- Email: [email protected]
Lower doses of tolvaptan in hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion
138
Letters to the Editor / Med Clin (Barc). 2016;145(3):136–139
A case of EDMD that started with a heart rhythm abnormality is presented below. Its presentation was an incidental finding but aided in the final diagnosis. An atrial flutter (AFL) of 30 bpm, with a high degree of asymptomatic atrioventricular block (AVB), was observed in a 41-year-old male during a medical examination. His mother had a pacemaker implanted 60 years earlier owing to slow AFL. His brother had a pacemaker implanted owing to AVB 15 years earlier, subsequently was diagnosed with EDMD and currently had dilated myocardiopathy with severe systolic dysfunction. Owing to this prior history, our patient had been examined by neurology when he was 17 years old, but no definitive diagnosis had been made. The patient was referred to our arrhythmia unit, and echocardiography showed dilation of the left ventricle with normal ejection fraction and marked dilation of both atria. An electrophysiological study was conducted with electroanatomical reconstruction of the right atrium (RA) using the EnSite NavXTM navigation system. This showed significant eschar (with a voltage lower than 0.1 mV) on most of the RA. The AFL had its origin in the left atrium and it was observed that the ABV was suprahisian. As the patient had extensive involvement of both atria, it was decided not to attempt ablation and indicate implantation of a VVIR pacemaker. After a year, a repeat echocardiogram was performed, and normalisation of the ventricular diameters (resolved “bradymyocardiopathy”) was observed. He was again referred to neurology, which did not find impairment characteristic of EDMD. The patient remained in follow-up in our arrhythmias unit, and 7 years after the implantation, with no cardiac episodes, he started to have muscle impairment. A physical examination then did demonstrate the presence of global areflexia, generalised atrophy in the upper limbs and limited cervical flexion, but with no impairment of the elbows or heels. A repeat muscle biopsy was performed, and was diagnostic for type 1 EDMD. A genetic study found the c.554delC mutation (p.Ser185fs51Stop) in the EMD gene linked to the X chromosome. Type 1 EDMD is caused by a mutation in the EMD gene, which codes for emerin, a protein that is expressed in skeletal and cardiac muscle cells. Most reported mutations cause a complete loss of emerin, although in some cases only a reduction in its formation is observed.2 In this case there was an incomplete form whose mutation was linked to the X chromosome. The patient’s mother had required pacemaker implantation since carriers are not exempt from developing symptoms, although this is uncommon.3,4 In these variants the myocardium may be affected,5 even in the absence of skeletal muscle involvement. This creates eschar, which causes atrial macro-reentry (AFL). AV conduction may also be affected, as in the case we present, in which AVB caused compensatory dilatation of the left ventricle. Thus, abnormalities in the electrical conduction of the heart are common, and it is rare to find individuals with a normal ECG beyond 35–40 years of age. ECG
Lower doses of tolvaptan in hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion夽 Tolvaptán a dosis bajas en la hiponatremia por síndrome de secreción inadecuada de vasopresina
夽 Please cite this article as: Sánchez Sobrino P, Fernández Catalina P, Lorenzo Solar M, Rego Iraeta A. Tolvaptán a dosis bajas en la hiponatremia por síndrome de secreción inadecuada de vasopresina. Med Clin (Barc). 2015;145:138–139.
abnormalities tend to appear after muscle weakness develops, although on rare occasions, as in this case, they may precede it. The atria tend to be more impaired than the ventricles, the most common findings being fibrillation and AFL.6 However, in more advanced stages, muscle cells are replaced with fibrous adipose tissue, which may cause dilated cardiomyopathy. For this reason, it is important to take an exhaustive medical history, gathering family histories and suspecting neuromuscular diseases in young patients who have atrial arrhythmias with associated high-grade AVB. At the same time, it is advisable to perform cardiology follow-up by means of regular ECG and echocardiography in patients already diagnosed with muscular dystrophies. Pacemaker implantation is indicated in all patients with a progressive conductive tissue disorder to reduce the risk of sudden death,7,8 although cases of sudden death despite a pacemaker have been reported. Currently, ICD implantation is not indicated in primary prevention in patients with EDMD without dilated myocardiopathy. References 1. Miller RG, Layzer RB, Mellenthin MA, Golabi M, Francoz RA, Mall JC, et al. Emery–Dreifuss muscular dystrophy with autosomal dominant transmission. Neurology. 1985;35:1230–3. 2. Ostlund C, Worman HJ. Nuclear envelope proteins and neuromuscular diseases. Muscle Nerve. 2003;27:393–406. 3. Manilal S, Recan D, Sewry CA, Hoeltzenbein M, Llense S, Leturcq F, et al. Mutations in Emery–Dreifuss muscular dystrophy and their effects on emerin protein expression. Hum Mol Genet. 1998;7:855–64. 4. Canki-Klain N, Recan D, Milicic D, Llense S, Leturcq F, Deburgrave N, et al. Clinical variability and molecular diagnosis in a four-generation family with X-linked Emery–Dreifuss muscular dystrophy. Croat Med J. 2000;41:389–95. 5. Sakata K, Shimizu M, Ino H, Yamaguchi M, Terai H, Fujino N, et al. High incidence of sudden cardiac death with conduction disturbances and atrial cardiomyopathy caused by a nonsense mutation in the STA gene. Circulation. 2005;111: 3352–8. 6. Emery AE. Emery–Dreifuss muscular dystrophy: a 40 year retrospective. Neuromuscul Disord. 2000;10:228–32. 7. Fidalgo-Andrés ML, Tascón Pérez J, Pérez Álvarez L, Roda Nicolás J, Martínez Ferrer J, de Juan Montiel J. Estimulación cardiaca en situaciones diversas. Rev Esp Cardiol Supl. 2007;7:82–101. 8. Meune C, van Berlo JH, Anselme F, Bonne G, Pinto YM, Duboc D. Primary prevention of sudden death in patients with lamin A/C gene mutations. N Engl J Med. 2006;354:209–10.
Luis Gonzalez-Torres a,∗ , Rocío Cozar-Leon a , Ernesto Diaz-Infante a , ˜ b Sara Eichau-Madueno a Unidad de Arritmias, Servicio de Cardiología, Hospital Universitario Virgen Macarena, Sevilla, Spain b Servicio de Neurología, Hospital Universitario Virgen Macarena, Sevilla, Spain ∗ Corresponding author. E-mail address: [email protected] (L. Gonzalez-Torres).
Dear Editor, Hyponatraemia is the most common electrolyte disorder in hospitalised patients.1 Various studies have demonstrated its association with greater morbidity, increased length of hospital stay and increased mortality.2 Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of hyponatraemia in the hospital setting.3 It is a unique variant, owing to both the difficulties involved in its proper diagnosis and its distinctive approach. Traditional treatments include fluid restriction and administration of furosemide and urea. However, sometimes these are insufficient to
Letters to the Editor / Med Clin (Barc). 2016;145(3):136–139
139
Table 1 Clinical and biochemical characteristics of the subjects. Subject
Sex
Age (years)
Cause of SIADH
Previous treatment
Initial natraemia (mEq/l)
Dose of tolvaptan
Time to correction (days)
1 2 3
F M M
90 74 79
Fluid restriction Urea 15 g/24 h Fluid restriction
122 129 123
7.5 mg q 24 h 7.5 mg q 48 h 7.5 mg q 24 h
6 7 16
4
M
92
Mesothelioma Serious TBI Acute exacerbation of COPD, septic arthritis Respiratory infection
Fluid restriction + furosemide
121
7.5 mg q 24 h
3
COPD, chronic obstructive pulmonary disease; F, female; SIADH, syndrome of inappropriate antidiuretic hormone secretion; TBI, traumatic brain injury; M, male.
resolve the syndrome or the patient does not tolerate them. Tolvaptan is an aquaretic drug approved in Europe for the treatment of SIADH. It has been demonstrated to be safe and effective, shortening hospital stays.4 However, as it is a powerful, fast-acting compound, it requires strict in-hospital laboratory monitoring at the start of treatment. In addition, it is recommended that the first dose be administered in the morning and that biochemical monitoring be performed 6, 12 and 24 h after it is administered.5 The summary of product characteristics for tolvaptan specifies starting with 15 mg daily. However, in clinical practice, we observe that lower doses are effective and cause gradual improvement that allows biochemical monitoring to be spaced out. We present our experience with 4 patients with hyponatraemia due to SIADH who were cared for in our department between May and December 2013. All of them had multiple comorbidities and were admitted for different reasons. They had hyponatraemia that was maintained after traditional treatments had failed or been stopped. Tolvaptan therapy was started at lower doses than those specified in the summary of product characteristics, and in no case did over-correction occur. The patients’ characteristics and evolution are summarised in Table 1. Tolvaptan is a selective ADH V2 receptor antagonist; therefore, it blocks the reabsorption of water from the collecting tubule. This helps eliminate free water through the kidneys, which concentrates plasma sodium. An excessive and rapid increase in natraemia carries a risk of developing osmotic demyelination syndrome. For this reason the guidelines recommend not increasing more than 10–12 mEq/l of sodium in the first 24 h. Free fluid intake is essential to prevent over-correction in the use of tolvaptan. This is difficult to ensure in certain groups of patients such as those that we present:
elderly people who do not show thirst, patients with fluctuations in level of consciousness and dependent or institutionalised subjects. In addition, in certain settings it is difficult to perform proper laboratory monitoring. In our experience, tolvaptan at lower doses than those specified in the summary of product characteristics is effective and safe; it resolves SIADH-related hyponatraemia without causing over-correction, and allows biochemical monitoring to be spaced out, thereby facilitating patient follow-up. References 1. Thompson C, Hoorn EJ. Hyponatraemia: an overview of frequency, clinical presentation and complications. Best Pract Res Clin Endocrinol Metab. 2012;26: S1–6. 2. Hoorn EJ, Zietse R. Hyponatremia and mortality: moving beyond associations. Am J Kidney Dis. 2013;62:139–49. 3. Ellison D, Berl T. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007;356:2064–72. 4. Dasta JF, Chiong JR, Christian R, Lin J. Evaluation of costs associated with tolvaptanmediated hospital length of stay reduction among US patients with the syndrome of inappropriate antidiuretic hormone secretion, based on SALT-1 and SALT-2 trials. Hosp Pract (1995). 2012;40:7–14. 5. Runkle I, Villabona C, Navarro A, Pose A, Formiga F, Tejedor A, et al. El tratamiento de la hiponatremia secundaria al síndrome de secreción inadecuada de la hormona antidiurética. Med Clin (Barc). 2013;141:e1–10.
Paula Sánchez Sobrino ∗ , Pablo Fernández Catalina, Mónica Lorenzo Solar, Antonia Rego Iraeta Servicio de Endocrinología y Nutrición, Área de Xestión Integrada Pontevedra-Salnés, Pontevedra, Spain ∗ Corresponding author. E-mail address: paula ss [email protected] (P. Sánchez Sobrino).
Letters to the Editor / Med Clin (Barc). 2016;145(3):136–139
A case of EDMD that started with a heart rhythm abnormality is presented below. Its presentation was an incidental finding but aided in the final diagnosis. An atrial flutter (AFL) of 30 bpm, with a high degree of asymptomatic atrioventricular block (AVB), was observed in a 41-year-old male during a medical examination. His mother had a pacemaker implanted 60 years earlier owing to slow AFL. His brother had a pacemaker implanted owing to AVB 15 years earlier, subsequently was diagnosed with EDMD and currently had dilated myocardiopathy with severe systolic dysfunction. Owing to this prior history, our patient had been examined by neurology when he was 17 years old, but no definitive diagnosis had been made. The patient was referred to our arrhythmia unit, and echocardiography showed dilation of the left ventricle with normal ejection fraction and marked dilation of both atria. An electrophysiological study was conducted with electroanatomical reconstruction of the right atrium (RA) using the EnSite NavXTM navigation system. This showed significant eschar (with a voltage lower than 0.1 mV) on most of the RA. The AFL had its origin in the left atrium and it was observed that the ABV was suprahisian. As the patient had extensive involvement of both atria, it was decided not to attempt ablation and indicate implantation of a VVIR pacemaker. After a year, a repeat echocardiogram was performed, and normalisation of the ventricular diameters (resolved “bradymyocardiopathy”) was observed. He was again referred to neurology, which did not find impairment characteristic of EDMD. The patient remained in follow-up in our arrhythmias unit, and 7 years after the implantation, with no cardiac episodes, he started to have muscle impairment. A physical examination then did demonstrate the presence of global areflexia, generalised atrophy in the upper limbs and limited cervical flexion, but with no impairment of the elbows or heels. A repeat muscle biopsy was performed, and was diagnostic for type 1 EDMD. A genetic study found the c.554delC mutation (p.Ser185fs51Stop) in the EMD gene linked to the X chromosome. Type 1 EDMD is caused by a mutation in the EMD gene, which codes for emerin, a protein that is expressed in skeletal and cardiac muscle cells. Most reported mutations cause a complete loss of emerin, although in some cases only a reduction in its formation is observed.2 In this case there was an incomplete form whose mutation was linked to the X chromosome. The patient’s mother had required pacemaker implantation since carriers are not exempt from developing symptoms, although this is uncommon.3,4 In these variants the myocardium may be affected,5 even in the absence of skeletal muscle involvement. This creates eschar, which causes atrial macro-reentry (AFL). AV conduction may also be affected, as in the case we present, in which AVB caused compensatory dilatation of the left ventricle. Thus, abnormalities in the electrical conduction of the heart are common, and it is rare to find individuals with a normal ECG beyond 35–40 years of age. ECG
Lower doses of tolvaptan in hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion夽 Tolvaptán a dosis bajas en la hiponatremia por síndrome de secreción inadecuada de vasopresina
夽 Please cite this article as: Sánchez Sobrino P, Fernández Catalina P, Lorenzo Solar M, Rego Iraeta A. Tolvaptán a dosis bajas en la hiponatremia por síndrome de secreción inadecuada de vasopresina. Med Clin (Barc). 2015;145:138–139.
abnormalities tend to appear after muscle weakness develops, although on rare occasions, as in this case, they may precede it. The atria tend to be more impaired than the ventricles, the most common findings being fibrillation and AFL.6 However, in more advanced stages, muscle cells are replaced with fibrous adipose tissue, which may cause dilated cardiomyopathy. For this reason, it is important to take an exhaustive medical history, gathering family histories and suspecting neuromuscular diseases in young patients who have atrial arrhythmias with associated high-grade AVB. At the same time, it is advisable to perform cardiology follow-up by means of regular ECG and echocardiography in patients already diagnosed with muscular dystrophies. Pacemaker implantation is indicated in all patients with a progressive conductive tissue disorder to reduce the risk of sudden death,7,8 although cases of sudden death despite a pacemaker have been reported. Currently, ICD implantation is not indicated in primary prevention in patients with EDMD without dilated myocardiopathy. References 1. Miller RG, Layzer RB, Mellenthin MA, Golabi M, Francoz RA, Mall JC, et al. Emery–Dreifuss muscular dystrophy with autosomal dominant transmission. Neurology. 1985;35:1230–3. 2. Ostlund C, Worman HJ. Nuclear envelope proteins and neuromuscular diseases. Muscle Nerve. 2003;27:393–406. 3. Manilal S, Recan D, Sewry CA, Hoeltzenbein M, Llense S, Leturcq F, et al. Mutations in Emery–Dreifuss muscular dystrophy and their effects on emerin protein expression. Hum Mol Genet. 1998;7:855–64. 4. Canki-Klain N, Recan D, Milicic D, Llense S, Leturcq F, Deburgrave N, et al. Clinical variability and molecular diagnosis in a four-generation family with X-linked Emery–Dreifuss muscular dystrophy. Croat Med J. 2000;41:389–95. 5. Sakata K, Shimizu M, Ino H, Yamaguchi M, Terai H, Fujino N, et al. High incidence of sudden cardiac death with conduction disturbances and atrial cardiomyopathy caused by a nonsense mutation in the STA gene. Circulation. 2005;111: 3352–8. 6. Emery AE. Emery–Dreifuss muscular dystrophy: a 40 year retrospective. Neuromuscul Disord. 2000;10:228–32. 7. Fidalgo-Andrés ML, Tascón Pérez J, Pérez Álvarez L, Roda Nicolás J, Martínez Ferrer J, de Juan Montiel J. Estimulación cardiaca en situaciones diversas. Rev Esp Cardiol Supl. 2007;7:82–101. 8. Meune C, van Berlo JH, Anselme F, Bonne G, Pinto YM, Duboc D. Primary prevention of sudden death in patients with lamin A/C gene mutations. N Engl J Med. 2006;354:209–10.
Luis Gonzalez-Torres a,∗ , Rocío Cozar-Leon a , Ernesto Diaz-Infante a , ˜ b Sara Eichau-Madueno a Unidad de Arritmias, Servicio de Cardiología, Hospital Universitario Virgen Macarena, Sevilla, Spain b Servicio de Neurología, Hospital Universitario Virgen Macarena, Sevilla, Spain ∗ Corresponding author. E-mail address: [email protected] (L. Gonzalez-Torres).
Dear Editor, Hyponatraemia is the most common electrolyte disorder in hospitalised patients.1 Various studies have demonstrated its association with greater morbidity, increased length of hospital stay and increased mortality.2 Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of hyponatraemia in the hospital setting.3 It is a unique variant, owing to both the difficulties involved in its proper diagnosis and its distinctive approach. Traditional treatments include fluid restriction and administration of furosemide and urea. However, sometimes these are insufficient to
Letters to the Editor / Med Clin (Barc). 2016;145(3):136–139
139
Table 1 Clinical and biochemical characteristics of the subjects. Subject
Sex
Age (years)
Cause of SIADH
Previous treatment
Initial natraemia (mEq/l)
Dose of tolvaptan
Time to correction (days)
1 2 3
F M M
90 74 79
Fluid restriction Urea 15 g/24 h Fluid restriction
122 129 123
7.5 mg q 24 h 7.5 mg q 48 h 7.5 mg q 24 h
6 7 16
4
M
92
Mesothelioma Serious TBI Acute exacerbation of COPD, septic arthritis Respiratory infection
Fluid restriction + furosemide
121
7.5 mg q 24 h
3
COPD, chronic obstructive pulmonary disease; F, female; SIADH, syndrome of inappropriate antidiuretic hormone secretion; TBI, traumatic brain injury; M, male.
resolve the syndrome or the patient does not tolerate them. Tolvaptan is an aquaretic drug approved in Europe for the treatment of SIADH. It has been demonstrated to be safe and effective, shortening hospital stays.4 However, as it is a powerful, fast-acting compound, it requires strict in-hospital laboratory monitoring at the start of treatment. In addition, it is recommended that the first dose be administered in the morning and that biochemical monitoring be performed 6, 12 and 24 h after it is administered.5 The summary of product characteristics for tolvaptan specifies starting with 15 mg daily. However, in clinical practice, we observe that lower doses are effective and cause gradual improvement that allows biochemical monitoring to be spaced out. We present our experience with 4 patients with hyponatraemia due to SIADH who were cared for in our department between May and December 2013. All of them had multiple comorbidities and were admitted for different reasons. They had hyponatraemia that was maintained after traditional treatments had failed or been stopped. Tolvaptan therapy was started at lower doses than those specified in the summary of product characteristics, and in no case did over-correction occur. The patients’ characteristics and evolution are summarised in Table 1. Tolvaptan is a selective ADH V2 receptor antagonist; therefore, it blocks the reabsorption of water from the collecting tubule. This helps eliminate free water through the kidneys, which concentrates plasma sodium. An excessive and rapid increase in natraemia carries a risk of developing osmotic demyelination syndrome. For this reason the guidelines recommend not increasing more than 10–12 mEq/l of sodium in the first 24 h. Free fluid intake is essential to prevent over-correction in the use of tolvaptan. This is difficult to ensure in certain groups of patients such as those that we present:
elderly people who do not show thirst, patients with fluctuations in level of consciousness and dependent or institutionalised subjects. In addition, in certain settings it is difficult to perform proper laboratory monitoring. In our experience, tolvaptan at lower doses than those specified in the summary of product characteristics is effective and safe; it resolves SIADH-related hyponatraemia without causing over-correction, and allows biochemical monitoring to be spaced out, thereby facilitating patient follow-up. References 1. Thompson C, Hoorn EJ. Hyponatraemia: an overview of frequency, clinical presentation and complications. Best Pract Res Clin Endocrinol Metab. 2012;26: S1–6. 2. Hoorn EJ, Zietse R. Hyponatremia and mortality: moving beyond associations. Am J Kidney Dis. 2013;62:139–49. 3. Ellison D, Berl T. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007;356:2064–72. 4. Dasta JF, Chiong JR, Christian R, Lin J. Evaluation of costs associated with tolvaptanmediated hospital length of stay reduction among US patients with the syndrome of inappropriate antidiuretic hormone secretion, based on SALT-1 and SALT-2 trials. Hosp Pract (1995). 2012;40:7–14. 5. Runkle I, Villabona C, Navarro A, Pose A, Formiga F, Tejedor A, et al. El tratamiento de la hiponatremia secundaria al síndrome de secreción inadecuada de la hormona antidiurética. Med Clin (Barc). 2013;141:e1–10.
Paula Sánchez Sobrino ∗ , Pablo Fernández Catalina, Mónica Lorenzo Solar, Antonia Rego Iraeta Servicio de Endocrinología y Nutrición, Área de Xestión Integrada Pontevedra-Salnés, Pontevedra, Spain ∗ Corresponding author. E-mail address: paula ss [email protected] (P. Sánchez Sobrino).