I study? What isthecontribution of this cases report aboutit. individual three found just have we but crisis secondary to pheochromocytoma, treatment for intraoperative hypertensive effect. It has been reported as a successful rapid onset, short half-life and noresidual with antagonist calcium a is Clevidipine problem? What dowe know aboutthis 2020;48(4):e937. Colombian Journal of Anesthesiology. pheochromocytoma surgeries: Caseseries. as an antihypertensive druginthree Martínez CE, Trillo-Urrutia L. Clevidipine Luis-García C,Arbonés-Aran E,Moreno- How to cite thisarticle? the hypertensive peakslesspronounced. preventively could have helped to make that initiatingtheclevidipineearly and before hypertensive crisis. We believe from thebeginning of thesurgery, doses low at clevidipine of infusion the a started we which report in cases three of series we Now peak. first hypertensive the during clevidipine of infusion the started we hospital, our in exeresis undergoing pheochromocytoma a Carol Luis-García feocromocitoma: Serie decasos Clevidipino comofármaco antihipertensivo de entrescirugías pheochromocytoma surgeries: Caseseries Clevidipine asan antihypertensive inthree drug doi: https://doi.org/10.5554/22562087.e937 Correspondence author: Passeig Marítim delaBarceloneta, 25,29,08003. Barcelona, España.Email: Department of Anaesthesiology, Hospital delMar, Parc deSalut Mar. Barcelona, Spain. n aprevious case of apatient OPEN a ,Elisa Arbonés-Aran Antihypertensive drugs;pheochromocytoma; adrenalectomy; catecholamines. Keywords less pronounced. surgery. in pheochromocytoma Starting theinfusion drug of clevidipinebefore thehypertensive peakscouldhelpto make antihypertensive them choice first a be could Clevidipine Discussion resection, tumor clevidipine infusion wasAfter stopped inallcases, and any patientrequired infusionminutes. of vasopressors. few a in controlled were peaks hypertensive patients, all In Results peaks. surgery, before theyhad presented , to to treat and try minimize hypertensive laparoscopic adrenalectomy. They allreceived clevidipineinfusion from thebeginning of the Weofreportseries a three casesof pheochromocytoma with patients werewho treated with Methods have arapid onset of action, short half-life and noresidual effect. should phase first the in used drugs antihypertensivereason, that Forhypotension. arterial suffer relative vasodilation and theresidual effect of antihypertensive drugs, whichresults in can patients excision, tumor After release. catecholamine to due crisis hypertensive of risk a is there handling), veins and tumor insufflation, (pneumoperitoneum phase surgical first Laparoscopic adrenalectomy is thetreatment of choiceof pheochromocytoma. During the Introduction This isan open access article under theCC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Copyright ©2020Sociedad Colombiana deAnestesiología yReanimación (S.C.A.R.E.). Lea laversión enespañol deeste artículo en www.revcolanest.com.co Abstract a , Carlos Eduardo Moreno-Martínez Received: 3December, 2019▶Accepted: 11February, 2020▶Online first:7 September, 2020 [email protected] a , Lourdes , Trillo-Urrutia a 1 CASE REPORT /6 2/6 colombian journal of anesthesiology. 2020;48(4):e937

Resumen

¿Qué sabemos acerca de este Introducción problema? La adrenalectomía laparoscópica es el tratamiento de elección del feocromocitoma. Durante El clevidipino es un antagonista del la primera fase quirúrgica (insuflación de neumoperitoneo, manipulación del tumor y de calcio de rápida aparición, vida me- las venas implicadas), existe el riesgo de que se desencadenen crisis hipertensivas debido a dia corta y sin efecto residual. Se ha la liberación de catecolaminas. Después de la extirpación del tumor, los pacientes pueden sufrir una vasodilatación relativa y el efecto residual de los fármacos antihipertensivos informado que es un tratamiento usados previamente, lo que resulta en hipotensión arterial. Por esa razón, los fármacos exitoso para la crisis hipertensiva antihipertensivos utilizados en la primera fase quirúrgica deben tener rápido inicio de acción, intraoperatoria secundaria al feocro- vida media corta y mínimo efecto residual. mocitoma, pero acabamos de encon- trar tres informes de casos individua- Métodos les sobre este fármaco. Se describe una serie de casos de tres pacientes con feocromocitoma que fueron tratados con adrenalectomía laparoscópica. Todos recibieron infusión de clevidipino desde el comienzo ¿Qué aporta este estudio de nuevo? de la cirugía, antes de presentar hipertensión arterial, para así intentar minimizar y tratar En un caso anterior de un paciente rápidamente los posibles picos hipertensivos. sometido a exéresis de feocromoci- toma en nuestro hospital, iniciamos Resultados la infusión de clevidipino durante el En todos los pacientes los picos hipertensivos se controlaron en pocos minutos. Después de la primer pico hipertensivo. Ahora in- resección del tumor, la infusión de clevidipino se detuvo en todos los casos y ningún paciente formamos de una serie de tres casos requirió perfusión de vasopresores. en los que comenzamos la infusión de clevidipino en dosis bajas desde Discusión el principio de la operación, antes de El clevidipino podría ser un fármaco antihipertensivo de primera elección en la cirugía de la crisis hipertensiva. Creemos que feocromocitoma. Iniciarlo antes de que ocurran los picos hipertensivos podría ayudar a que iniciar el clevidipino de manera tem- sean más leves. prana y preventiva podría haber ayu- dado a que los picos de hipertensión Palabras clave fueran menos pronunciados. Fármacos antihipertensivos; feocromocitoma; adrenalectomía; catecolaminas.

INTRODUCTION During surgery, there is a great risk of cate- capacitance and the residual effects of cholamine release, especially during insu- hypotensive drugs used before(5). To de- Pheochromocytoma is a tumor that fflation of the pneumoperitoneum and tu- crease it, it is recommended to do volume produces catecholamine and is located in mor manipulation (3). Severe hypertensive expansion during and after the surgery crises can occur even in patients who have with fluid therapy guided by hemodynamic the adrenal medulla in 80-85% of cases. It never had hypertension. It is recommen- objectives (6), and the hypotensive drug can be associated with systemic diseases ded to do a preoperative optimization with used before tumor resection must have a such as neurofibromatosis type 1. drugs that block the effect of catecholami- short half-life. Patients with pheochromocytoma ne: alpha blockers, bloc- Clevidipine is an intravenous calcium can suffer symptoms as palpitations, kers or angiotensin receptor inhibitors. For antagonist that has a rapid onset of action, arterial hypertension (AHT), diaphoresis patients with tachyarrhythmia, the use of short duration of effect, metabolism by or headache due to a high secretion of calcium channel blockers or beta-blockers plasma esterase and easy dose titration catecholamine. (previous treatment with alpha) is recom- (7,8). It could be a good antihypertensive Laparoscopic adrenalectomy is the mended (4). agent in these surgeries, but there are treatment of choice, except in very After tumor resection, the most just a few publications about it (8-10). large tumors or unresectable malignant common complication is severe arterial The following three cases describes its tumors (1-3). , due to an increased venous application in pheochromocytoma surgery. colombian journal of anesthesiology. 2020;48(4):e937 3/6

METHODS: CASES REPORT urinary levels of metanephrines and the catheter was placed for postoperative results of an image test after they had analgesia and was used since the end We present a series of three consecutive presented clinical manifestations (table 1). of the surgery in all patients. They were patients with pheochromocytoma They all received preoperative preparation monitored with Vigileo (company: Edwards that were treated with laparoscopic an had normal BP and HR before surgery Lifesciences)(6). adrenalectomy in our hospital between and on their arrival at the operating room In patients 1 and 2, the clevidipine infu- 2017 and 2018. Patients are satisfied with (table 1). They were operated under general sion was started at low doses a few minutes the treatment received and we have anesthesia: Anesthetic induction with after the anesthetic induction, despite the obtained the signed consent of all of them propofol, rocuronium and remifentanil. fact that they were normotensive, to try to to publish their clinical data. Anesthetic maintenance: sevofluorane avoid pronounced hypertensive peaks du- They were a man and two women in patients 1 and 2, desfluorane in patient ring the surgery. They had BP up to 169/77 between 54 and 73 years old that were 3, remifentanil infusion and bolus of -180/70 after the clevidipine infusion was diagnosed by an increase of plasma or rocuronium in all of them. An epidural started (figure 1). Patient 2 presented a sig-

table 1. Patients’ characteristics and diagnosis. Preoperative preparation and hemodynamic parameters.

Characteristics Patient 1 Patient 2 Patient 3 Age (years) 54 73 60 Gender Female Male Female

Diabetes, dyslipidemia, Hypertension, Ex-smoker, Chronic illneses hypothyroidism, glaucoma dyslipidemia dyslipidemia

Hypertensive crisis with Recurrent hypertensive crises, palpitations, headache, tremors, Hypertensive crisis and Signs and symptoms and sweating paresthesias in the extremities sweating and coughing with hemoptysis

Total metanephrines Total metanephrines in plasma: in 24h urine: Metanephrines in 24h urine: 92,7 pg/mL (0-90 pg/mL). 6.534 µg/24 h (0-302 µg/24 h). 5.210 µg/24 h Noraderenaline in plasma: Normetanephrine in 24h urine: 4.916 µg/24 h (0,01-390 µg/24 h). (0,01-320 µg/24 h) 3.856 pg/mL (0-420 pg/mL) Hormonal tests Noradrenaline in 24h urine: Noradrenaline in 24h urine: 730 µg/24 h (0-97 µg/24 h). Vanilmandelic acid in 24h urine: 1.736 nmol/d (0-97 µg/24h). Adrenaline in 24h urine: 19,9 mg/24 h (0,01-6,6 mg/24 h) Normetanephrines in plasma: 171µg/24h 0-20 µg/24 h. 4.424,4 pg/mL (0-196 pg/mL) Dopamine in 24h urine: 171 µg/24 h (65-400 µg/24 h)

CT: Solid left adrenal 47 mm mass. MR: Right adrenal 77x74 Gammagraphy with 99m CT: Left suprarenal 43x31x35 mm mm mass which is globally Image test Tecnecio-sestamibi: Suprarenal mass hyperdense with acute adrenal left capture hemorrhage 4/6 colombian journal of anesthesiology. 2020;48(4):e937

Characteristics Patient 1 Patient 2 Patient 3

Doxazosine retard 8 mg/24h Pre-surgery Doxazosine 4mg/24h Nifedipine retard 20mg/8h treatment 20 mg/8 h 10mg/8h Propranolol 10mg/8h

Maxium BP during 120/70 mmHg 135/70 mmHg 133/88 mmHg 48h pre surgery

Maxium HR during 100 bpm 75 bpm 85 bpm 48h pre surgery

CT= Computed tomography, MR= Magnetic resonance. source: Authors.

figure 1. and during surgery. nificant depression of the ST segment in de- rivation II of the electrocardiogram. It was in the context of hypertensive peak up to 180/70 mmHg and sinus tachycardia up to 120 beats per minute. It normalized when the tachycardia and hypertension decrea- sed. Patient 3 presented BP up to 217/107 during laryngoscopy. In that moment, the clevidipine infusion was started and BP was controlled in three minutes and remained stable (figure 1). After the clamping of all the veins involved, the clevidipine infusion was progressively reduced and could be removed in all of them. All patients presented episodes of arterial hypotension. In patients 1 and 2, hypotension was solved in less than 10 minutes just with fluid therapy guided by hemodynamic objectives. The hemodynamic objectives consisted of an increase of 10% or more in the cardiac index and the systolic volume index of the Vigileo monitoring system. The Patient 1: Blood pressure peaks up to 180/70 mmHg before and during tumor resection. fluid therapy that was necessary to achieve Punctual episodes of arterial hypotension after the tumor resection and the clamping of this objectives was 1 liter of plasmalyte in the veins involved. patient 1 and 0.5 liters in patients 2 and 3. Patient 2: Blood pressure peaks up to 180/70 mmHg and sinus tachycardia up to 120 beats Patient number 3 also required a punctual per minute before and during tumor resection. Punctual episodes of arterial hypotension 100 µg bolus of phenylephrine. They after the tumor resection and the clamping of the veins involved. remained normotensive until the end of Patient 3: Blood pressure up to 217/107 mmHg during laryngoscopy, before starting the in- the surgery. fusion of Clevidipine. All patients were extubated in the BP-Di= Diastolic blood pressure in millimeters of mercury (mmHg), BP-Si= Systolic blood operated room and transferred to recovery pressure in mmHg, HR= Heart rate in beats per minute. room. Patients 1 and 3 were discharched to source: Authors. conventional hospital ward in six hours. colombian journal of anesthesiology. 2020;48(4):e937 5/6

Patient 2 did not present symptoms or In a previous case in our hospital, we Right to privacy and informed consent electrocardiogram of myocardial ischemia started clevidipine infusion during the first after surgery. Troponin curve was initially hypertensive peak, managing to control The authors declare that no patient data ascending, reaching a maximum of 83 blood pressure quickly. However, even appear in this article. ng/l. The cardiologist’s diagnostic was though the hypertensive peaks lasted just The authors have obtained the informed myocardial damage in a hemodynamic a few minutes, the patient had very high consent of the patients and/or subjects context. The troponins normalized in 24h BP levels momentarily, even up to 279/122 referred to in the article. This document and the patient could be discharged from mmHg(8). In the three patients of this case work in the power of the correspondence resuscitation area. series, we started the infusion of clevidipine author. All of them remained with normal at low doses from the beginning of the BP during the whole hospital admission, surgery, after anesthetic induction, despite without the requirement of vasopressors the fact that they were normotensive. We ACKNOWLEDGEMENTS or antihypertensive drugs. They were all believe that this could have helped to make discharged from hospital in less than four the hypertensive peaks less pronounced Authors’ contributions days. (up to 180/70 mmHg after the clevidipine infusion was started). In future cases, if the patient does not present arterial CLG: Interpretation of results, data analysis DISCUSSION hypotension, we will consider starting and writing of the manuscript. clevidipine infusion at low doses before EAA: Data collection, study planning, CEMM: Data collection, data analysis. The second surgical period of pheochromo- the anesthetic induction, to try to minimize LTU: Conception of the original project, cytoma exeresis is associated with risk of possible hypertensive peaks during interpretation of results and approval of the hemodynamic instability, due to manipu- laryngoscopy, as occurred in patient 3 that manuscript. lation of the tumor and secondary relative presented BP up to 217/107. hypovolemia (5). Clevidipine could be an antihypertensive agent of first choice in these interventions. Clevidipine is an intravenous calcium Financial support and sponsorship antagonist with rapid onset, short half-life, We think that starting the infusion of clevidipine before the hypertensive peaks minimal effect on heart rate and myocardial None. oxygen consumption, dose-dependent could help to make them less pronounced. and linear effect, metabolized by plasma However, more studies are needed to ensure its role in pheochromocytoma esterase and with easy dose titration. Conflicts of interest surgery. It does not require dose adjustment by weight, renal or hepatic function (7,8). None. The risk of arterial hypotension after ETHICAL DISCLOSURES tumor resection is lower if the hypotensive drugs used before have a short half-life. Presentation of preliminary data Clevidipine has not residual hypotensive Protection of human and animal effect (7,8) after tumor resection, so the risk Euroanesthesia 2018, Copenhagen subjects. of hypotension might be lower. Denmark, 2-4 June, 2018. There are just a few publications The authors declare that no experiments about the use of clevidipine in this type of were performed on humans or animals for surgeries. Its use has been reported as a this study. REFERENCES successful treatment for an intraoperative hypertensive crisis secondary to an 1. Oleaga A, Goñi F. Feocromocitoma: undiagnosed pheochromocytoma(9). Confidentiality of data. Actualización diagnóstica y terapéutica. Endocrinol Nutr. 2008;55(5):202-16. DOI: It has been also described as a https://doi.org/10.1016/S1575-0922(08)70669-7 successful treatment of a patient with The authors declare that they have followed pheochromocytoma in the context of von the protocols of their work center on the pu- 2. Gardet V, Gatta B, Simonnet G, Tabarin A, HippelLindau disease(10). blication of patient data. Chene G, Ducassou F, Corcuff JB. Lessons from 6/6 colombian journal of anesthesiology. 2020;48(4):e937

an unpleasant surprise: a biochemical strategy 5. Bénay CE, Tahiri M, Lee L, Theodosopoulos 8. Luis C, Arbonés E, Teixell C, Lorente L, Trillo for the diagnosis of pheochromocytoma. J E, Madani A, Feldman LS, Mitmaker EJ. L. Clevidipino como antihipertensivo en Hypertens. 2001;19:1029-35. Selective strategy for intensive monitoring la cirugía de feocromocitoma. Rev Esp after pheocromocytoma resection. 3. Pacak K, Eisenhofer G, Ahlman H. Bornstein Anestesiol Reanim. 2018;65(4):225-8. DOI: SR, Giménez-Roqueplo AP, Grossman Surgery. 2016;159:275-83. DOI: https://doi. https://doi.org/10.1016/j.redar.2017.07.001 AB, Kimura N, Mannelli M, McNicol AM, org/10.1016/j.surg.2015.06.045 Tischler AS, International Symposium on 9. Kline JP. Use of clevidipine for intraoperative Pheochromocytoma. Pheochromocytoma: 6. García-Orellana M, Rivas G, Farré C, Trillo L. hypertension caused by an undiagnosed recommendations for clinical practice from Monitorización hemodinámica con sistema the First International Symposium. N Nat pheochromocytoma: A case report. AANA J. de onda de pulso durante la cirugía del Clin Pract Endocrinol Metab. 2007;3(2):92- 2010;78:288-90. 102. DOI: https://doi.org/10.1038/ feocromocitoma. Rev Esp Anestesiol Reanim. ncpendmet0396 2014;61(2):116-7. 10. Bettesworth JG, Martin DP, Tobias JD. 4. Tauzin-Fin P, Sesay M, Gosse P, Ballanger 7. Deeks ED, Keating GM, Keam SJ. Clevidipine: Intraoperative use of clevidipine in a P. Effects of perioperative alpha1 block on a review of its use in the management of patient with von Hippel-Lindau disease haemodynamic control during laparoscopic acute hypertension. Am J Cardiovascular with associated pheoch. J Cardiothorac Vasc surgery for phaeochromocytoma. Br J Anesth. 2013;27:749-51. DOI: https://doi. Anaesth. 2004;92:512-7. DOI: https://doi. Drugs. 2009;9(2): 117-34. DOI: https://doi. org/10.1093/bja/aeh083 org/10.1007/BF03256583 org/10.1053/j.jvca.2011.12.005