Scientific letter
Severe bradycardia probably associated to Oseltamivir in a pediatric patient with acute renal injury
Bradicadia severa probablemente asociada a Oseltamivir en un paciente pediátrico con fracaso renal agudo
a Pediatric Nephrology Department of Puerta del Mar University Hospital, Cadiz, Spain
b Pediatric Cardiology Department of Puerta del Mar University Hospital, Cadiz, Spain
c Biomedical Research and Innovation Institute of Cadiz (INiBICA), Research Unit, Puerta del Mar University Hospital, University of Cadiz, Spain
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array:1 [ 0 => array:2 [ "paginaInicial" => "140" "paginaFinal" => "142" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Ana Castellano-Martinez, Moises Rodriguez-Gonzalez" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Ana" "apellidos" => "Castellano-Martinez" "email" => array:1 [ 0 => "anacastellanomart@gmail.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Moises" "apellidos" => "Rodriguez-Gonzalez" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Pediatric Nephrology Department of Puerta del Mar University Hospital, Cadiz, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Pediatric Cardiology Department of Puerta del Mar University Hospital, Cadiz, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Biomedical Research and Innovation Institute of Cadiz (INiBICA), Research Unit, Puerta del Mar University Hospital, University of Cadiz, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Bradicadia severa probablemente asociada a Oseltamivir en un paciente pediátrico con fracaso renal agudo" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1571 "Ancho" => 2091 "Tamanyo" => 267351 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Cardiac rhythm monitoring of our patient. Panel A is the record of the HR variability during the first Holter performed the third day of treatment with Oseltamivir, showing a severe bradycardia for age. Panel B is a capture of the cardiac monitor of the patient the first day of treatment with Oseltamivir, showing a sinus bradycardia (30–50<span class="elsevierStyleHsp" style=""></span>bpm). Panel C is the record of the HR variability during the Holter performed after 48<span class="elsevierStyleHsp" style=""></span>h of the discontinuation of Oseltamivir, showing a complete recovery of normal HR for age.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Children constitute a high-risk population for the development of severe influenza regarding adult population. Current recommendations state that antiviral treatment should be provided to all children hospitalized with influenza or underlying medical conditions or those suffering from a severe illness.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a> Oseltamivir, a neuraminidase inhibitor (NI), represents the most widely used antiviral in children with influenza viral infection. We report a 10-year-old previously healthy female admitted to our PICU due to an acute kidney injury (AKI) (creatinine clearance <<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>ml/min/1.73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>), anemia (7.9<span class="elsevierStyleHsp" style=""></span>g/dl) with schistocytosis of 3.5% and thrombocytopenia (29,000/mm<span class="elsevierStyleSup">3</span>). She was conscious and did not require respiratory or hemodynamical support (SpO<span class="elsevierStyleInf">2</span> 100%, blood pressure 107/68<span class="elsevierStyleHsp" style=""></span>mmHg and heart rate (HR) 110<span class="elsevierStyleHsp" style=""></span>bpm). She was diagnosed as hemolytic-uremic syndrome (HUS), and supportive treatment with intravenous fluid therapy, blood products, omeprazole and acetaminophen was started. The patient presented flu-like symptoms from the previous 48<span class="elsevierStyleHsp" style=""></span>h, and in the etiological work-up study for HUS, a FilmArray Respiratory Panel detected H1N1 Influenza A as the trigger agent. We considered this clinical picture as a severe manifestation of the influenza virus infection, so treatment with oral Oseltamivir 30<span class="elsevierStyleHsp" style=""></span>mg od. (adjusted for AKI) was initiated. Twelve hours after the first dose we noticed a severe bradycardia on the cardiac monitor, with HR ranging from 30 to 57<span class="elsevierStyleHsp" style=""></span>bpm with a normal blood pressure (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The patient also started with vomiting but did not presented cardiac complaints. Serial ECG records showed sinus bradycardia and nodal rhythm with maximal HR of 60–70<span class="elsevierStyleHsp" style=""></span>bpm without other ECG abnormalities, including a normal QTc interval (400<span class="elsevierStyleHsp" style=""></span>ms). The 3rd day of treatment, a 24-h-Holter monitoring was performed evidencing a mean HR of 53<span class="elsevierStyleHsp" style=""></span>bpm, maximal 85<span class="elsevierStyleHsp" style=""></span>bpm and minimal 36<span class="elsevierStyleHsp" style=""></span>bpm, with 124 documented episodes of bradycardia regarding her age. Remarkably, the patient still presented severe anemia (hemoglobin of 6.2<span class="elsevierStyleHsp" style=""></span>g/dl), fever and clinical signs of dehydration at the time of this Holter monitoring. Cardiac biomarkers (hs-cTnT and NT-proBNP), thyroid function, chest X-ray and echocardiogram resulted in normal. Since she did not manifest cardiac symptoms, we decided to complete 5 days with Oseltamivir at same doses. Twenty-four hours after its withdrawal, we noticed a gradual recovery of HR up to normal values for age, that was confirmed with a new Holter monitoring. Oseltamivir seems to be an effective and well-tolerated therapy for acute influenza A and B infection in children. Nausea and vomiting, usually of mild–moderate intensity and short duration, are the most frequent side effects observed in children.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">2,3</span></a> Severe adverse reactions such as neuropsychiatric are less frequent.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">4</span></a> Although infrequent, cardiac adverse effects associated with Oseltamivir have been previously described in both animals and humans. In concrete, the development QTc interval prolongation and bradycardia seems to be closely related to the rapid increase of Oseltamivir carboxylate in plasma concentrations, even at first dose.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">5</span></a> Some facts make it possible for bradycardia to be associated with Oseltamivir in this case. Occasionally, bradyarrhythmias are the prominent feature in influenza infection due to acute myocarditis, that could be misinterpreted as drug-related adverse events.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">6,7</span></a> However, myocarditis and other secondary causes of bradycardia such as medications were ruled out in our patient. Also, there was a reasonable temporal sequence association between Oseltamivir administration and the appearance of bradycardia, which occurred even in the presence of concurrent causes of tachycardia. Finally, based on a Naranjo adverse drug reaction probability scale value of 5–6 points, bradycardia was considered as a probable side effect of Oseltamivir in our patient.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">8</span></a> Due to the increasing use of Oseltamivir in children, pediatricians must be aware of its possible severe adverse effects. This is especially important in those patients with cardiac or renal comorbidities who are indeed more likely to receive this medication. Oseltamivir is exclusively eliminated by renal excretion, and the dose should be adjusted with creatinine clearance <<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>ml/min/1.73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>. Although there was no hemodynamics repercussion in our healthy patient, bradycardia could be an adverse event with potentially severe consequences in patients with heart diseases. Therefore, we consider that cardiac monitoring should be warranted during Oseltamivir therapy in those high-risk patients.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0010" class="elsevierStylePara elsevierViewall">The authors have indicated they have no financial relationships relevant to this article to disclose.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflict of interest</span><p id="par0015" class="elsevierStylePara elsevierViewall">The authors have indicated they have no potential conflicts of interest to disclose.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflict of interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1571 "Ancho" => 2091 "Tamanyo" => 267351 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Cardiac rhythm monitoring of our patient. Panel A is the record of the HR variability during the first Holter performed the third day of treatment with Oseltamivir, showing a severe bradycardia for age. Panel B is a capture of the cardiac monitor of the patient the first day of treatment with Oseltamivir, showing a sinus bradycardia (30–50<span class="elsevierStyleHsp" style=""></span>bpm). Panel C is the record of the HR variability during the Holter performed after 48<span class="elsevierStyleHsp" style=""></span>h of the discontinuation of Oseltamivir, showing a complete recovery of normal HR for age.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:8 [ 0 => array:3 [ "identificador" => "bib0045" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Recommendations for prevention and control of influenza in children, 2018–2019" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Committee on Infectious Diseases" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1542/peds.2018-2367" "Revista" => array:5 [ "tituloSerie" => "Pediatrics" "fecha" => "2018" "volumen" => "142" "paginaInicial" => "e20182367" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30177511" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0050" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Safety and effectiveness of neuraminidase inhibitors for influenza treatment, prophylaxis, and outbreak control: a systematic review of systematic reviews and/or meta-analyses" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M.K. 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Roberts" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Clin Pharmacol Ther" "fecha" => "1981" "volumen" => "30" "paginaInicial" => "239" "paginaFinal" => "245" ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/2529993X/0000003800000003/v1_202003050625/S2529993X20300381/v1_202003050625/en/main.assets" "Apartado" => array:4 [ "identificador" => "63562" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Scientific letters" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/2529993X/0000003800000003/v1_202003050625/S2529993X20300381/v1_202003050625/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2529993X20300381?idApp=UINPBA00004N" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 0 | 4 |
| 2024 October | 9 | 3 | 12 |
| 2024 September | 13 | 5 | 18 |
| 2024 August | 17 | 4 | 21 |
| 2024 July | 10 | 6 | 16 |
| 2024 June | 14 | 5 | 19 |
| 2024 May | 3 | 5 | 8 |
| 2024 April | 5 | 2 | 7 |
| 2024 March | 12 | 8 | 20 |
| 2024 February | 15 | 3 | 18 |
| 2024 January | 10 | 5 | 15 |
| 2023 December | 8 | 6 | 14 |
| 2023 November | 8 | 14 | 22 |
| 2023 October | 14 | 11 | 25 |
| 2023 September | 14 | 3 | 17 |
| 2023 August | 11 | 7 | 18 |
| 2023 July | 3 | 3 | 6 |
| 2023 June | 5 | 13 | 18 |
| 2023 May | 6 | 6 | 12 |
| 2023 April | 2 | 8 | 10 |
| 2023 March | 8 | 6 | 14 |
| 2023 February | 6 | 4 | 10 |
| 2023 January | 12 | 2 | 14 |
| 2022 December | 10 | 3 | 13 |
| 2022 November | 8 | 7 | 15 |
| 2022 October | 9 | 6 | 15 |
| 2022 September | 9 | 16 | 25 |
| 2022 August | 9 | 9 | 18 |
| 2022 July | 10 | 7 | 17 |
| 2022 June | 11 | 7 | 18 |
| 2022 May | 9 | 10 | 19 |
| 2022 April | 8 | 10 | 18 |
| 2022 March | 15 | 8 | 23 |
| 2022 February | 5 | 9 | 14 |
| 2022 January | 11 | 4 | 15 |
| 2021 December | 8 | 9 | 17 |
| 2021 November | 10 | 6 | 16 |
| 2021 October | 7 | 8 | 15 |
| 2021 September | 6 | 8 | 14 |
| 2021 August | 8 | 6 | 14 |
| 2021 July | 6 | 7 | 13 |
| 2021 June | 7 | 10 | 17 |
| 2021 May | 14 | 9 | 23 |
| 2021 April | 20 | 18 | 38 |
| 2021 March | 10 | 37 | 47 |
| 2021 February | 8 | 19 | 27 |
| 2021 January | 9 | 7 | 16 |
| 2020 December | 5 | 3 | 8 |
| 2020 November | 3 | 1 | 4 |
| 2020 October | 7 | 0 | 7 |
| 2020 September | 6 | 6 | 12 |
| 2020 March | 1 | 0 | 1 |
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