Scientific Letter
Usefulness of ethomidate in patients with Cushing syndrome with severe arterial hypertension and hypopotassemia
Utilidad de etomidato en paciente con síndrome de Cushing con hipertensión arterial e hipopotasemia graves
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Yun Castilla, F. Rodríguez Amuedo, A. Morales Martínez, J.P. López Siguero, M.J. Martínez Aedo, G. Milano Manso" "autores" => array:6 [ 0 => array:4 [ "nombre" => "C." "apellidos" => "Yun Castilla" "email" => array:1 [ 0 => "cyuncastilla@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "F." "apellidos" => "Rodríguez Amuedo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "A." "apellidos" => "Morales Martínez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "J.P." 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"apellidos" => "Milano Manso" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Unidad de Gestión Clínica de Cuidados Críticos y Urgencias Pediátricas, Hospital Materno-Infantil, Málaga, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Unidad de Gestión Clínica de Pediatría, Sección de Endocrinología Pediátrica, Hospital Materno-Infantil, Málaga, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Utilidad de etomidato en paciente con síndrome de Cushing con hipertensión arterial e hipopotasemia graves" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Cushing syndrome (CS) has a low prevalence in children and is rarely a cause for admission to the Pediatric Intensive Care Unit (PICU). However, it may manifest with severe and potentially life-threatening electrolytic disorders and arterial hypertension. We present the case of a nursing infant with CS admitted to the PICU due to severe arterial hypertension and hypopotassemia, in which etomidate was used to counter cortisol synthesis.</p><p id="par0010" class="elsevierStylePara elsevierViewall">A 14-month-old infant girl was referred to our hospital due to suspected CS. The parents described hypotonus from 8 months of age, weight gain in the last four months, and recent rejection of food intake. The patient presented physical features consistent with CS, hypotonus, irritability and disconnection from the surroundings. The blood pressure was above percentile 99 for her age and size (200/120<span class="elsevierStyleHsp" style=""></span>mmHg). The brain CT and MRI scans revealed alteration of the supratentorial white matter in relation to edema. In the context of severe arterial hypertension, this was consistent with posterior reversible encephalopathy syndrome (PRES), with left thalamic hemorrhage. Echocardiography showed left ventricular hypertrophy. Maximum dose labetalol (3<span class="elsevierStyleHsp" style=""></span>mg/kg/h) was administered to control the blood pressure, followed by the combination of captopril, amlodipine and diuretics. Severe hypopotassemia was recorded (2.3<span class="elsevierStyleHsp" style=""></span>mEq/l) and was seen to persist despite high intravenous replacement doses (12<span class="elsevierStyleHsp" style=""></span>mEq/kg/day).</p><p id="par0015" class="elsevierStylePara elsevierViewall">The endocrine study confirmed the suspicion of primary CS (urinary free cortisol 7578<span class="elsevierStyleHsp" style=""></span>μg/m<span class="elsevierStyleSup">2</span>/24<span class="elsevierStyleHsp" style=""></span>h, plasma cortisol 1665<span class="elsevierStyleHsp" style=""></span>ng/ml). The measurement of ACTH (<5<span class="elsevierStyleHsp" style=""></span>pg/ml) showed CS to be independent of the hormone. The abdominal ultrasound and brain and adrenal gland CT and MRI studies revealed no tumor disease. Somatostatin receptor scintigraphic assessment revealed no pathological uptake. In view of the persistence of arterial hypertension and hypopotassemia, we introduced ketoconazole at increasing doses (200<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h), with scant clinical and laboratory test response (plasma cortisol 1548<span class="elsevierStyleHsp" style=""></span>ng/ml after 72<span class="elsevierStyleHsp" style=""></span>h of treatment). No liver toxicity was observed. We then added etomidate 0.03<span class="elsevierStyleHsp" style=""></span>mg/kg/h, which resulted in partial adrenal axis suppression, with a reduction of the cortisol levels to 309<span class="elsevierStyleHsp" style=""></span>ng/ml as determined 24<span class="elsevierStyleHsp" style=""></span>hours after the start of perfusion. Improved blood pressure control was thus achieved, allowing the suspension of labetalol. The potassium values also normalized, making it possible to reduce intravenous administration. Etomidate was continued during 5 days, with plasma cortisol control values maintained between 331 and 300<span class="elsevierStyleHsp" style=""></span>ng/ml. However, in the last 48 hours the patient developed septic shock secondary to central venous catheter-related <span class="elsevierStyleItalic">E. coli</span> bacteremia that proved refractory to vasoactive support and corticosteroid replacement therapy, leading to the death of the patient.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The necropsy study revealed cortical nodular hyperplasia of both adrenal glands. The PRKAR1A gene, associated to pigmented nodular adrenocortical disease,<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> and the only known gene associated to infant CS, proved negative.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Cushing syndrome is infrequent in infancy. Once plasma cortisol elevation is confirmed, the underlying cause must be investigated. The determination of plasma ACTH allows differentiation between ACTH-independent CS (<5<span class="elsevierStyleHsp" style=""></span>pg/ml) and ACTH-dependent CS (>15<span class="elsevierStyleHsp" style=""></span>pg/ml). Computed tomography and MRI are the imaging techniques of choice for identifying the possible tumor.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">2,3</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Surgery is the first treatment option. Medical management is required under circumstances that prove life-threatening for the patient, with the need to quickly lower the cortisol levels, such as severe water-electrolyte disturbances (hypopotassemia), severe arterial hypertension, immune suppression, or mental alterations.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> The main drug treatment options are based on adrenal steroid synthesis enzyme inhibition with ketoconazole or metyrapone (the most widely used agents), though ACTH receptor antagonists or ACTH suppressor drugs can also be used.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">4,5</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Ketoconazole is an imidazole derivative that blocks cortisol synthesis, and represents the most commonly used drug. Its main side effect is liver toxicity.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Etomidate is another imidazole agent used for the induction of anesthesia and in the rapid intubation sequence. Some authors have described increased mortality among septic patients in which the drug was used during intubation, though the purported causal relationship is subject to debate and has not been confirmed in later studies.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> Etomidate inhibits the P450 cytochrome-dependent enzymes implicated in steroidogenesis–a fact that makes it useful in the treatment of CS. It is used in persistent hypercortisolism refractory to usual treatment, particularly in unstable patients (hypertensive crises or psychosis), in order to improve the conditions with a view to allowing surgical treatment,<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> and can be maintained for days or weeks if necessary. It is the only drug administered via the intravenous route, and is therefore the agent of choice in patients with oral intolerance. Etomidate is also an alternative in cases of liver disease secondary to ketoconazole.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a> Considerable experience has been gained with the use of etomidate in adult CS, though few cases involving pediatric patients can be found in the literature. Mettauer and Brierley<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a> and Chan et al.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> used etomidate in two patients aged 14 and 6 years of age with acute psychosis and scant response to oral treatment, respectively–the drug being found to be safe and effective in reducing the cortisol levels before definitive surgery. Our patient was a nursing infant, and very few data referred to this age range are available in the literature.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The dose achieving adrenal gland arrest<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> is 0.04–0.05<span class="elsevierStyleHsp" style=""></span>mg/kg/h. The effect is titrated against the plasma cortisol levels, with the control of potassium and glucose. Partial block is considered to be represented by cortisol levels of 300–800<span class="elsevierStyleHsp" style=""></span>nmol/l, while complete block corresponds to levels of <150<span class="elsevierStyleHsp" style=""></span>nmol/l. In cases of complete block, we must always combine hydrocortisone replacement therapy in order to avoid acute adrenal gland insufficiency. In cases of partial block, hydrocortisone replacement therapy is not an absolute indication, but is nevertheless advisable.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Our patient presented CS with clinical instability, characterized by both hemodynamic and water-electrolyte alterations. Ketoconazole was not effective in reducing the cortisol concentrations, though reduction and consequent clinical stabilization was achieved with etomidate. Cortisol reduction was obtained with doses somewhat lower than those described in the literature (0.02–0.03<span class="elsevierStyleHsp" style=""></span>mg/kg/h). However, although cortisol normalization was achieved, the situation of septic shock led to the death of the patient.</p><p id="par0055" class="elsevierStylePara elsevierViewall">High glucocorticoid levels alter the immune system and increase the risk of infections. As a result, patients with hypercortisolism are more susceptible to systemic infections and sepsis caused by both bacteria and opportunistic organisms. In our patient, the existing immune suppression, combined with drug-induced adrenal response inhibition, could have contributed to the fatal outcome of the infection.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Financial support</span><p id="par0060" class="elsevierStylePara elsevierViewall">The authors have received no financial support for this study.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Financial support" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Yun Castilla C, Rodríguez Amuedo F, Morales Martínez A, López Siguero JP, Martínez Aedo MJ, Milano Manso G. Utilidad de etomidato en paciente con síndrome de Cushing con hipertensión arterial e hipopotasemia graves. Med Intensiva. 2017;41:321–322.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hormonal, radiological, NP-59 scintigraphy, and pathological correlations in patients with Cushing's syndrome due to primary pigmented nodular adrenocortical disease (PPNAD)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D. Vezzosi" 1 => "F. Tenenbaum" 2 => "L. Cazabat" 3 => "F. Tissier" 4 => "M. Bienvenu" 5 => "C.A. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 3 | 7 |
| 2024 October | 75 | 42 | 117 |
| 2024 September | 58 | 40 | 98 |
| 2024 August | 70 | 68 | 138 |
| 2024 July | 50 | 33 | 83 |
| 2024 June | 65 | 68 | 133 |
| 2024 May | 42 | 51 | 93 |
| 2024 April | 67 | 46 | 113 |
| 2024 March | 53 | 48 | 101 |
| 2024 February | 43 | 53 | 96 |
| 2024 January | 44 | 40 | 84 |
| 2023 December | 48 | 45 | 93 |
| 2023 November | 51 | 51 | 102 |
| 2023 October | 35 | 41 | 76 |
| 2023 September | 44 | 44 | 88 |
| 2023 August | 31 | 28 | 59 |
| 2023 July | 39 | 31 | 70 |
| 2023 June | 45 | 25 | 70 |
| 2023 May | 42 | 38 | 80 |
| 2023 April | 38 | 21 | 59 |
| 2023 March | 67 | 41 | 108 |
| 2023 February | 70 | 36 | 106 |
| 2023 January | 37 | 30 | 67 |
| 2022 December | 67 | 43 | 110 |
| 2022 November | 55 | 46 | 101 |
| 2022 October | 65 | 38 | 103 |
| 2022 September | 45 | 46 | 91 |
| 2022 August | 45 | 51 | 96 |
| 2022 July | 36 | 40 | 76 |
| 2022 June | 51 | 27 | 78 |
| 2022 May | 61 | 34 | 95 |
| 2022 April | 87 | 56 | 143 |
| 2022 March | 67 | 71 | 138 |
| 2022 February | 57 | 44 | 101 |
| 2022 January | 67 | 43 | 110 |
| 2021 December | 78 | 49 | 127 |
| 2021 November | 63 | 48 | 111 |
| 2021 October | 72 | 77 | 149 |
| 2021 September | 40 | 56 | 96 |
| 2021 August | 32 | 38 | 70 |
| 2021 July | 38 | 45 | 83 |
| 2021 June | 30 | 38 | 68 |
| 2021 May | 63 | 69 | 132 |
| 2021 April | 96 | 62 | 158 |
| 2021 March | 84 | 41 | 125 |
| 2021 February | 84 | 26 | 110 |
| 2021 January | 58 | 30 | 88 |
| 2020 December | 46 | 16 | 62 |
| 2020 November | 33 | 25 | 58 |
| 2020 October | 42 | 39 | 81 |
| 2020 September | 42 | 22 | 64 |
| 2020 August | 30 | 16 | 46 |
| 2020 July | 41 | 23 | 64 |
| 2020 June | 32 | 15 | 47 |
| 2020 May | 24 | 11 | 35 |
| 2020 April | 33 | 19 | 52 |
| 2020 March | 18 | 18 | 36 |
| 2020 February | 47 | 57 | 104 |
| 2020 January | 36 | 20 | 56 |
| 2019 December | 39 | 15 | 54 |
| 2019 November | 25 | 32 | 57 |
| 2019 October | 35 | 19 | 54 |
| 2019 September | 28 | 22 | 50 |
| 2019 August | 27 | 17 | 44 |
| 2019 July | 27 | 20 | 47 |
| 2019 June | 21 | 18 | 39 |
| 2019 May | 32 | 31 | 63 |
| 2019 April | 23 | 18 | 41 |
| 2019 March | 15 | 24 | 39 |
| 2019 February | 29 | 33 | 62 |
| 2019 January | 30 | 27 | 57 |
| 2018 December | 47 | 41 | 88 |
| 2018 November | 107 | 34 | 141 |
| 2018 October | 94 | 20 | 114 |
| 2018 September | 51 | 10 | 61 |
| 2018 August | 28 | 10 | 38 |
| 2018 July | 40 | 18 | 58 |
| 2018 June | 56 | 10 | 66 |
| 2018 May | 30 | 9 | 39 |
| 2018 April | 43 | 17 | 60 |
| 2018 March | 75 | 6 | 81 |
| 2018 February | 25 | 12 | 37 |
| 2018 January | 58 | 20 | 78 |
| 2017 December | 27 | 14 | 41 |
| 2017 November | 48 | 19 | 67 |
| 2017 October | 30 | 0 | 30 |
| 2017 September | 6 | 0 | 6 |
| 2017 July | 2 | 1 | 3 |
| 2017 June | 1 | 0 | 1 |
| 2017 May | 0 | 1 | 1 |
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