoformación en glándula suprarrenal derecha, bien definida, de 21 x 21 x 16 cm.

Figura 8. Severa hipertrofia concéntrica del ventrículo izquierdo con predominio septal. Masa ventricular izquierda de 390 g (V.N: 94 a 276 g).

(Figura 9). TAC de abdomen: lesión expansiva, no homogénea e irregular en área suprarrenal derecha sugestiva para feocromocitoma, (Figura 10). La paciente fue intervenida quirúrgicamente para la resección de la masa tumoral. Estudio anatomopatológico: tumoración suprarrenal derecha de aspecto adenomatoso (Figura 11), formada por láminas de células claras, nidos y trabéculas de células con citoplasma eosinófilo vacuolado en el cual se observan gránulos de color amarillo oscuro, atipias nucleares y binucleadas (Figuras 12,13).

Figura 9. Eco abdominal. Neoformación en glándula suprarrenasl derecha, bien delimitada de 21 x 21 x 26 cm.

Figura 10. TAC de abdomen: lesión expansiva, no homogénea e irregular en área suprarrenal derecha.

Figura 11. Corte de la tumoración suprarrenal derecha. En algunas zonas se aprecia tejido de color amarillo claro.

Figura 12. A mayor aumento se aprecian los cordones de células claras, con citoplasma eosinofílico vacuolado y gránulos de color amarillo.

Figura 13. A mayor aumento se aprecia que las células claras presentan uno o dos núcleos con atipias.

6ª Historia clínica: paciente masculino, de 50 años, quien consulta por presentar pérdida progresiva de la fuerza muscular en las cuatro extremidades, a predominio izquierdo y expresado por imposibilidad para levantarse de la cama por la mañana, después de varios intentos sólo logra sentarse en la cama pero imposibilitado para ponerse de pie y caminar. Fumador de 20 cigarrillos diarios. Hipertenso arterial desde hace 8 años, con tratamiento irregular. No asmático, no diabético.

Madre y 2 hermanos sufren de hipertensión arterial sistémica. Pulso 80 por minuto, presión arterial 160/120 mmHg, respiración 20 x m. SS ++/4 en área mitral, pulmones normales. Abdomen no se palpan tumoraciones. Exámenes paraclínicos: Hb. 13,4 g/dL, hematocrito 40 %, leucocitos 13 200 con 79 % de neutrófilos, plaquetas 280 000 x mm3, glicemia 142 mg/dL, creatinina 1,1 mg/dL, colesterol total 206 mg/dL (V.N. hasta 200 mg); HDL colesterol 27 mg/dL, LDL colesterol de 143 mg/dL, triglicéridos 181 mg/dL (V.N. hasta 160 mg/dL), cloro 106 l mEq/L, sodio 150 mEq/L (V.N. 140 a 148 mEq/L), potasio 2,3 mEq/L (V.N. 3,6 a 5,2 mEq/L), magnesio 1,70 mEq/L (V.N. 1,80 a 2,40 mEq/L). Exámenes especiales: catecolaminas (orina de 24 horas) 10, 67 (V.N. hasta 260 µg/24 h).

Catecolaminas (suero sanguíneo) 111,3 UI/mL (V.N. hasta 138 UI/mL); metanefrinas (suero sanguíneo) 166 µg/ (V.N. 20 a 320 µg); aldosterona (Suero sanguíneo) 8,9 UI/l (V.N. 4,7 a 21,5 UI/mL); 17 cetohidroxiesteroides urinarios 4,8 (V.N. 5 a 10 U/24 horas).

Ecosonograma abdomino-pélvico: riñones de forma, tamaño y situación normales. No se aprecian tumoraciones suprarrenales.

Tomografía helicoidal de abdomen: en la glándula suprarrenal izquierda se aprecia una pequeña imagen redondeada de 1,5 cm de diámetro, con densidad de partes blandas sugestiva de adenoma, sin que se puedan descartar otras patologías.

Estudio anatomopatológico: muestra de glándula suprarrenal izquierda.

Examen macroscópico: tamaño 7,5 x 4 x 1,5 cm. Superficie externa irregular pardo clara, con tejido adiposo. Al corte se observa de aspecto nodular, firme, de color amarillo ocre intenso, con un

nódulo de mayor tamaño, el cual mide 2 cm de diámetro, bien definido, sin cápsula visible (Figuras 14,15).

Figura 14. Glándula suprarrenal izquierda, la cual mide 7,5 x 4 x 1,5 cm. Al corte se observa el aspecto nodular, firme, de color amarillo ocre intenso.

Figura 15. Glándula suprarrenal izquierda, la cual mide 7,5 x 4 x 1,5 cm. Al corte se observa de aspecto nodular, firme, de color amarillo ocre intenso, con un nódulo de mayor tamaño, de 2 cm de diámetro, bien definido, sin cápsula visible.

Examen microscópico: configuración histológica glomerular-fascicular, con hemorragia antigua y reciente en el área periférica del campo, alternando con infiltrado linfocitario perivascular, en su totalidad conformado por células típicas, de núcleo hipercromático, pequeño, centrales o periféricos, bordeados por citoplasma amplio microvacuolado. Impresión diagnóstica: adenoma de la glándula suprarrenal. No existen indicios de malignidad en el material examinado. El adenoma se observa extirpado en su totalidad.

7º Historia clínica. Paciente masculino, de 38 años, quien consulta por aumento de peso por obesidad que abarca el tronco, el abdomen, la cara y el cuello; debilidad muscular de tipo proximal en miembros superiores e inferiores e hipertensión arterial. Refiere también labilidad emocional,

irritabilidad, depresión, ansiedad que ha conducido a estado de pánico. Nunca ha ingerido corticoesteroides. Examen físico: pulso 80 x m, P.A. 170/110 mm Hg. Obesidad troncular, facies redondeada ("facies de luna llena") con mejillas pronunciadas y rubicundas. Hay depósito de grasa en regiones supraclaviculares y cervical ("cuello de búfalo") y moderado hirsutismo. Amplias estrías atróficas cutáneas de color rojo violáceo, en la parte inferior del abdomen, en caderas, cara interna superior de los brazos, en las axilas y en los muslos. Exámenes de laboratorio: Hb. 17 g/dL, Hto 54 %, glicemia 180 mg/dL, sodio 145 mEq/L, cloro 96 mEq/L, pH 7,48 (alcalosis hipopotasémica e hipoclorémica).

Cortisol urinario: 90 µg/mL (V. de referencia 6 a 30 µg/mL).

A.C.T.H: 2,0 pg/mL (V. de referencia 10 a 90 pg/mL).

El diagnóstico definitivo clínico se estableció por la no disminución del cortisol urinario a menos de 25 µg/mL después de administrar dexametasona 0,5 mg cada 6 horas por 48 horas (4 mg en total).

Cortisol urinario: 88 ug/mL (V. de referencia 6 a 30 ug/mL).

A.C.T.H. 1,5 pg/mL. (V. de referencia 10 a 90 pg/mL).

Esta es una excelente prueba para determinar las causas del síndrome de Cushing; en el de origen hipofisario se consigue inhibir la secreción de ACTH y cortisol, mientras que esto no se logra en tumores suprarrenales o ectópicos. La determinación de ACTH y cortisol plasmático es también muy importante ya que en los síndromes de Cushing por tumores suprarrenales productores de cortisol, las concentraciones de ACTH son indetectables, en general por debajo de 5 pg/mL. También se descartan los de producción ectópica de ACTH y la enfermedad de Cushing causados por un adenoma hipofisario secretor de ACTH, ya que estas concentraciones son normales o elevadas en ambos casos.

Resonancia magnética nuclear de cráneo con Gadolinio: se demostró que la hipófisis era de tamaño normal. Este método ha permitido diagnosticar tumores de 3 a 4 mm de diámetro, sin embargo, el 40 % de los adenomas hipofisarios secretantes de ACTH no son visualizados por este procedimiento.

Ecosonograma y TAC abdominal: se pudo evidenciar la presencia de un tumor sólido en la glándula suprarrenal izquierda que mide 12 x 8 x 6 cm.

TAC de tórax: normal.

Tomando en cuenta la historia clínica, la determinación de cortisol y ACTH, la prueba de supresión con dexametasona y los hallazgos imagenológicos se establece el diagnóstico de síndrome de Cushing debido a tumor suprarrenal izquierdo y se indica la intervención quirúrgica, que consistió en la resección de la glándula suprarrenal izquierda.

Anatomía patológica. Macroscópico: se recibe tumor de la glándula suprarrenal izquierda, con un peso de 180 g.

Examen microscópico: se aprecian combinaciones irregulares de células claras y de células con escaso contenido lipídico que recuerdan las células compactas de la zona reticular normal. En algunas zonas se observan pigmentos de lipofuscina o neuromelanina. No hay mitosis atípica, la arquitectura es definida y no difusa, tampoco hay necrosis.

8º Historia clínica. Paciente femenina, de 23 años de edad, soltera, comerciante, natural de Guasdualito, Estado Portuguesa. Su enfermedad comienza con prurito generalizado, que es interpretado como reacción a los detergentes que usaba frecuentemente y sobre todo cuando pintó su casa. Fue tratada con antihistamínicos y corticoides durante semanas. Medicación ésta que la paciente atribuye a su aumento de peso y la aparición de edemas de miembros inferiores. Estuvo en tratamiento por alergólogos y homeópatas durante 8 meses, refiere que tomó más de 1 000 pastillas durante ese tratamiento. Sufre de rinitis y cefalea, tipo migraña. Asmática cuando pequeña.

Menarquía a los 11 años, no tiene hijos y posee un solo ovario. Estado general relativamente satisfactorio, llama la atención el acné y el hirsutismo. Pulso 80 x m. Presión arterial 130/80 mmHg; talla 1,53, peso 64 kg; I.M.C. 27 kg/m2 de superficie corporal. Aun cuando había tomado esteroides, el hirsutismo, la facies de luna llena, la anchura de las estrías atróficas de color vino tinto, el

aumento de peso y los edemas de miembros inferiores, nos indujeron a pensar en patología suprarrenal, tipo síndrome de Cushing. Se piden exámenes complementarios: Hb: 13,8 g/dL; Hto. 40 %; plaquetas, 220 000 m3. Glicemia 96 mg/dL; colesterol 240 mg/dL; triglicéridos 70 mg/dL; ácido úrico 3,7 mg/dL; IgE 36 UI/mL (V.N. 0,00 a 120 UI/mL), las pruebas alérgicas sólo dieron positivas para el polvo casero; complemento C3 90 (V.N. 60-160); complemento C4 20 (V.N. 2080). Bioquímica especial: catecolaminas (orina de 24 horas) 26,8 µg (V.N. hasta 260 µg/24 horas); catecolaminas suero 116,1 UI/mL (V.N. hasta 380 UI/mL); ácido vanilil-mandélico (orina de 24 horas) 0,51 mg (V:N: 1,22 – 7,8 mg/24 h); proteinuria 33,8 mg/24 horas (V.N. 150 mg/24); 17cetoesteroides urinarios 8,3 mg/24 (V.N. 5 a 10 mg/24 horas); aldosterona (suero sanguíneo) 8,0 mg (V.N. 5 a 30 mg/dL); androstenediona (suero sanguíneo) 3,8 mg/dL (V.N. 0,4 a 2,4 mg/dL); testosterona libre (suero sanguíneo) 8,3 pg/dL (V.N. 0.9 a 3,1 pg/dL); testosterona total (suero sanguíneo) 1,9 ng/dL (V.N: 0,0 a 0,6 ng/dL); cortisol plasmático 8,72 mg/mL (V.N. 6 a 30 mg/mL); A.C.T.H. 12,8 pg/mL (10 a 90 pg/mL).

Ecografía abdomino pelviana: se observa en el lóbulo hepático derecho una imagen redondeada hiperecogénica que mide 51 mm x 45 mm que podría corresponder a una lesión focal. Los riñones son simétricos, situación habitual, conservación de la relación córticomedular, miden 114 mm el derecho y 107 mm el izquierdo. Por encima del polo superior del riñón derecho se observa una tumoración que mide 92 x 43 x 60 mm. Útero y ovario derecho normales. Conclusión: imagen de masa intrahepática y de masa suprarrenal derecha.

TAC helicoidal de abdomen: se evidencia gran lesión de ocupación de espacio, de características heterogéneas, localizada en la glándula suprarrenal derecha, tiene zonas hipodensas centrales con densidades mixtas, el predominio es sólido. Con calcificación irregular, su límite superior está mal definida, con signos de infiltración a hígado, desplaza al riñón hacia abajo y tiene medidas aproximadas de 12 x 9 cm. Es una lesión primaria de la glándula suprarrenal y por las características tiene aspecto de adenocarcinoma. Se observa compresión de la vena cava inferior con defectos de relleno en su interior que sugieren trombosis de la misma. No hay adenomegalias retroperitoneales. A nivel del cuerpo de T12 hay lesión hipodensa de aspecto lítico que sugiere metástasis ósea (Figura 16).

Figura 16. TAC helicoidal de abdomen: se aprecia tumoración de gran tamaño con características no homogéneas con zonas hipo e hiperdensas en glándulas suprarrenal derecha.

Arteriografía aórtica, renales y suprarrenal derecha: hay elongación de la arteria hepática por la gran masa tumoral de la glándula suprarrenal derecha, de igual manera se demuestra el descenso de la arteria renal principal derecha por la masa tumoral. El examen ultra selectivo de la arteria suprarrenal derecha demuestra la existencia de una gran masa tumoral que se nutre exclusivamente por esta arteria o demuestra una gran vascularización de la masa tumoral por existencia de múltiples shunts arteriovenosos y presencia de venas de drenaje precoz. Existen zonas avasculares de la masa tumoral que se corresponden con las zonas de necrosis que se observan en la tomografía. ID. tumor suprarrenal derecho, (Figura 17).

Figura 17. Cateterismo selectivo de la arteria de la glándula suprarrenal derecha. Puede apreciarse la intensa vascularización de tipo tumoral.

Estudio anatomopatológico. Examen macroscópico: material recibido muestra de tumor adrenal derecho. Examen macroscópico: se recibe espécimen consistente de múltiples fragmentos irregulares de color pardo oscuros, variables entre 0,3 y 0,6 cm de consistencia blanda. Examen microscópico: se observan fragmentos tisulares, con islotes de necrosis, en los cuales observamos detritus tisulares, escaso infiltrado inflamatorio agudo y restos hemáticos, bordeados por lesión neoplásica de aspecto neuroendocrino, con proliferación de células de pequeño y mediano tamaño, de núcleos hipercromáticos, en áreas aisladas con patrón cromatínico y nucléolo poco prominente bordeados por citoplasma acidofílico, en áreas extensas. Las células proliferantes adquieren patrón arquitectural variable en pseudorosetas, trabéculas y cestas sólidas. En el espesor de la lesión observamos abundantes luces vasculares de pequeño y mediano tamaño, de paredes delgadas, congestivas, en áreas cercanas a finos tractos conectivos que lobula la lesión. Diagnóstico: tumoración neuroendocrina funcionante de glándula suprarrenal derecha con áreas de necrosis y escaso infiltrado inflamatorio agudo, cónsono con carcinoma suprarrenal.

DISCUSIÓN Para intentar dilucidar el problema diagnóstico diferencial entre afecciones benignas y malignas suprarrenales es necesario seguir los siguientes delineamientos:

1. Realizar una anamnesis cuidadosa. 2. Exploración física meticulosa. 3. Aplicación sensata de las pruebas de laboratorio. 4. Atención particularizada a los síntomas y signos de la hipersecreción hormonal suprarrenal. 5. Posteriormente hay que darle valor a: a. Cambios en el peso corporal. b. Hipertensión arterial. c. Presencia de signos de virilización. d.

Presencia de signos de feminización. e. Presencia de signos del síndrome de Cushing. f. La presencia de hipopotasemia.

6. Debe considerarse la posibilidad metastásica, incluso en pacientes sin antecedentes previos de lesión maligna de pulmones, mamas y melanomas. Cuando las metástasis son bilaterales puede producirse una enfermedad de Addison. 7. Las características imagenológicas de los tumores suprarrenales dan evidencia para el diagnóstico diferencial.

Así el aspecto tomográfico de un quiste suprarrenal es bastante característico y se evidencia como una tumoración lisa, redondeada, de baja densidad y de paredes delgadas (8). Sin embargo, sí se observa que un paciente con un quiste suprarrenal presenta síntomas relacionados con la patología enunciada, si su pared es gruesa o irregular, sí posee un componente de un tejido blando, se puede utilizar aspiración por aguja a través de la ecografía o la tomografía computadorizada: si el líquido aspirado es claro sugiere proceso benigno, mientras que el sanguinolento justifica la valoración citológica o un bloque celular. Son indicaciones para la extirpación del tumor la citología positiva para células neoplásicas. Pruebas de la existencia de aumento de la actividad hormonal y la recidiva después de la aspiración con aguja (9).

Puede ocurrir una hemorragia espontánea sin factores predisponentes, pero en general puede hacerlo como acompañante de diversos problemas como sepsis, trastornos de la coagulación o traumatismos. Suele ocurrir en la glándula suprarrenal derecha, debido a su localización muy vulnerable, por delante de la columna vertebral. Se deben realizar controles imagenológicos repetidos para controlar la resolución del hematoma y descartar la presencia de neoplasia (10).

Pincoffs en 1929 publicó por vez primera un paciente al cual se le diagnosticó un feocromocitoma antes de que fuese intervenido quirúrgicamente (11). El feocromocitoma es una tumoración generalmente benigna, desarrollado a expensas del tejido cromafín, secretor de catecolaminas del tipo norepinefrina y epinefrina. El término deriva de vocablos griegos que significan "color oscuro" por que el tumor toma ese color en presencia de sales de cromo. Habitualmente se localiza en la médula suprarrenal derecha, luego la izquierda, región para aórtica inferior, vejiga urinaria, intra aórtica e intratorácica. Las localizaciones extra adrenales se denominan paragangliomas y pueden comportarse desde el punto de vista bioquímico y clínico de igual manera que los feocromocitomas.

Los clínicos venimos utilizando para el feocromocitoma la regla del 10: diez por ciento son bilaterales, 10 % son extraadrenales, 10 % son malignos, 10 % pueden recidivar, 10 % tienen comportamiento familiar en el contexto de los síndromes NEM II A y NEM II B. No tienen relación con el sexo. En relación con la edad 80 % se diagnostican entre 30 a 60 años, 20 % en la infancia.

Tienen una frecuencia de 1/100 000 habitantes y el 0,1 % de los pacientes son hipertensos arteriales sistémicos y su peso oscila entre 20 a 300 g con peso medio de 100 g. La gravedad del cuadro clínico no está relacionado con el tamaño del tumor, dándose el caso de tumores muy grandes que son metabólicamente menos activos que tumores pequeños. Sintomatología: a. Hipertensión arterial sistémica, como sucedió en nuestro paciente Nº 2, se encuentra en el en 90 % de los casos (12,13). b. Crisis paroxística de hipertensión arterial acompañada de sudoración, palpitaciones y cefalea que puede durar entre pocos minutos a varias horas, suele iniciarse de manera brusca sin provocación aparente, simulando a veces infarto del miocardio (14) como sucedió en nuestro paciente Nº 1 o por stress, durante una anestesia, la palpación quirúrgica, el ejercicio físico. c. Síntomas generales adrenérgicos: nerviosismo, ansiedad, intolerancia al calor, palidez cutánea, debilidad general, astenia, náuseas con o sin vómitos, pérdida de peso, inhibición de la liberación de insulina con hiperglicemia y glucosuria, que producirán hipermetabolismo y aumento de la actividad lipolítica con pérdida de peso, hipercalcemia en los NEM I y NEM II por hiperparatiroidismo asociado.

Hipotensión arterial ortostática secundaria a la disminución del volumen plasmático y a la

inhibición de los reflejos simpáticos. Ambos factores predisponen al paciente con feocromocitoma no diagnosticado a la hipotensión y al shock, cuando se acompaña de dolor abdominal intenso puede simular abdomen agudo quirúrgico, como sucedió en nuestros pacientes Nº 3 y 4. Suele suceder en los feocromocitomas en los cuales predomina la secreción de epinefrina sobre la norepinefrina (15-21) o durante la cirugía o los grandes traumatismos; 10 % de los casos son de tipo familiar por herencia autosómica dominante, bien de manera independiente o como parte de un NEM II; cuando es bilateral se asocia con NEM tipo II A o el NEM tipo II B y puede asociarse a carcinoma medular del tiroides y a adenoma paratiroideo. En ocasiones se asocia con anomalías neuroectodérmicas, como la neurofibromatosis de Von Recklinghausen que aparece en el 5 % de los feocromocitomas y suele aparecer a una edad más temprana, en el tercer decenio de la vida y también puede asociarse a la esclerosis tuberosa, a enfermedades con hemangiomas como la enfermedad de von Hippel Lindau y la de Sturger Weber (21-23).

El tratamiento del feocromocitoma es quirúrgico, con un condicionamiento preoperatorio, realizando bloqueo alfa adrenérgico (fentolamina, prazocin, terazosin, doxazosin, fenoxibenzamina) para controlar la presión arterial y es necesario también expandir el volumen extracelular; con esto se procura reducir las posibles variaciones tensionales o las arritmias durante la anestesia o durante la intervención quirúrgica. Este tratamiento debe utilizarse 2 a 3 semanas previas al acto operatorio.

Posteriormente pueden indicarse betabloqueantes (propanolol, metoprolol, atenolol, esmolol) o un bloqueante alfa y beta adrenérgico tipo labetalol.

El término enfermedad de Cushing (24) se reserva a los síntomas y signos de hipercortisonismo causado por excesiva secreción de corticotropina por un tumor, que generalmente es un microadenoma hipofisario, menor de 1 cm de diámetro. Aparece en 6 personas por millón de habitantes. Los macroadenomas son muy raros y la hiperplasia y los carcinomas son extremadamente raros (25-29). Se denomina síndrome de Cushing suprarrenal no dependiente de ACTH al cuadro clínico producido por tumores suprarrenales secretores de cortisol.

El carcinoma adrenocortical es un tumor poco común que afecta solamente 1 a 2 personas por millón de habitantes. Generalmente se diagnostica en la edad adulta con una media de edad de 44 años. Aun cuando es potencialmente curable en las etapas iniciales, sólo el 30 % de estas neoplasias están confinadas en la glándula suprarrenal cuando se llega a término el diagnóstico. La mayor parte de los pacientes se presentan con síntomas relacionados con una excesiva secreción de hormonas; 60 % a 80 % de estos tumores son funcionales (30,31), como sucedió en nuestra paciente Nº 7 que se presentó con un síndrome de virilización. Los carcinomas no funcionantes pueden ser detectados por síntomas de invasión local por el tumor o sus metástasis. En la evaluación inicial se deben pedir exámenes imagenológicos (ecosonograma, tomografía helicoidal o resonancia magnética nuclear), además de los estudios hormonales correspondientes. La angiografía selectiva y la venografía suprarrenal pueden ser utilizadas en las lesiones más pequeñas y para separar los tumores de la glándula suprarrenal de los tumores del polo superior del riñón. La tomografía por emisión de positrones con fluorodeoxiglucosa marcada con fluor 18 identifica sitios insospechados de metástasis en 3 de 5 pacientes con carcinoma adrenal avanzado y confirmó su ausencia en otros 5 (32).

La supervivencia a los 5 años para los pacientes operados buscando la curación del paciente es aproximadamente del 40 %. Los pacientes que no tienen ninguna evidencia de invasión de los tejidos locales o diseminación a los ganglios linfáticos tienen un mejor pronóstico (33).

La función de ploidía del DNA utilizada como indicadora de pronóstico es todavía controversial (34). Algunos estudios muestran una correlación entre aneuploidía y pronóstico y otros no muestran ninguna correlación (35).

Los sitios más frecuente de metástasis son el peritoneo, pulmones, hígado y huesos, nuestra paciente Nº 7 falleció por metástasis hepáticas y peritoneales. Estos tumores metastáticos pueden tratarse paliativamente con terapia antihormonal con mitotane, un isómero del insecticida DDT, que suprime la producción de cortisol y por tanto disminuye sus niveles plasmáticos y urinarios;

quimioterapia sistémica o en el caso de lesiones localizadas con radioterapia. Los tumores adrenales avanzados llevan a la muerte en períodos menores de 8 meses, a menos que se logre una remisión completa (36-38).

Hasta ahora no hay evidencia convincente de que la terapia sistémica, aumente la duración de supervivencia de los pacientes con cáncer de la glándula suprarrenal.

Agradecimientos.

A los Drs. Ricardo Medina Bello y Oswaldo Guerra Sagarzazu por la toma del material de suprarrenales. A los Drs. Karl Bras, Guillermo Mujica Sevilla y la Dra. Magally de Wadskier por los estudios anatomopatológicos.

REFERENCIAS 1. Prinz RA, Brooks MH, Churchill R. Incidental asymptomatic adrenal masses detected by computed tomographic scanning. JAMA 1982;248:701704.

2. Caplan RH, Structt PJ, Wickus CG. Subclinical hormone secretion by incidentally discovered adrenal masses. Arch Surg 1994;129:291-296.

3. Abecassis M, McLoughlin MC, Langer B. Serendipitous adrenal masses. Prevalence, significance and management. Am J Surg 1985;149:783-788.

4. Copelannd PM. The incidentally discovered adrenal mass. Ann Intern Med 1983;98:940-945.

5. Kummerer RC, Staren ED, Nortrop C. Modern management of adrenocortical carcinoma. Contemp Surg 1992;41:23-29.

6. Bernardino ME. Management of the asymptomatic patient with unilateral adrenal mass. Radiology 1988;166:121-123.

7. Manzanilla-García HA, Martin Del Campo S, Romero-Guadarrama MB. Mielolipoma de la glándula suprarrenal sintomático. Presentación de un caso y revisión de la literatura. Rev Med Hosp Gen Mex 2000;63:124-127.

8. Conway D, Prinz RA. Adrenal cysts. Comtemp Surg 1988;33:77-80.

9. Tung GA, Papanicolaou N. Adrenal Cysts. Imaging and percutaneous aspiration. Radiology 1989;173:107-110.

10. Clark OH. Postoperative adrenal hemorrhage. Ann Surg 1975;182:124-129.

11. Pinkoffs MC. A case of paroxysmal hypertension associated with suprarenal tumor. Tr A Physicians 1929;44:295-299.

12. Kvale WF, Roth GM. Hipertensión permanente y paroxística resultado de feocromocitoma. Clin Med North Am 1961;45:467-478.

13. Engelman K, Hammond WG. Adrenaline production by intrathoracic pheochromocytoma. Lancet 1968;I:609-611.

14. Garzia R, Jennings JM. Feochromocytoma masquerading as a cardiomyopathy. Am J Cardiol 1972;29:568-571.

15. Richmond J, Frazer SC, Millar DR. Paroxymal hypotension due to an adrenaline secreting phechromocytoma. Lancet 1961;I:904-905.

16. Vestea S, Bazin Z, Badea G. Foecromocitom en crize de hipotensione arteriale. Med Int 1965;17:731-735.

17. Sack H, Koll J. Sustained hypotension and shock due to and adrenaline-secreting feochromocytoma. Lancet 1969;47:648-652.

18. Page RB, Raker JW, Berberiche FR. Pheochromocytoma with predominant epinephrine secretion. Am J Med 1969;47:648-649.

19. Hanrin B. Sustained hypotension and shock due to an adrenaline-secreting phechromocytome. Lancet 1962;I:123-124.

20. Sukerman E, López JE, Marcano-Torres M, Cabello-Trillo I. Feocromocitoma con shock simulando abdomen agudo quirúrgico. Rev Col Med Estado Carabobo 1974;4:209-221.

21. Tisherman SE, Tisherman BG, Tisherman SA, Dunmire S, Levey GS, Mulvihill JJ. Three-decade investigation of familiar pheochromocytoma, an allele of von Hippel - Lindau disease? Arch Intern Med 1993;153:2550-2556.

22. Crossey PA, Eng C, Ginalska-Malinowska M, Lennard TV, Wheeler DC, Ponder BA. Molecular genetic diagnosis of von Hippel – Lindau disease in familiar pheocromocytoma. J Med Genet 1995;32:885-886.

23. Grosss DJ, Avishai N, Meiner V, Filon D, Zbar B, Abeliovich D. Familial pheocromocytoma associated with a novel mutation in the von Hippel – Lindau gene. J Clin Endocrinol Metab 1996;81:147-149.

24. Cushing H. The basophil adenoma of the pituitary body and their clinical manifestation (Pituitary basophilism). Bull Johons Hopkins Hosp 1932;50:137-195.

25. Fahlbusch R, Buchfelder M, Müller OA. Transsfenoidal surgery for Cushing disease. J R Soc Med 1986;79:262-260.

26. Mampalam TJ, Tyrrel JB, Wilson CB. Transsfenoidal microsurgery for Cushing disease: A report of 216 cases. Ann Intern Med 1988;109:487493.

27. Kaiser FE, Orth DN, Mukai K, Oppenheimer JH. A pituitary parasellar tumor with extracranial metastases and high partiale suprasellar levels of adrenocorticotropin and related peptides. J Clin Endocrinol Metab 1983;57:649-653.

28. Nawata H, Higuchi K, Ikuyama S. Corticotropin-realeasing hormona adrenocorticotropin producing pituitary carcinoma with metastasis to the liver and lung in a patient with Cushing disease. J Clin Endocrinol Metab 1990;71:1068-1073.

29. Orth DN. Cushing´s Syndrome. New Engl J Med 1995;332:791-801.

30. Icard P, Chapuis Y, Andreassian B. Adrenocortical carcinoma in surgically treated patients: A retrospective study on 156 cases. Surgery 1992;112:972-979.

31. Luton JP, Cerdas S, Billaud L. Clinical features of adrenocortical carcinoma, prognostic factors and the effects of mitotane therapy. New Engl J Med 1990;322:1195-1201.

32. Becherer A, Vierhapper H, Potzi C. Adrenocortical carcinoma. Cancer Biotherapy and Radiopharmaceutical 2001;16:289-295.

33. Lee JE, Berger DH, El-Nagar AK. Surgical management, D.N.A. content and patient survival in adrenal cortical carcinoma. Surgery 1995;118:1090-1098.

34. Camuto P, Schinella R, Gillhrist K. Adrenal cortical carcinoma: Flow cytometric study of 22 cases and ECOG study. Urology 1991;37:380-384.

35. Haak HR, Cornelisse CJ, Hermans J. Nuclear DNA content and morphological characteristics in the prognosis of adrenocortical carcinoma. Br J Cancer 1993;68:151-155.

36. Brennan MF. Adrenocortical carcinoma. Cancer J Clinicians 1987;87:348-365.

37. Cohen K, Gottesman L, Brennan MF. Adrenocortical carcinoma. Surgery 1986;100:1170-1177.

38. Wooten MD, King DK. Adrenal cortical carcinoma: Epidemiology and treatment with mitotane. An a review of the literature. Cancer 1993;73:3145-3154.

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Services

Revista do Colégio Brasileiro de Cirurgiões Print ISSN 0100-6991

Rev. Col. Bras. Cir. vol.33 no.6 Rio de Janeiro Nov./Dec. 2006 doi: 10.1590/S0100-69912006000600014

ARTIGO DE REVISÃO

Tratamento cirúrgico da hipertensão arterial secundária com origem na glândula suprarenal Surgical treatment of secondary arterial hypertension originated from adrenal gland Ruy Garcia Marques , TCBC-RJI; Antonio Felipe SanjulianiII I Professor Adjunto Doutor e Chefe do Departamento de Cirurgia Geral da Faculdade de Ciências Médicas - UERJ; Coordenador da Disciplina de Técnica Operatória e Cirurgia Experimental – FCM – UERJ II Professor Adjunto Doutor do Departamento de Medicina Interna e do Curso de Pós-Graduação em Fisiopatologia Clínica e Experimental – CLINEX – Faculdade de Ciências Médicas – UERJ Endereço para correspondência

ABSTRACT Among the main etiologies of secondary arterial hypertension figure out the tumorous affections of adrenal gland, located on cortex – primary aldosteronism (Conn's syndrome) and Cushing's syndrome – or at glandular medulla – pheocromocytoma. Although these tumors are at most benign the surgical resection is needed in order to eliminate the disturbances provided by them and to limit the mass growth, being curative in about 80-90% of the cases. In this paper some particularities above surgical treatment of these diseases will be focused emphasizing the pre-operative prepare of the patients and the currently preconized approach.

Key words: Pancreas; Pancreaticoduodenectomy; Pancreas/ immunology; Pancreatitis; Carcinoma, ductal.

INTRODUÇÃO Dentre as principais causas de hipertensão arterial secundária, despontam as afecções tumorais que acometem a glândula supra-renal, sejam localizadas no córtex – aldosteronismo primário (síndrome de Conn) e síndrome de Cushing – ou na medula glandular – feocromocitoma. Embora, em sua maioria, esses tumores sejam benignos, a ressecção cirúrgica, curativa em cerca de 80% a 90% dos casos 1,2, é necessária para eliminar os distúrbios humorais deles decorrentes e para impedir o crescimento da massa. Neste artigo, algumas particularidades acerca do tratamento cirúrgico dessas enfermidades serão focalizadas, enfatizando o preparo pré-operatório dos pacientes e a forma de abordagem atualmente preconizada.

ADRENALECTOMIA A adrenalectomia pode ser realizada por dois métodos de acesso: o aberto (ou convencional) e o laparoscópico, ambos permitindo a abordagem transabdominal ou retroperitoneal das lesões.

A ressecção cirúrgica da glândula supra-renal pode ser total ou parcial. Quando o tumor é unilateral, geralmente se realiza a adrenalectomia total, mas, naqueles casos de ocorrência bilateral, deve-se sempre que possível almejar a preservação de parte do tecido glandular (adrenalectomia parcial), em ao menos um dos lados, para que se evite a insuficiência suprarenal pós-operatória e o indispensável uso de corticosteróides, por toda a vida.

No método aberto, as duas vias de acesso transabdominais mais utilizadas são a incisão mediana, supra- e/ou infra-umbilical, e a incisão subcostal, uni- ou bilateral, ambas permitindo a exploração da cavidade abdominal e possibilitando a ressecção de lesões bilaterais ou múltiplas. Especificamente para feocromocitomas, a incisão mediana permitiria, adicionalmente, a ressecção de eventuais paragangliomas. Essas incisões, pelo amplo campo operatório que propiciam, facilitam o controle vascular da glândula, minimizando a ocorrência de complicações operatórias. Entretanto, carreiam com si todo o potencial de morbidade inerente a qualquer operação que envolva a manipulação do conteúdo intra-abdominal. Em grandes tumores, muitos deles malignos, pode ser necessária a exploração cirúrgica através de incisões tóraco-abdominais, aumentando, sobremaneira, a morbidade associada ao procedimento.

As vias de acesso por lombotomias (nos flancos, por incisões póstero-laterais) ou por incisões posteriores (com o paciente posicionado em decúbito ventral), possibilitam a abordagem retroperitoneal das pequenas lesões da glândula supra-renal. A grande vantagem dessa abordagem é a diminuição da ocorrência de aderências e da lesão a órgãos intraabdominais.

Por não envolverem a abertura da cavidade abdominal, habitualmente permitem recuperação rápida do paciente, com alta hospitalar mais precoce. Como grande inconveniente, contudo, constata-se a total impossibilidade da exploração da cavidade abdominal por essas incisões, possibilitando, eventualmente, que seja deixada uma outra tumoração, inicialmente insuspeita, determinando a perpetuação do quadro clínico.3 Quando utilizadas para tratamento de lesões bilaterais, após o término da operação em um dos lados, o paciente é reposicionado, de modo a se conduzir a operação contralateral. As incisões posteriores podem ser longitudinais ou oblíquas, com ou sem ressecção da 12.ª costela, mas, por oferecerem campo operatório restrito, seu uso vem declinando, mormente após a introdução da adrenalectomia laparoscópica.

Desde a sua primeira descrição, em 1992,4 a adrenalectomia por vídeolaparoscópia tem tido utilização progressivamente maior, para tratamento de quase, todos os tumores da glândula supra-renal. Inicialmente, existiam apenas relatos isolados e seletivos de ressecções vídeolaparoscópicas para lesões tumorais da glândula suprarenal. À medida que o método foi se difundindo, com a disponibilização de novos instrumentos e a constatação de sua segurança, a operação minimamente invasiva foi ganhando adeptos. Ademais, propicia recuperação pós-operatória e retorno às atividades habituais mais precocemente, além da menor amplitude das incisões, provendo resultado cosmético superior, em comparação ao

método aberto ou convencional. Este fato vem sendo atestado em grande número de estudos comparativos retrospectivos na literatura médica4-7.

A adrenalectomia vídeolaparoscópica pode ser realizada tanto por via transabdominal (com posicionamento do paciente em decúbito dorsal ou lateral, direito ou esquerdo) quanto retroperitoneal (com posicionamento do paciente em decúbito lateral direito ou esquerdo, de acordo com a lateralidade da lesão). A Tabela 1 mostra as vantagens, desvantagens e principais indicações das principais vias laparoscópicas para acesso às glândulas supra-renais.

Em recente revisão da literatura existente sobre o assunto (2004), Assalia& Gagner(2004) analisando 2.550 procedimentos operatórios laparoscópicos sobre a glândula adrenal, relatados por diversos autores, entre 1990 e 2003, verificaram que a sua principal indicação é o aldosteronoma (síndrome de Conn), com 36,2% dos casos, seguida pela síndrome de Cushing (19,1%), por adenomas não-funcionantes (18,2%) e pelo feocromocitoma (18,0%).7 Nessa revisão, o percentual de complicações dos procedimentos laparoscópicos foi de 9,5% (40% de sangramento intra-e pós-operatório, 13% de complicações infecciosas, incluindo infecção de ferida operatória, e 6,4% de lesões em órgãos intra-abdominais, dentre outras), com taxa de conversão da operação para a via aberta de 3,6%, notadamente devido ao sangramento intra-operatório incontrolável. O maior número de complicações, especialmente as lesões em órgãos intra-abdominais, bem como o emprego de maior tempo operatório, ocorreram mais freqüentemente no início das diversas séries revistas. Como ocorre em todas as situações em que se adota qualquer nova modalidade técnica, a denominada "curva de aprendizado" do método associa-se a um índice maior de complicações e a um período de tempo mais elevado para sua realização. Contudo, na atualidade, o índice potencial de complicações, bem como o tempo operatório, para ambos os métodos, é similar. Mesmo sob o aspecto do custoefetividade, a adrenalectomia vídeolaparoscópica, computando- se todos os seus benefícios, não parece diferir da operação por via aberta, havendo relatos de que essa relação pode ser até melhor, em favor da primeira opção8. Dentre as inúmeras casuísticas compiladas e analisadas por Assalia& Gagner (2004), 7 algumas relataram comparações de parâmetros selecionados acerca de adrenalectomias convencionais (abertas) vs. vídeolaparoscópicas, que estão sumarizados na Tabela 2.

Algumas contra-indicações relativas para a ressecção vídeolaparoscópica incluem risco cardiopulmonar muito elevado e coagulopatia de grande magnitude, intratável. Entretanto, na atualidade, as únicas contra-indicações absolutas são a presença de grandes tumores malignos, com nítida invasão para estruturas vizinhas, e feocromocitomas metastáticos para linfonodos periaórticos7,9. À exceção desses casos, todos os tumores da glândula supra-renal menores que 6 cm podem ser habilmente ressecados por vídeolaparoscópia (para alguns autores, tumores até 10-12 cm também são potencialmente ressecáveis)10-12. Para tumores maiores ou não totalmente determinados pelos métodos de imagem e quando há concomitância de tumores extra-adrenais, o método aberto convencional ainda permanece sendo a escolha inicial. Entretanto, mesmo em alguns desses casos, tem-se indicado a adrenalectomia vídeo-assistida, quando não se determina totalmente, no pré-operatório, se o tumor pode ser completamente ressecado por vídeolaparoscopia. Nesses casos, a dissecção é iniciada por laparoscopia, com conversão planejada para um procedimento aberto para completar a dissecção, ou com a realização de uma incisão abdominal para introdução da mão do cirurgião para auxiliar na dissecção e para retirada de tumoração com maior dimensão. 3 Cabe ressaltar a realização de adrenalectomias laparoscópicas em regime ambulatorial, em pacientes com baixo risco e com pequenos tumores (principalmente, aldosteronomas) 13,14. e, mesmo, com operações robóticas,15,16 com resultados satisfatórios.

O perfeito conhecimento da anatomia das glândulas supra-renais é indispensável para o tratamento das afecções cirúrgicas que nela se instalam. São glândulas pequenas, com cerca de 3 a 6 g, cada uma, apresentando duas porções claramente distintas: córtex e medula. O córtex apresenta coloração amarelo-brilhante, e é dividido em três camadas: glomerulosa, fasciculada e reticular. Na região glomerulosa, responsável pela produção de mineralocorticóides, notadamente aldosterona, é que se situam os aldosteronomas (aldosteronismo primário – síndrome de Conn); na região fasciculada, onde ocorre a produção de glicocorticóides, é que se localizam os tumores causadores da síndrome de Cushing (ACTHindependente). A medula glandular, local de feocromocitoma, contém células cromafíns, de tonalidade vermelho- escuro, secretoras de catecolaminas (adrenalina e noradrenalina). A

glândula supra-renal direita, de formato piramidal, relaciona-se anteriormente com o fígado e com a veia cava inferior, e, posteriormente, com o músculo diafragma; a glândula esquerda, de formato semilunar, relaciona-se anteriormente com o pâncreas, baço e estômago, e, posteriormente, com o músculo diafragma. Apesar do rim direito situar-se mais inferiormente que o esquerdo, a glândula supra-renal direita localiza-se mais superiormente no retroperitônio, em relação à glândula contralateral 17,18.

Em ambos os lados, sua irrigação arterial provém de ramos das artérias frênica inferior, aorta e renal, que originam as artérias supra-renais superior, média e inferior, respectivamente 17,18.

Em geral, essas artérias não oferecem maior dificuldade para controle operatório. Contudo, por serem de pequeno calibre e muito friáveis, podem ser inadvertidamente lesadas durante qualquer procedimento cirúrgico sobre as glândulas.

A drenagem venosa se dá por uma única veia, mas que se dirige para locais distintos, conforme a lateralidade glandular. A veia supra-renal esquerda é tributária da veia renal ipsilateral, e se entende anteriormente sobre a glândula, sendo de fácil visualização durante a manipulação do órgão. Entretanto, à direita, além de mais curta, a veia supra-renal desemboca na parede póstero-lateral da veia cava inferior, o que a torna de mais difícil acesso17,18. Antes de sua manipulação, recomenda-se controle vascular proximal e distal da veia cava inferior, o que minimiza os riscos para a sua dissecção, ligadura e secção.

Os vasos linfáticos, mais abundantes na medula glandular, geralmente acompanham as veias supra-renais, dirigindo- se aos linfonodos que margeiam os grandes vasos abdominais17,18.

FEOCROMOCITOMA De todas as causas de hipertensão arterial secundária, a fisiopatologia do feocromocitoma é a melhor estudada, e o seu diagnóstico é, freqüentemente, o mais prontamente reconhecido.

Esses tumores, compostos por células cromafíns, são capazes de secretar, armazenar e liberar catecolaminas na corrente sangüínea, fazendo parte das chamadas células APUD (amine precursor uptake and decarboxilation), de origem neuroectodérmica. Estas células se localizam mais habitualmente na medula supra-renal, nos plexos neurais simpáticos – paragangliomas (plexos celíaco, mesentérico, renal, adrenal, hipogástrico, testicular e para-vertebral) e no órgão de Zuckerkandl (coleção de células para-aórticas, situadas junto à bifurcação da aorta) mas também podem ser encontradas na região cervical torácica19.

O feocromocitoma é um tumor neuroendócrino potencialmente letal, mais prevalente em mulheres de faixa etária intermediária, entre 30-50 anos de idade, freqüentemente como lesão solitária e benigna, mais comumente à direita que à esquerda, numa proporção de 5:3.20 Conhecido como o "tumor dos 10%", 10% dessas lesões podem ser bilaterais, múltiplas e extra-adrenais, 10% surgem em crianças, 10% são familiares, 10% são malignas e 10% apresentam recorrência no pós-operatório. 3,21-23 Embora geralmente benignos, 2% a 10% dos tumores localizados nas glândulas adrenais e 20% a 40% dos extra-adrenais são malignos, ressaltando-se que, em crianças, é maior a possibilidade de ocorrência de malignidade. A caracterização de malignidade, entretanto, só pode ser comprovada pela presença de metástases, haja vista que, mesmo nos tumores benignos, pode ocorrer invasão local. 3,23 Charles Mayo e Cesar Roux, em 1926, foram os primeiros a relatar a ressecção de feocromocitomas24. Desde essa época, o tratamento desses tumores persiste como um grande desafio para os cirurgiões, devido à importância do quadro clínico desencadeado e à necessidade estrita de cuidados pré e per-operatórios extremamente específicos. Até a cerca de 50 anos, a mortalidade operatória, nesses casos, aproximava-se dos 30%, mas com a crescente percepção de suas complicações potenciais e com o uso de extenso armamentário farmacológico, esse percentual, atualmente, é inferior a 2%25.

A seleção de pacientes para procedimentos abertos ou laparoscópicos deve ser individualizada.

A adrenalectomia por via aberta continua sendo a preferida para pacientes com grandes tumores, naqueles casos em que haja suspeita de malignidade, em massas irregulares, em tumorações extraadrenais ou múltiplas, e quando há ausência de plano de clivagem com órgãos vizinhos ou envolvimento nodal periaórtico, fundamentado em exames de imagem, como tomografia computadorizada, ressonância magnética ou cintilografia com metaiodobenzilguanidina. Para tumores menores do que 6 cm, uni- ou bilaterais, a ressecção por laparoscopia tem se tornado, progressivamente, a opção de escolha. Com a prática, o tempo operatório passa a ser similar, para ambas as vias de acesso, mas com uma importante

redução do tempo de internação hospitalar em pacientes submetidos ao acesso laparoscópico3,5.

A primeira adrenalectomia por vídeolaparoscópica para feocromocitoma foi realizada em 1992.4 O maior obstáculo à sua pronta generalização deveu-se ao receio de que o pneumoperitônio por CO2, parte indispensável do procedimento vídeo- laparoscópico, pudesse desencadear crises hipertensivas com ameaça à vida dos pacientes. Entretanto, com a sua cada vez mais contumaz utilização, tem-se verificado que, com uma perfeita integração peroperatória de cirurgiões e anestesistas, não existe maior risco para essa ocorrência, com diversos autores mostrando que a ressecção vídoelaparoscópica associa-se a alterações hemodinâmicas similares,26 ou até menores,27 em comparação ao método de acesso convencional.

Preparação do paciente para a operação A ressecção de um feocromocitoma ou de um paraganglioma bioquimicamente ativo apresenta grande potencial para complicações per- e pós-operatórias, haja vista a liberação de catecolaminas durante a manipulação do tumor. Efeitos hemodinâmicos e metabólicos significantes estão associados com um súbito decréscimo dos níveis de catecolaminas após a ressecção do tumor28. Avanços nas técnicas de localização dos tumores, preparação e manuseio anestésico adequados resultaram em evolução cirúrgica e pós-operatória significante, com diminuição notável da morbimortalidade operatória, notadamente nos últimos 30 anos19.

O preparo do paciente com feocromocitoma inclui a instituição de bloqueio alfa-adrenérgico, e, em algumas situações, bloqueio beta-adrenérgico. A utilização de antagonistas- alfa parece ser responsável por boa parte do decréscimo da mortalidade perioperatória 23. A fenoxibenzamina (dibenzyline®), um antagonista alfa-adrenérgico de longa ação, tem sido considerado o fármaco de escolha para controlar as alterações da pressão sangüínea e seus sintomas associados. Ela bloqueia os receptores alfa-adrenérgicos de forma nãocompetitiva e dificulta a ação das catecolaminas liberadas pelo tumor, além de permitir expansão de volume intravascular, mas, para tal, necessita ser utilizada por duas ou três semanas232. É iniciada antes da operação, ainda em regime ambulatorial.

A dose inicial é de 10 mg, por via oral, duas vezes ao dia, combinada com monitorização nãoinvasiva da pressão arterial nas posições supina e sentada. A dose é aumentada, por incrementos de 10 mg diários, até que ocorra estabilização da pressão arterial e redução nos sintomas, com dose média de 40 mg/ dia (até 100 mg/dia), com a maioria dos pacientes requerendo 10-14 dias de tratamento, antes da operação 19,25.

Contudo, não existe evidência de que o tratamento pré-operatório com fenoxibenzamina3 por mais do que 14 dias seja mais eficaz do que por quatro a sete dias, ao menos no que se refere ao efeito na pressão arterial per-operatória, na freqüência de pulso e na ocorrência de arritmias cardíacas28.

Elevações significantes da pressão arterial ainda podem ocorrer no per-operatório, especialmente durante a manipulação do tumor, a despeito de adequado bloqueio-alfa préoperatório23,29. Podem ocorrer hipotensão ortostática e taquicardia reflexa, o último secundário à inibição dos receptores alfa-2 pré-sinápticos em neurônios pós-gangliônicos, resultando em liberação de noradrenalina23. O bloqueio alfaadrenérgico também pode contribuir para o estado hipotensivo que se segue à remoção do tumor e pode mascarar a queda na pressão sangüínea, utilizada pelo cirurgião como parâmetro da completa remoção do tumor23.

Os efeitos da fenoxibenzamina dissipam-se em aproximadamente 36 horas (apresenta meiavida > 24 horas) e a administração de grande volume de fluidos intravenosos é freqüentemente necessária no período pós-operatório. Os pacientes tornam-se mais

Uso de bloqueadores alfa por dos o tres semanas antes de la Cirugía 2

3

sonolentos nas primeiras 24 horas após a operação, o que pode se dever a bloqueio alfa-2adrenérgico central persistente30.

Na ausência de arritmias, o pré-tratamento com agentes bloqueadores beta-adrenérgicos não é rotineiramente necessário, embora a associação de bloqueio alfa e beta possa permitir a recuperação do intenso estresse cardíaco e da cardiomiopatia induzidos por catecolaminas, que ocorre em até 60% desses pacientes22,31. Quando indicado, o bloqueio beta-adrenérgico é iniciado após a constatação clínica de eficácia do bloqueio-alfa, em pacientes que apresentam taquicardia persistente ou taquicardia reflexa relacionada ao início do bloqueio alfa, e naqueles com arritmias cardíacas. Entretanto, a eficácia do bloqueio beta-adrenérgico na prevenção de arritmias per-operatórias tem sido questionada32. É importante iniciar o bloqueio alfa antes do bloqueio betaadrenérgico, para evitar a situação de agonismo-beta, em resposta ao bloqueiobeta, em que o paciente apresenta intensa vasoconstricção do excesso alfa-adrenérgico, com risco de ocorrência de hipertensão extrema e aumento da sobrecarga cardíaca, que pode ocasionar edema pulmonar, eventualmente agravado pelo efeito inotrópico positivo do bloqueiobeta23,33.

O labetalol, um bloqueador alfa- e beta-adrenérgico, tem sido utilizado, na dose de até 200 mg, por via oral, quatro vezes ao dia, mas, ocasionalmente, pode precipitar o surgimento de crises hipertensivas. Outra opção é o uso de propranolol, com ação beta-adrenérgica específica, na dose de 40-320 mg/dia23,25.

Antagonistas alfa-1-adrenérgicos competitivos, como prazosin (6-20 mg/dia), doxazosin e terazosin, também podem ser utilizados e parecem oferecer inúmeras vantagens potenciais, comparados à fenoxibenzamina (não disponível em nosso meio). Essa classe de medicamentos não produz taquicardia reflexa, apresenta menor duração de ação e pode ser rapidamente ajustada após a operação, decrescendo a duração da hipotensão pós-operatória23,30. Com o seu uso, vislumbra-se não ser necessária a utilização do bloqueio beta-adrenérgico, a menos que o paciente apresente um tumor secretante seletivo de adrenalina, haja vista que os receptores alfa-2- adrenérgicos (que regulam a liberação de noradrenalina nas terminações nervosas cardíacas) não são antagonizados23,29. O uso combinado de fenoxibenzamina e prazosin também é utilizado, na tentativa de propiciar o controle da pressão arterial antes e durante a operação, e diminuir as complicações inerentes à hipotensão decorrente do uso isolado da fenoxibenzamina25.

Outra possibilidade seria o uso de fentolamina (Regitina®), por via endovenosa, ou mesmo por via oral (Vasomax®), por sua rápida ação no controle da pressão arterial. Todavia, como seu efeito é pouco duradouro, não é rotineiramente utilizada no pré-operatório. Em contraposição, no per-operatório, durante a manipulação tumoral, esse efeito é altamente desejável e a fentolamina (0,1 ml/kg) constitui uma das opções preferenciais para diminuir a pressão arterial decorrente da liberação de catecolamina 25. Antagonistas do canal de cálcio podem ser utilizados com segurança em pacientes normotensos que, ocasionalmente, apresentem episódios de hipertensão paroxística. Esses medicamentos não produzem hipotensão ortostática, além de poderem prevenir a ocorrência de vasoespasmo coronariano e miocardite, induzidos pela liberação de catecolaminas19,23.

O tratamento com metirosina (alfa-metil-paratirosina) no pré-operatório resulta na depleção dos estoques de catecolamina do tumor, por inibição competitiva da tirosinahidroxilase, provendo diminuição da labilidade pressórica e da perda sangüínea intra-operatória1. Com a depleção de catecolaminas, diminui a possibilidade de que o tumor reaja à estimulação 1. Esse fármaco pode ser útil em pacientes com insuficiência cardíaca congestiva, em que o bloqueio alfaadrenérgico produz taquicardia ou o bloqueio beta-adrenérgico diminui a performance cardíaca. Sua associação com um agente bloqueador alfa-adrenérgico pode resultar em melhor controle pressórico e menor necessidade de uso de outras medicações anti-hipertensivas durante a operação, comparado ao bloqueio-alfa isolado34. A metirosina também pode ser empregada para alívio de sintomas, em pacientes portadores de tumores irressecáveis, em que o bloqueio com outros fármacos é insuficiente.

Em pacientes com feocromocitoma, o volume intravascular encontra-se diminuído. Isso se manifesta por hemoconcentração e por mudanças ortotásticas da pressão arterial. A vasoconstricção mediada por alfa-adrenérgicos e, possivelmente, a alteração da permeabilidade capilar, são tidas como responsáveis por esses achados25. O bloqueio alfaadrenérgico, por si, pode possibilitar ao paciente a restauração do volume intravascular. Se

essa restauração é atingida, espera-se que a hemoconcentração resolva ou diminua antes da operação. Por vezes, contudo, há que se aumentar a oferta hídrica, tanto por via oral quanto por via intravenosa, por dois a três dias no pré-operatório.

Comumente, nos dias que antecedem a operação, se utiliza a sedação pré-operatória, com benzodiazepínicos ou outros agentes ansiolíticos, por diminuírem a ansiedade e prevenirem flutuações hemodinâmicas marcantes no período préoperatório imediato 19.

Há que se mencionar que o bloqueio alfa-adrenérgico antes da ressecção do feocromocitoma, apesar de comumente realizado e geralmente recomendado, 35 não é universalmente aceito como absolutamente necessário para o sucesso perioperatório34,36. Boutros et al36 e Steinsapir et al 34 acreditam que o avanço nas técnicas anestésicas e de monitorização, e a disponibilidade de fármacos de ação rápida na correção de alterações hemodinâmicas súbitas, tenham eliminado a necessidade do uso de bloqueio alfa-adrenérgico no preparo para ressecção desses tumores. Entretanto, a maioria dos autores continua preconizando a sua utilização, e, à luz do conhecimento atual, parece prudente se continuar utilizando o bloqueio alfa-adrenérgico, seguido pelo bloqueio betaadrenérgico, quando necessário, na preparação pré-operatória desses pacientes.

Manuseio per-operatório O perfeito entrosamento entre a equipe cirúrgica e o anestesiologista é crucial para o sucesso do manuseio perioperatório de pacientes com feocromocitomas. A discussão pré-operatória de complicações potenciais e a habilidade para trabalhar como uma equipe, suprimem muitos dos problemas que podem surgir durante a operação.

Algumas considerações anestésicas são mandatórias e devem ser instituídas: (1) administração de ansiolíticos; (2) estabelecimento de um cateter para mensuração da pressão arterial, antes da indução; (3) estabelecimento de um cateter intravenoso para administração de medicamentos antihipertensivos; (4) mensuração contínua da pressão venosa central; (5) tratamento das flutuações hemodinâmicas com antihipertensivos e antagonistas betaadrenérgicos; e (6) monitorização contínua para hipotensão e hipoglicemia, após o isolamento do tumor19.

Diversas técnicas anestésicas têm sido usadas para operações em pacientes portadores de feocromocitomas, mas sua descrição desvia-se da pretensão deste artigo. Infusões antihipertensivas de curta ação são preferidas para controle da pressão sangüínea, face à labilidade hemodinâmica antes da ressecção do tumor e a freqüência da hipotensão após.

No per-operatório, o tumor deve sofrer o mínimo possível de manipulação, para não desencadear liberação desenfreada de catecolaminas, com grande risco para o paciente, haja vista que pode ser de difícil controle. Sempre que o cirurgião for manusear o tumor, deve, primeiramente, avisar ao anestesiologista, para que ele se prepare para essa liberação de catecolaminas e possa agir, mesmo profilaticamente, para evitar riscos maiores para o paciente, sendo freqüentemente necessária a suplementação de bloqueadores alfa- e betaadrenérgicos30. Dripping de fentolamina (Regitina®) ou nitroprussiato de sódio são comumente utilizados, durante esse tempo operatório.

Uma vez confirmada a localização do tumor adrenal, o primeiro passo é a identificação, dissecção, ligadura e secção da veia supra-renal, para impedir a liberação de catecolaminas para a circulação sangüínea. Tal tarefa é muito mais facilitada quando se trata de um tumor adrenal à esquerda, haja vista a situação anterior da veia adrenal, desde a porção central da glândula até sua desembocadura na veia renal ipsilateral. Em contraposição, quando o tumor se situa na glândula suprarenal direita, torna-se muito mais difícil a ligadura da veia, devendose tomar cuidados adicionais que assegurem pronto controle proximal e distal da veia cava inferior.

Com a ligadura da veia adrenal, freqüentemente ocorre intensa hipotensão, que deve ser coibida por extensa administração de fluidos. Por vezes, essa hipotensão é tão acentuada que enseja a necessidade de administração de agentes hipertensores, até mesmo de adrenalina, por via intravenosa. Procede-se, então, à ligadura dos ramos arteriais, liberação de possíveis aderências a órgãos vizinhos e ressecção da lesão.

Alguns autores preconizam o uso de fenoldopam, no lugar da fentolamina ou do nitroprussiato, por sua vantagem em não apresentar metabolitos tóxicos. Esse medicamento age por estimulação dos receptores dopaminérgicos-1 que causam vasodilatação periférica enquanto,

simultaneamente, propiciam o aumento do fluxo sangüíneo renal. Sua dose varia entre 0,2 e 0,8 µg/kg/min3.

O uso intra-operatório de sulfato de magnésio, com administração em bolus de 40-60 mg/kg, antes da intubação traqueal, seguido por uma infusão de 2 g/h, tem sido advogada, pela inibição da liberação de catecolamina da medula adrenal e por suas propriedades antiarrítmicas e vasodilatadoras37.

Com cuidadoso manuseio pré- e per-operatório, a incidência de complicações perioperatórias significantes não costuma ser de grande magnitude. Entretanto, a despeito de cuidadosa preparação para a operação, cerca de 30% dos pacientes ainda apresentam um curso perioperatório extremamente lábil. Pacientes com pressões sistólicas mais elevadas, com tumores de grande dimensão, com tumores recorrentes, altas concentrações urinárias de metanefrina e tempo operatório prolongado parecem ser mais propensos a apresentarem essas complicações ou evoluir para morte no período perioperatório2,29. Não há, entretanto, correlação dos níveis de catecolaminas com o risco dessa ocorrência 29.

A recorrência pode ocorrer em cerca de 10% dos casos, e mesmo quando a lesão é benigna, a transformação maligna deve sempre ser considerada. Evidências clínica, bioquímica e radiográfica de recorrência podem levar anos para tornarem- se evidentes3.

Nos últimos 30 anos (1975-2005), 38 pacientes portadores de feocromocitomas foram operados no Hospital Universitário Pedro Ernesto (Departamento de Cirurgia Geral – Faculdade de Ciências Médicas – UERJ). Há que se ressaltar que a maior parte dos pacientes com hipertensão arterial secundária com etiologia na glândula supra-renal, notadamente nos primeiros 20 anos dessa casuística, foi operada pelo Professor Humberto da Silva Peixoto, grande estudioso e entusiasta da Cirurgia Endócrina. Dos 38 tumores, 36 localizavam-se na glândula supra-renal (18 à direita, 14 à esquerda e quatro bilaterais), um em órgão de Zuckerkandl e outro em bexiga (Figura 1). Desses pacientes com tumorações localizadas em ambas as glândulas supra-renais, três (irmãs) apresentavam neoplasia endócrina múltipla tipo IIA (NEM-IIA), com concomitância de carcinoma medular da tireóide.

Houve nítida predominância do sexo feminino (27 pacientes – 71% dos casos). A distribuição dos pacientes por faixa etária está ilustrada na Tabela 3, mostrando preponderância de acometimento nas quarta e quinta décadas.

Em sua grande maioria, os pacientes apresentavam hipertensão arterial paroxística, associada a cefaléia e vômitos; um deles apresentava hipotensão postural, como aspecto clínico preponderante; naquele com feocromocitoma localizado em bexiga, a descarga de catecolaminas era evidenciada à micção. A quase totalidade dos pacientes foi submetida a bloqueio alfa-adrenérgico pré-operatório com fenoxibenzamina (20-40 mg/dia, em duas tomadas), seguido por bloqueio betaadrenérgico com propranolol (40-120 mg/dia, em duas tomadas). Benzodiazepínicos foram utilizados, na dose de 30 mg/ dia (em três tomadas), nos três dias que antecederam as operações. Todos foram submetidos à administração intravenosa adicional de fluidos, nos dois dias prévios às operações. O controle per-operatório da hipertensão desencadeada pela manipulação tumoral foi conseguido com gotejamento de fentolamina; a hipotensão pós-ligadura da veia adrenal direita, em alguns casos, suscitou a utilização de adrenalina intravenosa (aliado a reposição copiosa de fluidos intravenosos).

Trinta e cinco tumores eram benignos (92,1% dos casos), e apenas três malignos: um paciente com metástases hepáticas à operação e dois outros com recorrência tumoral (metástases hepáticas), ambos reoperados cerca de um ano após a primeira intervenção cirúrgica.

Somente os três últimos pacientes de nossa casuística foram operados por via de acesso laparoscópica transabdominal (dois com tumores em adrenal direita e um à esquerda). Desses, os dois primeiros pacientes não apresentaram complicações; a última paciente, ainda na fase de recuperação intra-hospitalar, curiosamente, apresentou quadro de apendicite aguda, sendo realizado apendicectomia (também por vídeolaparoscópia), com boa evolução. Os demais foram submetidos a operações por via de acesso aberta transabdominal (incisões medianas supra- e/ou infra-umbilicais ou subcostais direita e/ou esquerda). Nesses últimos pacientes, algumas complicações ocorreram: duas nefrectomias (por infiltração renal, em casos de doenças malignas), uma esplenectomia (por laceração esplênica acidental de grande monta) e um óbito per-operatório (por sangramento incontrolável, durante adrenalectomia direita).

No período pós-operatório imediato, ainda na Unidade Intensiva, em todos os pacientes ocorreu a normalização da pressão arterial, com ausência de paroxismos. Nos dois pacientes em que houve a recorrência tumoral (por metástases hepáticas), a hipertensão arterial paroxística tornou a surgir nove e dez meses, após a operação inicial.

ALDOSTERONISMO PRIMÁRIO – SÍNDROME DE CONN O adenoma adrenal é a principal causa desta enfermidade (82% a 92%), mas ela também pode se dever a neoplasia maligna e hiperplasia do córtex glandular. Com adenomas, a ressecção cirúrgica comumente leva à regressão da hipocalemia (88% a 100% dos casos)7,10,38. embora hipertensão arterial persistente, mas de controle mais facilitado, possa ocorrer em 12% a 34% dos pacientes, mesmo na ausência de alteração hormonal recorrente39. A etiologia para essa hipertensão persistente ainda não foi determinada, mas acredita-se que o quadro clínico de longo tempo, a coexistência da hipertensão arterial primária, a idade e a história familiar de hipertensão podem determinar essa ocorrência 39,40.

Em contraposição, quando a doença é causada por hiperplasia glandular (usualmente bilateral), a efetividade do tratamento cirúrgico (adrenalectomia subtotal) é baixa, reservandose a indicação operatória somente para aqueles casos em que o tratamento medicamentoso com espironolactona ou outros fármacos não seja eficaz 18,38. Somente em certos tipos de hiperplasia localizados em uma única glândula, nãoresponsivos à terapia medicamentosa, a ressecção cirúrgica pode, eventualmente, apresentar bons resultados 18.

As vias de acesso são as mesmas já mencionadas anteriormente. Contudo, na atualidade, a ressecção total ou parcial de aldosteronomas constitui uma das principais indicações para a utilização da via de acesso laparoscópica (transabdominal ou retroperitoneal), com resultados comparáveis ao da técnica aberta, mas com recuperação pós-operatória muito mais precoce, tornando-a a principal escolha. Esse fato se deve a que, nesta enfermidade, os tumores são geralmente pequenos (< 3 cm), sendo rara a ocorrência de tumores maiores que 6 cm7,10,12,18,39. Como a unilateralidade da lesão é a regra, no que se refere a aldosteronomas, a utilização da via de acesso posterior, com ressecção da 12.ª costela (procedimento de Young), também encontra indicação, mas também vem sendo preterida, a favor da ressecção laparoscópica7,38.

O único fator nitidamente associado com uma resposta favorável após a adrenalectomia por aldosteronismo primário, é o achado histopatológico de um adenoma cortical. Embora alguns casos de hiperplasia também possam ser curados ou parcialmente controlados com a operação, possivelmente devido à redução de células da camada glandular glomerulosa, os resultados usualmente são bastante inferiores18. Outros fatores associados com a cura são a resposta pré-operatória à espironolactona, a idade inferior a 44 anos, o tempo de duração da hipertensão (quanto menor, melhor a resposta) e a ausência de história familiar para hipertensão41.

Nos últimos 32 anos (1973-2005), 16 pacientes portadores de aldosteronismo primário foram operados no Hospital Universitário Pedro Ernesto (Departamento de Cirurgia Geral – Faculdade de Ciências Médicas – UERJ). Foram 12 adenomas, um carcinoma e três hiperplasias glandulares (esses três últimos operados no início da casuística). Os adenomas localizaram-se, preferencialmente, na glândula adrenal direita (oito pacientes – 66,6%); o único carcinoma,

estava localizado na glândula esquerda (idade – 45 anos). Ocorreu preponderância do sexo feminino, com 12 pacientes (75%). A idade variou entre 17-69 anos, com prevalência nas quinta e sexta décadas (Tabela 3).

Os três pacientes com hiperplasia glandular apresentaram persistência da hipertensão arterial, mas com controle facilitado com o uso de anti-hipertensivos. Dos pacientes com adenomas, à exceção do paciente mais idoso (69 anos), todos apresentaram abolição do quadro clínico e laboratorial. Esse único paciente apresentava hipertensão arterial de longa data, no préoperatório, e persistiu hipertenso (embora em menor grau), em fácil controle com antihipertensivos. Em outro desses pacientes com adenomas, como persistia hipertenso, após 30 dias de pós-operatório, detectou-se um tumor na glândula contralateral; foi reoperado, advindo abolição dos sinais e sintomas.

Somente os três últimos pacientes de nossa casuística foram operados por via de acesso laparoscópica transabdominal (dois com tumores em adrenal esquerda e um à direita). Os demais foram submetidos a operações por variadas vias de acesso aberto: nas hiperplasias glandulares, foram realizadas incisões medianas supra-umbilicais; no paciente com carcinoma, a incisão utilizada foi a subcostal; nos demais, incisão subcostal ipsilateral ou incisões posteriores, com ressecção da 12.ª costela.

SÍNDROME DE CUSHING A síndrome de Cushing é causada pela hipersecreção de adrenocorticotropina (ACTH) (síndrome de Cushing dependente de ACTH – doença de Cushing), pela hipersecreção adrenal primária de glicocorticóides (síndrome de Cushing independente de ACTH).ou pela secreção ectópica de ACTH42. Inicialmente, a adrenalectomia era utilizada para tratamento de ambas as situações, síndrome e doença de Cushing, de origem adrenal ou hipofisária, respectivamente.

Posteriormente, a ressecção transesfenoidal do adenoma pituitário mostrouse superior à adrenalectomia, para tratamento da doença de Cushing (dependente de ACTH)43.

Dos pacientes com síndrome de Cushing, 2/3 são causadas pela doença de Cushing, em que, na maioria dos casos (aproximadamente 90%), microadenomas pituitários estão presentes 44.

A secreção ectópica de ACTH, responsável por cerca de 15% dos casos de síndrome de Cushing, está freqüentemente associada com carcinomas de pulmão e outras neoplasias, tumores carcinóides e outros tumores endócrinos (incluindo feocromocitoma) 42.

Na atualidade, a adrenalectomia está indicada para pacientes com doença na glândula suprarenal (20% a 30% dos casos), síndrome ectópica de secreção de ACTH ou na doença hipofisária refratária a outros tratamentos44. Nessas duas últimas situações, quando indicada, realiza-se a adrenalectomia total bilateral.

A síndrome de Cushing decorrente de doença na glândula supra-renal pode se dever a adenomas (9% a 15% dos casos), carcinomas (5% a 10% dos casos) ou hiperplasia adrenal primária (aproximadamente 5% dos casos)42,44. Adenomas, geralmente, apresentam diâmetros menores do que 5 cm; lesões maiores, freqüentemente, são malignas, na maioria das vezes levando ao surgimento de síndrome adrenogenital. Nesses casos, a adrenalectomia (total ou subtotal, uni- ou bilateral, conforme o acometimento) é a opção preferencial para o tratamento da síndrome de Cushing44.

Até cerca de 1970, a via de acesso de escolha era a transabdominal (por incisão mediana ou subcostal). A operação aberta, tanto na síndrome quanto na doença de Cushing, com utilização de grandes incisões, em pacientes com alteração da cicatrização e resistência reduzida à infecção, estava associada a mais de 40% de complicações (hérnias incisionais, esplenectomias incidentais, quadros infecciosos intra-abdominais e da ferida operatória, e hemorragia pós-operatória, dentre outras) e taxas de mortalidade entre 2% e 6% 45. Com o tempo, as vias de acessos posteriores e laterais (flancos), com abordagem retroperitoneal das lesões, passaram a ser as mais utilizadas. Essas incisões eram utilizadas mesmo quando a indicação era a adrenalectomia bilateral, necessitando mudança de posicionamento na mesa operatória para abordagem da glândula contralateral. Desde meados da década de 1990, contudo, a adrenalectomia laparoscópica retroperitoneal passou a ser o tratamento de escolha para as lesões benignas42,44.

Nos últimos 30 anos (1970-2000), 21 pacientes portadores de síndrome de Cushing decorrente de doença na glândula supra-renal foram operados no Hospital Universitário Pedro Ernesto (Departamento de Cirurgia Geral – Faculdade de Ciências Médicas – UERJ). Foram 12

adenomas, dois carcinomas e sete hiperplasias glandulares (esses sete últimos operados na primeira década da casuística). Os adenomas apresentaram distribuição quase equivalente, nas duas glândulas, com sete localizando-se à esquerda e seis à direita; os dois carcinomas estavam localizados na glândula direita (pacientes com 42 e 56 anos). Ocorreu preponderância do sexo feminino, com 17 pacientes (80,9%). A idade variou entre 17-56 anos, com prevalência nas quarta e quinta décadas (Tabela 3).

Quatro dos pacientes com hiperplasia glandular, que persistiram hipertensos após a adrenalectomia, foram posteriormente operados para ressecção transesfenoidal de microadenomas hipofisários. Dos pacientes com adenomas, em oito, a pressão arterial retornou ao normal, além de regressão importante de sinais da síndrome de Cushing; um persistiu com hipertensão de fácil controle; os dois outros evoluíram para o óbito, um peroperatório (por sangramento intenso incontrolável) e outro no pós-operatório recente (com quadro de sepse abdominal por peritonite aguda grave). Os dois pacientes com carcinoma adrenocortical apresentavam tumores de grande extensão, falecendo ainda dentro do primeiro ano de pós-operatório.

Nenhum dos pacientes de nossa casuística foi operado por vídeolaparoscópia (possivelmente porque, nos últimos cinco anos, nenhum paciente com síndrome de Cushing foi operado no nosso serviço). Todos foram submetidos a operações por variadas vias de acesso aberto: nas hiperplasias glandulares, foram realizadas incisões medianas supra-umbilicais; nos adenomas, a via de acesso variou entre a incisão mediana e as incisões posteriores, com ressecção da 12.ª costela; um dos pacientes com carcinoma foi operado por incisão mediana supraumbilical, e o outro, que evoluiu para óbito durante o procedimento cirúrgico, por incisão posterior.

CONSIDERAÇÕES FINAIS O tratamento cirúrgico das afecções da glândula supra- renal que determinam a ocorrência de hipertensão arterial secundária é, no mais das vezes, gratificante, propiciando a cura dos pacientes ou, ao menos, um controle mais facilitado da doença endócrina. A cuidadosa seleção de pacientes, o adequado preparo pré-operatório e a técnica operatória primorosa são essenciais para se alcançar essa meta. Há cerca de dez anos, a via de acesso para tratamento da maioria desses tumores vem sofrendo uma nítida mudança, notadamente daqueles com até 6 cm de diâmetro, passando da abordagem aberta (convencional) para a abordagem laparoscópica, com importantes benefícios para os pacientes.

REFERÊNCIAS 1. Pacak K, Linehan WM, Eisenhofer G, Walther MM, Goldstein DS. Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med. 2001;134(4):315-29. [ Links ] 2. Plouin PF, Duclos JM, Soppelsa F, Boublil G, Cahtellier G. Factors associated with perioperative morbidity and mortality in patients with pheochromocytoma: analysis of 165 operations at a single center. J Clin Endocrinol Metab.

2001; 86(4):1480-6. [ Links ] 3. Bentrem DJ, Pappas SG, Ahuja Y, Murayama KM, Angelos P. Contemporary surgical management of pheochromocytoma. Am J Surg. 2002;184(6):621-4; discussion 624-5. [ Links ] 4. Gagner M, Lacroix A, Bolte E. Laparoscopic adrenalectomy in Cushing's syndrome and pheochromocytoma. N Engl J Med. 1992; 327(14):1033. [ Links ] 5. Prinz RA. A comparison of laparoscopic and open adrenalectomies. Arch Surg. 1995;130(5):489-92; discussion 4924. [ Links ] 6. Dudley NE, Harrison BJ. Comparison of open posterior versus transperitoneal laparoscopic adrenalectomy. Br J Surg. 1999;86(5):656-60. [ Links ] 7. Assalia A, Gagner M. Laparoscopic adrenalectomy. Br J Surg. 2004;91(10):1259-74. [ Links ] 8. Schell SR, Talamini MA, Udelsman R. Laparoscopic adrenalectomy for nonmalignant disease: improved safety, morbidity, and cost-effectiveness. Surg Endosc. 1999;13(1):30-4. [ Links ] 9. Gagner M, Pomp A, Heniford BT, Pharand D, Lacroix A. Laparoscopic adrenalectomy: lessons learned from 100 consecutive procedures. Ann Surg. 1997;226(3):238-46; discussion 246-7. [ Links ] 10. Lezoche E, Guerrieri M, Paganini AM, Feliciotti F, Zenobi P, Antognini F, Mantero F. Laparoscopic adrenalectomy by the anterior transperitoneal approach: results of 108 operations in unselected cases. Surg Endosc. 2000;14(10):9205. [ Links ] 11. MacGillivray DC, Whalen GF, Malchoff CD, Oppenheim DS, Shichman SJ. Laparoscopic resection of large adrenal tumors. Ann Surg Oncol. 2002;9(5):480-5. [ Links ] 12. Miccoli P, Raffaelli M, Berti P, Materazzi G, Massi M, Bernini G. Adrenal surgery before and after the introduction of laparoscopic adrenalectomy. Br J Surg. 2002;89(6):779-82. [ Links ] 13. Gill IS, Hobart MG, Schweizer D, et al. Outpatient adrenalectomy. J Urol. 2000; 163(3):717-20. [ Links ] 14. Edwin B, Raeder I, Trondsen E, Kaaresen R, Buanes T. Outpatient laparoscopic adrenalectomy in patients with Conn's syndrome. Surg Endosc. 2001;15(6):589-91. Epub 2001 Mar 13. [ Links ]

15. Gill IS, Sung GT, Hsu TH, Meraney AM. Robotic remote laparoscopic nephrectomy and adrenalectomy: the initial experience. J Urol. 2000;164(6):2082-5. [ Links ] 16. Young JA, Chapman WH 3rd, Kim VB, Albrecht RJ, Nq PC, Nifong LW, Chitwood WR Jr. Robotic-assisted adrenalectomy for adrenal incidentaloma: case and review of the technique. Surg Laparosc Endosc Percutan Tech.

2002;12(2):126-30. [ Links ] 17. Ortiz V, Kiehl R. Glândulas supra-renais. In: Petroianu A, editor. Anatomia cirúrgica. 1.ª ed. Rio de Janeiro: Guanabara Koogan; 1999. p. 546-8. [ Links ] 18. Desai MM, Gill IS. Primary aldosteronism – Surgical approaches. In: Mansoor GA, editor. 1st ed. Secondary hypertension. New Jersey: Human Press; 2004. p. 149-76. [ Links ] 19. Kinney MA, Narr BJ, Warner MA. Perioperative management of pheochromocytoma. J Cardiothorac Vasc Anesth.

2002;16(3):359-69. [ Links ] 20. Goldstein RE, O'Neill JA Jr, Holcomb GW 3rd, Morgan WM 3rd, Neblett WW 3rd, Oates JA, Brown N, Nadeau J, Smith B, Page DL, Abumrad NN, Scott HW Jr. Clinical experience over 48 years with pheochromocytoma. Ann Surg.

1999;229(6):755-64; discussion 764-6. [ Links ] 21. Suzuki K. Surgical management of pheochromocytoma. Biomed Pharmacother. 2000; 54 (Suppl 1):150S6S. [ Links ] 22. Connery LE, Coursin DB. Assessment and therapy of selected endocrine disorders. Anesthesiol Clin North Am. 2004; 22(1):93-123. [ Links ] 23. Bravo EL. Pheochromocytoma. Curr Ther Endocrinol Metab. 1997;6:195-7. [ Links ] 24. Welbourn RB. Early surgical history of phaeochromocytoma. Br J Surg. 1987;74(7):594-6. [ Links ] 25. Malchoff CD, MacGillivray D, Shichman S. Pheochromocytoma treatment. In: Mansoor GA, editor. 1st ed.

Secondary hypertension. New Jersey: Human Press; 2004. p. 235-49. [ Links ] 26. Sprung J, O'Hara JF Jr, Gill IS, Abdelmalak B, Sarnaik A, Bravo EL. Anesthetic aspects of laparoscopic and open adrenalectomy for pheochromocytoma. Urology. 2000; 55(3):339-43. [ Links ] 27. Fernandez-Cruz L, Taura P, Saenz A, Benarroch G, Sabater L. Laparoscopic approach for pheochromocytoma: hemodynamic changes and catecholamine secretion. World J Surg. 1996;20(7):762-8; discussion 768. [ Links ] 28. Orchard T, Grant CS, van Heerden JA, Weaver A, Irvin GL, Pommier R, Doppman JL. Pheochromocytoma: continuing evolution of surgical therapy. Surgery. 1993;114(6):1153-9. [ Links ] 29. Kinney MA, Warner MA, van Heerden JA, Horlocker TT, Young Jr WF, Schroeder DR, Maxson PM, Warner MA. Perianesthetic risks and outcomes of pheochromocytoma and paraganglioma resection. Anesth Analg.

2000;91(5):1118-23. [ Links ] 30. Prys-Roberts C. Phaeochromocytoma – recent progress in its management. Br J Anaesth. 2000; 85(1):44-57.

Erratum in: Br J Anaesth 2001;86(4):605. [ Links ] 31. Pullerits J, Ein S, Balfe JW. Anesthesia for phaeochromocytoma. Can J Anaesth. 1988; 35(5):526-34. [ Links ] 32. Shupak RC. Difficult anesthetic management during pheochromocytoma surgery. J Clin Anesth .1999;11(3):24750. [ Links ] 33. Sloand EM, Thompson BT. Propranolol-induced pulmonary edema and shock in a patient with pheochromocytoma.

Arch Intern Med. 1984;144(1):173-4. [ Links ] 34. Steinsapir J, Car AA, Prisant LM, Bransome ED Jr. Metyrosine and pheochromocytoma. Arch Intern Med. 1997;157(8):901-6. [ Links ] 35. Roizen MF, Hunt TK, Beaupre PN, Kremer P, Firmin R, Chang CN, Alpert RA, Thomas CJ, Tyrrell JB, Cahalan MK The effect of alpha-adrenergic blockade on cardiac performance and tissue oxygen delivery during excision of pheochromocytoma. Surgery. 1983;94(6):941-5. [ Links ] 36. Boutros AR, Bravo EL, Zanettin G, Straffon RA. Perioperative management of 63 patients with pheochromocytoma.

Cleve Clin J Med. 1990; 57(7):613-7. [ Links ] 37. Pivalizza EG. Magnesium sulfate and epidural anesthesia in pheochromocytoma and severe coronary artery disease. Anesth Analg. 1995;81(2):414-6. [ Links ] 38. Miyake O, Okuyama A. Surgical management of primary aldosteronism. Biomed Pharmacother. 2000; 54(Suppl 1):S146- 9. [ Links ] 39. Rossi H, Kim A, Prinz RA. Primary hyperaldosteronism in the era of laparoscopic adrenalectomy. Am Surg.

2002;68(3):253-6; discussion 256-7. [ Links ] 40. Young WF Jr. Primary aldosteronism: management issues. Ann N Y Acad Sci. 2002; 970:61-76. [ Links ] 41. Sawka AM, Young WF Jr, Thompson GB, Grant CS, Farley DR, Leibson C, van Heerden JA. Primary aldosteronism: factors associated with normalization of blood pressure after surgery. Arch Intern Med. 2001;135(4):25861. [ Links ] 42. Whithworth JA, Mangos GJ, Kelly JJ. Hypertension in Cushing's syndrome. In: Mansoor GA, editor. Secondary hypertension. 1st ed. New Jersey: Human Press; 2004. p. 195-220. [ Links ] 43. Hardy J. Transphenoidal microsurgery of the normal and pathological pituitary. Clin Neurosurg. 1969;16:185-217. [ Links ] 44. Norton JA, Li M, Gillary J, Le HN. Cushing's syndrome. Curr Probl Surg. 2001;38(7):487-545. [ Links ] 45. Chapuis Y, Pitre J, Conti F, Abboud B, Pras-Jude N, Luton JP. Role and operative risk of bilateral adrenalectomy in hypercortisolism. World J Surg. 1996;20(7):775-9; discussion 779-80. [ Links ]

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Formato Documento Electrónico (ABNT) RODRIGUEZ GARCIA, Nuria et al . Carcinoma renal y feocromocitoma ipsilateral. Arch. Esp. Urol., Madrid, v. 58, n. 4, 2005. Disponível em: <http://scielo.isciii.es/scielo.php?script=sci_arttext&pid=S0004-06142005000400013&lng=es&nrm=iso>. Acesso em: 24 Abr 2008. Prépublicação.

Formato Documento Electrónico (Vancouver) Rodríguez García Nuria, Pascual Mateo Carlos, Llanes González Luis, Escalera Almendros Carlos, Berenguer Sánchez Antonio. Carcinoma renal y feocromocitoma ipsilateral. Arch. Esp. Urol. [periódico en la Internet]. 2005 Mayo [citado 2008 Abr 24] ; 58(4): 360-362. Disponible en: http://scielo.isciii.es/scielo.php?script=sci_arttext&pid=S0004-06142005000400013&lng=es&nrm=iso.

Casos Clínicos

CARCINOMA RENAL FEOCROMOCITOMA IPSILATERAL. Nuria Rodríguez García, Carlos Pascual Mateo, Carlos Escalera Almendros y Antonio Berenguer Sánchez.

Servicio de Urología. Hospital Universitario de Getafe. Madrid. España

Luis

Llanes

Y González,

Resumen.- OBJETIVO: presentación de un caso de asociación entre cáncer renal y feocromocitoma ipsilateral, tratado mediante cirugía laparoscópica.

MÉTODO: describimos el caso de una paciente de 67 años que presenta dolor lumbar izquierdo e infecciones urinarias de repetición. Se practicaron ecografía y CT abdominal, que revelaron carcinoma renal y masa suprarrenal ipsilateral confirmada con RMN. Con diagnóstico de carcinoma renal izquierdo y probable metástasis suprarrenal se realizó nefrectomía y suprarrenalectomía izquierda laparoscópica.

RESULTADOS: el estudio anatomopatológico de la pieza quirúrgica demostró un carcinoma de células renales cromófobo y un feocromocitoma suprarrenal.

CONCLUSIONES: la asociación de carcinoma renal y feocromocitoma es infrecuente, como así los sugiere la escasa bibliografía al respecto. La presencia de una masa suprarrenal en un paciente con historia de tumor primario suele corresponder frecuentemente a una enfermedad metastásica pero no debe descartarse un proceso neoplásico primario suprarrenal.

Palabras clave: Carcinoma renal. Feocromocitoma.

Summary.- OBJECTIVES: To report one case of associated renal cancer and ipsilateral pheochromocytoma treated by laparoscopic surgery.

METHODS: We describe the case of a 67-year-old female presenting with left lumbar pain and recurrent urinary tract infections. Ultrasound and abdominal CT scan were performed revealing renal carcinoma and ipsilateral adrenal mass, which was confirmed by MRI. With the diagnosis of left renal carcinoma and possible adrenal metastasis, laparoscopic left nephrectomy and adrenalectomy were performed.

RESULTS: Pathologic study of the specimen reported a chromophobic renal cell carcinoma and adrenal pheochromocytoma.

CONCLUSIONS: The association of renal carcinoma and pheochromocytoma is unfrequent, as suggested by the limited available bibliography on the topic. The presence of an adrenal mass in a patient with history of primary tumor is frequently secondary to metastasic disease, although primary adrenal neoplasia should not be discarded.

Keywords: Renal carcinoma. Pheochromocytoma Correspondencia Nuria Servicio Hospital Ctra de 28905 Getafe Madrid.. (España) Trabajo recibido: 29 de noviembre de 2004

Rodríguez de de Toledo,

Km.

García.

Urología.

Getafe 12,500.

INTRODUCCIÓN El feocromocitoma es un tumor poco frecuente, más prevalente en individuos entre 30 y 50 años y más frecuente en mujeres. En algunas familias se hereda de forma autonómica dominante, asociada a síndromes neurectodérmicos, siendo en estos casos su incidencia mayor. Hasta el 17% de los casos de feocromocitoma pueden ser clínicamente silentes. En el resto, la presentación es en forma de crisis hipertensivas paroxísticas, que se acompañan de cefalea, dolor precordial y ansiedad. Ante la sospecha de este tumor se debe efectuar una determinación de catecolaminas en sangre u orina (1).

CASO CLÍNICO Mujer de 67 años con antecedentes médicos de hiperlipemia, hipertensión sin tratamiento farmacológico y hernia de hiato. Es remitida a nuestro servicio por dolor lumbar izquierdo e infecciones urinarias de repetición. Se practicó ecografía que evidenció una masa renal izquierda de 3,7 centímetros en polo superior, de características heterogéneas. El TAC abdominal confirmó una masa renal izquierda compatible con carcinoma renal y lesión nodular suprarrenal ipsilateral. Se realizó RMN para definir mejor las características de la lesión suprarrenal, no cumpliendo ésta las características de adenoma, por lo que se diagnostica como posible metástasis. Se realizó nefrectomía y suprarrenalectomía izquierdas laparoscópica, durante la cual la paciente presentó tensión arterial y frecuencia cardíaca normales. En el postoperatorio inmediato la paciente presentaba tensiones arteriales sistólicas de 150-185 y diastólicas de 75-85 mmmHg. A los cinco días de la intervención se instauró un cuadro de deterioro del estado general e hipertensión (170/90- 190/100 mmHg) refractaria a la administración de enalapril y captopril. Un nuevo TAC abdominal identificó un derrame pleural bilateral sin otros hallazgos de interés. Se pautó tratamiento diurético y antagonistas receptor angiotensina-2 (ARA-2), con lo que se consiguió un buen control de la tensión arterial.

Tras este episodio la evolución de la paciente fue satisfactoria.

La anatomía patológica identificó un carcinoma renal tipo cromófobo con extensión a grasa perirrenal (pT3aNxMx) y feocromocitoma en glándula suprarrenal.

DISCUSIÓN Toda masa suprarrenal, aún siendo asintomática , debe ser filiada para descartar que se trate de un tumor funcionante, evitándose así los riesgos que implica una cirugía. En un 4% de todos los pacientes sometidos a TAC abdominal o torácico se encuentran masas suprarrenales (incidentalomas). En los casos en que ésto constituye un hallazgo en el estudio de una neoplasia recientemente diagnosticada, se asume muchas veces que se trata de lesiones metastásicas. El origen más frecuente de metástasis en las suprarrenales son, por orden de frecuencia: carcinoma renal, melanoma, cáncer colorrectal, pulmón y próstata (2).

Asumir dicha naturaleza metastásica puede implicar llevar a cabo una terapia inapropiada e incluso retrasar el tratamiento del tumor primario. La asociación de carcinoma renal y feocromocitoma es excepcional; en una revisión bibliográfica de 33 años (1961-2001), se han hallado cinco casos más (3,4,5). Existen pocos estudios que analicen la evaluación y tratamiento quirúrgico de las masas suprarrenales en pacientes con historia de una enfermedad maligna. Además, en los estudios sobre incidentalomas suelen excluirse los pacientes con neoplasias extra-adrenales sincrónicas o metacrónicas. Así mismo, en aquellos estudios sobre adrenalectomía se excluyen pacientes con tumores suprarrenales primarios (2).

Por tanto, las metástasis suprarrenales son la causa más frecuente de masa suprarrenal en pacientes con las neoplasias antes citadas, pero no debe descartarse un tumor primario a menos que se practiquen las

pruebas diagnósticas pertinentes. Es llamativo en esta paciente la ausencia de crisis hipertensivas y el cortejo sintomático del feocromocitoma incluso durante la inducción anestésica, lo que nos hizo pensar que nos hallábamos ante una metástasis del carcinoma renal. Las elevaciones tensionales que acontecen en el postoperatorio temprano de nuestra paciente reflejan cambios en la distribución de líquidos así como inestabilidad autonómica (3). En estos casos suele ser efectivo el empleo de diuréticos, beta bloqueantes y bloqueantes de los canales del calcio. En casos de refractariedad sería necesario tratamiento con fentolamina; la respuesta a este fármaco sugeriría que la exéresis del feocromocitoma no ha sido completa y sería necesaria una segunda intervención, previa determinación de catecolaminas en orina y sangre (1,6).

BIBLIOGRAFIA y LECTURAS RECOMENDADAS (*lectura de interés y **lectura fundamental) 1. KLINGLER, H.C.; KLINGLER, P.J.; MARTIN, J.K. y cols.: "Pheochromocytoma". Urology, 57, 2001. **2. JEFFRY, T.; MD CARLTON, C.; BARNETT, JR. y cols.: "Evaluation and surgical resection adrenal masses in patients with a history of extra-adrenal malignancy". Surgery, 130: 1060, 2001. **3. EGEA, J.; FERNÁNDEZ DEL BUSTO, E.; GONZÁLEZ DE ZÁRATE, J. y cols.: "Emergencia hipertensiva durante la cirugía de un carcinoma renal asociado a feocromocitoma no diagnosticado". Arch.

Esp. Urol., 54: 707, 2001.

4. OZENZ, A.; RUACAN, S.; BAYKAL, A.: "Renal cell carcinoma and ipsilateral pheochromocytoma with neoplasm-to-neoplasm metastasis". J. Urol., 157: 1831, 1997.

5. SAGE, D.; HASSAN, T.; GRANDE-GOBURDHUN, J. y cols.: "Association of pheochromocitoma with homolateral clear cell renal carcinoma". Ann. Pathol., 11: 186, 1991.

6. LO, C.Y.; VAN HEERDEN, J.A.; SOREIDE, J.A. y cols.: "Adrenalectomy for metastasis disease to the adrenal glands". Br. J. Surgery, 83: 528, 1996. © 2008 INIESTARES, S.A. C/ General Ampudia, 14 28003 Madrid-España Tel.: 91 535 78 92

urologia@arch-espanoles-de-urologia.es

Base de datos MedLine: http://www.ncbi.nlm.nih.gov/PubMed/ TERMINOS DE BÚSQUEDA:

Pheochromocytoma and perioperative management Items 1 - 82 of 82 One page.

1: Eur J Anaesthesiol. 2008 Jan;25(1):79-80.

Related Articles, Links

Perioperative management of late metastasis of phaeochromocytoma in clavicle.

Ramos I, González I, Martínez R, Trillo L, Sánchez J. Publication Types: Letter

PMID: 18228643 [PubMed - in process] 2: Anasthesiol Intensivmed Notfallmed Schmerzther. 2008 Jan;43(1):20-7; quiz 28.

Related Articles, Links

[Anaesthesia for patients with phaeochromocytoma - specifics, potential complications and drug strategies] [Article in German] Knüttgen D, Wappler F. Klinik für Anästhesio logie und operative Intensivmedizin des Krankenhauses Köln-Merheim. knuettgend@klinikenkoeln.de Perioperative management of patients with phaeochromocytoma requires detailed knowledge on the pathophysiology and potential complications. Intraoperatively, hypertensive crisis and tachyarrhythmias may occur resulting from massive catecholamine release. Thus, preoperative treatment with the alpha-antagonist phenoxybenzamine4 is obligatory. In contrast, sodium 4

dibenzyline (Phenoxybenzamine

Hydrochloride)

capsule

[WellSpring Pharmaceutical Corporation] DESCRIPTION Each Dibenzyline capsule, with red cap and body, is imprinted WPC 001 and 10 mg, and contains 10 mg of Phenoxybenzamine Hydrochloride USP. Inactive ingredients consist of D&C Red No. 33, FD&C Red No. 3, FD&C Yellow No. 6, Gelatin NF, Lactose NF, Sodium Lauryl Sulfate NF and Silicon Dioxide NF. Dibenzyline is N-(2-Chloroethyl)-N-(1-methyl-2-phenoxyethyl)benzylamine hydrochloride:

Phenoxybenzamine hydrochloride is a colorless, crystalline powder with a molecular weight of 340.3, which melts between 136°and 141°C. It is soluble in water, alcohol and chloroform; insoluble in ether.

CLINICAL PHARMACOLOGY Dibenzyline (phenoxybenzamine hydrochloride) is a long-acting, adrenergic, alpha-receptor-blocking agent, which can produce and maintain "chemical sympathectomy" by oral administration. It increases blood flow to the skin, mucosa and abdominal viscera, and lowers both supine and erect blood pressures. It has no effect on the parasympathetic system.

Twenty to 30 percent of orally administered phenoxybenzamine appears to be absorbed in the active form. ¹ The half-life of orally administered phenoxybenzamine hydrochloride is not known; however, the half-life of intravenously administered drug is approximately 24 hours. Demonstrable effects with intravenous administration persist for at least 3 to 4 days, and the effects of daily administration are cumulative for nearly a week. ¹ INDICATION AND USAGE Dibenzyline is indicated in the treatment of pheochromocytoma, to control episodes of hypertension and sweating. If tachycardia is excessive, it may be necessary to use a beta-blocking agent concomitantly.

CONTRAINDICATIONS Conditions where a fall in blood pressure may be undesirable; hypersensitivity to the drug or any of its components.

WARNING Dibenzyline-induced alpha-adrenergic blockade leaves beta-adrenergic receptors unopposed. Compounds that stimulate both types of receptors may, therefore, produce an exaggerated hypotensive response and tachycardia.

PRECAUTIONS General−Administer with caution in patients with marked cerebral or coronary arteriosclerosis or renal damage. Adrenergic blocking effect may aggravate symptoms of respiratory infections.

Drug Interactions ²−Dibenzyline (phenoxybenzamine hydrochloride) may interact with compounds that stimulate both alpha- and beta-adrenergic receptors (i.e., epinephrine) to produce an exaggerated hypotensive response and tachycardia.(See WARNING.) Dibenzyline blocks hyperthermia production by levarterenol, and blocks hypothermia production by reserpine.

Carcinogenesis and Mutagenesis Case reports of carcinoma in humans after long-term treatment with phenoxybenzamine have been reported.

Hence long-term use of phenoxybenzamine is not recommended. ³, ⁴ Carefully weigh the benefits to risks before prescribing this drug.

Phenoxybenzamine hydrochloride showed in vitro mutagenic activity in the Ames test and mouse lymphoma assay; it did not show mutagenic activity in vivo in the micronucleus test in mice. In rats and mice, repeated intraperitoneal administration of phenoxybenzamine hydrochloride (three times per week for up to 52 weeks) resulted in peritoneal sarcomas. Chronic oral dosing in rats (for up to 2 years) produced malignant tumors of the small intestine and non-glandular stomach, as well as ulcerative and/or erosive gastritis of the glandular stomach. Whereas squamous cell carcinomas of the non-glandular stomach were observed at all tested doses of phenoxybenzamine hydrochloride, there was a no-observed-effect-level of 10 mg/kg for tumors (carcinomas and sarcomas) of the small intestine. This dose is, on a body surface area basis, about twice the maximum recommended human dosage of 20 mg b.i.d.

Pregnancy Teratogenic Effects Pregnancy Category C. Adequate reproductive studies in animals have not been performed with Dibenzyline (phenoxybenzamine hydrochloride). It is also not known whether Dibenzyline can cause fetal harm when administered to a pregnant woman. Dibenzyline should be given to a pregnant woman only if clearly needed.

Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from phenoxybenzamine hydrochloride, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS The following adverse reactions have been observed, but there are insufficient data to support an estimate of their frequency.

Autonomic Nervous System* :Postural hypotension, tachycardia, inhibition of ejaculation, nasal congestion, miosis. *These so-called "side effects" are actually evidence of adrenergic blockade and vary according to the degree of blockade.

Miscellaneous: Gastrointestinal irritation, drowsiness, fatigue.

OVERDOSAGE SYMPTOMS-These are largely the result of blocking of the sympathetic nervous system and of the circulating epinephrine. They may include postural hypotension, resulting in dizziness or fainting; tachycardia, particularly postural; vomiting; lethargy; shock.

TREATMENT When symptoms and signs of overdosage exist, discontinue the drug. Treatment of circulatory failure, if present, is a prime consideration. In cases of mild overdosage, recumbent position with legs elevated usually

nitroprusside is the substance of choice for intraoperative control of blood pressure. alpha-blocking agents may be used in phaeochromocytoma but only under sufficient alpha-blockade. Removal of a malignant tumour of the adrenal gland may induce massive haemorrhage, and thus anaesthetic management has to be modified.

Publication Types: English Abstract Review PMID: 18196488 [PubMed - indexed for MEDLINE] 3: Can J Urol. 2007 Dec;14(6):3757-60.

Related Articles, Links

Pheochromocytoma of the urinary bladder.

Safwat AS, Bissada NK.

restores cerebral circulation. In the more severe cases, the usual measures to combat shock should be instituted. Usual pressor agents are not effective. Epinephrine is contraindicated because it stimulates both alpha- and beta- receptors; since alpha- receptors are blocked, the net effect of epinephrine administration is vasodilation and a further drop in blood pressure (epinephrine reversal).

The patient may have to be kept flat for 24 hours or more in the case of overdose, as the effect of the drug is prolonged. Leg bandages and an abdominal binder may shorten the period of disability.

I.V. Infusion of levarterenol bitartrate ** may be used to combat severe hypotensive reactions, because it stimulates alpha-receptors primarily. Although Dibenzyline (phenoxybenzamine hydrochloride) is an alpha adrenergic blocking agent, a sufficient dose of levarterenol bitartrate will overcome this effect.

The oral LD50 for phenoxybenzamine hydrochloride is approximately 2000 mg/kg in rats and approximately 500 mg/kg in guinea pigs.

DOSAGE AND ADMINISTRATION The dosage should be adjusted to fit the needs of each patient. Small initial doses should be slowly increased until the desired effect is obtained or the side effects from blockade become troublesome. After each increase, the patient should be observed on that level before instituting another increase. The dosage should be carried to a point where symptomatic relief and/or objective improvement are obtained, but not so high that the side effects from blockade become troublesome.

Initially, 10 mg of Dibenzyline (phenoxybenzamine hydrochloride) twice a day. Dosage should be increased every other day, usually to 20 to 40 mg 2 or 3 times a day, until an optimal dosage is obtained, as judged by blood pressure control.

Long-term use of phenoxybenzamine is not recommended (see PRECAUTIONS Carciongenesis and Mutagenesis) STORAGE Store at 25°C (77°F); excursions permitted to 15°- 30°C (59°- 86°F) [See USP Controlled Room Temperature].

HOW SUPPLIED Dibenzyline (phenoxybenzamine hydrochloride) capsules, 10 mg, in bottles of 100 (NDC 65197-001-01).

REFERENCES 1.

Weiner, N.: Drugs That Inhibit Adrenergic Nerves and Block Adrenergic Receptors, in Goodman, L., and Gilman, A., The Pharmacological Basis of Therapeutics, ed. 6, New York, Macmillan Publishing Co., 1980, p. 179; p. 182.

2.

Martin, E.W.: Drug Interactions Index 1978/1979, Philadelphia, J.B. Lippincott Co., 1978, pp. 209-210.

3.

Nettesheim O, Hoffken G, Gahr M, Breidert M: Haematemesis and dysphagia in a 20-year-old woman with congenital spine malformation and situs inversus partialis [German]. Zeitschrift fur Gastroenterologie. 2003; 41(4):319-24.

4.

Vaidyanathan S, Mansour P, Soni BM, Hughes PL, Singh G: Chronic lymphocytic leukaemia, synchronous small cell carcinoma and squamous neoplasia of the urinary bladder in a paraplegic man following long-term phenoxybenzamine therapy. Spinal Cord. 2006;44(3):188-91.

** Available as Levophed® Bitartrate (brand of norepinephrine bitartrate) from Abbott Laboratories.

Department of Urology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205-7199, USA. OBJECTIVE: Pheochromocytoma of the urinary bladder is rare. Herein, we report our experience with pheochromocytoma of the urinary bladder in three patients. MATERIALS AND METHODS: Records of three consecutive patients diagnosed with bladder pheochromocytoma were reviewed.

Patients' age, sex, presentation, associated conditions, diagnostic and imaging modalities utilized, management and follow up were recorded. RESULTS: The three patients included one child and two adults. An 11-year-old female presented with hematuria and bladder mass. Transurethral biopsy was non-diagnostic and she underwent partial cystectomy with eventual diagnosis of pheochromocytoma. Of the two adults, one was a 35-year-old female with history of gestational tumor who was being followed with computed tomography (CT) scan. A bladder mass was incidentally discovered. Transurethral resection of bladder tumor revealed pheochromocytoma and she underwent partial cystectomy. In retrospect, she has had symptoms related to micturition. The third patient is a 32-year-old male, who presented with fainting on voiding which suggested pheochromocytoma. He was also managed with partial cystectomy. There were no perioperative complications in any of the three patients. CONCLUSIONS: Pheochromocytoma of the urinary bladder has unique characteristics. A high index of suspicion should be present in patients who present with suggestive symptoms associated with voiding. In this series, all patients were successfully managed with partial cystectomy.

Publication Types: Case Reports PMID: 18163929 [PubMed - indexed for MEDLINE] 4: Interact Cardiovasc Thorac Surg. 2006 Aug;5(4):505-6. Epub 2006 Apr 13.

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Off-pump myocardial revascularizaton in a Jehovah's Witness patient with pheochromocytoma.

Baciewicz FA, Williams M. Division of Cardiothoracic Surgery, Wayne State University, 3990 John R, Suite 2102, Harper, Professional Building, Detroit, MI 48201, USA. Fbaciewi@DMC.org We present a female Jehovah's Witness patient with concomitant severe left main and left anterior descending coronary artery disease and pheochromocytoma who underwent successful off-pump myocardial revascularization. Perioperative management of this patient included alpha-blockade with Doxazosin followed by beta-blockade with Metoprolol. A short-acting Phentolamine was used for alpha-blockade before surgery. Because she refused transfusion of blood and blood products, erythropoietin and iron was used to increase her hemoglobin in both the preoperative and postoperative periods. Intraoperative strategy included off-pump myocardial revascularization, the use of a pulmonary catheter to monitor hemodynamics, the use of norepinephrine and epinephrine to increase blood pressure, the employment of the cell saver, and transesophageal echocardiography.

PMID: 17670629 [PubMed]

5: J Pak Med Assoc. 2007 Mar;57(3):140-6.

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Perioperative management of pheochromocytoma: anaesthetic implications.

Ahmed A. Department of Anaesthesia, Aga Khan University Hospital, Karachi.

Pheochromocytoma is a catecholamine producing tumour that can cause severe hypertension and other systemic disturbances. The perioperative management of pheochromocytoma remains a complicated anaesthesia challenge requiring intensive preoperative preparation and vigilant intraoperative and postoperative care. In this article the perioperative management of pheochromocytoma is reviewed by first summarizing its pathophysiology, clinical aspects and diagnosis, then highlighting the preoperative optimization of the patient and finally describing the intraoperative and postoperative anaesthetic management in the light of the current information.

Publication Types: Review PMID: 17432020 [PubMed - indexed for MEDLINE] 6: Anasthesiol Intensivmed Notfallmed Schmerzther. 2007 Mar;42(3):170-8.

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[Anaesthesia for patients with adrenal gland diseases] [Article in German] Knüttgen D, Wappler F. Klinik für Anästhesiologie und operative Intensivmedizin, Krankenhauses Köln-Merheim.

Perioperative management of patients with adrenal gland diseases requires detailed information on the individual endocrine status and the potential complications. Typical signs of primary hyperaldosteronism (Conn's syndrome) comprise arterial hypertension, hypokalaemia and metabolic alkalosis. In such cases preoperative treatment with spironolactone is highly recommended. In patients with hypercortisolism (Cushing's syndrome) the following concomitant disorders must be considered particularly: arterial hypertension, osteoporosis, vulnerable skin, diabetes mellitus, and increased risk for infection and thromboembolism. In all patients with proven or suspected adrenocortical insufficiency (i.e. Addison's disease, after removal of a cortisol producing tumour or as the result of long-term therapy with glucocorticoids) consequent perioperative supplementation of hydrocortisone is mandatory. In patients with phaeochromcytoma hypertensive crisis and tachyarrhythmias may occur intraoperatively resulting from massive catecholamine release. Thus, preoperative treatment with the beta-antagonist phenoxybenzamine is obligatory. In contrast, nitroprusside is the substance of choice for intraoperative control of blood pressure. beta-blocking agents may be used in phaeochromocytoma but only under sufficient beta-blockade. Removal of a malignant tumour of the adrenal gland may induce massive haemorrhage, and thus anaesthetic

management has to be modified.

Publication Types: English Abstract PMID: 17366436 [PubMed - indexed for MEDLINE] 7: Paediatr Anaesth. 2007 Mar;17(3):295-6.

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Anesthetic management of bilateral pheochromocytoma with paradoxical hypotension in a 11-year-old child.

Batra YK, Rajeev S, Menon P, Saxena AK, Rao KL. PMID: 17263749 [PubMed - indexed for MEDLINE] 8: Chang Gung Med J. 2006 Sep-Oct;29(5):468-73.

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Comparative study of laparoscopic and open adrenalectomy.

Wu CT, Chiang YJ, Chou CC, Liu KL, Lee SH, Chang YH, Chuang CK. Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University. 5, Fushing Street, Gueishan Shiang, Taoyuan, Taiwan 333, ROC. BACKGROUND: Laparoscopic adrenalectomy (LA) had become the preferred operation for management of adrenal neoplasm. We conducted this cohort study to evaluate the outcome of laparoscopic and open adrenalectomy (OA). METHODS: A total of 67 patients with complete medical records were included in this study. Thirty patients underwent OA and the other 37 patients received LA. The intraoperative and perioperative data analyses focused on surgery time, blood loss, pain scale rating, resumption of oral feeding, hospital stay, complications and convalescence.

RESULTS: LA was completed in all 37 patients without conversion to OA or mortality. The surgery times (203.4 vs. 192.9, p = 0.776) were similar for both OA and LA groups. There was less blood loss in the LA group (355.0 vs. 104.0, p = 0.021). The postoperative pain scale rating was lower in the LA group (5.6 vs. 4.5 p = 0.035) as was analgesia demand (57.4 vs. 3.7, p < 0.001).

Oral feeding resumed earlier in the LA group (91.7 vs. 16.4, p < 0.001) and these patients had a shorter postoperative hospital stay (8.4 vs. 3.9, p < 0.001). The complication rate in both groups was similar. In the LA group, patients with primary aldosteronism had shorter surgery times and less blood loss than patients with other tumor types (p < 0.05). CONCLUSIONS: LA results in good surgical outcome without increased risks. We suggest that LA should be the preferred choice for management of adrenal neoplasms. We also suggest that surgeons inexperienced in LA consider beginning with a case of primary hyperaldosteronism.

Publication Types: Comparative Study

PMID: 17214390 [PubMed - indexed for MEDLINE] 9: J Am Soc Echocardiogr. 2006 Dec;19(12):1466-70.

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Reduced myocardial contractility assessed by tissue Doppler echocardiography is associated with increased risk during adrenal surgery of patients with pheochromocytoma: report of a preliminary study.

Meune C, Bertherat J, Dousset B, Jude N, Bertagna X, Duboc D, Weber S. Department of Cardiology, Cochin Hospital, Paris V RenĂŠ Descartes University, AP-HP, Paris, France. christophe.meune@cch.aphp.fr BACKGROUND: Depressed myocardial contractility, although rarely reported in pheochromocytoma, might be underestimated. It may be a determinant of perioperative risk during adrenal surgery. METHODS: We prospectively studied consecutive patients with pheochromocytoma; myocardial function examined by standard and tissue Doppler echocardiography was compared with matched control subjects. The incidence of hemodynamic collapse during adrenal surgery was measured. RESULTS: A total of 15 patients were included (8 men, 46 [17] years, hypertension in 10). All but one had a normal left ventricular ejection fraction.

However, compared with control subjects, they had a depressed systolic strain rate (SR) (1.8 [2.1] vs 4.1 [2.2] s(-1), P = .007). Furthermore, 6 of 8 patients with systolic SR less than 2 s(-1) experienced intraoperative collapse, versus 1 of 7 with SR greater than 2 s(-1) (P = .041). No association was observed with other variables. CONCLUSIONS: Patients with pheochromocytoma may have depressed myocardial contractility detected by tissue Doppler echocardiography despite a normal standard echocardiogram. A systolic SR less than 2 s(-1) was associated with an increased risk of perioperative collapse.

Publication Types: Controlled Clinical Trial PMID: 17138031 [PubMed - indexed for MEDLINE] 10: Pediatrics. 2006 Sep;118(3):1109-17.

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Pheochromocytoma and paraganglioma in children: a review of medical and surgical management at a tertiary care center.

Pham TH, Moir C, Thompson GB, Zarroug AE, Hamner CE, Farley D, van Heerden J, Lteif AN, Young WF Jr. Department of General and Pediatric Surgery, Mayo Clinic, Rochester, Minnesota 55905, USA. OBJECTIVE: The aim of this study was to review our institutional experience managing pheochromocytomas and paragangliomas in children. METHODS: A retrospective chart review of

the Mayo Clinic database from 1975 to 2005 identified 30 patients < 18 years of age with histologically confirmed pheochromocytoma or paraganglioma. RESULTS: There were 12 patients with pheochromocytomas and 18 with paragangliomas. The most common presenting symptoms were hypertension (64%), palpitation (53%), headache (47%), and mass-related effects (30%). Nine patients (30%) had a genetic mutation or documented family history of pheochromocytoma or paraganglioma. Fourteen patients (47%) had malignant disease, whereas 16 (53%) had benign disease. Logistic analysis showed that statistically significant risk factors for malignancy were (1) paraganglioma, (2) apparently sporadic, as opposed to familial, pheochromocytoma or paraganglioma, and (3) tumor size of > 6 cm. Surgical resection was performed for 28 patients (93%), with perioperative mortality and major morbidity rates of 0% and 10%, respectively.

Resection achieved symptomatic relief for 25 patients (83%). All patients with benign disease appeared cured after resection. For patients with malignant disease, the 5- and 10-year diseasespecific survival rates were 78% and 31%, respectively, and the mean survival time was 157 +/- 32 months. CONCLUSIONS: The incidence of malignant pheochromocytoma/paraganglioma was high in children (47%), particularly those with apparently sporadic disease, paraganglioma, and tumor diameters of > 6 cm. Patients with a known genetic mutation or familial pheochromocytoma/paraganglioma were more likely to achieve resection with negative microscopic margins and had improved disease-specific mortality rates. Surgical resection remains the treatment of choice for pheochromocytoma and paraganglioma.

PMID: 16951005 [PubMed - indexed for MEDLINE] 11: J Pediatr Surg. 2006 Aug;41(8):e15-7.

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Perioperative circulating blood volume analysis in management of a 13-year-old female patient with an extraadrenal pheochromocytoma and refractory ventricular tachycardia: a case report.

Iijima T, Iwao Y, Ito Y. Department of Anesthesiology, Kyorin University School of Medicine, Mitaka-City, Tokyo 1818611, Japan. iijmt@kyorin-u.ac.jp This report describes the use of discrete real-time monitoring of blood volume (BV) and cardiac index (CI) by a dye densitography analyzer before, during, and after removal of a pheochromocytoma. The BV expanded by about 1.1 L and CI increased by about 2.2-fold after the tumor was removed. In lieu of a rapid catecholamine determination, the hemodynamic data were used to choose a supplemental catecholamine to stabilize the patient during and after the protracted surgery. This case demonstrates the importance of hemodynamic monitoring (BV and CI) to predict or detect cardiac and other complications, particularly in young patients with catecholaminesecreting tumors.

Publication Types: Case Reports PMID: 16863830 [PubMed - indexed for MEDLINE] 12: Eur Arch Otorhinolaryngol. 2006 Jan;263(1):23-31. Epub 2005 Nov 30.

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Familial paraganglioma.

IĹ&#x;ik AC, Erem C, ImamoÄ&#x;lu M, Cinel A, Sari A, Maral G. Department of Otolaryngology, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey. uisik@ktu.edu.tr Paragangliomas are unusual tumors that are sometimes familial. We treated a family who exhibited multiple head and neck paragangliomas (HNPGs) and pheochromocytomas. The purpose was to determine the clinical characteristics of paragangliomas with familial history and to define a better standardized proceeding in the management of these tumors. Patients diagnosed with head and neck paragangliomas and identified retrospectively through clinical otolaryngology practices were given a medical and family history questionnaire. We studied a family who exhibited familial paragangliomas. This relationship was examined by reviewing the medical records of family members with verified tumors, carrying out neck computed tomography or magnetic resonance imaging on their relatives to look for tumors that had been unrecognized in the past. All patients underwent a complete head and neck examination. The initial evaluation usually included CT and/or MRI. Computed tomography and magnetic resonance imaging contributed additional information about tumor extension. Angiography was performed in every patient with carotid body tumor, with one undergoing therapeutic embolization to reduce the tumor size. Eleven tumors were identified in four patients with a familial history. Familial disease was initially determined by pedigree analysis. Four patients with a median age of 31 years (range: 25-42) underwent surgery.

Median follow-up was 5 years (range 2-14); carotid angiography provided essential mainstays for the definite diagnosis. All patients underwent successful surgical resection of the tumor after the appropriate preoperative preparation. There were no perioperative deaths or hemiplegia. Three patients had bilaterality carotid body paragangliomas. One patient had three paragangliomas, and two patients had bilateral carotid body paragangliomas associated with pheochromocytoma.

Clinically functioning tumors and malignant tumors were not identified, and none of the patients died after surgery. During follow-up, none of the patients developed recurrence or metastatic disease. The carotid body paraganglioma (CBPG) and glomus vagale manifested as asymptomatic neck masses. The clinical pheochromocytomas typically present with uncontrolled hypertension. In conclusion, paragangliomas are rare, with multicentricity being more common in patients with a familial history. In patients with familial paragangliomas, high-resolution computed tomography and magnetic resonance imaging are recommended for early screening and contributed additional information about the tumor extension and definitive treatment. Early surgery is recommended to minimize major risks.

Publication Types: Case Reports PMID: 16320027 [PubMed - indexed for MEDLINE] 13: Med J Aust. 2005 Aug 15;183(4):201-4.

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Phaeochromocytoma: current concepts.

Alderazi Y, Yeh MW, Robinson BG, Benn DE, Sywak MS, Learoyd DL, Delbridge LW, Sidhu SB. Royal North Shore Hospital and University of Sydney, Sydney, NSW, Australia.

The discovery of novel mutations in genes encoding succinate dehydrogenase subunits has revealed that familial phaeochromocytomas are much more common than previously thought. Genetic screening should be offered to patients with apparently sporadic phaeochromocytomas and their firstdegree relatives. An increasing proportion of phaeochromocytomas present preclinically on genetic testing or as "incidentalomas" on abdominal imaging, rather than with classic symptoms and signs. Clinical suspicion should prompt measurement of plasma levels of free metanephrine or 24hour urinary catecholamine and metanephrine levels, followed, if positive, by tumour localisation studies. With appropriate perioperative care, surgical management of phaeochromocytomas is safe and effective. Most tumours can be removed laparoscopically.

Publication Types: Review

PMID: 16097921 [PubMed - indexed for MEDLINE]

http://www.mja.com.au/public/issues/183_04_150805/ald10166_fm.html Clinical Update

Phaeochromocytoma: current concepts Yaser Alderazi, Michael W Yeh, Bruce G Robinson, Diana E Benn, Mark S Sywak, Diana L Learoyd, Leigh W Delbridge and Stan B Sidhu MJA 2005; 183 (4): 201-204

Abstract The discovery of novel mutations in genes encoding succinate dehydrogenase subunits has revealed that familial phaeochromocytomas are much more common than previously thought.  Genetic screening should be offered to patients with apparently sporadic phaeochromocytomas and their first-degree relatives.  An increasing proportion of phaeochromocytomas present preclinically on genetic testing or as ―incidentalomas‖ on abdominal imaging, rather than with classic symptoms and signs.  Clinical suspicion should prompt measurement of plasma levels of free metanephrine or 24-hour urinary catecholamine and metanephrine levels, followed, if positive, by tumour localisation studies.  With appropriate perioperative care, surgical management of phaeochromocytomas is safe and effective. Most tumours can be removed laparoscopically. 

P

haeochromocytomas are rare neoplasms of the chromaffin cells derived from

the embryonic neural crest. They are found in fewer than 0.2% of patients with hypertension.1 Most are derived from the adrenal medulla, but the term is also often

used for extra-adrenal tumours of the sympathetic nervous system, which may arise in the abdomen, pelvis, thorax, and neck. Both the clinical and biochemical features of phaeo-chromocytomas result largely from the overproduction of catecholamines. Phaeochromocytoma has been called the â&#x20AC;&#x2022;10% tumourâ&#x20AC;&#x2013;, suggesting that 10% are bilateral, 10% malignant, 10% extra-adrenal, and 10% familial. However, in the past 5 years, advances in our understanding of the genetics of this disease and in clinical research have compelled us to re-evaluate this axiom. We review these new insights, with particular attention to familial syndromes, biochemical and radiographic evaluation, and surgical and adjuvant therapy.

Genetic basis of phaeochromocytoma It has been known for some time that phaeochromocytomas present as a component of the familial syndromes multiple endocrine neoplasia type 2, von Hippelâ&#x20AC;&#x201C;Lindau disease, and, rarely, neurofibromatosis type 1. Germline mutations have been identified in these diseases in, respectively, the proto-oncogene RET, and the tumour suppressor genes VHL and NF12 (Box 1).

More recently, germline mutations in the genes encoding succinate dehydrogenase subunit D (SDHD) and subunit B (SDHB) have been described in patients with phaeochromocytomas.3,4 These genes encode subunits of mitochondrial complex II. The mechanism by which the mutations cause tumours remains to be elucidated.

However, hypotheses include mitochondrial-mediated failure of apoptosis,3 or even activation of the angiogenic pathway.

Both maternal and paternal inheritance of SDHB mutations resulting in disease phenotype have been shown in familial phaeochromocytomas.6 Recently, a study of 271 predominantly Polish and German patients with non-syndromic (apparently sporadic) phaeochromocytoma found that 66 (24%) were carrying a germline mutation in RET, VHL, SDHD, or SDHB;7 these patients were more likely to present at a young age than those lacking any of these mutations (mean, 25 versus 44 years), and were also more likely to have multifocal disease and extra-adrenal tumours.

Other investigators have reported the prevalence of familial disease to range from 21% to 30%.8,9 Although all these cohort studies may be affected by selection bias because of geographic limitations, taken together they strongly suggest that germline mutations are responsible for phaeochromocytoma in a familial setting more often than previously estimated. Undoubtedly, the discovery of the involvement of SDH genes in phaeochromocytoma is the major factor driving this trend, as the main technical advance in genetic surveys performed since 2001 has been the inclusion of screening for mutations in these genes. Novel loci that may account for additional familial cases of phaeochromocytoma remain to be characterised.10,11 The clinical implication of these findings is that genetic screening should be offered more widely. In fact, it has been recommended that all patients presenting with apparently sporadic phaeochromocytoma should be offered routine analysis for mutations in SDHB, SDHD, VHL, and RET.7 A positive result should prompt biochemical testing and imaging studies (discussed below), as well as the offer of genetic testing and counselling to all first-degree relatives of the patient.

Clinical presentation In the past, phaeochromocytoma has been described to present with a characteristic triad of headache, diaphoresis, and palpitations.12 It remains true that the presence of one or more of these paroxysmal symptoms in association with hypertension should alert the physician. However, the era of such classic presentations may be waning, as an increasing proportion of phaeochromocytomas are detected at an early stage, before clinical signs and symptoms become apparent. This may be attributable to more widespread application of genetic testing as more patients present with subclinical disease (eg, asymptomatic catecholamine excess) in the setting of a strong family history and with abnormalities on abdominal imaging studies.

Clinically inapparent adrenal masses, or â&#x20AC;&#x2022;incidentalomasâ&#x20AC;&#x2013;, are common in the general population, found in 2.1% of autopsies and 1%â&#x20AC;&#x201C;4% of abdominal imaging studies.13 Fewer than 10% of such lesions are subsequently determined to be phaeochromocytomas. Conversely, in a recent study of 39 consecutive patients undergoing laparoscopic adrenalectomy for phaeochromocytoma at a single centre, 17 patients (44%) had initially presented with adrenal incidentalomas.14 A US National Institutes of Health expert panel in 2003 recommended biochemical evaluation of all patients with incidentally discovered adrenal masses, and surgical removal of lesions proven to hypersecrete catecholamines.13

Biochemical investigations Measurements of urinary catecholamines and their metabolites, metanephrines, over 24 hours have been the mainstay of biochemical diagnosis of phaeochromocytoma for many years. These tests are widely available and have been confirmed to be 99% specific when appropriate cut-off values are used (roughly twice the upper limit of the reference range).15 When measurements of urinary catecholamines and their metabolites are considered as a grouped test (positive when levels of any single compound are elevated), an acceptable sensitivity of 88% is achieved.

However, a large multicentre cohort study in 2002 found that measurement of plasma levels of free metanephrines by high-pressure liquid chromatography detected phaeochromocytomas with a sensitivity of 99%.16 The advantage of assaying metanephrines is that they are produced continuously, resulting in steadystate levels. In contrast, catecholamines are released episodically. The high sensitivity of this test has been confirmed by two other studies, and there is growing consensus that a negative result on this single test is sufficient to exclude phaeochromocytoma.17 Difficulty arises when plasma levels of free metanephrines are raised, as the specificity is only 85%. Given the low prevalence of phaeochromocytoma, it is estimated that 30 people have false-positive results for every one patient with phaeochromocytoma identified.15 A number of drugs and medical conditions (most notably congestive cardiac failure, major depression and panic disorder) are known to confound measurement of both plasma and urinary catecholamines and their metabolites.18 In a recent study, tricyclic antidepressants and phenoxybenzamine accounted for 45% of false-positive elevations of plasma nor-epinephrine and normetanephrine levels.19 This report also demonstrated that clonidine suppression

testing (measurement of plasma free normetanephrine level after oral administration of 0.3 mg clonidine) may help clarify equivocal test results. Another major drawback of plasma free metanephrine testing is its limited availability in comparison with urine testing.

Other tests, such as catecholamine stimulation testing with glucagon, histamine, tyramine or naloxone, are largely obsolete.

Localisation studies In general, imaging studies are justified only after the diagnosis of phaeochromocytoma has been established biochemically. Currently available imaging methods for localisation of phaeochromocytoma can be grouped into anatomic modalities (computed tomography [CT] and magnetic resonance imaging [MRI]) and functional imaging modalities (scintigraphy). CT and MRI (Box 2A) have a sensitivity of 90%â&#x20AC;&#x201C;95%, with MRI being superior for detecting extra-adrenal tumours. However, both offer poor specificity (as low as 50% in some reports).20 The most commonly used functional study for detecting phaeochromocytoma is scintigraphy with 131I-labelled metaiodobenzylguanidine (131I-MIBG), which has specificity of over 95% but sensitivity of only 77%â&#x20AC;&#x201C;90%.21 Scintigraphy using MIBG labelled with 123I instead of 131I is reported to yield superior images, but the short half-life of this isotope (13.2 hours) limits its use to metropolitan centres with a nearby cyclotron (Box 2B).

Since 1990, five novel functional imaging techniques have been developed and compared with established methods. These comprise somatostatin receptor scintigraphy with 111In-pentetreotide, and positron emission tomography (PET) using 18F-fluorodeoxyglucose, 11C-hydroxyephedrine, 18F-dihydroxyphenylalanine, and most recently 6-18F-fluorodopamine.21 Although none of these techniques is in clinical use to date, PET with 6-18F-fluorodopamine was found to have 100% sensitivity in the detection of metastatic phaeochromocytoma in a recent study of 16 patients.22 Seven of these patients had negative 131I-MIBG scans, and the technique detected substantially more metastatic foci than 131I-MIBG scanning.

Surgical management Surgical excision remains the cornerstone of treatment for phaeochromocytoma, achieving cure in more than 90% of cases. An audit of surgery for phaeochromocytoma at a single centre over 23 years found that medical and surgical advances have greatly reduced adverse perioperative events.9 The overall mortality rate was 2.4%. Non-fatal complications occurred in 38 of 165 operations (involving 147 patients), most notably splenic injuries requiring splenectomy in 13 patients. The authors attributed this primarily to the surgical technique used (open bilateral exploration), as only three splenic complications occurred during the last 10 years of the study, when focused exploration was generally used.

Complications were most strongly associated with repeat surgery, although high preoperative systolic blood pressure and high urinary metanephrine secretion were also independent risk factors.

Preoperative patient preparation with α-adrenergic blockade (commonly achieved with prazosin5 or phenoxybenzamine) and volume expansion have accounted for 5

PRAZOSIN MARCA MINIPRES EN COLOMBIA – SOLAMENTE PARA ADMINISTRACIÓN POR VÍA

NO SIRVE DURANTE LA CIRUGÍA

ORAL MINIPRES SR - PFIZER Antihipertensivo.

Composición.Prazosin clorhidrato en cápsulas de 1 y 2mg.

Propiedades. MINIPRES SR® disminuye la resistencia vascular periférica total. El efecto terapéutico habitual es una disminución de la presión sanguínea que no se acompaña de cambios clínicamente significativos en el gasto cardíaco, frecuencia cardíaca, flujo sanguíneo renal y filtración glomerular. No se ha desarrollado tolerancia con su empleo clínico a largo plazo. No se presentan elevaciones de rebote después de suspender bruscamente el tratamiento con MINIPRES SR®. Estudios hemodinámicos en pacientes con insuficiencia ventricular izquierda indican que el efecto terapéutico se debe a reducción en la presión de llenado del ventrículo izquierdo, a reducción de la impedancia cardíaca y aumento del gasto cardíaco sin incremento del consumo de oxígeno por parte del miocardio. Estos efectos se asocian a la vasodilatación balanceada que produce en arteriolas y venas. El empleo de MINIPRES SR® en insuficiencia ventricular izquierda no induce taquicardia refleja; y en pacientes normotensos, la reducción de la presión sanguínea es mínima, o no aparece.El fenómeno y la enfermedad de Raynaud han sido tratados exitosamente con MINIPRES SR®. La acción vasodilatadora del fármaco aumenta el flujo sanguíneo a las partes afectadas, disminuyendo los signos y síntomas y la frecuencia y duración de los ataques. Después de su administración oral a voluntarios sanos y a hipertensos, las concentraciones plasmáticas alcanzan su máximo en tres horas, con una vida media plasmática de 10.8 horas. La droga tiene una gran afinidad por las proteínas del plasma.

Indicaciones. Antihipertensivo. Tratamiento de la hipertensión arterial de diversa etiología y de todos los grados de severidad. Puede utilizarse como agente inicial único o puede -emplearse en el programa general de tratamiento, concomitantemente con un diurético y/u otro medicamento antihipertensor.

MINIPRES SR® también está indicado en el tratamiento de la insuficiencia ventricular izquierda. En estos casos puede adicionarse al régimen terapéutico de aquellos pacientes que no han respondido satisfactoriamente o que se han vuelto refractarios a los tratamientos convencionales con diuréticos, adicionados o no de glucósidos cardiotónicos. MINIPRES SR® se indica en el fenómeno y enfermedad de Raynaud.

Dosificación. Pacientes que no reciben tratamiento antihipertensor: se recomienda que el tratamiento se inicie con 1mg al momento de acostarse; luego 1mg 1 vez al día por 3-7 días. A menos que la respuesta indique que el paciente es muy sensible, esta dosis debe aumentarse a 2mg 1 vez al día por otros 3 a 7 días, y luego a 4mg 1 vez al día. Después, de acuerdo con la respuesta de la tensión arterial, la dosis diaria podrá aumentarse gradualmente hasta 20mg. Dosis inicial sugerida: 1mg al momento de acostarse. Después 1mg 1 vez al día. Luego, si fuere necesario, 2mg y después 4mg 1 vez al día. Dosis de mantenimiento: 1-20mg 1 vez al día. Pacientes que reciben diuréticos con control inadecuado de la tensión arterial: el diurético deberá reducirse a la dosis de mantenimiento para el agente en particular.

Iniciar MINIPRES SR® 1mg al momento de acostarse el primer día, y continuar con 1mg diario. Después del período inicial de observación, la dosis de MINIPRES SR® debe aumentarse gradualmente de acuerdo con la respuesta del paciente.Pacientes que reciben otros agentes antihipertensores pero con control inadecuado: debido a que pueden esperarse algunos efectos aditivos, la dosis de los otros medicamentos (por ejemplo, bloqueadores betaadrenérgicos, alfametildopa, reserpina, clonidina, etc.) deberá reducirse e iniciar MINIPRES SR® tal como en el caso anterior. Pacientes con grados moderados o severos de insuficiencia renal: la evidencia a la fecha demuestra que MINIPRES SR® no compromete aún más la función renal cuando se utiliza en pacientes con alteraciones renales. Puesto que algunos enfermos de esta categoría han respondido a dosis bajas de MINIPRES SR® se recomienda iniciar el tratamiento con 1mg diario, haciendo los aumentos con cautela. Insuficiencia ventricular izquierda: la dosis inicial recomendada es 1mg al día. Esta dosis debe ajustarse de acuerdo con la respuesta clínica del paciente, basada en cuidadosa evaluación de los signos cardiopulmonares y de estudios hemodinámicos cuando estén indicados.Los ajustes pueden hacerse cada 2-3 días y el paciente debe estar bajo riguroso control médico. En pacientes descompensados, gravemente enfermos, puede ser necesaria una rápida titulación en 1-2 días, lo cual se hace mucho mejor cuando se dispone de laboratorio de hemodinamia. Las dosis terapéuticas oscilan entre 4 y 20mg diarios. Para mantener en algunos pacientes una respuesta clínica óptima pueden ser necesarios ajustes de la dosis durante el tratamiento. Dosis inicial sugerida: 1mg al día, aumentando hasta 4mg diarios. Dosis usual de mantenimiento: 4-20mg 1 vez al día. Fenómeno y enfermedad de Raynaud: se recomienda dosis inicial de 1mg diario, durante 3-7 días, que debe ajustarse de acuerdo con la respuesta del paciente. Dosis inicial sugerida: 1mg diario. Dosis usual de mantenimiento: 2-4mg diarios. Máxima dosis: 6mg.

Contraindicaciones. MINIPRES SR® está contraindicado en pacientes con sensibilidad conocida a las quinazolinas.

Efectos secundarios. Los efectos colaterales más comúnmente asociados con el tratamiento con

the most significant reductions in perioperative mortality.23 Improved localising studies have enabled focused adrenalectomy. Laparoscopic adrenalectomy has become the procedure of choice for most patients (Box 3), with open adrenalectomy generally reserved for large tumours or those known preoperatively to be malignant. Although large tumours are more likely to be malignant, the upper limit of size appropriate for laparoscopic resection remains at the discretion of the individual surgeon.24

Malignant phaeochromocytoma It is generally accepted that about 10% of phaeochromocytomas are malignant.

However, we now know that certain subgroups of patients are at particularly high risk. A recent comparison of SDHB and SDHD mutation carriers showed that SDHB carriers were significantly more likely to have malignant tumours, as defined by the identification of tumours in the lungs or bones.5

Criteria for malignancy MINIPRES SR® son: mareo, cefalea, somnolencia, astenia, debilidad, náuseas y palpitaciones. En la mayoría de los casos los efectos secundarios han desaparecido al continuar el tratamiento o han sido tolerados sin disminuir la dosis del medicamento. Los siguientes efectos secundarios se han asociado al tratamiento con MINIPRES SR®: vómitos, diarrea, constipación, malestar o dolor abdominal, edema, hipotensión ortostática, disnea, lipotimia, taquicardia, nerviosismo, vértigo, alucinaciones, depresión, parestesias, rash, prurito, alopecia, liquen plano, polaquiuria, impotencia, priapismo, visión borrosa, enrojecimiento de la esclerótica, epistaxis, tinnitus, boca seca, congestión nasal, diaforesis, fiebre, AAN positivos y artralgia. En la mayoría de las veces estas reacciones son leves o moderadas, desaparecen sin necesidad de interrumpir el tratamiento o se toleran aun manteniendo la misma dosificación.

Precauciones. Hipertensión: un muy reducido porcentaje de pacientes ha respondido de una manera brusca y exagerada a la dosis inicial de MINIPRES SR®. Hipotensión postural, que se evidencia por mareos, debilidad y en raras oportunidades, pérdida de conciencia, puede aparecer al comienzo del tratamiento. El efecto es autolimitado y en la mayoría de los casos no recurre después del período inicial de tratamiento o durante los ajustes subsecuentes de dosis. Esta respuesta no está relacionada con la severidad de la hipertensión.

Insuficiencia ventricular izquierda: cuando se administra MINIPRES SR® por primera vez a pacientes que están siendo tratados enérgicamente con diuréticos u otros vasodilatadores, la resultante disminución de la presión de llenado del ventrículo izquierdo puede acompañarse de una baja significativa del gasto cardíaco y presión sanguínea. En el fenómeno y enfermedad de Raynaud se debe monitorear cuidadosamente la tensión arterial, especialmente al comienzo del tratamiento.

Advertencias.Embarazo y lactancia: aunque no se han observado efectos teratogénicos en animales de experimentación, la seguridad de MINIPRES SR® no ha sido establecida en embarazo y lactancia. Prazosin se ha empleado solo o en combinación con otros antihipertensores en la hipertensión severa del embarazo. No se han informado anomalías fetales o neonatales con el uso de prazosin. Como no hay estudios bien controlados que establezcan la seguridad de MINIPRES SR® en embarazadas, sólo se usará cuando, en opinión del médico, el posible beneficio justifique los riesgos potenciales para la madre y el feto.

MINIPRES SR® se excreta en pequeñas cantidades en la leche materna; en consecuencia, cuando se administre a madres que están lactando se debe ser muy cauteloso. Niños: no se recomienda el uso de MINIPRES SR® en el tratamiento de niños menores de 12 años, pues en ese grupo no se han establecido sus condiciones de seguridad.Insuficiencia ventricular izquierda: MINIPRES SR® no se recomienda en el tratamiento de insuficiencia ventricular izquierda producida por obstrucción mecánica como: estenosis valvular aórtica, estenosis mitral, embolia pulmonar y enfermedad pericárdica restrictiva.

Interacciones. Al adicionar un diurético u otro antihipertensor a MINIPRES SR® se observa aumento del efecto hipotensor. Interacciones con exámenes de laboratorio: pueden presentarse falsos positivos en los exámenes de orina para detectar feocromocitoma (ácido vanililmandélico y metoxihidroxifenil glisol).

Sobredosificación. Si la sobredosificación produce hipotensión, es de primordial importancia dar soporte al sistema cardiovascular.Presentación. Caja por 30 cápsulas de 1mg (Reg. San. No. INVIMA M-013271). Caja por 30 cápsulas de 2mg (Reg. San. No. INVIMA M-013251).

Despite attempts to establish histopathological criteria to distinguish benign from malignant phaeochromocytomas,25 malignancy remains best defined by the presence of metastases. Metastatic implants are detected by imaging studies demonstrating neoplasia at sites distant from the primary tumour, where neuroectodermal tissues are not normally found.

Gene expression analysis has recently raised the possibility that molecular markers might predict clinical tumour behaviour.

Human telomerase reverse transcriptase is more commonly expressed in malignant phaeochromocytomas compared with benign phaeochromocytomas.26 A number of other molecular markers, including proangiogenic factors, have been examined in preclinical studies in the past 5 years.10 Expression analysis using a matrix of genes known to promote tumour progression may eventually allow for accurate determination of prognosis.

Management of malignant phaeochromocytomas Phaeochromocytomas are generally radioresistant, and chemotherapy most often produces only temporary improvement. Thus, the management of malignant phaeochromocytoma has centred on palliation: medical control of hypertension, surgical debulking, and combination chemotherapy.27 Since the 1980s, some specialised centres have treated patients with high-dose 131I-MIBG radionuclide therapy,28 with overall initial improvement in symptoms (75%), hormonal response (45%) and tumour size (30%). However, long-term benefit is rare, and tumour recrudescence is usual. In 1999, a study in six patients showed that bimodal therapy with 131I-MIBG and combination cytotoxic chemotherapy produced additive effects in reducing tumour volume and function.29

Conclusions Phaeochromocytoma remains a challenging entity to diagnose and to treat. In the future, genetic screening of at-risk individuals should identify an increasing number of patients with early stage disease. Biochemical testing of plasma or urinary analytes should be used for initial screening of patients with hypertension and suggestive features. After appropriate tumour localisation, most patients with phaeochromocytoma can be treated by minimally invasive techniques. We await further advances from preclinical studies of the diagnosis and treatment of malignant phaeochromocytoma.

1 Gene mutations associated with familial phaeochromocytoma 3-5 Lifetime risk of tumour (%)

Gene Syndrome

Other manifestations

RET

Multiple endocrine neoplasia type 2A

Medullary thyroid carcinoma, hyperparathyroidism

40%

RET

Multiple endocrine neoplasia type 2B

Medullary thyroid carcinoma, mucosal (oral) neuromas, intestinal ganglioneuromas, marfanoid habitus

40%

VHL

Von Hippelâ&#x20AC;&#x201C;Lindau disease

Multiple infratentorial haemangioblastomas and retinal

10%â&#x20AC;&#x201C;20%

angiomas, renal cell (clear cell) carcinoma, renal and pancreatic cysts, papillary cystadenomas of the reproductive tract and ear NF1

Neurofibromatosis type Peripheral neurofibromas, cafĂŠ-au-lait 1 spots, intertriginous freckling, Lisch nodules, optic gliomas, bony abnormalities, other CNS tumours

< 5%

SDHD Familial phaeochromocytoma/ paraganglioma

None identified

Unknown

SDHB Familial phaeochromocytoma/ paraganglioma

Possibly renal cell carcinoma

Unknown

SDHD = succinate dehydrogenase subunit D. SDHB = succinate dehydrogenase subunit B. CNS = central nervous system.

2 Radiographic findings in phaeochromocytoma

A Magnetic resonance imaging (T2-weighted) showing left adrenal mass with high signal intensity (arrow).

B Whole-body scintigraphy with 123l-metaiodobenzylguanidine, showing focal radiotracer uptake indicative of a left extra-adrenal phaeochromocytoma (side of uptake is inferior to the usual position of the adrenal gland).

3 Laparoscopic adrenalectomy

A Four subcostal ports are most commonly used, with the patient lying on the side.

B Cut surface of 7 cm diameter phaeochromocytoma replacing the entire adrenal gland, showing central necrosis.

Competing interests None identified.

References 1.

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29.

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Plouin PF, Duclos JM, Soppelsa F, et al. Factors associated with peri-operative morbidity and mortality in patients with pheochromocytoma: analysis of 165 operations at a single center. J Clin Endocrinol Metab 2001; 86: 1480-1486. <PubMed> Eisenhofer G, Bornstein SR, Brouwers FM, et al. Malignant pheochromocytoma: current status and initiatives for future progress. Endocr Relat Cancer 2004; 11: 423-436. <PubMed> Opocher G, Schiavi F, Vettori A, et al. Fine analysis of the short arm of chromosome 1 in sporadic and familial pheochromocytoma. Clin Endocrinol (Oxf) 2003; 59: 707-715. <PubMed> Pommier RF, Brennan MF. Management of adrenal neoplasms. Curr Probl Surg 1991; 28: 657-739. <PubMed> Grumbach MM, Biller BM, Braunstein GD, et al. Management of the clinically inapparent adrenal mass (―incidentaloma‖). Ann Intern Med 2003; 138: 424-429. <PubMed> Cheah WK, Clark OH, Horn JK, et al. Laparoscopic adrenalectomy for pheochromocytoma. World J Surg 2002; 26: 10481051. <PubMed> Kudva YC, Sawka AM, Young WF Jr. Clinical review 164: the laboratory diagnosis of adrenal pheochromocytoma: the Mayo Clinic experience. J Clin Endocrinol Metab 2003; 88: 4533-4539. <PubMed> Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 2002; 287: 1427-1434. <PubMed> Sawka AM, Prebtani AP, Thabane L, et al. A systematic review of the literature examining the diagnostic efficacy of measurement of fractionated plasma free metanephrines in the biochemical diagnosis of pheochromocytoma. BMC Endocr Disord 2004; 4: 2. <PubMed> Harding JL, Yeh MW, Coleman MJ, et al. Potential pitfalls in the diagnosis of phaeochromocytoma. Med J Aust 2005; 182: 637-639. <eMJA full text> <PubMed> Eisenhofer G, Goldstein DS, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results. J Clin Endocrinol Metab 2003; 88: 2656-2666. <PubMed> Jalil ND, Pattou FN, Combemale F, et al. Effectiveness and limits of preoperative imaging studies for the localisation of pheochromocytomas and paragangliomas: a review of 282 cases. French Association of Surgery (AFC), and The French Association of Endocrine Surgeons (AFCE). Eur J Surg 1998; 164: 23-28. <PubMed> Ilias I, Pacak K. Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab 2004; 89: 479-491. <PubMed> Ilias I, Yu J, Carrasquillo JA, et al. Superiority of 6-[18F]-fluorodopamine positron emission tomography versus [131I]metaiodobenzylguanidine scintigraphy in the localization of metastatic pheochromocytoma. J Clin Endocrinol Metab 2003; 88: 40834087. <PubMed> Duh QY. Evolving surgical management for patients with pheochromocytoma. J Clin Endocrinol Metab 2001; 86: 1477-1479. <PubMed> Shen WT, Sturgeon C, Clark OH, et al. Should pheochromocytoma size influence surgical approach? A comparison of 90 malignant and 60 benign pheochromocytomas. Surgery 2004; 136: 1129-1137. <PubMed> Thompson LD. Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol 2002; 26: 551-566. <PubMed> Elder EE, Xu D, Hoog A, et al. KI-67 AND hTERT expression can aid in the distinction between malignant and benign pheochromocytoma and paraganglioma. Mod Pathol 2003; 16: 246-255. <PubMed> Edstrom Elder E, Hjelm Skog AL, Hoog A, Hamberger B. The management of benign and malignant pheochromocytoma and abdominal paraganglioma. Eur J Surg Oncol 2003; 29: 278-283. <PubMed> Loh KC, Fitzgerald PA, Matthay KK, et al. The treatment of malignant pheochromocytoma with iodine131 metaiodobenzylguanidine (131I-MIBG): a comprehensive review of 116 reported patients. J Endocrinol Invest 1997; 20: 648-658. <PubMed> Sisson JC, Shapiro B, Shulkin BL, et al. Treatment of malignant pheochromocytomas with 131-I metaiodobenzylguanidine and chemotherapy. Am J Clin Oncol 1999; 22: 364-370. <PubMed> (Received 3 Mar 2005, accepted 30 May 2005)

Royal North Shore Hospital and University of Sydney, Sydney, NSW. Yaser Alderazi, MB BS, Fellow; Michael W Yeh, MD, Endocrine Surgery Fellow [equal contributor to Alderazi]; Bruce G Robinson, MD, FRACP, Professor of Endocrinology and Head of Division of Medicine; Diana E Benn, PhD, Senior Hospital Scientist, Kolling Institute of Medical Research; Mark S Sywak, FRACS, Clinical Lecturer; Diana L Learoyd, PhD, FRACP, Senior Lecturer; Leigh

W Delbridge, MD, FRACS, Professor of Surgery; Stan B Sidhu, PhD, FRACS, Clinical Senior Lecturer.

Correspondence: Dr Stan Sidhu, Department of Surgery, Royal North Shore Hospital, St Leonards, NSW 2065. stansidhuATnebsc.com.au AntiSpam note: To avoid spam, authors' email addresses are written with AT in place of the usual symbol, and we have removed "mail to" links. Replace AT with the correct symbol to get a valid address. ŠThe Medical Journal of Australia 2005 www.mja.com.au PRINT ISSN: 0025-729X ONLINE ISSN: 1326-5377

14: J Clin Anesth. 2005 Jun;17(4):296-9.

Related Articles, Links

Cesarean section at 28 weeks' gestation with resection of pheochromocytoma: perioperative antihypertensive management.

Kariya N, Nishi S, Hosono Y, Hamaoka N, Nishikawa K, Asada A. Department of Anesthesiology and Intensive Care Medicine, Osaka City University Medical School, Osaka 545-8586, Japan. n_kariya@hotmail.com Pregnancy complicated by pheochromocytoma is potentially fatal. Pregnancy and labor increase the risk of hypertensive crisis as it may occur with the sudden release of catecholamine accompanying uterine contractility and straining. However, antepartum diagnosis reduces both maternal and fetal mortality, allowing for safe cesarean section and resection of tumor. We describe the management of perioperative hypertension for combined cesarean section and pheochromocytoma resection.

Publication Types: Case Reports PMID: 15950857 [PubMed - indexed for MEDLINE] 15: Anesth Analg. 2005 Apr;100(4):972-5.

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The perioperative management of a patient with complex single ventricle physiology and pheochromocytoma.

Sparks JW, Seefelder C, Shamberger RC, McGowan FX. Division of Periopertive Medicine, Department of Anesthesiology, Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA. Pheochromocytoma is associated with intense physiologic effects of alpha- and beta-adrenergic stimulation from catecholamine secretion. Perioperative management for these patients includes alpha-adrenergic receptor blockade, intravascular volume replacement, and, if necessary, betaadrenergic receptor blockade. Significant perioperative changes in preload and afterload, fluid status, heart rate and rhythm, and inotropy can occur and may be contrary to anesthetic management

goals for patients with certain conditions of congenital heart disease. We report the perioperative management with doxazosin of a patient with single ventricle physiology and cavo-pulmonary and aorto-pulmonary lung perfusion who presented for resection of a pheochromocytoma.

Publication Types: Case Reports PMID: 15781508 [PubMed - indexed for MEDLINE] 16: Masui. 2004 Dec;53(12):1396-403.

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[Anesthetic management with propofol during pheochromocytoma resection under bispectral index monitoring] [Article in Japanese] Utada K, Ishida K, Nakamura M, Morimoto Y, Yamashita S, Sakabe T. Department of Anesthesiology-Resuscitology, Yamaguchi University School of Medicine, Ube 755-8505.

In three patients undergoing pheochromocytoma resection under propofol/fentanyl anesthesia, bispectral index (BIS) was monitored for assessment of hypnotic effect. In two patients, arterial blood concentrations of propofol were measured by high performance liquid chromatography (HPLC), and compared with those of the estimated blood concentrations. Until resection of the tumor, propofol was infused at a rate of 10 mg x kg(-1) x hr(-1). After resection of the tumor, propofol dosage was reduced to 3-6 mg x kg(-1) x hr(-1), keeping the BIS values around 60. Rapid infusion of fluid and norepinephrine was required to maintain blood pressure after removal of the tumor in two patients. In one patient, blood pressure was maintained well without rapid infusion of fluid or vasopressor. Arterial blood concentration of propofol after resection of the tumor was equal to the estimated blood concentration (3.04 vs 3.02 microg x ml(-1)) in a patient without rapid infusion of fluid. In a patient with rapid infusion of fluid, the arterial blood concentration was lower than the estimated blood concentration (2.59 vs 3.58 microg x ml(-1)). The anesthetic depth can not be estimated accurately by hemodynamic changes in the patients undergoing pheochromocytoma resection. BIS monitoring should be recommended for adjustment of propofol dosage after pheochromocytoma resection.

Publication Types: Case Reports English Abstract PMID: 15682802 [PubMed - indexed for MEDLINE]

Regitine Medicamento vital no disponible en Colombia segĂşn decreto 481 de 2004

17: Masui. 2004 Dec;53(12):1391-5.

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[Lessons learned from anesthetic management of pheochromocytoma resection: a report of three cases] [Article in Japanese] Chang KH, Sugano T, Hanaoka K. Department of Anesthesiology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655.

The anesthetic management of patients with pheochromocytoma, in which drastic hemodynamic changes may occur, is still a challenge to even the most experienced anesthesiologist, although the perioperative mortality has been reduced remarkably. We report three patients who developed unexpected major complications during elective resection of a pheochromocytoma. The Case 1 patient was a 46 year-old woman who developed ventricular tachycardia immediately after administration of ephedrine for transient hypotension induced by excessive phentolamine6. Even a

Phentolamine marca comercial REGITINE: En COLOMBIA es considerado un medicamento vital NO DISPONIBLE. (según Invima) 6

Regitine® Hay que solicitar la importación del producto a menos que en hospital lo tengan. Como es intravenoso sí se puede emplear durante la cirugía. Entonces sí se necesitaría, según el criterio del grupo médico.

Decreto 481 de 2004 Medicamentos vitales no disponibles ( …)Artículo 8º. Autorización de importación para un paciente específico. La importación de un medicamento vital no disponible, para un paciente específico, podrá ser realizada por el mismo paciente o por una persona natural o jurídica pública o privada legalmente constituida previo cumplimiento de los siguientes requisitos: 1. Solicitud expresa de la autorización de importación presentada ante el Invima.

2. Nombre completo del paciente y su documento de identidad.

3. Principio activo en su denominación genérica y composición del medicamento.

4. Fórmula médica y resumen de la historia clínica en donde se indique la dosis, tiempo de duración del tratamiento, nombre del medicamento y cantidad, la cual debe estar firmada por el médico tratante, con indicación y número de su tarjeta profesional.

5. Copia del recibo de consignación correspondiente.

Parágrafo. La autorización de importación de los medicamentos vitales no disponibles se concede por una sola vez y podrá ser nuevamente solicitada según prescripción médica.

Artículo 9º. Autorización de importación de medicamentos vitales no disponibles para uso exclusivo en casos de urgencia clínica. En el caso de medicamentos vitales no disponibles de uso exclusivo en urgencia clínica, se podrá autorizar la importación de cantidades no comerciales sin la documentación referida al paciente, en cuyo evento bastará la sustentación médica correspondiente.

Esta es la base jurídica

Artículo 10. Autorización de importación para más de un paciente de medicamentos vitales no disponibles. El Invima podrá autorizar la importación de medicamentos vitales no disponibles para más de un paciente, siempre que se cumplan los siguientes requisitos: 1. El solicitante podrá ser cualquier entidad pública o privada legalmente constituida, debidamente autorizada para la distribución de medicamentos de acuerdo con las normas vigentes o aquellas que las modifiquen o sustituyan.

2. La documentación a adjuntar será la siguiente: a) Certificado de venta libre o certificado ajustado a los requisitos previstos por la Organización Mundial de la Salud, OMS, para productos objeto de comercio internacional; b) Certificado de existencia y representación legal del solicitante; c) Certificado de análisis.

Tomado de: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1821 phentolamine mesylate for injection, USP Vials Rx only Prescribing Information DESCRIPTION Regitine, phentolamine mesylate for injection, USP, is an antihypertensive, available in vials for intravenous and intramuscular administration. Each vial contains phentolamine mesylate USP, 5 mg, and mannitol USP, 25 mg, in sterile, lyophilized form.

Phentolamine mesylate is 4,5-dihydro-2-[N-(m-hydroxyphenyl)-N-(p-methylphenyl) aminomethyl]-1H-imidazole 1:1 methanesulfonate, and its structural formula is (…)

Phentolamine mesylate for injection, USP, is a white or off-white, odorless crystalline powder with a molecular weight of 377.46. Its solutions are acid to litmus.

It is freely soluble in water and in alcohol, and slightly soluble in chloroform. It melts at about 178ºC. CLINICAL PHARMACOLOGY Regitine produces an alpha-adrenergic block of relatively short duration. It also has direct, but less marked, positive inotropic and chronotropic effects on cardiac muscle and vasodilator effects on vascular smooth muscle.

Regitine has a half-life in the blood of 19 minutes following intravenous administration. Approximately 13% of a single intravenous dose appears in the urine as unchanged drug.

INDICATIONS AND USAGE Regitine is indicated for the prevention or control of hypertensive episodes that may occur in a patient with pheochromocytoma as a result of stress or manipulation during preoperative preparation and surgical excision.

Regitine is indicated for the prevention or treatment of dermal necrosis and sloughing following intravenous administration or extravasation of norepinephrine.

Regitine is also indicated for the diagnosis of pheochromocytoma by the Regitine blocking test.

CONTRAINDICATIONS Myocardial infarction, history of myocardial infarction, coronary insufficiency, angina, or other evidence suggestive of coronary artery disease; hypersensitivity to phentolamine or related compounds.

WARNINGS Myocardial infarction, cerebrovascular spasm, and cerebrovascular occlusion have been reported to occur following the administration of Regitine, usually in association with marked hypotensive episodes.

For screening tests in patients with hypertension, the generally available urinary assay of catecholamines or other biochemical assays have largely replaced the Regitine and other pharmacological tests for reasons of accuracy and safety. None of the chemical or pharmacological tests is infallible in the diagnosis of pheochromocytoma. The Regitine blocking test is not the procedure of choice and should be reserved for cases in which additional confirmatory evidence is necessary and the relative risks involved in conducting the test have been considered.

PRECAUTIONS General Tachycardia and cardiac arrhythmias may occur with the use of Regitine or other alpha-adrenergic blocking agents. When possible, administration of cardiac glycosides should be deferred until cardiac rhythm returns to normal.

Drug Interactions See DOSAGE AND ADMINISTRATION, Diagnosis of pheochromocytoma, Preparation.

Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies, mutagenicity studies, and fertility studies have not been conducted with Regitine.

Pregnancy Category C Administration of Regitine to pregnant rats and mice at oral doses 24-30 times the usual daily human dose (based on a 60-kg human) resulted in slightly decreased growth and slight skeletal immaturity of the fetuses. Immaturity was manifested by increased incidence of incomplete or unossified calcanei and phalangeal nuclei of the hind limb and of incompletely ossified sternebrae. At oral doses 60 times the usual daily human dose (based on a 60-kg human), a slightly lower rate of implantation was found in the rat. Regitine did not affect embryonic or fetal development in the rabbit at oral doses 20 times the usual daily human dose (based on a 60-kg human). No teratogenic or embryotoxic effects were observed in the rat, mouse, or rabbit studies.

There are no adequate and well-controlled studies in pregnant women. Regitine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Regitine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use See DOSAGE AND ADMINISTRATION. ADVERSE REACTIONS Acute and prolonged hypotensive episodes, tachycardia, and cardiac arrhythmias have been reported. In addition, weakness, dizziness, flushing, orthostatic hypotension, nasal stuffiness, nausea, vomiting, and diarrhea may occur.

OVERDOSAGE Acute Toxicity No deaths due to acute poisoning with Regitine have been reported.

Oral LD50â&#x20AC;&#x2122;s (mg/kg): mice, 1000; rats, 1250.

Signs and Symptoms Overdosage with Regitine is characterized chiefly by cardiovascular disturbances, such as arrhythmias, tachycardia, hypotension, and possibly shock. In addition, the following might occur: excitation, headache, sweating, pupillary contraction, visual disturbances; nausea, vomiting, diarrhea; hypoglycemia.

Treatment There is no specific antidote.

A decrease in blood pressure to dangerous levels or other evidence of shocklike conditions should be treated vigorously and promptly. The patientâ&#x20AC;&#x2122;s legs should be kept raised and a plasma expander should be administered. If necessary, intravenous infusion of norepinephrine, titrated to maintain blood pressure at the normotensive level, and all available supportive measures should be included. Epinephrine should not be used, since it may cause a paradoxical reduction in blood pressure.

DOSAGE AND ADMINISTRATION The reconstituted solution should be used upon preparation and should not be stored.

Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

1. Prevention or control of hypertensive episodes in the patient with pheochromocytoma.

For preoperative reduction of elevated blood pressure, 5 mg of Regitine (1 mg for children) is injected intravenously or intramuscularly 1 or 2 hours before surgery, and repeated if necessary.

During surgery, Regitine (5 mg for adults, 1 mg for children) is administered intravenously as indicated, to help prevent or control paroxysms of hypertension, tachycardia, respiratory depression, convulsions, or other effects of epinephrine intoxication. (Postoperatively, norepinephrine may be given to control the hypotension that commonly follows complete removal of a pheochromocytoma.)

2. Prevention or treatment of dermal necrosis and sloughing following intravenous administration or extravasation of norepinephrine.

For Prevention: 10 mg of Regitine is added to each liter of solution containing norepinephrine. The pressor effect of norepinephrine is not affected.

For Treatment: 5-10 mg of Regitine in 10 mL of saline is injected into the area of extravasation within 12 hours.

3. Diagnosis of pheochromocytoma â&#x20AC;&#x201D; Regitine blocking test.

The test is most reliable in detecting pheochromocytoma in patients with sustained hypertension and least reliable in those with paroxysmal hypertension. False-positive tests may occur in patients with hypertension without pheochromocytoma. a. Intravenous Preparation The CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections should be reviewed. Sedatives, analgesics, and all other medications except those that might be deemed essential (such as digitalis and insulin) are withheld for at least 24 hours, and preferably 48-72 hours, prior to the test. Antihypertensive drugs are withheld until blood pressure returns to the untreated, hypertensive level. This test is not performed on a patient who is normotensive.

Procedure The patient is kept at rest in the supine position throughout the test, preferably in a quiet, darkened room. Injection of Regitine is delayed until blood pressure is stabilized, as evidenced by blood pressure readings taken every 10 minutes for at least 30 minutes.

Five milligrams of Regitine is dissolved in 1 mL of Sterile Water for Injection. The dose for adults is 5 mg; for children, 1 mg.

The syringe needle is inserted into the vein, and injection is delayed until pressor response to venipuncture has subsided.

Regitine is injected rapidly. Blood pressure is recorded immediately after injection, at 30-second intervals for the first 3 minutes, and at 60-second intervals for the next 7 minutes.

Interpretation A positive response, suggestive of pheochromocytoma, is indicated when the blood pressure is reduced more than 35 mmHg systolic and 25 mmHg diastolic. A typical positive response is a reduction in pressure of 60 mmHg systolic and 25 mmHg diastolic. Usually, maximal effect is evident within 2 minutes after injection. A return

mild beta adrenergic agent may cause extraordinary stimulation to myocardium under alpha blockade. The Case 2 patient was a 44 year-old man who needed intensive vasodilating therapy due to an exaggerated cardiovascular response to intraoperative surgical stress. He developed severe metabolic acidosis resembling hyperdynamic shock before resection of the tumor, although blood pressure was controlled within the expected range. The Case 3 patient was a 60 year-old woman who did not receive preoperative alpha blocker therapy because she lacked cardiovascular symptoms. However, she revealed a high level of systemic vascular resistance after induction of general anesthesia and needed moderate inotropic support to compensate for an abrupt reduction of vascular resistance after resection of the tumor. The pathophysiology of the disease is complex and anesthetic care must be tailored in accordance with each patient's situation.

Publication Types: Case Reports

to preinjection pressure commonly occurs within 15-30 minutes but may occur more rapidly.

If blood pressure decreases to a dangerous level, the patient should be treated as outlined under OVERDOSAGE. A positive response should always be confirmed by other diagnostic procedures, preferably by measurement of urinary catecholamines or their metabolites.

A negative response is indicated when the blood pressure is elevated, unchanged, or reduced less than 35 mmHg systolic and 25 mmHg diastolic after injection of Regitine. A negative response to this test does not exclude the diagnosis of pheochromocytoma, especially in patients with paroxysmal hypertension in whom the incidence of false-negative responses is high. b. Intramuscular If the intramuscular test for pheochromocytoma is preferred, preparation is the same as for the intravenous test. Five milligrams of Regitine is then dissolved in 1 mL of Sterile Water for Injection. The dose for adults is 5 mg intramuscularly; for children, 3 mg. Blood pressure is recorded every 5 minutes for 30-45 minutes following injection. A positive response is indicated when the blood pressure is reduced 35 mmHg systolic and 25 mmHg diastolic, or more, within 20 minutes following injection.

HOW SUPPLIED Vials— each containing 5 mg of phentolamine mesylate for injection, USP, and 25 mg of mannitol, USP, in lyophilized form.

Cartons of 2…………………………………………………………….NDC 00836830-02 The reconstituted solution should be used upon preparation and should not be stored.

Store between 15ºC and 30ºC (59ºF-86ºF).

665490 C98-25 (Rev. 6/98) Distributed by Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©1998 Novartis

English Abstract PMID: 15682801 [PubMed - indexed for MEDLINE] 18: Masui. 2004 Nov;53(11):1273-5.

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[Anesthetic management for removal of pheochromocytoma in a patient after repair of tetralogy of Fallot] [Article in Japanese] Yano T, Maruta T, Kawano T, Hamakawa T, Suzuki N, Takasaki M. Department of Anesthesiology, Miyazaki Medical College, University of Miyazaki, Miyazaki 8891692.

A 45-year-old woman after repair of tetralogy of Fallot at the age of 19, was admitted to the hospital for treatment of paroxysmal hypertension. She was diagnosed with pheochromocytoma of the left adrenal gland, and was scheduled for removal of pheochromocytoma. She received doxazosin for preoperative preparation. Anesthesia was induced with propofol and vecuronium, and maintained with intermittent fentanyl and sevoflurane in nitrous oxide and oxygen. Before induction of anesthesia, magnesium sulfate 40 mg x kg(-1) was injected, and followed by continuous infusion of 40 mg x kg(-1) x hr(-1) until the removal of pheochromocytoma. Under neuromuscular monitoring, vecuronium was administered prudently. Cardiac output was continuously monitored with pulmonary arterial catheter and transesophageal aortic blood flow monitor. Blood pressure and heart rate were stable even though the tumor was handled, and no additional vasodilator therapy was needed. After surgery, prolonged neuromuscular blockade caused by magnesium sulfate was not observed. We consider that successful management was feasible by administration of magnesium sulfate and preoperative administration of alpha1 blocker, under adequate perioperative monitoring.

Publication Types: Case Reports English Abstract PMID: 15587179 [PubMed - indexed for MEDLINE] 19: World J Surg. 2004 Nov;28(11):1180-5.

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Does robotic adrenalectomy improve patient quality of life when compared to laparoscopic adrenalectomy?

Brunaud L, Bresler L, Zarnegar R, Ayav A, Cormier L, Tretou S, Boissel P. Department of Visceral, Digestive and Endocrine Surgery, CHU Nancy-Brabois, University of Nancy, Nancy, France. labrunaud@chunancy.fr The purpose of this study was to evaluate and compare perioperative quality of life in patients after

laparoscopic versus robotic adrenalectomy. From November 2000 through August 2003, 33 consecutive patients underwent laparoscopic (n = 14) and robotic (n = 19) adrenalectomy. Data were obtained prospectively during management and by patient questionnaire (SF36, State-Trait Anxiety Inventory) preoperatively and postoperatively, at day 4 and at 6 weeks. Physical functioning, role limitations due to physical health problems, and bodily pain (Physical SF36 scores) were decreased at day 4 (p = 0.004) in all patients when compared to preoperative levels; and became similar to preoperative levels after 6 weeks. Patients who underwent robotic adrenalectomy had an increased score at 6 weeks of role limitations due to emotional problems (Mental SF36 score) (p = 0.03). No other significant difference was observed between patients after laparoscopic or robotic adrenalectomy. Although state anxiety was decreased postoperatively at day 4 and at 6 weeks (p = 0.01) in all patients, there was no significant difference between laparoscopic and robotic adrenalectomy. Postoperative pain was similar in both groups but had a tendency to be higher when patients underwent a left adrenalectomy (p = 0.07). Similarly, state anxiety had a tendency to be higher postoperatively at day 4 in patients after left adrenalectomies (p = 0.06). This study provides an evaluation of perioperative quality of life in patients after minimally invasive (laparoscopic and/or robotic) adrenalectomy. We observed no major difference between patients who underwent laparoscopic or robotic adrenalectomy. Thus, patients' perioperative quality of life is not a justifiable parameter on which to base promotion of robotic adrenalectomies.

Publication Types: Comparative Study PMID: 15490066 [PubMed - indexed for MEDLINE] 20: Anesthesiol Clin North America. 2004 Mar;22(1):93-123.

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Assessment and therapy of selected endocrine disorders.

Connery LE, Coursin DB. Department of Surgery, Long Island Jewish Medical Center, 270-05 76(th) Avenue, New Hyde Park, NY 11040, USA. lconnery@charter.net Diabetes remains the most commonly encountered endocrinopathy with the incidence of type 2 doubling in the past decade. The prevalence of diabetes is projected to continue to increase dramatically over the next several decades unless major public health initiatives are successful in stemming this growth. Both type I and 2 diabetics more frequently require surgical and critical care than their non-diabetic counterparts. Type 1 and 2 diabetics also sustain greater peri-operative morbidity and mortality. Careful preoperative assessment and appropriate perioperative intervention may limit this.There is increasing evidence that maintenance of normal blood glucose in the perioperative period and during critical illness is beneficial for diabetic and non-diabetic patients.

More data will hopefully be forthcoming to substantiate recent reports and identify the mechanisms of improved outcome. Thyroid disease remains a commonly encountered pathology that is more readily identified and controlled in the modern era of radioimmune assays of thyroid hormone and successful medical and surgical therapies. Severe hypothyroidism and thyroid storm are associated with significant increases in perioperative morbidity and mortality. Recognition of these entities or those at risk for developing them post operatively is crucial in initiating timely and effective therapy. Primary Al is uncommon, but results in glucocorticoid and mineralocorticoid deficiency.

Tertiary Al is far more common, most often secondary to iatrogenic therapy with exogenous glucocorticoids for the management of chronic diseases such as connective tissue disorders, antirejection regimes, and severe asthma. Glucocorticoid replacement or supplementation is needed on a case-by-case basis and should be individualized based on chronic steroid dose, duration, and stress of the surgical procedure. Perioperative steroid dosing regimes now recommend lower doses for shorter periods than previously suggested. More recently Al has been recognized in two populations, elderly patients undergoing major surgery and a subgroup of patients with septic shock. Timely diagnosis using synthetic ACTH stimulation testing and stress glucocorticoid, and possibly mineralocorticoid therapy, seems to reverse these processes and improve recovery.

Although uncommon, patients with pheochromocytoma who undergo open or laparoscopic resections remain diagnostic and therapeutic challenges. Perioperative outcome seems to have improved, in part, related to newer therapies and less invasive surgeries when indicated. The appropriate preoperative assessment and management of patients with various endocrinopathies is important to optimize outcome and limit avoidable complications. Hopefully additional evidence based guidelines will be forth-coming particularly in caring for the ever increasingly encountered perioperative diabetic.

Publication Types: Review PMID: 15109693 [PubMed - indexed for MEDLINE] 21: Surg Endosc. 2004 Apr;18(4):621-5. Epub 2004 Mar 19.

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Laparoscopic adrenalectomy for pheochromocytoma. A comparison to aldosteronoma and incidentaloma.

Kalady MF, McKinlay R, Olson JA Jr, Pinheiro J, Lagoo S, Park A, Eubanks WS. Department of Surgery, Duke University Medical Center, 3110, Durham, NC 27710, USA. BACKGROUND: Laparoscopic adrenalectomy is a safe and effective treatment for most surgical diseases of the adrenal gland. However it has been suggested that catecholamine effects associated with pheochromocytoma render the laparoscopic approach a more challenging and a more morbid procedure. The purpose of this study was to compare the operative characteristics and outcomes of laparoscopic adrenalectomy for pheochromocytoma to those of aldosteronoma and incidentaloma.

METHOD: Patient records and operative reports were retrospectively reviewed for demographics, diagnoses, operative management, and outcomes for patients undergoing laparoscopic adrenalectomy between June 1994 and July 2002 at two academic medical centers. A total of 74 patients were included and analyzed by diagnosis. Differences were considered statistically significant at p < 0.05. RESULTS: Twenty-eight patients with pheochromocytoma, 27 with aldosteronoma, and 19 with incidentally discovered nonfunctioning adrenal masses underwent laparascopic adrenalectomy. Patients undergoing resection for pheochromocytoma trended toward more operative blood loss (150 ml) compared to aldosteronoma (88 ml) and incidentaloma (75 ml).

Eight patients were converted to an open procedure for a 10.8% conversion rate. The mean operative time was 171 min and there was a 10.8% perioperative complication rate. The mean hospital stay was 3.4 days. These results were not statistically significant between diagnostic groups. CONCLUSION: Despite concern about increased operative times and morbidity associated

with pheochromocytoma, our experience supports that laparoscopic adrenalectomy may be performed as safely as, and achieve outcomes similar to, those for other diseases.

Publication Types: Comparative Study Evaluation Studies Multicenter Study Review PMID: 15026894 [PubMed - indexed for MEDLINE] 22: Br J Anaesth. 2004 Apr;92(4):512-7. Epub 2004 Feb 6.

Related Articles, Links Comment in: Br J Anaesth. 2004 Sep;93(3):472-3; author reply 473.

Effects of perioperative alpha1 block on haemodynamic control during laparoscopic surgery for phaeochromocytoma.

Tauzin-Fin P, Sesay M, Gosse P, Ballanger P. Department of Anaesthesia, Pellegrin University Hospital, 33076 Bordeaux Cedex, France. patrick.tauzin-fin@chu-bordeaux.fr BACKGROUND: Laparoscopic surgery for phaeochromocytoma can cause excessive catechol amine release with severe hypertension and sinus tachycardia. i.v. calcium antagonists may be used to prevent increases in blood pressure during phaeochromocytoma resection. We investigated the effects of perioperative alpha(1) adrenergic block with urapidil on intraoperative haemodynamic events. The aim was to block the alpha(1) adrenergic receptors before any acute catecholamine release, to prevent any severe rise in blood pressure. METHODS: Eighteen patients with a phaeochromocytoma received a continuous i.v. infusion of urapidil 10-15 mg h(-1) for 3 days before surgery and until the adrenal gland had been removed. Plasma catecholamine concentrations were measured before surgery, after induction of anaesthesia, at the end of pneumoperitoneal insufflation, during gland manipulation, after gland resection, and in the recovery room after extubation. Arterial pressure was recorded concomitantly. Hypertensive events were treated with boluses of nicardipine with or without esmolol. RESULTS: All patients had the adrenal tumour removed without any severe rise in blood pressure or other complication. Creation of a pneumoperitoneum and adrenal gland manipulation induced significant catecholamine release associated with hypertension in 6 and 12 patients, respectively. No correlation was found between hypertensive events and plasma catecholamine levels suggesting alpha(1) receptor block with urapidil is efficacious. CONCLUSIONS: Perioperative alpha(1) block using i.v. urapidil is a safe and efficient alternative during surgical management of phaeochromocytoma.

Publication Types: Clinical Trial Randomized Controlled Trial PMID: 14766711 [PubMed - indexed for MEDLINE]

23: Can J Anaesth. 2004 Feb;51(2):134-8.

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Pheochromocytoma and pregnancy: a case report and review of anesthetic management.

Dugas G, Fuller J, Singh S, Watson J. Department of Anesthesia and Perioperative Medicine, St. Joseph's Health Care, University of Western Ontario, London, Ontario, Canada.

PURPOSE: To describe a patient diagnosed with pheochromocytoma in the third trimester of pregnancy and discuss the perioperative and anesthetic management. CLINICAL FEATURES: A 32-yr-old previously healthy woman (gravida 4, para 2) presented to our tertiary care obstetrical hospital at 34 weeks five days gestation with a history of labile blood pressure and severe hypertension. A week prior to admission she began having episodes of severe headache, dizziness, sweating and nausea. On a routine obstetric visit she was noted to be severely hypertensive with a blood pressure of 200/120 mmHg. Biochemical investigations confirmed the diagnosis of pheochromocytoma and magnetic resonance imaging demonstrated a 3 cm x 3 cm right adrenal mass. The patient was invasively monitored in the intensive care unit and treated with alphafollowed by beta-blockade with phenoxybenzamine and metoprolol. A multidisciplinary conference was organized involving endocrinology, anesthesiology, general surgery and obstetrics to determine the most appropriate management of the patient. An uncomplicated laparoscopic adrenalectomy was performed following a period of recovery after an uneventful elective Cesarean delivery.

CONCLUSIONS: The primary goals in the management of pheochromocytoma in pregnancy are early diagnosis, avoidance of a hypertensive crisis during delivery and definitive surgical treatment.

Timing of surgical resection will depend on the gestational age at which diagnosis is made.

Cesarean section is the preferred mode of delivery when the tumour is still present. This case illustrates that with antenatal diagnosis, advanced methods of tumour localization, adequate preoperative adrenergic blockade and team planning, pheochromocytoma in pregnancy can be treated successfully.

Publication Types: Case Reports PMID: 14766689 [PubMed - indexed for MEDLINE] 24: Chin Med J (Engl). 2003 Oct;116(10):1527-31.

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Clinical features of pheochromocytoma and perioperative anesthetic management.

Luo A, Guo X, Yi J, Ren H, Huang Y, Ye T. Department of Anesthesia, Peking Union Medical College Hospital, Beijing 100730, China. luoailun@public.pumch.ac.cn

OBJECTIVE: To investigate clinical features of pheochromocytoma and summarize experiences of anesthetic management during the perioperative period. METHODS: Two hundred and fifty eight patients who were diagnosed with pheochromocytoma in our hospital were reviewed retrospectively for clinical features. According to different preoperative pharmalogical preparations, perioperative mortalities were analyzed in three periods (Period 1: January 1955 - December 1975; Period 2: January 1976 - December 1994; Period 3: January 1995 - July 2001). In Period 3, hemodynamic changes in the patients undergoing different anesthetic methods were analyzed. RESULTS: About 5.8% (15/258) of pheochromocytoma was an integral part of multiple endocrine neoplasia (MEN) type II or mixed type. Sixty percent (149/249) of the patients who had undergone surgery possessed evidence of catecholamine cardiac toxicity preoperatively. Impaired glucose tolerance was found in 59% (147/249) of the patients before surgery. Perioperative mortality was significantly decreased from 8% (5/60) in Period 1 to 1.2% (1/75) in Period 2 (P < 0.01). No perioperative deaths occurred in Period 3. The volume infused during the operation was significantly higher both in the epidural anesthesia group (3474 ml +/- 624 ml, P < 0.01) and in the epidural plus general anesthesia group (3654 ml +/- 475 ml, P < 0.01) than in the general anesthesia group (2534 ml +/- 512 ml). There were favorable hemodynamic characteristics in patients before removal of the tumor in the epidural anesthesia group and in the epidural plus general anesthesia group, as compared with the general anesthesia group. CONCLUSIONS: A positive surgical outcome of the excision of pheochromocytoma depends on multiple factors, including careful assessment of potential vital organ damage before surgery and restoration of blood volume by establishing alpha-blockade preoperatively, meticulous anesthetic management of patients during surgery, and appropriate circulatory support after surgery.

PMID: 14570616 [PubMed - indexed for MEDLINE] En: http://www.cmj.org/Periodical/paperlist.asp?id=LW7388&linkintype=pubmed

Clinical features of pheochromocytoma and perioperative anesthetic management LUO Ailun ÂÞ°®Â×, GUO Xiangyang ¹ùÏòÑô, YI Jie Ò× ½Ü, REN Hongzhi ÈκéÖÇ, HUANG Yuguang »ÆÓî¹â, YE Tiehu Ò¶Ìú»¢ LUO Ailun ÂÞ°®Â× Department of Anesthesia£¬ Peking Union Medical College Hospital£¬ Beijing 100730, China; GUO Xiangyang ¹ùÏòÑô Department of Anesthesia£¬ Peking Union Medical College Hospital£Beijing 100730, China; YI Jie Ò× ½Ü Department of Anesthesia£¬ Peking Union Medical College Hospital£¬ Beijing 100730, China; REN Hongzhi ÈκéÖÇ Department of Anesthesia£¬ Peking Union Medical College Hospital£¬ Beijing 100730, China; HUANG Yuguang »ÆÓî¹â Department of Anesthesia£Peking Union Medical College Hospital£¬ Beijing 100730, China; YE Tiehu Ò¶Ìú»¢ Department of Anesthesia£¬ Peking Union Medical College Hospital£¬ Beijing 100730, China Correspondence to: Luo Ailun Department of Anesthesia, Peking Union Medical College Hospital, Beijing 100730, China (Tel:86-10-65295593 Fax:86-10-65295593 Email:luoailun@public.pumch.ac.cn ) Keywords: pheochromocytoma¡¤catecholamine¡¤anesthesia Abstract:

Objective To investigate clinical features of pheochromocytoma and summarize experiences of anesthetic management during the perioperative period.

Methods Two hundred and fifty eight patients who were diagnosed with pheochromocytoma in our hospital were reviewed retrospectively for clinical features. According to different preoperative pharmalogical preparations, perioperative mortalities were analyzed in three periods (Period 1: January 1955-December 1975; Period 2: January 1976-December 1994; Period 3: January 1995-July 2001). In Period 3, hemodynamic changes in the patients undergoing different anesthetic methods were analyzed.

Results About 5.8% (15/258) of pheochromocytoma was an integral part of multiple endocrine neoplasia (MEN) type ¢ò or mixed type. Sixty percent (149/249) of the patients who had undergone surgery possessed

evidence of catecholamine cardiac toxicity preoperatively. Impaired glucose tolerance was found in 59% (147/249) of the patients before surgery. Perioperative mortality was significantly decreased from 8% (5/60) in Period 1 to 1.2% (1/75) in Period 2 (P<0.01). No perioperative deaths occurred in Period 3. The volume infused during the operation was significantly higher both in the epidural anesthesia group (3474 ml¡À624 ml, P<0.01) and in the epidural plus general anesthesia group (3654 ml¡À475 ml, P<0.01) than in the general anesthesia group (2534 ml¡À512 ml). There were favorable hemodynamic characteristics in patients before removal of the tumor in the epidural anesthesia group and in the epidural plus general anesthesia group, as compared with the general anesthesia group.

Conclusions A positive surgical outcome of the excision of pheochromocytoma depends on multiple factors, including careful assessment of potential vital organ damage before surgery and restoration of blood volume by establishing ¦Á-blockade preoperatively, meticulous anesthetic management of patients during surgery, and appropriate circulatory support after surgery.

CMJ 2003;116(10):1527-1531 ¡¤LogIn/LogOut ¡¤Fulltext PDF(-) Free ¡¤Abstract download TXT | XML ¡¤Articles in CMJ by LUO Ailun GUO Xiangyang ¡¤Articles in PubMed by LUO A GUO X ¡¤Put into my bookshelf ¡¤Email to Friend ¡¤Email to author ¡¤Visit:3967 ¡¤Download:2892 ¡¤Advanced Search ¡¤Related Articles ¡¤Change font size: ¡¤Cannot read some characters Although surgical treatment for pheochromocytoma and its perioperative management has been well developed in recent years, anesthetic management is still highly stressful in certain circumstances, such as coexistent endocrine tumors, occult pheochromocytoma and cardiovascular impairment.£Û1-3£Ý The purpose of this study was to investigate the clinical features of pheochromo-cytoma and summarize the experiences of anesthetic management in the perioperative period.

METHODS A retrospective review was conducted in the patients who were clinically or pathologically diagnosed with pheochromocytoma in our hospital between January 1955 and July 2001.

General information The following data were collected: demographics, clinical and pathological diagnosis, image examinations (including abdominal ultrasonograpy, CT scan, MRI), 131I-meta-iodobenzylguanidine (131I-MIBG), biochemical exam-inations, and therapeutic strategies.

Perioperative mortalities in different periods According to different preoperative pharmacological preparation, perioperative mortalities were analyzed in three periods (Period 1: January 1955-December 1975; Period 2: January 1976-December 1994; Period 3: January 1995-July 2001). In Period 1, only sedatives such as benzodiazepine were administered. In Period 2, phenoxybenzamine, an ¦Á-blocker, was routinely administered for preoperative preparation, which was sometimes combined with propranolol if tachycardia occurred. In Period 3, in addition to medications administered in Period 2, a decrease in preoperative hematocrit by 5% together with an increase in body weight was applied as one of the clinical markers of restored blood volume. In this period, urapidil and esmolol were clinically available for both preoperative preparation and intraoperative antihypertensive agents.

Changes of hemodynamic parameters during surgery under different anesthesia The anesthetic charts of the patients in Period 3 were analyzed for intraoperative hemodynamic changes.

According to anesthetic charts, the patients were divided into three groups: general anesthesia, epidural anesthesia, and general plus epidural anesthesia groups. In the general anesthesia group, anesthesia was induced with either 5 mg/kg sodium thiopental or propofol of 1 mg/kg-2mg/kg i.v., followed by 1 mg/kg-2 mg/kg succinylcholine to facilitate endotracheal intubation. Anesthesia was maintained with inhalation of isoflurane or enflurane and nitrous oxide in oxygen (nitrous oxide¡Ãoxygen=2¡Ã1), supplemented with fentanyl injection intermittently. Muscle relaxation during the operation was

maintained with intermittent boluses of pancuronium or vecuronium. In the epidural anesthesia group, a catheter was inserted into epidural space between T10 and T11 under local anesthesia. A mixture of 1% xylocaine and 0.25% tetracaine was used and the blocked level was adjusted after 5 ml testing dose.

During epidural anesthesia, the patients were sedated with intravenous injection of diazepam or midazolam.

The following data were collected and analyzed: surgical procedures, anesthetic methods, and intraoperative invasive hemodynamic parameters, including pulmonary artery wedge pressure (PAWP), right atrial pressure (RAP), systemic vascular resistance (SVR), cardiac index (CI), left ventricular stroke work index (LVSWI), and mean arterial blood pressure (MAP). Blood loss and infused fluid volume, percentage of administration of vasodilators and inotropics during surgery were also recorded.

Statistical analysis Hemodynamic parameters during the surgery were analyzed with analysis of variance. Percentages of administering cardiovascular agents during the surgery and perioperative mortalities in different periods were analyzed with ¦Ö2 test. All data were expressed as mean¡ÀSD. A P value less than 0.05 was considered statistically significant.

RESULTS General information The patients' age ranged from 7 to 70 years (mean, 35 years). Male patients were 159 and female patients were 99. The duration of the disease was from 20 days to 15 years (average, 2 years).

Pheochro-mocytomas were located in the medulla of the adrenal gland in 87% (224/258) of the patients and outside the adrenal gland in 13% (34/258) of the patients. Most pheochromo-cytomas (76%, 206/258) secreted norepinephrine either alone or more commonly combined with epinephrine. About 15% (39/258) of the pheochromocytomas secreted predominantly epinephrine. The remaining 9% (23/258) of the pheochromocytomas were asymptomatic and incidentally identified during routine health examinations or in the course of treatment for other diseases. About 5.8% (15/258) of pheochromocytomas was presented as a part of multiple endocrine neoplasias (MEN). Eleven patients presented with MEN type ¢òa (Sipple syndrome), the main constituents of which were medullary thyroid carcinoma, hyperparathyroidism, and pheochromocytoma; one presented with MEN type ¢òb, including medullary thyroid carcinoma, pheochromo-cytoma and mucosal neuromas; and three presented with mixed MEN, which consisted of pheochromocytoma and MEN type ¢ñ (Wermer's syndrome), including pancreatic islet-cell tumor and hyperplasia or neoplasia of the pituitary and parathyroid glands. Excisions of pheochromocytomas were performed in 249 patients. The surgical procedures included unilateral abdominal adrenalectomy (212 cases), bilateral abdominal adrenalectomy (7 cases), and removal of ectopic abdominal pheochromocytoma (30 cases). The remaining 9 inoperable patients underwent chemotherapy and nuclear therapy with 131I-MIBG. About 60% (149/249) of the surgical patients had presentations of catecholamine cardiac toxicity before the surgery, which was manifested as abnormal ST-T segment, acute myocardial infarction, acute pulmonary edema and cardiomyopathy. Glucose tolerance tests were abnormal in 59% (147/249) of the patients before the surgery, while it returned to normal in 39% (97/249) patients postoperatively.

Perioperative mortalities in different periods In Period 1, the perioperative mortality was 8% (5/60). The causes of death were congestive heart failure (2 patients), myocardial infarction (1 patient), multiple organ failure (1 patient) or cerebral hemorrhage (1 patient). However, perioperative mortality dropped significantly to 1.2% (1/78, P<0.01) in Period 2.

The patient died of multiple organ failure after a complicated surgical procedure for multiple pheochromocytomas involving the inferior vena cava. There were no perioperative deaths in Period 3.

Changes of hemodynamic parameters during surgery under different anesthesi Sixty-six anesthetic charts with complete hemodynamic parameters were selected from 111 charts in Period 3. The highest hemodynamics before and the lowest hemodynamics after the resection of the tumor as well as the amount of fluid infused intravenously were analyzed. Surgical procedures for excision of pheochromocytomas were performed under general anesthesia, epidural anesthesia or general anesthesia combined with epidural anesthesia in 33, 18 and 15 cases respectively. Before tumor resection, both RAP and PAWP were at the upper limits, irrespective of the form of anesthetic method selected. However, significantly lowered systemic vascular resistance was presented in the epidural anesthesia group and the epidural plus general anesthesia group. After removal of the tumor, there was an overall decline in all hemodynamics in all the groups, with significant decreases in SVR, CI, LVSWI and MAP ( Table 1 ). MAP was significantly higher in the general anesthesia group than in the other two groups both before and after resection of the tumor.

Compared with the general anesthesia group, the percentage of using vasodilators before tumor resection in general anesthesia group was significantly higher than those in the epidural and epidural plus general anesthesia groups ( Table 2 ). However, there was no significant difference in the percentage of catecholamine administrated among different groups ( Table 3 ).

The volume supplied during the operation was significantly higher both in the epidural anesthesia group (3474 ml¡À624 ml, including Ringer's solution 2500 ml¡À485 ml£¬ gelofusine 570 ml¡À110 ml£¬ and

packed red blood cells 512 ml¡À72 ml, P<0.01) and the epidural plus general anesthesia group (3654 ml¡À475 ml, including Ringer's solution 2734 ml¡À318 ml£¬ gelofusine 627 ml¡À147 ml£¬ and packed red blood cells 541 ml¡À91 ml, P<0.01) than the general anesthesia group (2534 ml¡À512 ml, including Ringer's solution 1874 ml¡À512 ml£¬ gelofusine 471 ml¡À107 ml£¬ and packed red blood cells 410 ml¡À70 ml).

DISCUSSION Preoperative image examinations play an important role in surgical treatment of pheochromocytoma and anesthetic management In this series, about 9% of pheochromocytomas existed sporadically or coexisted with other endocrine tumors. For those patients who are highly suspected of pheochromocytoma but lack biochemical evidence, application of image examinations with high specificity for pheochromocytoma such as MIBG should be considered to confirm the diagnosis.£Û4£Ý If pheochromocytomas are found to coexist with MEN preoperatively, excision of pheochromocytoma should be scheduled first in order to avoid fluctuation of blood pressure and unexpected cardiac and cerebral vascular events due to the surge of catecholamine during the operation designated for removal another coexistent tumor. In the meantime, it should be

hypercalcemia as a consequence of hyperparathyroidism and low blood glucose levels resulting from insulinoma might coexist with pheochromocytoma.7 If pheochromocytomas are present in both adrenal noted that endocrine diseases such as

glands and bilateral adrenalectomy is anticipated, supplemental cortisone treatment should be instituted at the time of preoperative medication and after bilateral adrenalectomy. The aim of this maneuver is to prevent postoperative acute hypoadrenocorticism and refractory hypotension.

Our data also show that more than half of the patients had the presentations of catecholamine cardiac toxicity, which is in accordance with previous reports.£Û5,6£Ý It is suggested that the severity of impaired cardiovascular function should be carefully evaluated by electrocardiographic and echocardiographic examinations. For patients whose pheochromocytoma is complicated with cardiomyopathy, it is prudent to discontinue the use of long acting antihypertensive drugs and ¦Âblockers in order to avoid prolonged hypotension due to the residual effects of these drugs after the removal of pheochromocytoma.

Changes of hemodynamics in different anesthetic groups and related management Considering the fact that with such a long period of clinical data analyzed, obvious differences in perioperative administration of drugs, surgical tech-niques, and anesthetic management may exist in different periods, we only chose complete anesthetic charts in Period 3. The results indicate that epidural block significantly reduces systemic vascular resistance, which is beneficial to maintain stable blood pressure before removal of the tumour and contributes significantly to the sparing effect on the use of vasodilators. After the removal of the pheochromocytoma, there was no significant difference among the three groups in the percentage of catecholamine administration, indicating that epidural anesthesia and epidural plus general anesthesia may have advantages over general anesthesia alone. However, it has been reported that epidural anesthesia may result in severe hypotension after the removal of the pheochromocytoma, and that epidural anesthesia may affect pulmonary alveolar ventilation in sedated patients.£Û7£Ý Therefore, epidural combined with general anesthesia may be a better choice for this kind of surgery.

As for the management of hemodynamics during surgery, it is generally efficacious to administer nitroprusside and or phentolamine to control the hypertensive responses during the surgical manipulation. In case of hypertension with tachycardia, a combination of esmolol and an ultra short ¦Âblocker is helpful. After excision of the pheochromocytoma, selection of catecholamine and titration of dosage should be made based on the type of catecholamine secreted by the tumor and the severity of hypotension.

In the present data, it is shown that both SVR and CI are reduced after the resection of the tumor.

However, CI should be theoretically increased after the reduction of SVR. The paradoxical phenomenon observed in the present study may be related to the abrupt reduction of endogenous catecholamine in the blood after the removal of the tumor. In addition, it is shown that the number of catecholamine receptors distributed in the cardiovascular system in patients with pheochromocytoma is decreased due to the long-term action of high level of catecholamine secreted by pheochromocytoma, which is a receptor down regulation.£Û6£Ý The number of catecholamine receptors could not recover to the level of normal conditions within a short period after tumor resection.£Û5£Ý All these pathophysiological changes may be associated with the simultaneous decline of SVR and CI after tumor resection.

Necessity of monitoring blood glucose and adjusting fluid to be infused during the perioperative period In the present study, glucose tolerance tests were abnormal in about 59% patients preoperatively and only 39% of them returned to normal after the surgery. The hyperglycemia status before the removal of

7

INTERESANTE PARA TENERLO EN CUENTA, DENTRO DE LOS PARACLÍNICOS REALIZADOS.

the pheochromocytoma may be related to a high level of circulating catecholamines, that act on the ¦Áreceptors of the pancreatic ¦Â cells and suppress insulin release.£Û1£Ý The increased catecholamines also increase glycogenolysis and free fatty acid levels in the blood, and as a consequence, provide alternate energy substrates and decreased glucose clearance from the blood. On the other hand, hypoglycemia may occur within minutes after removal of the tumor as ¦Á-induced suppression of insulin release wanes.£Û8,9£Ý The suppression of ¦Â-cell function disappears and plasma insulin levels rise, resulting in postoperative hypoglycemia and even loss of consciousness and respiratory arrest in serious cases.£Û10£Ý It should be noted that the classic symptoms of hypoglycemia might be masked during anesthesia and in the postoperative period when patients are under treatment of analgesics and sedatives. Consequently, monitoring blood glucose in the perioperative period and adjusting the type of fluid infused according to the monitored results may be necessary for some patients.

Importance of preoperative hypertension control by administration of vasodilators and restoration of blood volume The overall level of surgical treatment for pheo-chromocytoma depends on multiple factors, including adequate preoperative preparation, surgical techniques, intraoperative anesthetic management, and postoperative support for vital organ dysfunction. Therefore, even though we studied the clinical outcome by distinguishing different periods with preoperative pharmacological preparation, the markedly reduced mortality rates observed in Periods 2 and 3 may just reflect overall improvement in the treatment for pheochromocytoma, since all these factors are being improved simultaneously as time goes on.

Nevertheless, the preoperative administration of a ¦Á-blocker to control hypertensive status of pheochromocytoma and restore of blood volume is crucial to the outcome of surgical treatment and should not be overlooked.£Û11£Ý REFERENCES 1.Hull CJ. Pheochromocytoma: diagnosis, preoperative preparation and anesthetic management. Br J Anaesth 1986;58:1453-1458.

2.Pullerits J, Ein S, Balfe JW. Anesthesia for pheochromo-cytoma. Can J Anaesth 1988;35:526-534.

3.Prys-Roberts C. Pheochromocytoma: recent progress in its management. Br J Anaesth 2000;85:44-57.

4.Wiseman GA, Kvols LK. Therapy of neuroendocrine tumors with radiolabeled MIBG and somatostatin analogues.

Semin Nucl Med 1995;25:272-278.

5.Gilsanz FJ, Luengo C, Conejero P, et al. Cardiomyopathy and pheochromocytoma. Anesthesia 1983;38:888-891.

6.Fripp RR, Lee JC, Downing SE. Inotropic responsiveness of the heart in catecholamine cardiomyopathy. Am Heart J 1981;101:17-21.

7.Roizen MF, Horrigon RW, Koike M. A prospective randomized trial of four anesthetic techniques for resection of pheochromocytoma. Anaesthesiology 1982;57:A43.

8.Cousins MJ, Rubin RB. The intraoperative management of pheochromocytoma with total epidural sympathetic blockade. Br J Anaesth 1974;46:78-81.

9.Levin H, Heefetz M. Pheochromocytoma and severe protracted postoperative hypoglycaemia. Can J Anaesth 1990;37:477-478.

10.Channa AB, Mofti AB, Taylor GW, et al. Hypoglycaemic encephalopathy following surgery on phaeochromocyotma.

Anesthesia 1987;42:1298-1320.

11.Roizen MF, Hunt TK, Beaupre PN, et al. The effect of alpha-adrenergic blockade on cardiac performance and tissue oxygen delivery during excision of pheochromocytoma. Surgery 1998;94:941-945.

25: J Am Vet Med Assoc. 2003 Sep 1;223(5):654-62.

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Surgical management of adrenal gland tumors with and without associated tumor thrombi in dogs: 40 cases (1994-2001).

Kyles AE, Feldman EC, De Cock HE, Kass PH, Mathews KG, Hardie EM, Nelson RW, Ilkiw JE, Gregory CR. Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA. OBJECTIVE: To compare pathologic findings and results of adrenalectomy for adrenal gland

tumors in dogs with and without vena caval tumor thrombi. DESIGN: Retrospective study.

ANIMALS: 40 dogs with adrenal gland tumors. PROCEDURE: Medical records were examined.

An exact logistic regression analysis was used to evaluate associations between tumor type or rightsided versus left-sided tumor involvement and development of caval tumor thrombi and associations between tumor thrombi, tumor type, or right- versus left-sided location and perioperative complications and mortality rate. Survival was compared between dogs with and without tumor thrombi. RESULTS: Caval thrombi were detected in 25% of dogs, including 3 of 28 (11%) dogs with an adrenocortical tumor and 6 of 11 dogs with a pheochromocytoma. A caval tumor thrombus was detected in 6 of 17 right-sided and 4 of 20 left-sided tumors. Sensitivity and specificity of abdominal ultrasonography for detection of caval thrombi were 80 and 90%, respectively. Intraoperative and postoperative complications developed in 15 and 51% of dogs, respectively. The mortality rate was 22%. There were no significant differences in perioperative morbidity and mortality rates between dogs with and without tumor thrombi. CONCLUSIONS AND CLINICAL RELEVANCE: Caval thrombi associated with adrenal gland tumors are amenable to adrenalectomy and thrombectomy without significantly increased perioperative morbidity and mortality rates, assuming the surgeon is experienced in appropriate techniques.

PMID: 12959384 [PubMed - indexed for MEDLINE] 26: Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2002 Aug;24(4):424-6.

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[Perioperative anesthetic management for the excision of phaeochromocytoma complicated with catecholamine cardiomyopathy] [Article in Chinese] Guo XY, Luo AL, Gong ZY, Ren HZ, Yie TH, Huang YG. Department of Anaesthesia, PUMC Hospital, CAMS, PUMC, Beijing 100730, China. xyg34@hotmail.com OBJECTIVE: To summarize experience of perioperative anesthetic management for patients undergone excision of pheochromocytoma and complicated with catecholamine cardiomyopathy.

METHODS: Perioperative anesthetic management for surgical treatment of three cases of pheochromocytoma complicated with catecholamine cardiomyopathy was described and discussed according to literature reports. RESULTS: The catecholamine cardiomyopathy of the three cases presented with left ventricular hypertrophy, congestive cardiac failure and acute myocardial infarction. After removal of the pheochromocytoma under general anesthesia, a prolonged hypotension occurred in all of the three cases. In order to maintain stable hemodynamics, large dose of catecholamine was required after surgery. All of the three patients were survived and discharged.

CONCLUSIONS: It is suggested that myocardial dysfunction may be another important factor for the prolonged hypotension after removal of the tumor. Meticulous preoperative assessment of heart function is of primary importance for the management of anaesthesia during surgical procedures. 8 Publication Types: Case Reports English Abstract

8

IMPORTANTE RESULTADO DEL ECOCARDIOGRAMA PREQUIRĂ&#x161;RGICO.

PMID: 12905668 [PubMed - indexed for MEDLINE] 27: Ann Chir. 2003 May;128(4):232-6.

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[Current management of pheochromocytoma: about 50 cases] [Article in French] Cherki S, Causeret S, Lifante JC, Mabrut JY, Sin S, Berger N, Peix JL. Service de chirurgie générale, hôpital de l'Antiquaille, 1, rue de l'Antiquaille, 69321 cedex 05, Lyon, France.

STUDY AIM: The aim of this retrospective study was to assess our experience of the laparoscopic surgery of pheochromocytoma.We report indications and results of laparoscopic and open adrenalectomy for pheochromocytoma. PATIENTS AND METHODS: Between january 1994 and may 2002, 50 patients underwent laparoscopic or open adrenalectomy for pheocromocytoma. The perioperative hemodynamic parameters were assessed for each patient. In each case, urinary metanephrine levels were measured at the second month postoperatively. The long term outcome was assessed in 44 patients. The mean follow-up was 39 months. RESULTS: Ten patients underwent open adrenalectomy: 8 patients for unilateral tumors (tumor size was > 8 cm in 7 cases) and 2 patients for bilateral tumors (1 recurrence and 1 cystic polylobed tumor). Fourty patients underwent laparoscopic adrenalectomy: in 32 cases, including 1 patient with a bilateral tumor, no conversion was performed (tumor size was < 5 cm in 29 cases). In 8 cases (20%), a conversion to an open operation was performed. The reasons to convert were bleeding and periadrenal fibrosis in 7 cases. In laparoscopic adrenalectomy group, hemodynamic troubles were not more frequent, the hospital stay was shorter and there was no recurrence. CONCLUSION: Laparoscopic adrenalectomy is the Gold standard procedure for patients with pheochromocytoma. But open adrenalectomy is sometimes indicated: tumor size > 8 cm, periadrenal fibrosis, and recurrence tumor.

Publication Types: English Abstract PMID: 12853019 [PubMed - indexed for MEDLINE] 28: Chin Med J (Engl). 2003 Feb;116(2):208-11.

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Clinical features and anesthetic management of multiple endocrine neoplasia associated

with pheochromocytoma. 9 Luo A, Guo X, Ren H, Huang Y, Ye T. Department of Anesthesia, Peking Union Medical College Hospital, Beijing 100730, China. luoailun@public.pumch.ac.cn OBJECTIVE: To investigate clinical features and anesthetic management of multiple endocrine neoplasia (MEN) associated with pheochromocytoma. METHODS: Medical records of patients who were diagnosed as multiple endocrine neoplasia associated with pheochromocytoma in our hospital from April 1977 to April 2001 were reviewed retrospectively. The demographic data, clinical presentations, family history, biochemical examinations, type of MEN, sequence of different surgical procedures, anesthetic methods and hemodynamics during surgery were analyzed.

RESULTS: Thirteen cases of MEN associated with pheochromocytoma were investigated, accounting for 6% (13/213) of the pheochromocytoma patients admitted into our hospital. Nine of the 13 patients presented as type IIa MEN (Sipple syndrome), one as type IIb MEN, and three as mixed MEN. Four patients with type IIa MEN had a family history of similar disease. Five patients with other coexisting endocrine disorders first underwent excision of the pheochromocytomas, although only two had hypertensive symptoms at the time of admittance. Seven patients without histories of hypertension received surgical treatment for pheochromocytoma secondly. The excision of pheochromocytoma was performed under general anesthesia in 8 patients and epidural block in 4 patients. Marked hemodynamic fluctuation was recorded in 8 patients. No perioperative death was recorded. CONCLUSION: Pheochromocytoma may be linked to other endocrine disorders during MEN, either as the main clinical presentation or most frequently as an occult tumor. Recognition of this feature of pheochromocytoma is of importance to the improvement of diagnosis and treatment both for pheochromocytoma and MEN. PMID: 12775231 [PubMed - indexed for MEDLINE] 29: Br J Anaesth. 2003 Mar;90(3):380-2.

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Use of a 'hospital-at-home' service for patient optimization before resection of phaeochromocytoma.

Emerson CE, Rainbird A. Department of Anaesthesia, The Queen Elizabeth Hospital, Woodville Road, Woodville, Adelaide, SA 5011, Australia.

The perioperative management of phaeochromocytoma remains a complicated anaesthetic challenge, often requiring a prolonged preoperative hospital stay or numerous outpatient clinic visits. This is not only inconvenient for the patient, it also puts them at additional risk of acquiring hospital infections and is expensive to the health service. We present a patient with a phaeochromocytoma who was successfully managed preoperatively with phenoxybenzamine in the community by a 'hospital-at-home' service. She required no other antihypertensives before 9

Raz贸n de valoraci贸n por onc贸logo endocrino. En Instituto Nacional de Cancerolog铆a hay varios.

operation, although glyceryl trinitrate and magnesium sulphate were used before induction of anaesthesia. Apart from intervention for a chest infection on day 3, she had a relatively smooth hospital course and returned home on day 13. We suggest that this may be an appropriate management option for selected patients.

Publication Types: Case Reports PMID: 12594154 [PubMed - indexed for MEDLINE] 30: J Urol. 2003 Mar;169(3):895-8.

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Surgical management of multi-organ visceral tumors in patients with von HippelLindau disease: a single stage approach.

Hwang JJ, Uchio EM, Pavlovich CP, Pautler SE, Libutti SK, Linehan WM, Walther MM. Urological Oncology Branch, National Cancer Institute, National Institute of Health, Bethesda, Maryland, USA. PURPOSE: We assessed surgical feasibility of a 1-stage multi-organ approach for multiple visceral tumors in patients with von Hippel-Lindau disease. MATERIALS AND METHODS: A total of 14 men and 15 women with von Hippel-Lindau disease underwent simultaneous multi-organ surgery for multiple adrenal, renal and pancreatic tumors at the National Cancer Institute between 1988 and 2001. Perioperative and followup data were analyzed retrospectively. The Mann-Whitney U test was used for statistical analysis. RESULTS: Surgery involving 2 or more organs (mean 2.4 procedures per patient, range 2 to 4) was performed in all patients and concurrent pancreatic operations were performed in 12 (41%). Overall a combined 71 procedures, were performed including 4 cases (13%) treated laparoscopically. Mean +/- SD operative time and estimated blood loss were 464 +/- 142 minutes (range 206 to 830) and 2,798 +/- 4,285 cc (300 to 20,000), respectively. In 16 patients (55%) blood transfusion was administered intraoperatively. At a median followup of 21 months (range 5 to 151) renal tumors recurred in 8 patients (28%), requiring further kidney operations, but no patient had pancreatic or adrenal recurrence. The overall complication rate was 38%, and there was no operative mortality. CONCLUSIONS: A single stage surgical approach for multi-organ visceral tumors is a viable option for patients with von Hippel-Lindau disease. With careful patient selection and surgical planning combined procedures can be safely performed in 1 operative setting.

PMID: 12576808 [PubMed - indexed for MEDLINE] 31: Med Clin North Am. 2003 Jan;87(1):175-92.

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Perioperative evaluation and management of the patient with endocrine dysfunction.

Schiff RL, Welsh GA. General Medical Consult Service, Loyola University Medical Center, Maywood, IL, USA. rschiff@lumc.edu Whenever possible, endocrine disorders should be identified and evaluated prior to surgery. A plan

for perioperative management of diabetes should be based on the type of diabetes, what diabetes medications are taken, the status of diabetes control, and what type of surgery is planned.

Perioperative management of diabetes must include bedside glucose monitoring. Patients with mild hypothyroidism can safely proceed with elective surgery. Elective surgery should be postponed for patients with moderate or severe hypothyroidism. Patients who have mild hyperthyroidism can undergo elective surgery with preoperative beta blockade. Elective surgery should not be done on patients with moderate or severe hyperthyroidism until they are euthyroid. Patients with pheochromocytoma need to be identified and properly treated before surgery to prevent perioperative cardiovascular complications. Patients who take endogenous steroids should have the status of their HPA axis determined prior to surgery. If the patient is undergoing moderate or major surgical stress and has documented or presumed HPA suppression, then stress doses of steroids should be give perioperatively.

Publication Types: Review PMID: 12575889 [PubMed - indexed for MEDLINE] 32: Di Yi Jun Yi Da Xue Xue Bao. 2002 Dec;22(12):1145-7.

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[Misdiagnosis of corticomedullary mixed pathological changes in adrenals: report of 4 cases] [Article in Chinese] Hu WL, Cao QY, He HX, L J, Li QR, Wang YL, Nie HB, Yang H, Huang XT, Zhu YS, Deng ZX, Wang W. Department of Urology, Guangzhou General Hospital of Guangzhou Command, Urological Center of Guangzhou Command, Guangzhou 510010, China.

Pathological changes usually occur independently in the adrenal cortex and medulla because of their distinct embryonic origins, and changes involving both the cortex and medulla are rare. We report 4 cases of corticomedullary mixed pathological changes adrenal glands. CT scanning of the adrenal glands showed unilateral abnormalities in all the 4 cases, 3 of which were diagnosed as aldosteronism and the other pheochromocytoma before surgery. Unilateral adrenalectomy was performed in the 4 patients 3 being cured and discharged. The other 1 had recurrence 18 months postoperatively with suspected pathological changes on the other side. Subsequent pathological examination confirmed the suspicion in both the cortex and medulla of the other adrenal gland. In cases with clinical presentations as simultaneous onset of aldosteronism and catecholamine responses, pathological changes in both the cortex and medulla of the adrenal glands should be considered. Perioperative management of such cases should be the same as that in cases of catecholamine responses, and the diagnosis relies on histopathological examination.

Publication Types: Case Reports English Abstract PMID: 12480602 [PubMed - indexed for MEDLINE] 33: J Chir (Paris). 2002 Sep;139(4):205-13.

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[Diagnostic and therapeutic strategy for an incidental finding of an adrenal mass] [Article in French] Alves A, Scatton O, Dousset B. Service de Chirurgie Digestive, H么pital Cochin, Paris, France.

The incidental finding of an unsuspected adrenal mass ranges from 0.5% to 5% in abdominal CT series. The optimal diagnostic approach to such masses is to diagnose malignant or secretory tumors requiring excision and to otherwise avoid unnecessary surgery. Physical examination generally contributes little. A standard biochemical evaluation should include the measurement of 24 hour urinary catecholamines and metanephrine, urinary free cortisol and plasma cortisol levels at 8 a.m. and 8 p.m. combined with an overnight low-dose dexamethasone suppression test, serum potassium assay, and determination of upright plasma aldosterone to plasma renin activity. These tests will serve to screen for pheochromocytoma, subclinical Cushing's syndrome, and primary hyperaldosteronism respectively. Imaging characteristics suggestive of malignancy include: size greater than 4 cm., heterogeneous lesion and/or density greater than 20 Hounsfield Units on CT scan, slow enhancement with delayed washout after intravenous contrast injection on CT scan, and slightly decreased signal intensity in out of phase (fat suppressed) MR acquisition. Fine-needle aspiration biopsy should be performed only if metastatic disease is suspected. Adrenal scintigraphy with iodocholesterol may be useful where adenoma with subclinical Cushing's syndrome or solid tumor is suspected. In summary, the following strategy is recommended for the management of adrenal incidentalomas : mass lesions larger than 4 cm. and hormone-secreting tumors should be removed. All non-secreting adrenal incidentalomas smaller than 4 cm. in diameter should be followed by serial imaging at regular intervals (6, 12, and 36 months) and by endocrine reevaluation at one year.

Publication Types: English Abstract Review PMID: 12410136 [PubMed - indexed for MEDLINE] 34: Can J Anaesth. 2002 Aug-Sep;49(7):682-6.

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Variable hemodynamic fluctuations during resection of multicentric extraadrenal pheochromocytomas.

[Article in English, French] Baraka A, Siddik-Sayyid S, Jalbout M, Yaacoub C. Department of Anesthesiology, American University of Beirut-Medical Center, Beirut, Lebanon. abaraka@aub.edu.lb PURPOSE: To report the perioperative management and the serious hemodynamic fluctuations during manipulation of an organ of Zuckerkandl tumour in a patient undergoing resection of multicentric extraadrenal pheochromocytomas. CLINICAL FINDINGS: A 28-yr-old man who had

undergone at age 12 a laparotomy for excision of an extraadrenal pheochromocytoma complained of paroxysmal headache, occasional sweating and palpitations. The arterial blood pressure (BP) was 200/100 mmHg. A 24-hr-urine collection showed catecholamines 5076 microg x 24 hr(-1) (normal < 25 microg x 24 hr(-1)). Computed tomography of the abdomen revealed two retroperitoneal masses, one adjacent to the lower pole of the right kidney and a second larger mass located at the aortic bifurcation in the region of the organ of Zuckerkandl. The patient was scheduled for excision of multiple extraadrenal pheochromocytomas. He was prepared preoperatively for two weeks with prazosin 1 mg po q six hours and propranolol 10 mg tid. Manipulation of the infrarenal tumour was uneventful but manipulation of the Zuckerkandl tumour resulted in severe hypertensive episodes with BP ranging from 200/100 to 320/120 mmHg. Surgery was interrupted temporarily; the hypertensive crisis was controlled by the infusion of sodium nitroprusside and by iv phentolamine and esmolol10. CONCLUSION: In a patient undergoing resection of recurrent multicentric extraadrenal pheochromoctyomas, severe hypertensive episodes occurred during manipulation of one tumour but not during manipulation of the other. This may be attributed to inadequate preparation of the patient, difficult surgical dissection of the large Zuckerkandl pheochromocytoma, and/or secondary to an excessive and different pattern of release of catecholamines during manipulation of the Zuckerkandl tumour.

Publication Types: Case Reports PMID: 12193485 [PubMed - indexed for MEDLINE] 35: World J Surg. 2002 Aug;26(8):1037-42. Epub 2002 Jun 19.

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Efficacy and safety of doxazosin for perioperative management of patients with pheochromocytoma.

Prys-Roberts C, Farndon JR. Sir Humphry Davy Department of Anaesthesia, University of Bristol, Level 7, Bristol Royal Infirmary, UK. cedric.prysroberts@btinternet.com Despite adverse side effects, phenoxybenzamine has been widely used for the preoperative management of patients with pheochromocytoma. Doxazosin, a specific a 1-adrenoceptor antagonist, has a pharmacologic profile more suited to controlling blood pressure in such patients. A sequential study of 35 patients with pheochromocytoma encompassed a definite and prescribed change in preoperative drug management from phenoxybenzamine to doxazosin. Hemodynamic, pharmacologic, and biochemical indicators of a- and b-adrenoceptor blockade were measured before, during, and after anesthesia and surgery in 8 patients pretreated with phenoxybenzamine and 27 patients pretreated with doxazosin. Doxazosin (2-16 mg/day) was as effective as phenoxybenzamine in controlling arterial pressure and heart rate before and during surgery, but doxazosin caused fewer undesirable side effects both before and after surgery. Following phenoxybenzamine therapy substantial a 1-adrenoceptor blockade, detected as a right shift of phenylephrine dose-response curves, persisted for more than 2 days postoperatively, whereas after doxazosin it was undetectable on the first postoperative day. Doxazosin provided safe, efficacious 10

Manejo preoperatorio con PRAZOSIN y PROPRANOLOL.

pre- and perioperative control of arterial pressure. In patients with predominantly norepinephrinesecreting tumors, pretreatment 24-hour urinary norepinephrine excretion gave an indication of the daily doxazosin requirement.

Publication Types: Clinical Trial PMID: 12192533 [PubMed - indexed for MEDLINE] 36: Ann Fr Anesth Reanim. 2002 Jun;21(6):464-70.

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[Laparoscopic adrenalectomy for pheochromocytoma. Perioperative blockade with urapidil] [Article in French] Tauzin-Fin P, Krol-Houdek MC, Gosse P, Ballanger P. Département d'anesthésie-réanimation III, hôpital Pellegrin-Tondu, 5, place Amélie Raba-Léon, 33076 Bordeaux, France. secretariat.ballanger@bu-u-bordeaux2.fr OBJECTIVE: To investigate the effects of coeliosurgery by catecholamine assays and the use of urapidil in the management of phaeochromocytoma. STUDY DESIGN: Prospective cohort study.

PATIENTS: Nine consecutive patients from April 1997 to April 2001. METHODS: Urapidil (250 mg.j-1) was administered by continuous intravenous infusion three days before surgery and continued throughout anaesthesia. Plasma catecholamine concentrations were measured before surgery, after induction of anaesthesia, during insufflation, after adrenalectomy and in the recovery room. Haemodynamic disorders were treated by nicardipine +/- esmolol bolus doses. RESULTS: Creation of pneumoperitoneum and adrenal gland manipulations resulted in significant catecholamine releases associated with hypertension in five and eight patients respectively.

Preventive urapidil use enabled easy control of blood pressure variations by additive antihypertensive drugs. CONCLUSION: Perioperative alpha 1 blockade by urapidil enables an effective and easy control of acute preoperative haemodynamic changes.

Publication Types: Clinical Trial English Abstract PMID: 12134591 [PubMed - indexed for MEDLINE] 37: Zhonghua Yi Xue Za Zhi. 2002 Apr 25;82(8):523-6.

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[Clinical features of pheochromocytoma and anesthetic management during perioperative

period] [Article in Chinese] Guo X, Luo A, Huang Y, Ren H, Ye T. Department of Anesthesia, Peking Union Medical College Hospital, Beijing 100730, China.

OBJECTIVE: To investigate the clinical features of pheochromocytoma and summarize the experience of anesthetic management during perioperative period. METHODS: Two hundred and fifty eight medical records of patients who were diagnosed as pheochromocytoma in Peking Union Medical College Hospital were reviewed retrospectively for clinical features, anesthetic management and perioperative mortality. RESULTS: About 5.8% (15/258) of pheochromocytomas was an integral part of multiple endocrine neoplasia (MEN) type II or mixed type. Sixty percent (149/249) of the patients undergoing surgery possessed evidence of catecholamine cardiac toxicity preoperatively, including abnormal ECG, myocardial hypertrophy and decreased left ventricular ejective fraction. Impaired glucose tolerance was found in 59% (147/249) of patients before surgery. The volume infused during operation was significantly higher both in the epidural anesthesia group (3 474 ml +/- 624 ml, q(1) = 5.72, P < 0.01) and in the epidural plus general anesthesia group (3 654 ml +/- 475 ml, q(2) = 5.83, P < 0.01) than that in the general anesthesia group (2 534 ml +/- 512 ml). There were favorable hemodynamic characteristics before removal of the tumor in the epidural anesthesia group and epidural plus general anesthesia group, as compared with in the general anesthesia group. Perioperative mortality was significantly decreased from 8% (5/60) in period 1 (from 1955 to 1975) to 1.2% (1/75) in period 2 (from 1976 to 1994) (chi(2) = 4.05, P < 0.01). No perioperative death (0/111) occurred in period 3 (from 1995 to 2001).

CONCLUSION: A good surgical outcome for the excision of pheochromocytoma depends on multiple factors, including careful assessment of potential end organ damages and restoration of blood volume by establishing alpha-blockade during the preoperative period, meticulous anesthetic management during surgery, and appropriate circulatory support after surgery.

Publication Types: English Abstract PMID: 12133496 [PubMed - indexed for MEDLINE] 38: J Cardiothorac Vasc Anesth. 2002 Jun;16(3):359-69.

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Perioperative management of pheochromocytoma.

Kinney MA, Narr BJ, Warner MA. Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA. kinney.michelle@mayo.edu Publication Types: Research Support, Non-U.S. Gov't Review

PMID: 12073213 [PubMed - indexed for MEDLINE] 39: Ann Surg. 2002 May;235(5):713-20; discussion 720-1.

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Adrenalectomy for familial pheochromocytoma in the laparoscopic era.

Brunt LM, Lairmore TC, Doherty GM, Quasebarth MA, DeBenedetti M, Moley JF. Department of Surgery, Section of Endocrine and Oncologic Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA. bruntm@msnotes.wustl.edu OBJECTIVE: To report the results of treatment of patients with familial pheochromocytomas in the laparoscopic era. SUMMARY BACKGROUND DATA: The optimal surgical management of pheochromocytomas that arise in familial neoplasia syndromes may be complicated by bilateral involvement and associated endocrinopathies. METHODS: Twenty-one patients with familial pheochromocytomas (15 with multiple endocrine neoplasia [MEN] 2A, 4 with MEN 2B, 1 each with von Hippel-Lindau and neurofibromatosis type 1) underwent adrenalectomy between December 1993 and July 2001. Clinical, biochemical, and pathologic data were obtained by retrospective review of perioperative medical records, postoperative biochemical testing, and patient questionnaire. RESULTS: Mean age at diagnosis was 37 +/- 11 years. Twenty of the 21 patients had elevated urine catecholamines, and all had radiographic evidence of an adrenal tumor or tumors. Pheochromocytoma-related symptoms were present in 11 patients (52%). One patient with MEN 2B underwent open adrenalectomy due to previous adrenal surgery and megacolon.

Laparoscopic adrenalectomy was attempted in the remaining 20 patients (9 right, 11 left, 2 bilateral). Two patients (9.1%) were converted to open adrenalectomy. Intraoperative hypertensive episodes occurred in 15 patients (71%) and were easily controlled medically. Mean operative time was 216 +/- 57 minutes, mean postoperative length of stay was 3.1 +/- 1.3 days, and mean tumor size was 3.1 +/- 1.0 cm. Minor complications occurred in three patients (14.3%) and major complications in two patients (9.5%). During a mean follow-up of 57 months, a contralateral pheochromocytoma developed in four patients with MEN 2 (33%); three of them underwent adrenalectomy. There have been no long-term complications related to hypertension or adrenalectomy. CONCLUSIONS: This study is the largest series of patients with familial pheochromocytoma undergoing adrenalectomy during the laparoscopic era. The results suggest that the laparoscopic approach is safe and effective for managing unilateral or bilateral adrenal medullary disease in this population.

PMID: 11981218 [PubMed - indexed for MEDLINE] 40: Zhonghua Wai Ke Za Zhi. 1999 Nov;37(11):674-6.

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[Atypical pheochromocytoma] [Article in Chinese] Lin Z, Chen S, Zheng S, Xu E.

Department of Urology, Union Hospital, Fujian Medical University, Fuzhou 350001.

OBJECTIVE: To improve the diagnosis and treatment of atypical pheochromocytoma. METHODS: 51 cases of pheochromocytoma were treated from July 1985 to August 1998. RESULTS: Of the 51 cases, 19 were atypical, and were characterized by silent tumor, pheochromocytoma in pregnancy, bilateral tumor, extraadrenal tumor, malignant tumor, and recurrent tumor. Open operation was performed for all kinds of cases in accordance with their special characteristics. CONCLUSIONS: Surgical extirpation is the only means for the treatment of atypical pheochromocytoma and meticulous perioperative management is essential.

Publication Types: English Abstract PMID: 11829924 [PubMed - indexed for MEDLINE] 41: Ir Med J. 2001 Jul-Aug;94(7):200-3.

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47 years of phaeochromocytomas.

O'Halloran T, McGreal G, McDermott E, O'Higgins N. Department of Surgery, St. Vincent's Hospital, Dublin.

Thirty three patients with phaeochromocytomas had surgery in St. Vincent's Hospital between 1950 and 1997. 32 patients had hypertension, 32 had palpitations and 30 had excessive sweating. All patients had at least one of these cardinal symptoms. Diagnostic tests changed over this period. In the early cases the phentolamine test was used, later diagnosis was confirmed by measurement of urinary VMA and catecholamines. IVP, CT, ultrasound or MIBG scanning were used to locate the tumours. Before 1967, 3 of 17 patients died peri-operatively, 2 of these from strokes and one from pulmonary embolism. Since then, all patients have survived surgery. Four of the women had phaeochromocytomas diagnosed during pregnancy. Two of the 33 patients had tumours that were malignant, the remainder being benign. One patient has died from metastatic disease. This series illustrates the changing trends in the surgical management of phaeochromocytomas.

PMID: 11693208 [PubMed - indexed for MEDLINE] 42: J Clin Endocrinol Metab. 2001 Apr;86(4):1480-6.

Related Articles, Links Comment in: J Clin Endocrinol Metab. 2001 Apr;86(4):1477-9.

Factors associated with perioperative morbidity and mortality in patients with pheochromocytoma: analysis of 165 operations at a single center.

Plouin PF, Duclos JM, Soppelsa F, Boublil G, Chatellier G.

Department of Hypertension, Hôpital Broussais-Saint Joseph, 75908 Paris Cedex 15, France. pierrefrancois.plouin@egp.ap-hop-paris.fr To identify preoperative factors associated with 30-day morbidity and mortality after pheochromocytoma surgery, we carried out an external review of the records of all patients undergoing pheochromocytoma surgery from 1975 to 1997 at a single center. One hundred and forty-seven patients, including 23 with malignant tumors at the time of the first operation, underwent 165 operations. Death, resection of a neighboring organ, further surgery, secondary transfer to an intensive care unit, and any events associated with a surgical stay exceeding 10 days were defined as complications. Mortality and morbidity were 4 of 165 (2.4%) and 38 of 161 (23.6%), respectively. Morbidity included 13 spleen resections and hematomas. Spleen complications were not related to tumor location, but were probably due to the operative strategy used, a transperitoneal complete abdominal exploration including both adrenal glands.

Complications were independently associated with preoperative systolic blood pressure [odds ratio (OR), 1.14/cm Hg], urinary metanephrine excretion (OR, 1.18/10 micromol x day), and with the number of operations (repeat vs. first operation OR, 5.36). In conclusion, pheochromocytoma resection consistently involves a risk of complications. Spleen damage should be prevented by complete preoperative localization studies and an elective or laparoscopic surgical approach.

Careful blood pressure control should help prevent complications. Patients with high secretion tumors and those undergoing repeat intervention are at high risk of complications and should be referred to centers familiar with pheochromocytoma management.

Publication Types: Research Support, Non-U.S. Gov't PMID: 11297571 [PubMed - indexed for MEDLINE]

Special Articles

Factors Associated with Perioperative Morbidity and Mortality in Patients with Pheochromocytoma: Analysis of 165 Operations at a Single Center1 Pierre-François Plouin, Jean-Marc Duclos, Frederique Soppelsa, Gaetan Boublil and Gilles Chatellier Departments of Hypertension, Urology, and Medical Informatics, Hôpital Broussais-Saint Joseph, 75908 Paris Cedex 15; and Gestion Essais Cliniques, Etudes Statistiques Monitoring, 92120 Montrouge, France Address all correspondence and requests for reprints to: Dr. Pierre-François Plouin, Hypertension Unit, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75908 Paris Cedex 15, France. E-mail: pierre-francois.plouin@egp.aphop-paris.fr.

Abstract

To identify preoperative factors associated with 30-day morbidity and mortality after pheochromocytoma surgery, we carried out an external review of the records of all patients undergoing pheochromocytoma surgery from 1975 to 1997 at a single center. One hundred and forty-seven patients, including 23 with malignant tumors at the time of the first operation, underwent 165 operations. Death, resection of a neighboring organ, further surgery, secondary transfer to an intensive care unit, and any events associated with a surgical stay exceeding 10 days were defined as complications. Mortality and morbidity were 4 of 165 (2.4%) and 38 of 161 (23.6%), respectively. Morbidity included 13 spleen resections and hematomas. Spleen complications were not related to tumor location, but were probably due to the operative strategy used, a transperitoneal complete abdominal exploration including both adrenal glands.

Complications were independently associated with preoperative systolic blood pressure [odds ratio (OR), 1.14/cm Hg], urinary metanephrine excretion (OR, 1.18/10 µmol·day), and with the number of operations (repeat vs. first operation OR, 5.36). In conclusion, pheochromocytoma resection consistently involves a risk of complications. Spleen damage should be prevented by complete preoperative localization studies and an elective or laparoscopic surgical approach. Careful blood pressure control should help prevent complications. Patients with high secretion tumors and those undergoing repeat intervention are at high risk of complications and should be referred to centers familiar with pheochromocytoma management.

Introduction PHEOCHROMOCYTOMA is a catecholamine-secreting neoplasm of adrenal or extraadrenal chromaffin tissue. It is a life-threatening condition because catecholamine secretion is unpredictable, resulting in hypertension, arrhythmia, and/or hyperglycemia (1, 2). Three to 13% of the tumors are malignant, and recurrences occur in 6–23% of cases (1, 2, 3, 4, 5, 6, 7, 8, 9).

Although pheochromocytoma has been considered to be a curable cause of hypertension since the early report of Charles Mayo in 1927 (10), hypertension may persist in a substantial proportion of patients without malignancy or recurrence (9). Surgery is indicated in all cases, however, because the large variation in catecholamine output prevents the stable pharmacological control of heart rate and blood pressure (BP) and because tumor resection is the only way to prevent or limit subsequent tumor growth.

As preoperative management, anesthesia, and surgery may be complex and involve large and acute variations in BP and heart rate, patients with pheochromocytoma should be referred to centers with extensive experience of the disease (1, 2). Little is known, however, about the rate of perioperative complications of pheochromocytoma surgery. We searched the literature published over the last 10 yr for series with at least 50 pheochromocytoma operations. We retrieved 9 reports quantifying operative mortality and morbidity (3, 4, 5, 6, 7, 8, 11, 12, 13) (if several reports were published from the same institution, we included only the most recent report). The reported mortality rates were 0– 6.7%, and the morbidity rates were 3.3–36.1%. There are several plausible explanations for this wide range, including referral biases, incomplete reporting, and ambiguities in the definition of complications.

We report preoperative and postoperative complications in a large series of consecutive patients with pheochromocytoma referred to a single center. Preoperative management was assumed by a single physician (P.F.P.), and a single surgeon (J.M.D.) operated on all patients. To limit reporting biases, we obtained an external review of the medical, anesthetic, and surgical records of all

operations performed in this center on patients with pheochromocytoma. Complications were defined before data collection. To detect risk indicators for complications, we analyzed the clinical, biological, and tumoral features of the patients who suffered complications.

Materials and Methods Initial assessment and treatment The procedures used for pheochromocytoma diagnosis were consistent with institutional guidelines and have been described previously (9, 14, 15, 16, 17). Family history and phenotypic signs of multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau disease, and neurofibromatosis 1 were analyzed to identify any underlying familial disease (9, 18). Histological evidence of pheochromocytoma was obtained in all patients. BP was determined using a mercury sphygmomanometer after patients had spent a mean of 15 min in the horizontal position. Patients were hospitalized in the hypertension department for imaging studies and preparation for intervention, including adaptation of antihypertensive treatment if necessary. They were transferred to the urology department on the day before the operation. The mean of two consecutive readings obtained immediately before transfer to the Department of Urology was taken as the preoperative BP determination. Patients with sustained hypertension were mostly given - and Ă&#x;-adrenergic antagonists before surgery. Antihypertensive medication was given to lower BP to 140/90 mm Hg or lower. Anesthesia was achieved using a combination of flunitrazepam, fentanyl, and thiopental, and curarization was achieved using vecuronium. Radial artery pressure, pulmonary artery pressure, and electrocardiograph were monitored continuously. Infusions of nitroprusside, nicardipine, and antiarrhythmic agents were prepared in advance and administered as soon as necessary. Controlled ventilation was established, enabling a positive end expiratory pressure to be achieved if pulmonary wedge pressure increased. Volume replacement was determined by pulmonary wedge pressure levels. Our routine operation technique involved a median transperitoneal approach, making it possible to explore both adrenal glands, the organ of Zuckerkandl, the urinary bladder, and the periaortic and pericaval lymphatic chains. Left adrenalectomy was performed after medial visceral rotation of the spleen and the tail of the pancreas. In this series, extending from 1975 to 1997, we used laparoscopic adrenalectomy in only a few cases with MEN 2 and small adrenal tumors. Tumor extirpation involved the adjacent adrenal gland (in cases of adrenal tumors) and/or any other possible tumors, lymph nodes, or visceral metastases.

Clinical, tumoral, and complication criteria Sustained hypertension was diagnosed in patients with a BP of 140/90 mm Hg or more in the absence of paroxysmal symptoms and in those taking antihypertensive drugs. Hyperglycemia was defined as two plasma glucose assay results above 7 mmoL/L (19). Pheochromocytoma site and size were confirmed at surgery. Malignancy was defined as histological evidence of tumor cells at sites at which chromaffin tissue is not normally present and/or evidence of distant metastases documented by computed tomographic scan or scintigraphy (9, 20, 21). Recurrence was defined as the reappearance of disease after complete tumor eradication confirmed by negative biochemical and imaging tests (9). A malignant recurrence was defined according to the malignancy criteria described above; other recurrences were deemed benign. In addition to reinterventions for tumor persistence or recurrence, some reinterventions were required for the resection of new tumors affecting the contralateral adrenal gland or ectopic chromaffin tissue in patients with familial pheochromocytoma.

Complications were defined before data collection and analysis. Any adverse event occurring between the induction of anesthesia and the 30th day after the operation that was life threatening,

resulted in death or permanent or substantial disability, or was associated with extended hospitalization was considered to be a perioperative complication. Complications included mortality from any cause, nonfatal cardiovascular events, thromboembolism, resection of a neighboring organ, further surgery, and any infectious or incision problem extending hospitalization in the surgical department beyond ten days. We also documented episodes of hypoglycemia that did not fulfill the above criteria for complication.

Study population and data collection Between September 1975 and December 1997, pheochromocytoma was diagnosed in 164 patients referred to the Department of Hypertension. This list of patients was merged with that of patients operated on for pheochromocytoma in the Department of Urology during the same period. Eleven patients later underwent surgery elsewhere at the request of their personal physician or surgeon, and another 6, who had previously undergone surgery elsewhere, were referred for nonsurgical management of a malignant pheochromocytoma. Therefore, the records of 147 patients were available for analysis of perioperative outcome. Sixteen of 23 patients with malignant pheochromocytoma and 14 of 124 with benign pheochromocytoma had persistent tumors, tumor recurrence, or new tumors requiring surgery. Sixteen operations had been performed before referral.

Therefore, 165 operations were analyzed. An independent clinical research assistant reviewed the medical, anesthetic, and surgical records of all these patients and input relevant perioperative data into a computer file.

Data analysis Differences between means were assessed using t test or Mann-Whitney test as appropriate. The 2 test or Fisherâ&#x20AC;&#x2122;s exact test was used to compare qualitative variables. We looked for univariate associations between the presence or absence of complications, the year of the operation, the number of previous operations if any, and the following patient and tumor characteristics: age, sex, history of cardiovascular events, the presence of an underlying familial disease, sustained hypertension or hyperglycemia, preoperative BP levels, urinary metanephrine excretion, plasma catecholamine concentration, tumor status (benign or malignant), and tumor site and size. We could not test the statistical relationship between the risk of complications and the surgical technique because the same surgical approach was used in almost all the patients. Variables significantly associated with the presence of complications were entered in a logistic regression model to determine which variables were independently associated with the risk of complication. Data were analyzed with StatView 5.0 statistical software (SAS Institute, Inc., Cary, NC). P < 0.05 was considered significant.

Results Features at presentation The characteristics of the patients at first operation are summarized in Table 1 . The patients were 13â&#x20AC;&#x201C;82 yr old. Pheochromocytoma was associated with a familial disease in 31 patients.

Hypertension was sustained in 129 (87.8%) patients, and 46 (31.3%) were hyperglycemic. Fifteen patients had a personal history of cardiovascular events (myocardial infarction, 8; stroke, 7).

Pheochromocytoma at first operation was in the right adrenal gland in 79 patients and in the left in 42. It was bilateral in seven patients and extraadrenal in 19: in the Zuckerkandl body (n = 10), renal hilum (n = 5), prostate (n = 2), mediastinum (n = 1), or pericardium (n = 1). Twenty-three patients, including 6 with extraadrenal tumors, had malignant pheochromocytoma at the first operation.

Malignant tumors were significantly larger than benign tumors (Table 1 ). Surgery was performed

using a median transperitoneal approach in 156 operations, a flank incision in 4 operations, and thoracotomy in the 2 cases of thoracic pheochromocytoma, and 3 patients with MEN 2 and small adrenal tumors underwent laparoscopic surgery.

View this table: Table 1. Characteristics of the patients at first operation and the number of [in this window] operations [in a new window]

Reinterventions Thirty patients needed one or more reinterventions for a persistent, recurrent, or new tumor 91 Âą 73 months (range, 1â&#x20AC;&#x201C;231 months) after the initial operation (Table 1 ). The proportion of patients needing reintervention was higher in cases with a malignant tumor at first operation than in those with benign tumor. Nine patients with sporadic, initially benign tumors developed a true recurrence requiring surgery. Eight of these recurrences were malignant. Reintervention was also needed for the occurrence of a new tumor in 7 of the 31 patients with familial disease. All new tumors were benign.

Complications Patients with complications are listed in Table 2 , according to benign/malignant status and in ascending order of tumor diameter. Perioperative mortality was 4 of 165 or 2.4%. Patient 7, with a history of asthma and benign pheochromocytoma, died with an abrupt collapsus without arrhythmia on induction of anesthesia, presumably of anaphylactic shock. Another 3 patients with large malignant tumors also died. Patient 22 died of pulmonary edema during the operation. Patient 24 had undergone an initial adrenal resection and bilateral nephrectomy 1 yr earlier for malignant pheochromocytoma and bilateral renal cell cancer; he died suddenly during hemodialysis within 1 day of reintervention. Patient 26 had MEN 2 with bilateral malignant pheochromocytoma; a liver metastasis biopsy led to postoperative bleeding, and the patient died during a subsequent emergency operation.

Table 2. Patients with complicated operations (the 11 patients who underwent splenectomy with no other complication are listed in Table 3) Patients Age No. (yr)/sex

Operation

Yr

Tumor characteristics

Rank Status Site

Size (mm)

Outcome

Comments

1

34/M

1997

2

B

L

20

ICU

Atelectasis and respiratory failure in a patient with VHL and a pancreatic tumor

2

39/F

1993

1

B

R

20

PD

Recurrent nerve paralysis complicating Swan-

Ganz catheter insertion 3

49/M

1979

1

B

L

30

R, OR

Splenectomy and pancreatitis in a patient with NF1

4

17/M

1976

1

B

R

35

PD

Reversible paraplegia following intraoperative hypotension

5

71/F

1985

1

B

E

40

ICU

Hemothorax following resection of a mediastinal tumor

6

51/F

1997

1

B

L

40

7

64/F

1985

1

B

R

40

D

Died of anaphylactic shock following induction of anesthesia

8

36/M

1995

2

B

L

40

R

MEN2; intraoperative cardiac arrest; postoperative drainage of an hematoma

9

53/F

1996

1

B

L

52

R

Surgical drainage of a hematoma

10

30/F

1980

1

B

E

60

OR

Nephrectomy during resection of a left renal hilum tumor

11

45/M

1994

1

B

R

60

R

Surgical drainage of a hematoma

12

13/F

1992

1

B

R

60

PD

Segmental right renal infarction

13

26/M

1991

1

B

R

70

ICU

Intraoperative pneumothorax

14

27/M

1985

1

B

Bi

70+30

15

72/F

1987

1

B

R

80

16

37/M

1994

1

B

E

85

Splenic hematoma with ipsilateral pleural effusion

MEN2; intraoperative cardiac arrest ICU

Hypoventilation requiring assistance Partial cystectomy in

a patient with a vesical tumor; urinary tract infection 17

46/F

1992

1

B

R

110

Postoperative pleural effusion

18

40/F

1977

1

B

R

180

R

Surgical drainage of a hematoma

18

56/F

1993

2

M

Meta

25

ICU

Acute renal failure in a patient with chronic renal failure

19

32/M

1995

2

M

Meta

45

OR

Cholecystectomy

20

46/F

1994

3

M

Meta

55

PD

Hydronephrosis following ureteral dissection

21

27/M

1983

1

M

L

70

R, PD

Ventricular arrhythmia, cerebral anoxia and stupor

22

55/M

1984

2

M

R

90

D

Death from cardiovascular failure

23

42/M

1978

1

M

L

90

R

Surgical drainage of a subphrenic collection

24

49/M

1992

2

M

Meta

100

D

Sudden death in a patient with VHL and a history of binephrectomy

25

70/M

1993

1

M

Bi

100+20 ICU

Multiorgan failure in a patient with NF1 and liver metastases

26

62/M

1986

1

M

Bi

100+28 D, R

Patient with MEN2; died of hemorrhagic shock

27

48/F

1984

1

M

R

160

-

Postoperative pleural effusion

28

37/M

1988

2

M

Meta

ND

R

Surgical drainage of a hematoma

29

50/M

1982

2

M

Meta

ND

ICU

Management in ICU of a patient with spinal compression and paraplegia

30

59/M

1990

4

M

Meta

ND

ICU

Postoperative septic

shock Tumor status: B, benign; M, malignant. Tumor site: L, left; R, right; Bi, bilateral; E, ectopic; Meta, metastasis. Complications: D, death; OR, organ resection; PD, persistent damage; R, repeat operation; ICU, transfer to intensive care unit. VHL, von Hippel Lindau; MEN2, multiple endocrine neoplasia type 2; NF1, neurofibromatosis 1; ND, not determined. Note that patient 18 underwent two operations with complications.

There were 38 operations with nonfatal complications (23.0%). Life-threatening arrhythmia occurred in 4 patients. Patient 4, with malignant hypertension but benign pheochromocytoma, suffered ventricular arrhythmia and hypotension after tumor resection, resulting in reversible paraplegia. He recovered normal mobility within 3 months with no persistent motor or sexual consequences. Patients 8 and 14, brothers with MEN 2, suffered preoperative cardiac arrest lasting less than 1 min, with no postoperative consequences. Patient 21, with malignant pheochromocytoma, developed diarrhea and hypokalemia during the night before the operation and suffered ventricular arrhythmia at tumor resection, resulting in collapsus, cerebral anoxia, and irreversible stupor. Other complications included infectious or incision problems requiring further surgery, admission to an intensive care unit, or extended hospitalization and in 14 cases resection of a neighboring organ. Patient 10, with pheochromocytoma arising in the left renal hilum, underwent left nephrectomy. Patient 19, with a malignant recurrence of a Zuckerkandl body tumor, underwent cholecystectomy. Twelve patients (patient 3 in Table 2 and the 11 patients in Table 3 ) underwent splenectomy, and patient 6 had a splenic hematoma (see Table 2 ). Patients undergoing splenectomy had pheochromocytoma arising on either the left or the right side, either benign or malignant, with a tumor diameter of 30â&#x20AC;&#x201C;140 mm (Table 3 ). No postoperative hernia was reported in this series of patients, who, in most cases, underwent surgery via midline incision.

Table 3. Patients who underwent splenectomy with no other complication (see also patients 3 and 6 in Table 2) Patient No.

Operation Age (yr)/sex

Yr

Rank

Tumor characteristics Status

Site

Size (mm)

31

39/M

1976

1

B

R

30

32

45/M

1978

1

B

R

30

33

27/F

1977

1

B

R

30

34

48/F

1996

2

B

R

30

35

68/F

1987

1

B

L

50

36

46/F

1981

1

B

L

50

37

46/F

1990

1

B

Bi

60

38

49/F

1980

1

B

R

90

39

37/M

1985

1

B

L

140

40

44/F

1987

3

M

Meta

30

41

46/F

1996

2

M

Meta

ND

B, Benign; M, malignant. L, left; R, right; Bi, bilateral; Meta, metastasis; ND, not determined.

Factors associated with complications Perioperative features for operations with complications were compared with those for operations without complications (Table 4 ). There were no significant differences in the numbers of patients with familial disease or a history of previous cardiovascular disease, the age and sex of the patients, the median year of operation, or the proportion of patients with hyperglycemia or sustained hypertension. Preoperative treatment score, defined as the number of antihypertensive agents administered, did not differ between cases with and without complications; nor did the proportion of patients given the -adrenergic antagonist prazosine, a ß-blocker, or another antihypertensive agent (see Table 4 ). Preoperative systolic BP was significantly higher in operations with complications that in those without complications. Mean urinary metanephrine excretion in operations with complications was twice that in those without, but there was no difference in plasma catecholamine concentration. Complications occurred more frequently in operations on patients who had undergone a previous pheochromocytoma operation and in those involving patients with a malignant tumor. Tumor size and site were not related to the occurrence of complications.

Table 4. Perioperative features in operations without and with complications

Preoperative characteristics

Without complications (n = With complications (n = 123) 42)

Patients with Familial disease

27 (22.0)

9 (21.4)

Previous cardiovascular event

12 (9.8)

5 (11.9)

Men

55 (44.7)

21 (50.0)

Age (yr)

41 ± 14

45 ± 14

Median yr of operation

1990

1987

Patients with hyperglycemia

36 (29.3)

17 (40.5)

Antihypertensive medication

74 (60.2)

29 (69.0)

Including prazosine

60 (48.8)

21 (50.0)

Including ß-blocker

48 (39.0)

20 (47.6)

Systolic blood pressure (mm Hg)

138 ± 27

152 ± 361

Diastolic blood pressure (mm Hg)

87 ± 17

90 ± 20

Urinary metanephrines (µmol/day)

21.1 [1.7–128]

29.7 [4–413]1

Plasma noradrenaline (nmol/L)

14.7 [0.5–242]

16.1 [0.5–565]

Plasma adrenaline (nmol/L)

0.53 [0–19.7]

1.04 [0–26.9]

15 (12.2)

4 (9.5)

Patients with extraadrenal tumor Tumor diameter (mm)

55 ± 29

62 ± 38

Patients having undergone 1 previous operation

21 (17.1)

13 (31.1)1

Patients with malignant tumor

23 (18.7)

15 (35.7)1

Values are the number (percentage), median [range], or mean ± SD, as appropriate.

1

P < 0.05, operations with complications vs. those without complications.

Multivariate analysis, including patient’s age, the rank of operation (repeat operation vs. first operation), preoperative systolic BP and urinary metanephrine excretion, and tumor status (benign or malignant), showed that complications were independently related to the rank of operation and to preoperative systolic BP and urinary metanephrine excretion (Table 5 ), but not to tumor status.

The same logistic model was applied to spleen complications (n = 13), and only preoperative systolic BP was significantly associated with the occurrence of splenectomy or of splenic hematoma [odds ratio (OR), 1.189; 95% confidence interval, 1.003–1.409; P = 0.046]. Finally, we analyzed predictors of perioperative complications in first operations and in repeat operations. The ORs for the risk of complications associated with high urinary metanephrine excretion and with high preoperative systolic BP were very similar for all operations, first operations, or repeat operations (see Table 5 ).

Table 5. Predictors of the risk of perioperative complications: logistic regression analysis Variable

Odds ratio

95% confidence interval

P value

All patients (n = 165) Operation rank, repeat vs. first

5.288

1.292–21.65

0.021

Urinary metanephrine excretion, per 10 µmol/day

1.184

1.064–1.318

0.002

Preoperative systolic blood pressure, per 10 mm Hg

1.138

0.999–1.296

0.052

Tumor status, malignant vs. benign

1.211

0.421–3.482

0.723

Urinary metanephrine excretion, per 10 µmol/day

1.172

1.043–1.317

0.007

Preoperative systolic blood pressure, per 10 mm Hg

1.138

0.987–1.312

0.076

Tumor status, malignant vs. benign

1.735

0.386–7.809

0.473

Patients undergoing first operation (n = 131)1

Patients undergoing repeat operation (n = 34)

1

Urinary metanephrine excretion, per 10 µmol/day

1.157

0.909–1.472

0.237

Preoperative systolic blood pressure, per 10 mm Hg

1.338

0.928–.931

0.119

Tumor status, malignant vs. benign

0.401

0.058–2.785

0.356

Sixteen operations had been performed before referral.

Hypoglycemia and adrenal insufficiency Twenty-five operations were followed by episodes of hypoglycemia requiring the infusion of hypertonic glucose solution. There was no significant difference in the proportion of patients with preoperative hyperglycemia [8 of 25 (32.0%) vs. 43 of 131 (32.8%)], malignant pheochromocytoma [3 of 25 (12.0%) vs. 31 of 131 (23.7%)], or in preoperative plasma catecholamine concentrations between cases with and without hypoglycemia. Sixteen operations were followed by adrenal insufficiency. This was an expected consequence of adrenal resection as all affected patients had undergone resection of both adrenal glands for bilateral (synchronous or nonsynchronous) and/or malignant pheochromocytoma, except 1 patient who had a benign pheochromocytoma and ectopic ACTH syndrome. This previously reported patient (22) presented with Cushing disease and suffered transient postoperative adrenal insufficiency.

Discussion This analysis of perioperative complications in pheochromocytoma surgery generated several key findings. Pheochromocytoma surgery was frequently complicated in this series, with mortality and morbidity rates of 2.4% and 23.6%, respectively. These figures are in the same range as those of other contemporary reports (0–6.7% and 3.3–36.1% for mortality and morbidity, respectively) (3, 4, 5, 6, 7, 8, 11, 12, 13). We observed a high frequency of spleen complications. Finally, we

found that complications were independently related to preoperative systolic BP and metanephrine excretion and to operation rank.

These findings have implications for the prevention of complications.

The strengths of our study are the external review of a large series of records from consecutive patients, with benign, recurrent, and malignant pheochromocytomas prepared for surgery in a single unit and operated on by the same surgeon, and the definition of complications before data collection and analysis. Previous reports of perioperative complications in pheochromocytoma surgery were self-audits, were limited to mortality or preoperative complications, and/or did not define the criteria for the presence of complications beforehand. They may therefore have underestimated the true prevalence of complications (23, 24, 25). The weaknesses of our study are its retrospective nature and the consequences of the a priori definition of complications. Mild complications, such as wound infections and urinary tract infections of less than 10-day duration, were rarely identified and probably underreported in patients’ records. In contrast, some operations involving resection of a neighboring organ (nephrectomy during resection of a left renal hilum tumor in patient 10 and cholecystectomy in patient 19) were considered complicated according to predefined criteria, whereas the surgeon considered these resections appropriate to ensure complete tumor excision or prevention of postoperative cholecystitis. Exclusion of these two cases would not have altered the overall results of the analysis, however. This series of operations performed from 1975 to 1997

mostly concerns the era of open surgery. A lower frequency of complications, a shorter hospital stay, and a lower level of postoperative scars are expected from laparoscopic surgery. Our results cannot be used, however, for historical comparison between open and laparoscopic pheochromocytoma surgery, because a selection bias would be introduced by the selection for open surgery of patients with large, recurring, or malignant pheochromocytomas, whereas patients selected for laparoscopic surgery usually have nonmalignant tumors of 6 cm or less (26, 27, 28).

One unexpected finding was the high incidence of spleen complications, 13 of 165 (7.9%), including 12 splenectomies and 1 splenic hematoma. Spontaneous spleen rupture and preoperative spleen complications have been reported in patients with pheochromocytoma (29, 30, 31, 32), but without quantification. In this series, spleen complications were observed in patients with pheochromocytomas on either the left or right side and were not related to tumor size. The operative strategy used, an open midline incision with routine exploration of both adrenal glands and of the area around the aorta and vena cava, probably contributed to the high frequency of splenectomies. In multivariate analysis, the risk of spleen complications was also associated with the level of preoperative systolic BP. Spleen capacitance is altered by acute changes in BP and plasma catecholamine concentrations (33, 34). Poor BP control may lead to acute changes in spleen volume and to a higher susceptibility to spleen trauma during abdominal exploration and spleen mobilization. In recent years improvements in preoperative tumor location have made possible less extensive abdominal exploration during pheochromocytoma surgery, and more attention has been paid to the long-term consequences of splenectomy (35). This may explain why spleen complications occurred in only three cases in the last 10 yr. The excellent preoperative localization studies that are possible nowadays have rendered general exploration unnecessary, and indeed such exploration is no longer justified.

All operations were performed by one of us (J.M.D.), using a median transperitoneal approach in 156 of 165 (95.4%) cases, and the median year of operation did not differ between operations with or without complications. Consequently, the incidence of complications could not be related to the surgeonâ&#x20AC;&#x2122;s experience, and it was not possible to test the statistical relationship between the risk of complication and the operation technique used. Only 3 patients underwent laparoscopic adrenalectomy. These patients had small adrenal tumors detected by screening in a family with NEM 2. This small number of patients precluded any comparison between the transperitoneal and the laparoscopic approaches. Complication rates were similar after resection of adrenal or extraadrenal pheochromocytomas. The overall incidence of complications was related to preoperative urinary metanephrine excretion and systolic BP and was much higher at reintervention than at first intervention.

Urinary metanephrine excretion and systolic BP were independent predictors of complications. In multivariate analysis, urinary metanephrine excretion was associated with complications after all (OR, 1.184; P = 0.002), first (OR, 1.172; P = 0.007), and repeat (OR, 1.157; P = 0.237) operations.

Although P values were increasing because of decreasing statistical power, the OR for the association between preoperative systolic BP and complications was also very consistent, yielding 1.138/10 mm Hg for all operations (P = 0.052), 1.138 for first operations (P = 0.076), and 1.338 for repeat operations (P = 0.119). Metanephrine excretion is positively related to catecholamine turnover (36) and tumor size (9) and is much higher in patients with malignant pheochromocytoma than in those with a benign tumor (9). We found no relationship between plasma catecholamine concentrations and the incidence of complications, probably because plasma catecholamine levels are highly variable in patients with pheochromocytoma, whereas determination of metanephrine excretion provides an integration of pheochromocytoma metabolic activity over a 24-h period (14).

Preoperative systolic BP was significantly related to the incidence of complications. This relationship does not necessarily imply that adequate BP control can prevent complications, because resistant hypertension may be an independent marker of cases at high risk. The relationship was independent, however, of plasma catecholamine levels, urinary metanephrine excretion, and tumor

size and status (benign/malignant). High BP levels and, more specifically, the permanent component of hypertension may be reduced by antihypertensive agents in subjects with pheochromocytoma (11, 16, 37). We therefore suggest that BP should be normalized whenever possible before pheochromocytoma surgery to reduce the incidence of complications. Competitive adrenergic antagonists such as prazosine are frequently used as the first-line treatment because they do not expose the patient to the risk of postoperative hypotension (11, 16). Longer acting antagonists, such as phenoxybenzamine and/or the catecholamine synthesis inhibitor, metyrosine, may be used in patients who are difficult to manage (37).

The incidence of complications after repeat intervention was much higher than that after the initial pheochromocytoma resection (OR, 5.29). Fibrosis after previous operations; extended dissection of the adrenal, periaortic, or pericaval sites of new tumors or lymph node metastases; and/or the presence of metastases extending into neighboring organs all account for the high risk of complication at reintervention. In this series we considered that subjects at high risk should be screened for recurrence (9) and that focal recurrences (mostly lymph node recurrences) were indications for reintervention. There is no evidence, however, that the early detection and resection of recurrences prolong survival (38). Given the high frequency of complications after reintervention, the treatment indications and methods should be discussed with an experienced surgeon after considering conservative management. Nonsurgical pheochromocytoma management by chemotherapy, the application of therapeutic doses of meta-iodobenzyl guanidine, or both (39, 40) is at best palliative, however. Medication with metyrosine with or without phenoxybenzamine (37) or somatostatin analogs (41, 42) may help control BP and alleviate symptoms in patients with pheochromocytoma, but has no antiproliferative effect.

In conclusion, physicians and patients should be informed that surgery for pheochromocytoma consistently involves a risk of complications, including spleen damage. Careful BP control probably helps prevent complications. Patients with high secretion tumors and those undergoing repeat intervention, generally for malignant recurrence, are at high risk of complications and should be referred to centers familiar with surgical and nonsurgical pheochromocytoma management.

Footnotes 1

This work was supported in part by Grant AOM95201 from the Assistance Publique-Hôpitaux de Paris, Délégation à la Recherche Clinique, for the COMETE Network.

Received June 15, 2000.

Revised October 24, 2000.

Revised December 22, 2000.

Accepted January 6, 2001.

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43: Int Anesthesiol Clin. 2000 Fall;38(4):31-67.

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Perioperative management of selected endocrine disorders.

Graham GW, Unger BP, Coursin DB. Department of Anesthesiology, University of Wisconsin Hospitals and Clinics, Madison 53792, USA.

Anesthesiologists routinely encounter patients with endocrine disorders. Good perioperative outcome depends on preoperative identification, risk stratification and optimization of the patients' endocrinopathies and their sequelae; intraoperative control of metabolic and physiological parameters; and appropriate postoperative pain management, stress modulation, and evaluation of neurological, cardiovascular, and renal function.

Publication Types: Review PMID: 11100416 [PubMed - indexed for MEDLINE] 44: Paediatr Anaesth. 2000;10(5):463-76.

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The perioperative management of children with phaeochromocytoma.

Hack HA. Royal Children's Hospital, Flemington Road, Parkville 3052, Victoria, Australia.

The safe anaesthetic management of a child with a phaeochromocytoma requires an understanding of the pathophysiology of the disease, together with a thorough knowledge of its pharmacology, in order to avoid or minimize the potentially harmful cardiovascular changes that may occur during anaesthesia. Although there is a considerable amount of information on the management of the adult with phaeochromocytoma, much less has been written concerning children with the disease.

Children differ significantly from adults in the incidence, location, presentation and management of this condition and these differences are discussed here together with some of the more controversial issues of management.

Publication Types: Review PMID: 11012949 [PubMed - indexed for MEDLINE] 45: J Med Assoc Thai. 2000 Aug;83(8):921-7.

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Surgery and anesthesia for pheochromocytoma--a series of 40 operations.

Lertakyamanee N, Lertakyamanee J, Somprakit P, Nimmanwudipong T, Buranakitjaroen P, Bhavakula K, Sindhavananda K. Department of Surgery, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Pheochromocytoma is a catecholamine-producing tumor which can be life-threatening. A series of 40 operations in 39 pheochromocytoma patients at a tertiary hospital in Thailand from 1976 to 1997 was reported. The patients were 30 females and 9 males; aged 7-73 years. One man had 2 operations 5 years apart. The most common symptoms and signs were palpitation, headache and hypertension. Preoperative management consisted of control of blood pressure and restoration of intravascular volume by using prazosin, an alpha adrenergic blocker. New imaging techniques have improved the ability to localize the tumors; 20 were found in the right adrenal glands, 14 in the left, 1 patient had bilateral tumors, 4 in Organs of Zuckerkandl and 1 patient had metastatic liver nodules. The operative procedures were 39 laparotomies and 1 laparoscopic surgery. The surgical and anaesthetic procedures were presented, and nitroprusside was used to control intraoperative blood pressure. Removal of tumors was successful in all cases except for 1 mortality due to injury of the liver and massive blood loss. Other complications were postoperative pulmonary edema and renal vein thrombosis. One patient had MEN type 2 and five cases were malignant.

Pheochromocytoma can be cured by surgery, but cooperation among surgeons, anesthesiologists and internists is very important.

PMID: 10998847 [PubMed - indexed for MEDLINE] 46: Can J Anaesth. 2000 Jun;47(6):566-71.

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Anesthesia for laparoscopic adrenalectomy (pheochromocytoma) in an anemic adult Jehovah's Witness.

Chiu M, Crosby ET, Yelle JD. Department of Anesthesiology, University of Ottawa and the Ottawa Hospital, Ontario, Canada.

PURPOSE: To report the anesthetic management of an anemic Jehovah's Witness patient presenting for laparoscopic adrenalectomy for pheochromocytoma. CLINICAL FEATURES: A 49-yr-old woman presented with hemodynamic instability progressing to cardiogenic shock and subsequent acute renal failure. Her course was complicated by anemia. An adrenal pheochromocytoma was diagnosed. Preoperatively, alpha- and beta-adrenergic blockade was instituted with phenoxybenzamine and metoprolol therapy and her anemia was treated with erythropoietin. She underwent laparoscopic resection of the adrenal tumour. A cell saver device was employed and attached to the laparoscopic suction-irrigation apparatus to provide salvage capability in the event of a major hemorrhage. The surgical intervention was uneventful and well tolerated. The patient was discharged home and well on follow-up. CONCLUSIONS: Cell salvage is the only mechanism currently acceptable to Jehovah's Witnesses which will allow for perioperative salvage and replacement of blood loss. Its use is encouraged in all situations in which surgical hemorrhage is anticipated.

Publication Types: Case Reports PMID: 10875721 [PubMed - indexed for MEDLINE] 47: Anaesth Intensive Care. 1999 Dec;27(6):646-9.

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Mydriasis and acute pulmonary oedema complicating laparoscopic removal of phaechromocytoma.

Tauzin-Fin P, Hilbert G, Krol-Houdek M, Gosse P, Maurette P. Department of Anesthesiology, Hospital Pellegrin-Tondu, Bordeaux, France.

This report describes the perioperative management of an adrenergic crisis occurring following insufflation of the peritoneum for planned laparoscopic surgery for phaechromocytoma. Despite preoperative alpha and beta adrenergic blockade, the occurrence of acute severe hypertension, mydriasis and pulmonary oedema prior to direct surgical manipulation caused the procedure to be abandoned. The severity of the event was unusual and most likely contributed to by haemorrhagic necrosis of the tumour releasing catecholamines. Serum levels of noradrenaline and adrenaline at the time were 744,600 and 166,940 pg.ml-1 respectively. Treatment included bolus doses of esmolol, nicardipine and urapidil (an alpha 1 adrenergic antagonist) by constant intravenous infusion and mechanical ventilation. Postoperative cerebral CT scan was normal. An abdominal CT showed central haemorrhagic necrosis of the tumour. Two weeks later, open surgical removal of the phaeochromocytoma was successfully performed under general anaesthesia. Induction of pneumoperitoneum for laparoscopy may be particularly hazardous in a patient with a phaeochromocytoma.

Publication Types: Case Reports PMID: 10631422 [PubMed - indexed for MEDLINE] 48: Masui. 1999 Sep;48(9):1014-6.

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[Repeated postoperative hypoglycemia in a woman with multiple pheochromocytomas] [Article in Japanese] Suzuki A, Taguchi S, Wakayama S. Department of Anesthesia, Labor Welfare Corporation, Aomori Rousai Hospital, Hachinohe.

A case of repeated postoperative hypoglycemia following removal of multiple pheochromocytomas in a non-diabetic 23-year-old woman is presented. Although the hypoglycemia did not occur after the first operation, it was recognized after the second and third operations. The blood sugar levels were 54 mg.dl-1 and 25 mg.dl-1, respectively, and continuous intravenous glucose infusion was necessary for about 15 hours postoperatively. This complication may be related to sudden withdrawal of catecholamines. Frequent monitoring of blood sugar level as well as cardiovascular

system is important for perioperative management of pheochromocytoma11.

Publication Types: Case Reports English Abstract PMID: 10513180 [PubMed - indexed for MEDLINE] 49: Langenbecks Arch Chir Suppl Kongressbd. 1998;115:221-7.

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[Endocrine surgery from the viewpoint of the pediatric surgeon] [Article in German] Bennek J, Tröbs RB. Klinik und Poliklinik für Kinderchirurgie, Universität Leipzig.

The extent of surgery for thyroid tumors is discussed. Prophylactic thyroidectomy in MEN II a and b is advocated. Pancreatic surgery is necessary in cases of nesidioblastosis, islet cell carcinoma, papillary-cystic neoplasia and pancreaticoblastoma. Gastrointestinal tumors with hormonal activity are very rare. "Incidental carcinoid" is occasionally found. Early detection of Zollinger-Ellison syndrome in childhood usually allows for complete removal of a gastrinoma. Benign and malignant neoplasms of the adrenals warrant radical surgery. We report one case of minimally invasive bilateral removal of the adrenals for nodular hyperplasia. Pheochromocytoma in childhood presents several peculiarities influencing perioperative management. It may occur as part of MEN II a.

Publication Types: English Abstract PMID: 9931615 [PubMed - indexed for MEDLINE] 50: Acta Anaesthesiol Scand. 1998 Oct;42(9):1114-9.

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Haemodynamic heterogeneity and treatment with the calcium channel blocker nicardipine during phaeochromocytoma surgery.

Colson P, Ryckwaert F, Ribstein J, Mann C, Dareau S. Service d'Anesthésie Réanimation B, Hopital Arnaud de Villeneuve, Montpellier, France.

BACKGROUND: Favourable outcome of phaeochromocytoma surgery requires that paroxysmal hypertension and arrhythmia be controlled, and that hypotension be prevented. Is nicardipine, a calcium channel blocking drug, always adequate? METHODS: Nineteen consecutive patients underwent surgery for phaeochromocytoma. Management was standardised with regards to 11

Para POP inmediato y en la casa. Tener Glucómetro

anaesthesia and antihypertensive treatment. Nicardipine was used as a vasodilator and was given in order to maintain systemic vascular resistance lower than 1600 dyn.s.cm-5. RESULTS: Hypertension did not occur at any time during surgery in 6/19 patients. Blood pressure rose acutely in 3/19 patients at the time of tracheal intubation or surgical approach to the tumour, and was controlled by increased depth of anaesthesia. Hypertensive episodes occurred in 11/19 patients during tumour manipulation. Nicardipine always succeeded in maintaining low systemic vascular resistance but its dosage varied widely between patients (0.5 to 70 mg), a fact that may be accounted for by the striking intersubject variability of haemodynamic behaviour during surgery. In 7/11 patients, despite nicardipine treatment, sustained increase in blood pressure persisted with increased cardiac index, but low systemic vascular resistance. Following tumour removal, transient serious hypotension (MAP < 60 mmHg) occurred in 4 patients, and was corrected by fluid volume expansion. Perioperative incidence of hypertension or hypotension was not related to preoperative clinical status. CONCLUSION: Adequate management of patients operated upon for phaeochromocytoma requires invasive monitoring, since the mechanisms underlying hypertensive crises are heterogeneous with regards to systemic vascular resistance and not predictable from preoperative data. Nicardipine provides a good control of vasoconstriction during phaeochromocytoma surgery with limited risk of serious hypotension after tumour removal.

PMID: 9809099 [PubMed - indexed for MEDLINE] 51: Anaesth Intensive Care. 1998 Apr;26(2):196-200.

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The preoperative phaeochromocytoma.

Russell

WJ,

Metcalfe

IR,

management Tonkin

AL,

Frewin

of DB.

Department of Anaesthesia and Intensive Care, Royal Adelaide Hospital, South Australia.

Although the preoperative use of alpha-receptor antagonist drugs is generally accepted for patients with phaeochromocytoma, evidence on the most appropriate treatment and its timing is scarce. In this retrospective study, the effectiveness of the preoperative preparation of fourteen patients who required surgical excision of a phaeochromocytoma was examined in the light of their operative stability. A simple score was developed of blood pressure stability by scoring the need for additional antihypertensive agents intraoperatively before, and blood pressure support after, tumour removal. A higher score indicated greater instability. Twelve patients received phenoxybenzamine and their stability was superior to the two patients treated with labetalol and with prazosin. There was no correlation between the duration of treatment with phenoxybenzamine and the operative stability (r = 0.18 P = 0.55 Spearman). The five patients who were treated with phenoxybenzamine for longer than 10 days did not have better perioperative blood pressure stability than the five patients who had treatment for less than a week. Predictive factors for intra-operative blood pressure stability were also sought. The degree of postural hypotension after treatment with phenoxybenzamine did not predict operative stability (r = -0.31, P = 0.33 Spearman). However, the peak total catecholamine level found during surgery correlated quite well with

more operative instability (r = 0.65, P = 0.031, Spearman), suggesting that patients with phaeochromocytomas with high production of catecholamines are more likely to show cardiovascular instability.

PMID: 9564401 [PubMed - indexed for MEDLINE] 52: Int Anesthesiol Clin. 1997 Fall;35(4):99-127.

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Pheochromocytomas and anesthesia.

O'Riordan JA. Department of Anesthesia, St. George's Hospital, London, England.

The management of patients with pheochromocytoma remains a challenge for the anesthetist despite the advent of new drugs and techniques. Safe anesthesia still depends on adequate preoperative preparation and assessment together with careful monitoring during the perioperative period.

Publication Types: Review PMID: 9444533 [PubMed - indexed for MEDLINE] 53: J Neurosurg. 1997 Nov;87(5):764-7.

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Pheochromocytoma and multiple intracranial aneurysms: is it a coincidence? Case report.

Erbengi A, Inci S. Department of Neurosurgery, School of Medicine, University of Hacettepe, Ankara, Turkey.

The authors present a case of multiple intracranial aneurysms associated with a pheochromocytoma.

The aneurysms were successfully clipped, and a suprarenal tumor located on the left side was totally removed. To the authors' knowledge this is the fourth reported case of these combined entities in the literature. The authors speculate on the possible etiopathogenesis of the relationship between intracranial aneurysms and attacks of hypertension caused by the presence of neoplasms that discharge acute and irregular levels of catecholamines, especially pheochromocytomas.

Perioperative management designed to avoid undesired complications in this rare association is also discussed.

Publication Types: Case Reports Review PMID: 9347988 [PubMed - indexed for MEDLINE]

54: Int J Obstet Anesth. 1997 Apr;6(2):112-7.

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Anesthesia for combined cesarean section and extra-adrenal pheochromocytoma resection: a case report and literature review.

Cammarano WB, Gray AT, Rosen MA, Lim KH. Department of Anesthesia, University of California School of Medicine, San Francisco, California, USA. Pheochromocytoma during pregnancy is unusual, with approximately 250 cases now reported in the literature. The current case describes the anesthetic management of a patient with a large extraadrenal pheochromocytoma who underwent a combined cesarean section and tumor removal in which perioperative hemodynamic control was difficult despite high-dose a-adrenergic blockade. In this case it is believed that difficulty in perioperative hemodynamic management was related to mechanical stimulation of the tumor by the gravid uterus. Review of published case reports since 1980 reveals that a pheochromocytoma during pregnancy may be diagnosed in an extra-adrenal location relatively more commonly compared to non-pregnant patients. Established criteria exist for the adequacy of alpha- and beta-adrebergic blockade for the management of pheochromocytoma in the non-pregnant patient. We discuss how these criteria apply to pregnant patients with pheochromocytoma, and suggest possible modifications to the criteria.

PMID: 15321292 [PubMed] 55: Endocr Pract. 1997 Mar-Apr;3(2):98-105.

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Pheochromocytoma.

Mena A, Lawson M, Kabadi UM. Endocrine Section, VA Medical Center, Phoenix, Arizona, 85012, USA. OBJECTIVE: To characterize the symptoms associated with pheochromocytoma and discuss the diagnosis and management of this tumor. METHODS: We review the clinical manifestations in patients with pheochromocytoma, the biochemical and imaging studies recommended for diagnosis and localization of the tumor, and the available strategies for treatment. RESULTS: Pheochromocytoma is a tumor of chromaffin cells that originates in either the adrenal medulla or the extra-adrenal sympathetic tissues. It is usually unilateral and benign. Frequent initial symptoms include headache, sweating, and palpitations, with or without increased blood pressure. In many patients, hypertension is accelerated during a paroxysm. Pheochromocytoma may also occur as a part of multiple endocrine neoplasia type IIA and B. Several common syndromes, such as panic disorders and hyperthyroidism, may mimic pheochromocytoma; however, pheochromocytoma should be suspected in the presence of hypertension, tachycardia, and throbbing headache,

especially occurring as paroxysmal episodes. The physiologic diagnosis of pheochromocytoma is established by biochemical tests of levels of plasma and urinary catecholamines or their metabolites (or both). In most patients, anatomic localization is achieved with computed tomography or magnetic resonance imaging, metaiodobenzylguanidine scintigraphy, labeled somatostatin scans, or positron emission tomography. The management preferentially includes surgical removal of the pheochromocytoma after preparation with appropriate medical therapy to avoid hypertensive crisis during the perioperative period. Patients with contraindications to a major surgical procedure or with malignant pheochromocytoma and metastatic disease, however, may be treated with multiple drugs--for example, alpha- and beta-adrenergic blockers and direct vasodilators to neutralize the effects of high levels of circulating catecholamines and alpha-methyl-metatyrosine to inhibit catecholamine synthesis. CONCLUSION: The presence of suggestive clinical features in patients with hypertension should prompt clinicians to undertake appropriate diagnostic testing because surgical resection of a pheochromocytoma will yield a cure in many cases.

PMID: 15251484 [PubMed] 56: Zentralbl Chir. 1997;122(6):460-6.

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[Anesthetic management in pheochromocytoma] [Article in German] Strecker U, Lipp M. Klink f체r An채sthesiologie, Johannes Gutenberg-Universit채t Mainz.

Consequent preoperative alpha-receptor blockade, as well as improved surgical technique, anaesthetic management and monitoring have reduced perioperative mortality below 3%.

Nevertheless, serious problems are still to be expected during the resection of "complicated" pheochromocytoma.

"Complicated" in this context means one or more of the following conditions: missing preparation, severe technical surgical difficulties (e.g. location in the liver), concomitant disorders (e.g. coronary arterial disease), pregnancy and/ or great consequential damages (e.g. cardiomyopathia).

Therapy of hemodynamic crisis during "complicated" resection of pheochromocytoma requires differentiated pharmacological combinations considering concomitant disorders. For instance multiple various combinations of phenoxibenzamine, natriumuitropussid, adenosine, magnesiumsulphate, esmolol, diltiazem have been used successfully in concomitant coronary art disease.

Absolute preferences are not established. Similarly in the anaesthetic management, a determination of a preferred procedure is still missing.

All anaesthetic possibilities should be used carefully directed with two aims: first minimise indirect release of catecholamines through effective vegetative damping and prevention of stress; second to

support therapy of hemodynamic crises through ingenious use of effect and side effects of the anaesthetic drugs.

Experiences and excellent cooperation between surgery, endocrinology and anaesthesiology are essential for successful prevention of perioperative complications.

Publication Types: English Abstract Review PMID: 9334113 [PubMed - indexed for MEDLINE] 57: Ann Chir. 1997;51(4):352-60.

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[Anesthesia-resuscitation in surgery for pheochromocytoma] [Article in French] Tavernier B, Hautier MB, Spérandio M, Proye C, Scherpereel P. Service d'Anesthésie-Réanimation Chirurgicale 2, Hôpital Claude-Huriez, CHU de Lille.

The perioperative mortality related to cardiovascular complications has been almost completely eliminated in phaeochromocytoma surgery. The anaesthetic management has mainly evolved through refinements in haemodynamic control during the operation. Neither preoperative preparation nor general anaesthesia can totally prevent haemodynamic disturbances during surgical manipulation of the tumour or after removal of the tumour. General anaesthesia, with high doses of opioids, remains the most usual technique. Intraoperative monitoring should include an arterial catheter and a pulmonary arterial catheter. Although a number of antihypertensive drugs have been tested, the preventive use of nicardipine i.v. may provide a simple and effective haemodynamic control. Esmolol, an ultrashort acting agent, ensures a dose-related cardiac beta 1-blockade. It is used for the treatment of arrhythmia and cardiac adrenergic stimulation, which causes tachycardia and increases cardiac output. Volume loading is recognised as the treatment of choice for hypotension following tumour removal. During the postoperative period, the great hazard is hypoglycaemia, and plasma glucose levels should be monitored over the immediate postoperative hours.

Publication Types: English Abstract Review PMID: 9297860 [PubMed - indexed for MEDLINE] 58: World J Surg. 1996 Sep;20(7):788-92; discussion 792-3.

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Adrenaloma: a call for more aggressive management.

Linos DA, Stylopoulos N, Raptis SA.

Department of Surgery, Athens Medical School, Mikras Asias 75, Goudi, Athens 115 27, Greece.

We review our experience from the surgical management of 57 patients (24 males, 33 females) with a mean age of 48.5 years who underwent adrenalectomy because of the computed tomography (CT) finding of a "nonfunctioning" adrenal tumor (adrenaloma). We found that CT consistently underestimated the real histologic size of the adrenal tumor (p = 0.001). Of the 57 resected tumors, 23 were cortical adenomas, 7 myelolipomas, 8 adrenal cysts, 11 nodular hyperplasias, 2 primary adenocarcinomas, 2 metastatic carcinomas, and 4 pheochromocytomas. The mean diameter was 5.89 cm and the mean weight 114.07 g. The mean diameter of the resected primary adenocarcinomas was 3.0 cm and 4.5 cm, respectively. The operative mortality was zero and the perioperative morbidity minimal. The mean operating time was 137 minutes (range 60-240 minutes). The posterior approach had the shortest operating time and the laparoscopic approach the shortest hospital stay and the least postoperative need for narcotics. During the 6.2 years mean follow-up period, five patients with preoperative hypertension remained normotensive, and both patients with the resected primary adenocarcinomas are alive without recurrence. We suggest a more liberal surgical approach to patients with adrenalomas because: (1) even small tumors can be malignant or potentially lethal (e.g., pheochromocytomas); (2) some tumors that appear to be nonfunctioning may in reality be functioning; and (3) other nonfunctioning tumors may, with time (and without prior notice), function. The low risk of adrenalectomy especially via the laparoscopic approach can provide an early definitive diagnosis and treatment, avoiding the cost of repeated CT scans and other studies as suggested by the currently prevailing conservative management of these tumors.

PMID: 8678952 [PubMed - indexed for MEDLINE] 59: J Gynecol Obstet Biol Reprod (Paris). 1995;24(5):543-8.

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[Pheochromocytoma and pregnancy. Two case reports] [Article in French] Barhmi R, el Haddoury M, Ghrab B, Elbouhali A, Tachinante R, Nabil S, Tazi AS, Alaoui I. Service de RĂŠanimation, MaternitĂŠ de Souissi, Rabat, Maroc.

Pheochromocytoma is an uncommon tumour, young patients are involved. Diagnosis during pregnancy is scarcely made. Pheochromocytoma in pregnancy is a dramatic life threatening association for mother and foetus. High maternal and fetal morbidity and mortality can be reduced by a prompt diagnosis and treatment. We report two cases of pheochromocytoma associated with pregnancy, the prognosis of the first case was poor with stillbirth, the outcome was favourable in the second case for both mother and foetus. The authors emphasize the need of rapid diagnosis and treatment to improve outcome and the importance of perioperative management of these patients.

Publication Types: Case Reports English Abstract Review

PMID: 7499744 [PubMed - indexed for MEDLINE] 60: South Med J. 1994 Nov;87(11):1164-7.

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Intrapericardial pheochromocytoma complicated by massive intraoperative hemorrhage.

Williams KS, Temeck BK, Pass HI. Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Md 20892.

Middle mediastinal pheochromocytomas are exceedingly rare. Because so few cases have been reported, consensus has not been reached regarding the anesthetic management of patients with these tumors. The use of cardiopulmonary bypass (CPB) for the resection of intrapericardial pheochromocytomas has met with varied success. We report the first documented case of successful anesthetic and surgical management of an acute, massive hemorrhage during the dissection of an intrapericardial pheochromocytoma, which was managed without cardiopulmonary bypass.

Perioperative anesthetic considerations, including the risks and benefits of CPB, are discussed.

Publication Types: Case Reports PMID: 7973908 [PubMed - indexed for MEDLINE] 61: Schweiz Med Wochenschr. 1994 Jun 4;124(22):953-6.

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[Surgery in pheochromocytoma. 12-year development] [Article in German] Kocher T, von Fl端e M, Zuber M, Staub JJ, Scheidegger D, Harder F. Departement Chirurgie, Kantonsspital Basel.

Hypertension (sustained and/or paroxysmal) is the most common symptom of pheochromocytoma.

Correct evaluation nearly always leads to the diagnosis, and complete surgical excision is the definitive treatment. Our study deals with preoperative evaluation, operative morbidity and longterm results after surgery. During the 12-year period (1981-1992) 31 patients (48 years, 25-85) with pheochromocytoma were treated at our institution. The selected preoperative management was reviewed on the basis of patient records. Long-term follow-up was carried out consecutively and personally. All patients received alpha-adrenergic blockers to achieve preoperative normotension and volume repletion. All resections were performed by laparotomy; two of the early cases were extended into the chest. 27 of 29 patients (93.1%) had elevated levels of urinary vanillylmandelic acid; a similar sensitivity was noted in the urinary catecholamines (24/26 = 92.3%). In anatomical localization CT-scan was accurate in 100% (27/27). MIGB scintigraphy was of help in 21 of 23 (91.3%) and, in the most recent patients, MRI was helpful in 3 of 3 (100%). No patient died during

the first 30 days after surgery. One patient developed an anaphylactic reaction after cephalosporin administration (morbidity: 3.2%). 2 patients (6.4%) with malignant pheochromocytoma developed a recurrent tumor during the follow-up period. Resection of pheochromocytomas by laparotomy has a low perioperative morbidity and mortality after standardized preparation. A positive MIBG scintigraphy allows extra-adrenal localization. Better resolution and multiplanar imaging are the advantages of MRI. Perioperative management and new imaging techniques--eliminating arteriography and venous sampling among others--have simplified surgical treatment and improved its safety.

Publication Types: English Abstract PMID: 7913249 [PubMed - indexed for MEDLINE] 62: Surgery. 1993 Dec;114(6):1153-8; discussion 1158-9.

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Pheochromocytoma--continuing evolution of surgical therapy.

Orchard T, Grant CS, van Heerden JA, Weaver A. Department of Surgery, Mayo Clinic, Rochester, MN 55905.

BACKGROUND. The management of pheochromocytoma has evolved through refinements in diagnosis, localization, and pharmacologic therapy for hemodynamic control both before and during operation. To provide a benchmark for comparison and to assess the feasibility of surgical resection using a posterior or laparoscopic approach, we reviewed the overall management and outcome of 110 patients who underwent primary resection of pheochromocytoma or paraganglioma between 1980 and January 1992 at the Mayo Clinic. METHODS. Patient records were reviewed for demographic information, associated conditions, symptoms, laboratory evaluation, localizing techniques, preoperative adrenergic blockade, intraoperative hemodynamics, tumor location, pathologic conditions, and outcome. RESULTS. The most prominent symptoms included headaches, sweating, and palpitations. Forty-seven percent of patients had sustained hypertension, and classic paroxysmal attacks were present in 72%. The combination of urinary metanephrines and vanillylmandelic acid had a sensitivity of 98% in detecting the disease. The positive and negative predictive values for localization of tumors by computed tomography scan were 95% and 100%, respectively. With routine alpha- and beta-blockade, there were no complications associated with intraoperative hypertension. Perioperative mortality was less than 1% and morbidity was 16%.

More than 90% of patients were restored to a condition of normotension; only 20% of these required medication. CONCLUSIONS. Surgical resection of these tumors, via a transabdominal approach, can be accomplished safely and hospitalization usually extends a week. Today the diagnosis, localization, preoperative blockade, intraoperative hemodynamic control, and postoperative management have reached a level sufficient to permit either a posterior or laparoscopic approach, but only if they can be mastered technically.

PMID: 8256222 [PubMed - indexed for MEDLINE] 63: Clin Pediatr (Phila). 1993 Aug;32(8):507-8.

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Comment on: Clin Pediatr (Phila). 1992 Oct;31(10):583-9.

Perioperative management of pheochromocytoma in children.

Ellis D. Publication Types: Comment Letter PMID: 8403752 [PubMed - indexed for MEDLINE] 64: CRNA. 1993 Aug;4(3):133-41.

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Anesthetic management of patients with pheochromocytomas: a report of three cases.

Maree S, Curll N, Emerson P. The perioperative management of patients with pheochromocytoma is a challenge to even the most seasoned practitioner. Preoperative preparation, close monitoring, and anticipation of hemodynamic changes is critical for a successful outcome.

Publication Types: Case Reports PMID: 8260911 [PubMed - indexed for MEDLINE] 65: Oral Surg Oral Med Oral Pathol. 1993 Mar;75(3):290-1.

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Dental treatment in a patient with malignant pheochromocytoma and severe uncontrolled high blood pressure.

Findler M, Mazor Z, Galili D, Garfunkel AA. Hospital Oral Medicine Service, Faculty of Dental Medicine, Hebrew University-Hadassah School of Dental Medicine.

A young female with severely uncontrolled hypertension suspected to result from malignant pheochromocytoma underwent combined medical and dental care for the treatment of acute dental pain. The dental treatment was performed with the patient under intravenous sedation and careful perioperative management with the use of high doses of alpha and beta receptor blocking agents.

The procedure was completed without intraoperative problems and an uneventful posttreatment course.

Publication Types: Case Reports PMID: 8097035 [PubMed - indexed for MEDLINE] 66: Clin Pediatr (Phila). 1992 Oct;31(10):583-9.

Related Articles, Links Comment in: Clin Pediatr (Phila). 1993 Aug;32(8):507-8.

The perioperative management of pheochromocytoma in children.

Turner MC, Lieberman E, DeQuattro V. University of Southern California School of Medicine, Los Angeles.

The perioperative experiences of 15 children and adolescents who underwent a total of 18 surgical procedures for resection of a pheochromocytoma were analyzed to determine clinical or hemodynamic events associated with intraoperative or postoperative complications. Of the pre- and intraoperative factors assessed, only preoperative resolution of symptoms and normalization of blood pressure were predictive of uncomplicated outcome. No intraoperative factors were statistically associated with outcome, but the four patients with complicated outcomes had had aggressively administered intraoperative fluids. Noninvasive measures of cardiac function did not help predict outcome; however, echocardiography results were available only for six patients. Two of the patients with complicated outcomes had cardiac dysfunction, suggesting undiagnosed catecholamine-induced cardiomyopathy in the other two with complicated outcomes. Intraoperative fluids should be given based on intraoperative blood pressures, the presence or absence of prior adrenergic blockade, and assessment of preoperative myocardial function. If preoperative myocardial dysfunction is revealed, intraoperative measurement of right atrial and pulmonary capillary wedge pressures may be indicated.

PMID: 1395364 [PubMed - indexed for MEDLINE] 67: Ann Surg. 1990 Oct;212(4):472-6; discussion 476-7.

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Experience with cardiopulmonary bypass and deep hypothermic circulatory arrest in the management of retroperitoneal tumors with large vena caval thrombi.

Novick AC, Kaye MC, Cosgrove DM, Angermeier K, Pontes JE, Montie JE, Streem SB, Klein E, Stewart R, Goormastic M. Department of Urology, Cleveland Clinic Foundation, OH 44195.

From June 1984 to September 1989, 43 patients with large vena caval tumor thrombi from retroperitoneal malignancies underwent surgical treatment with cardiopulmonary bypass (CPB) and

deep hypothermic circulatory arrest (DHCA). The primary malignancies were renal cell carcinoma (RCC) (n = 39), renal pelvic transitional cell carcinoma (n = 1), adrenal pheochromocytoma (n = 1), and renal (n = 1) or retroperitoneal (n = 1) sarcoma. The level of the caval thrombus was either suprahepatic (n = 27), intrahepatic (n = 14), or subhepatic (n = 2). In all cases the primary tumor and caval thrombus were completely removed. Concomitant procedures included coronary artery bypass grafting (n = 5), pulmonary resection (n = 2), and hepatic lobectomy (n = 1). The time of circulatory arrest ranged from 10 to 44 minutes (mean, 23.5 minutes). There were two operative deaths (4.7%), neither of them due to to the use of DHCA. Major postoperative complications occurred in 13 patients (30.2%). There were no ischemic or neurologic complications and no cases of perioperative tumor embolization. The median postoperative hospital stay was 9 days. Twentytwo patients (51%) are alive and enjoying a good quality of life. The 3-year patient survival rates in patients with localized (n = 24) versus metastatic (n = 15) RCC are 63.9% and 10.9%, respectively (p = 0.02). We conclude that CPB with DHCA facilities excision of retroperitoneal malignancies with large caval thrombi and provides the potential for cure with low morbidity and mortality rates.

PMID: 2222013 [PubMed - indexed for MEDLINE] 68: Cleve Clin J Med. 1990 Oct;57(7):613-7.

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Perioperative management of 63 patients with pheochromocytoma.

Boutros AR, Bravo EL, Zanettin G, Straffon RA. Division of Anesthesiology, Cleveland Clinic Foundation, Ohio 44195.

During a 10-year period, 60 patients with confirmed diagnoses of pheochromocytoma underwent a total of 63 surgical procedure. To control extreme blood pressure elevations, 6 patients received phenoxybenzamine preoperatively and 28 patients received prazosin. The remaining 29 patients received neither drug. Intravenous sodium nitroprusside and nitroglycerin, alone or in combination, were used in all but 10 patients to control intraoperative hypertensive episodes. One patient died after surgery due to pre-existing intracranial malignant tumor. All other patients were discharged from the hospital with no clinical evidence of stroke or myocardial infarction. We conclude that pheochromocytoma patients can undergo successful surgery without preoperative profound and long-lasting alpha adrenergic blockade.

PMID: 2121390 [PubMed - indexed for MEDLINE] 69: Am Surg. 1990 Jul;56(7):398-403.

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Sub-clinical Cushing's syndrome in patients with adrenal gland incidentalomas.

Pitfalls in diagnosis and management.

McLeod MK, Thompson NW, Gross MD, Bondeson AG, Bondeson L. Department of Surgery, University of Michigan Medical Center Ann Arbor 48109-0331.

Widespread use of contemporary imaging techniques (ultrasound, computerized axial tomography,

and magnetic resonance imaging scans) have led to the incidental discovery of asymptomatic adrenal neoplasms with increasing frequency. Patients with such adrenal "incidentalomas" typically have no clinical manifestations of adrenal cortical hyperfunction at the time of discovery. We have studied 122 patients with asymptomatic adrenal masses ranging in size from 2 to 7 cm in diameter from 1978 to 1988. Selected patients, after adrenal metastases, pheochromocytoma, myelolipomas, and cysts were ruled out, were further evaluated for adrenal cortical hyperfunction by measuring urinary 17-hydroxysteroids, 17-ketosteroids, and free cortisol, serum A.M., P.M. cortisol, and plasma ACTH levels. These values were also measured before and after dexamethasone suppression. NP-59 adrenal scintiscans were performed on all patients. Six patients were identified with sub-clinical Cushing's syndrome. Baseline cortisol levels were normal in each of these patients. Loss of diurnal rhythm appeared to be the most sensitive indicator of abnormal adrenal cortical function. When adrenalectomy is performed in such patients, especially when contralateral adrenal gland suppression is evidenced by NP-59 scanning or other biochemical assessment, perioperative steroids should be administered in a manner similar to that used for patients with symptomatic Cushing's syndrome. Unilateral adrenalectomy in a patient with an asymptomatic adrenal adenoma, insufficiently studied, may result in Addisonian crisis.

Publication Types: Case Reports PMID: 2164335 [PubMed - indexed for MEDLINE] 70: Masui. 1990 May;39(5):639-43.

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[Anesthetic management for resection of cardiac pheochromocytoma] [Article in Japanese] Shibata K, Matsumoto T, Yamamoto K, Kobayashi T, Murakami S. Department of Anesthesiology, School of Medicine, Kanazawa University.

Cardiac pheochromocytoma is a rare disease, and there have been few reports concerning anesthetic management for the resection. This is a report of a 46-year-old man with cardiac pheochromocytoma with the perioperative changes in plasma catecholamine concentrations.

Anesthesia was maintained with enflurane (0.5-2.0%) and 50% nitrous oxide in oxygen. Additional fentanyl (900 micrograms) was given as required. Intravenous administration of nitroglycerin in a dose of 5-20 micrograms.kg-1.min-1 was effective for prevention of intraoperative hypertension.

After cardiopulmonary bypass and cardioplegic arrest were instituted, the manipulation of the tumor had no effect upon the blood pressure. A serious increase in plasma norepinephrine concentration occurred during both bicaval cannulation and manipulation of the tumor. Although the anesthetic management for resection of adrenal pheochromocytoma has been well-documented, that of cardiac pheochromocytoma requires following specific considerations. 1) Serious hypertension and arrhythmias may occur during manipulation of the heart. 2) It is possible to dissect the tumor safely after isolation of the heart from systemic circulation. It is of great interest that the blood pressure remained almost unchanged during cardiopulmonary bypass despite a marked increase in catecholamine concentrations. 3) Operative mortality rate is high.

Publication Types:

Case Reports English Abstract PMID: 2384959 [PubMed - indexed for MEDLINE] 71: Urol Clin North Am. 1989 Aug;16(3):597-606.

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Perioperative complications of adrenal surgery.

Angermeier KW, Montie JE. Department of Urology, Cleveland Clinic Foundation, Ohio.

Complications of adrenal surgery may be medical or surgical. The latter are related to the operative approach as well as to the type and extent of the adrenal lesion and are in general similar to those seen in other open procedures. The medical complications include adrenal insufficiency as a result of bilateral adrenalectomy or continuing contralateral suppression, as well as more specific problems resulting from the physiological derangements of Cushing's syndrome, pheochromocytoma, and primary aldosteronism. Nevertheless, with meticulous preoperative management and postoperative care, adrenal surgery can be performed with low morbidity and mortality rates.

Publication Types: Review PMID: 2665283 [PubMed - indexed for MEDLINE] 72: J Natl Med Assoc. 1989 Jul;81(7):777-9.

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Recent advances in the surgical management of pheochromocytoma.

Hoover EL, Weaver WL. Improvements in biochemical assays, radiographic imaging, and perioperative monitoring; the availability of selective adrenergic blockers; and a better understanding of the pathophysiology of the disease have all contributed to the reduction in mortality and morbidity in patients with pheochromocytomas. Twenty-four-hour urinary catecholamines are more reliable than blood levels in detecting pheochromocytomas. The diagnosis may be confirmed by elevated epinephrine fractions when total catecholamine levels are normal. Computerized tomography is the preferred imaging tool, although ultrasound and magnetic resonance are preferred during pregnancy. 131I iobenguane scanning is useful in locating extra-adrenal disease and may have a role in the treatment of metastases. Total alpha-adrenergic blockade with phenoxybenzamine versus selective (alpha 1) blockage with prazosin are equally effective preoperatively. Invasive monitoring is necessary in all patients, and agents to control arrhythmias, hypertension, hypotension, and cardiac arrest are prepared in advance. Patients with benign lesions have an excellent cure rate, and those with malignancies have effective palliation of their symptoms.

Publication Types: Research Support, Non-U.S. Gov't Review PMID: 2666677 [PubMed - indexed for MEDLINE] 73: Can J Anaesth. 1989 Mar;36(2):215-8.

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Perioperative management for resection of a malignant non-chromaffin paraganglioma of the bladder.

Splinter WM, Milne B, Nickel C, Loomis C. Department of Anaesthesia, Queen's University, Kingston, Ontario.

The perioperative management of a 39-year-old patient with a rare, catecholamine producing, nonchromaffin paraganglioma of the bladder is presented. Although the management of this patient was comparable with a patient with a phaeochromocytoma, this case was complicated by marked release of catecholamines, high requirements for vasodilator therapy preoperatively, the presence of a malignant tumour with metastases and an atypical presentation. Preoperatively the diagnosis was a non-metastatic bladder phaeochromocytoma and the blood pressure was controlled with prazosin, nifedipine and propranolol. Anaesthesia was induced with fentanyl, lidocaine, thiopentone and vecuronium and was maintained with nitrous oxide, isoflurane, fentanyl and vecuronium. The patient was haemodynamically stable throughout the operative and postoperative period.

Publication Types: Case Reports PMID: 2539911 [PubMed - indexed for MEDLINE] 74: Z Kinderchir. 1988 Aug;43(4):252-61.

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[Surgery of the juvenile adrenal glands. Surgical protocol, intra- and perioperative monitoring] [Article in German] Koltai JL, Hoffman-von Kap-herr S, Schranz D, Klein A. Klinik und Poliklinik f체r Kinderchirurgie im Klinikum, Johannes-Gutenberg-Universit채t Mainz.

Surgical and non-surgical conditions of the adrenal cortex and medulla are presented. Besides general principles of operative treatment (e.g. surgical approach, safe operative technique, bilateral exploration) specific aspects associated with this procedure in childhood are discussed. The perioperative management and pharmacotherapeutical preparation (e.g. hormonal substitution) are emphasized.

Publication Types: English Abstract Review PMID: 2845684 [PubMed - indexed for MEDLINE] 75: Arch Surg. 1988 May;123(5):626-30.

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Advances in the diagnosis and treatment of pheochromocytoma.

Havlik RJ, Cahow CE, Kinder BK. Department of Surgery, Yale University School of Medicine, New Haven, CT 06510-8062.

Diagnosis and management of pheochromocytoma, once dangerous and uncertain, have been dramatically altered in recent years by advances in imaging, assays, and pharmaceuticals. During the past ten years we have treated 18 patients who had pheochromocytoma. Biochemical diagnosis was made in all patients by measurement of 24-hour urinary total catecholamine excretion or by epinephrine-norepinephrine fractionation. Determination of epinephrine-norepinephrine ratios was instrumental in making the diagnosis of pheochromocytoma in two patients in whom total catecholamine levels were normal. Localization of the pheochromocytoma in the most recently treated cases was accomplished by ultrasound, computed tomography, or iodine I 131 iobenguane (iodine I 131 metaiodobenzylguanidine) scanning. Nine patients in the series were prepared for surgery with phenoxybenzamine hydrochloride and six with prazosin hydrochloride. Preoperative total alpha-adrenergic blockade with phenoxybenzamine offered no advantage over selective blockade with prazosin 12in terms of perioperative fluid requirements or intraoperative hemodynamic stability.

PMID: 3282495 [PubMed - indexed for MEDLINE] 76: Can Anaesth Soc J. 1985 May;32(3 Pt 1):278-82.

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Perioperative management of a patient with a malignant pheochromocytoma.

Miller D, Robblee JA. A case report is presented of a patient with a known malignant pheochromocytoma, who was to undergo an orthopaedic procedure using methylmethacrylate bone cement. Preoperative preparation of the patient included the use of prazosin and metyrosine. Epidural blockade was chosen as the anaesthetic technique for intraoperative management. Surgical fixation with methylmethacrylate did not produce profound or prolonged hypotension despite sudden massive blood loss prior to its use.

Epidural morphine was administered for postoperative pain control.

Publication Types: 12

Prazosin MInipres se puede emplear tan efectivamente como fenoxibenzamina.

Case Reports PMID: 4005679 [PubMed - indexed for MEDLINE] 77: Cardiology. 1985;72 Suppl 1:174-8.

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Anesthetic management in patients with pheochromocytoma.

Hauss GM, Van Aken H, Lawin P. In expert hands, perioperative mortality of elective removal of pheochromocytoma can almost be completely eliminated. Isoflurane and enflurane plus nitrous oxide have proved to be suitable anesthetic agents and there are potent drugs for the treatment of intraoperative cardiovascular disturbances. The major factor responsible for mortality reduction is a well-balanced pre-, peri- and postoperative fluid replacement.

PMID: 4053127 [PubMed - indexed for MEDLINE] 78: Nippon Geka Gakkai Zasshi. 1984 Sep;85(9):1030-4.

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[Current problems in adrenal surgery] [Article in Japanese] Tanimura H, Kobayashi N. Retrospective study on diagnosis and management during the perioperative period of patients with adrenal tumors who underwent adrenalectomy in the Second Department of Surgery Kyoto University, from 1960 to 1983, was carried out. Most of the patients presented with functioning tumors; primary aldosteronism (43 cases), Cushing's syndrome (53 cases), pheochromocytoma (39 cases), and DOC-producing tumor (1 case), whereas, only 3 cases were non-functioning adenoma and cyst. Although recent development of CT has permitted easy and non-invasive diagnosis of adrenal tumors, aldosterone-producing tumors may be overlooked due to their small sizes, because their CT value is identical to that of fatty tissue. Moreover, blood sampling from vena cava at various levels is also necessary in patients with extra-adrenal pheochromocytomas. The preoperative control of blood pressure by alpha- and beta-adrenergic blocking agents was a prerequisite, and the clinical course was uneventful following intraoperative additive use of sodium nitroprusside in patients with pheochromocytoma. Autotransplantation of the adrenal cortex into the rectus muscle was performed in three patients with bilateral pheochromocytoma and two of them could return to work. Non-functioning adrenal tumors have been found increasingly by routine CT study without previous suspicion and the surgical indication of these tumors must be discussed in more detail in the future.

Publication Types: English Abstract

PMID: 6503958 [PubMed - indexed for MEDLINE] 79: Anasth Intensivther Notfallmed. 1983 Oct;18(5):265-9.

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[Perioperative therapy in juvenile pheochromocytoma] [Article in German] Abel M, Struck E, Schindera F, Deilmann M, Birmelin M. The article reports on the paediatric-anaesthesiological treatment of 6 phaeochromocytomas in 5 children who were 8 to 16 years of age. Therapeutic recommendations for the perioperative medication of infantile phaeochromocytoma patients are involved. The therapeutic aim of this study was the management of the effects of phaeochromocytoma before and after extirpation of the tumour, the effect of the phaeochromocytoma being of an alpha-adrenergic and beta-adrenergic cardiovascular nature and transmitted by catecholamines. Preoperative stabilization of blood pressure by means of the alpha-blocker phenoxybenzamine and a subsequent intraoperative, controlled reduction of blood pressure by means of sodium nitroprusside were found to be an effective, safe and easily appreciated therapeutic concept for the perioperative care of paediatric phaeochromocytoma patients. Considerable individual differences in dose an duration of the necessary preoperative phenoxybenzamine administration rendered ward control of therapy recommendable. The risk of complete alpha-sympathicolysis by additive drug effects during premedication and induction of anaesthesia, had to be taken into consideration for conducting phenoxybenzamine therapy. Additional administration of the beta-blocker pindolol successfully controlled the intraoperatively manifested tachycardial heart rhythm phases without provoking any complicating arrhythmias. During the entire perioperative treatment of the patients it is mandatory to ensure sufficient substitution of intravascular volume to prevent hypotensive complications. Our patients did not need any cardiac and sympathicomimetic drugs as postoperative administration.

None of the patients had any perioperative complications worth mentioning.

Publication Types: Case Reports English Abstract PMID: 6660444 [PubMed - indexed for MEDLINE] 80: Urology. 1983 May;21(5):505-7.

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Perioperative management in undiagnosed pheochromocytoma.

Bready LL, Hoff BH, Lamm DL, Dyer M. Pheochromocytoma which is diagnosed intraoperatively carries a high morbidity and mortality.

Successful management of the patient with unsuspected pheochromocytoma requires a high index of suspicion and aggressive pharmacologic intervention.

Publication Types: Case Reports PMID: 6134374 [PubMed - indexed for MEDLINE] 81: Arch Surg. 1980 Oct;115(10):1224-5.

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Current surgical management of pheochromocytoma during pregnancy.

Fudge TL, McKinnon WM, Geary WL. The diagnosis of pheochromocytoma during pregnancy has rarely been made correctly prior to delivery, only 42 cases having been reported. Antepartum diagnosis markedly decreases the maternal and fetal mortality. We report a case of pheochromocytoma manifesting during the third trimester of pregnancy. Preoperative control of blood pressure with phenoxybenzamine and phentolamine therapy was carried out. Simultaneous cesarean section and excision of the tumor resulted in a healthy mother and newborn infant. We review the perioperative and intraoperative management of patients with a pheochromocytoma during pregnancy.

Publication Types: Case Reports PMID: 7425838 [PubMed - indexed for MEDLINE] 82: Mt Sinai J Med. 1979 Jul-Aug;46(4):345-53.

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The perioperative management of patients with pheochromocytoma.

Pratilas V, Pratila MG, Dimich I. PMID: 314565 [PubMed - indexed for MEDLINE] Items 1 - 82 of 82