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Warren AM, Grossmann M, Christ-Crain M, Russell N. Syndrome of Inappropriate Antidiuresis: From Pathophysiology to Management. Endocr Rev 2023; 44:819-861. [PMID: 36974717 PMCID: PMC10502587 DOI: 10.1210/endrev/bnad010] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 02/19/2023] [Accepted: 03/27/2023] [Indexed: 03/29/2023]
Abstract
Hyponatremia is the most common electrolyte disorder, affecting more than 15% of patients in the hospital. Syndrome of inappropriate antidiuresis (SIAD) is the most frequent cause of hypotonic hyponatremia, mediated by nonosmotic release of arginine vasopressin (AVP, previously known as antidiuretic hormone), which acts on the renal V2 receptors to promote water retention. There are a variety of underlying causes of SIAD, including malignancy, pulmonary pathology, and central nervous system pathology. In clinical practice, the etiology of hyponatremia is frequently multifactorial and the management approach may need to evolve during treatment of a single episode. It is therefore important to regularly reassess clinical status and biochemistry, while remaining alert to potential underlying etiological factors that may become more apparent during the course of treatment. In the absence of severe symptoms requiring urgent intervention, fluid restriction (FR) is widely endorsed as the first-line treatment for SIAD in current guidelines, but there is considerable controversy regarding second-line therapy in instances where FR is unsuccessful, which occurs in around half of cases. We review the epidemiology, pathophysiology, and differential diagnosis of SIAD, and summarize recent evidence for therapeutic options beyond FR, with a focus on tolvaptan, urea, and sodium-glucose cotransporter 2 inhibitors.
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Affiliation(s)
- Annabelle M Warren
- Department of Medicine, University of Melbourne, Victoria 3010, Australia
- Department of Endocrinology, The Austin Hospital, Victoria 3084, Australia
| | - Mathis Grossmann
- Department of Medicine, University of Melbourne, Victoria 3010, Australia
- Department of Endocrinology, The Austin Hospital, Victoria 3084, Australia
| | - Mirjam Christ-Crain
- Department of Endocrinology, Diabetology and Metabolism, University Hospital Basel, Basel 4031, Switzerland
- Department of Clinical Research, University of Basel and University Hospital Basel, Basel 4031, Switzerland
| | - Nicholas Russell
- Department of Medicine, University of Melbourne, Victoria 3010, Australia
- Department of Endocrinology, The Austin Hospital, Victoria 3084, Australia
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Gankam Kengne F. Adaptation of the Brain to Hyponatremia and Its Clinical Implications. J Clin Med 2023; 12:jcm12051714. [PMID: 36902500 PMCID: PMC10002753 DOI: 10.3390/jcm12051714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/12/2023] [Accepted: 02/17/2023] [Indexed: 02/25/2023] Open
Abstract
Hyponatremia is the most common electrolyte disorder, occurring in up to 25% of hospitalized patients. Hypo-osmotic hyponatremia when severe and left untreated invariably results in cell swelling, which can lead to fatal consequences, especially in the central nervous system. The brain is particularly vulnerable to the consequences of decreased extracellular osmolarity; because of being encased in the rigid skull, it cannot withstand persistent swelling. Moreover, serum sodium is the major determinant of extracellular ionic balance, which in turn governs crucial brain functions such as the excitability of neurons. For these reasons, the human brain has developed specific ways to adapt to hyponatremia and prevent brain edema. On the other hand, it is well known that rapid correction of chronic and severe hyponatremia can lead to brain demyelination, a condition known as osmotic demyelination syndrome. In this paper, we will discuss the mechanisms of brain adaptation to acute and chronic hyponatremia and the neurological symptoms of these conditions as well as the pathophysiology and prevention of osmotic demyelination syndrome.
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Kheetan M, Ogu I, Shapiro JI, Khitan ZJ. Acute and Chronic Hyponatremia. Front Med (Lausanne) 2021; 8:693738. [PMID: 34414205 PMCID: PMC8369240 DOI: 10.3389/fmed.2021.693738] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 07/12/2021] [Indexed: 02/05/2023] Open
Abstract
Hyponatremia is the most common electrolyte disorder in clinical practice. Catastrophic complications can occur from severe acute hyponatremia and from inappropriate management of acute and chronic hyponatremia. It is essential to define the hypotonic state associated with hyponatremia in order to plan therapy. Understanding cerebral defense mechanisms to hyponatremia are key factors to its manifestations and classification and subsequently to its management. Hypotonic hyponatremia is differentiated on the basis of urine osmolality, urine electrolytes and volume status and its treatment is decided based on chronicity and the presence or absence of central nervous (CNS) symptoms. Proper knowledge of sodium and water homeostasis is essential in individualizing therapeutic plans and avoid iatrogenic complications while managing this disorder.
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Affiliation(s)
| | | | | | - Zeid J. Khitan
- Department of Internal Medicine, The Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
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4
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Nelson NR, Tompkins MG, Thompson Bastin ML. Plasma exchange as treatment for osmotic demyelination syndrome: Case report and review of current literature. Transfus Apher Sci 2019; 58:102663. [PMID: 31759898 DOI: 10.1016/j.transci.2019.10.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 10/12/2019] [Accepted: 10/15/2019] [Indexed: 10/25/2022]
Abstract
Osmotic demyelination syndrome (ODS) is characterized by widespread degeneration of myelin within the central nervous system and has no established treatment. A limited number of cases have reported positive outcomes with plasma exchange in the treatment of ODS associated with chronic alcohol abuse or liver transplantation. We report the case of a 23-year-old female presenting with ODS following rapid correction of hyponatremia, which was attributed to hypoalbuminemia, volume overload, and malnutrition secondary to ulcerative colitis. Our patient received four plasma exchange sessions over the course of five days for a total plasma exchange of 15,500 mL. Unfortunately, the patient did not achieve significant neurologic recovery following completion of the plasma exchange regimen. This is the first report of the failure of this novel approach in the management of a patient with ODS, suggesting benefit in a limited patient population. We describe the proposed mechanism of plasma exchange in the treatment of ODS and provide a review of existing literature.
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Affiliation(s)
- Nicholas R Nelson
- University of Kentucky HealthCare, Department of Pharmacy Services, United States.
| | - Madeline G Tompkins
- University of Kentucky College of Pharmacy, Department of Pharmacy Practice and Science, United States
| | - Melissa L Thompson Bastin
- University of Kentucky HealthCare, Department of Pharmacy Services, United States; University of Kentucky College of Pharmacy, Department of Pharmacy Practice and Science, United States.
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Burton AG, Hopper K. Hyponatremia in dogs and cats. J Vet Emerg Crit Care (San Antonio) 2019; 29:461-471. [DOI: 10.1111/vec.12881] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 08/04/2017] [Accepted: 09/06/2017] [Indexed: 01/10/2023]
Affiliation(s)
| | - Kate Hopper
- Department of Veterinary Surgical and Radiological SciencesUniversity of California Davis CA
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Nicaise C, Marneffe C, Bouchat J, Gilloteaux J. Osmotic Demyelination: From an Oligodendrocyte to an Astrocyte Perspective. Int J Mol Sci 2019; 20:E1124. [PMID: 30841618 PMCID: PMC6429405 DOI: 10.3390/ijms20051124] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 02/26/2019] [Accepted: 02/27/2019] [Indexed: 12/15/2022] Open
Abstract
Osmotic demyelination syndrome (ODS) is a disorder of the central myelin that is often associated with a precipitous rise of serum sodium. Remarkably, while the myelin and oligodendrocytes of specific brain areas degenerate during the disease, neighboring neurons and axons appear unspoiled, and neuroinflammation appears only once demyelination is well established. In addition to blood‒brain barrier breakdown and microglia activation, astrocyte death is among one of the earliest events during ODS pathology. This review will focus on various aspects of biochemical, molecular and cellular aspects of oligodendrocyte and astrocyte changes in ODS-susceptible brain regions, with an emphasis on the crosstalk between those two glial cells. Emerging evidence pointing to the initiating role of astrocytes in region-specific degeneration are discussed.
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Affiliation(s)
| | - Catherine Marneffe
- Laboratory of Glia Biology (VIB-KU Leuven Center for Brain & Disease Research), Department of Neuroscience, KU Leuven, 3000 Leuven, Belgium.
| | - Joanna Bouchat
- URPhyM-NARILIS, Université de Namur, 5000 Namur, Belgium.
| | - Jacques Gilloteaux
- URPhyM-NARILIS, Université de Namur, 5000 Namur, Belgium.
- Department of Anatomical Sciences, St George's University School of Medicine, Newcastle upon Tyne NE1 8ST, UK.
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Baldrighi M, Sainaghi PP, Bellan M, Bartoli E, Castello LM. Hyperglycemic Hyperosmolar State: A Pragmatic Approach to Properly Manage Sodium Derangements. Curr Diabetes Rev 2018; 14:534-541. [PMID: 29557753 PMCID: PMC6237920 DOI: 10.2174/1573399814666180320091451] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 02/26/2018] [Accepted: 03/13/2018] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Although hypovolemia remains the most relevant problem during acute decompensated diabetes in its clinical manifestations (diabetic ketoacidosis, DKA, and hyperglycemic hyperosmolar state, HHS), the electrolyte derangements caused by the global hydroelectrolytic imbalance usually complicate the clinical picture at presentation and may be worsened by the treatment itself. AIM This review article is focused on the management of dysnatremias during hyperglycemic hyperosmolar state with the aim of providing clinicians a useful tool to early identify the sodium derangement in order to address properly its treatment. DISCUSSION The plasma sodium concentration is modified by most of the therapeutic measures commonly required in such patients and the physician needs to consider these interactions when treating HHS. Moreover, an improper management of plasma sodium concentration (PNa+) and plasma osmolality during treatment has been associated with two rare potentially life-threatening complications (cerebral edema and osmotic demyelination syndrome). Identifying the correct composition of the fluids that need to be infused to restore volume losses is crucial to prevent complications. CONCLUSION A quantitative approach based on the comparison between the measured PNa+ (PNa+ M) and the PNa+ expected in the presence of an exclusive water shift (PNa+ G) may provide more thorough information about the true hydroelectrolytic status of the patient and may therefore, guide the physician in the initial management of HHS. On the basis of data derived from our previous studies, we propose a 7-step algorithm to compute an accurate estimate of PNa+ G.
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Affiliation(s)
| | | | | | | | - Luigi M. Castello
- Address correspondence to this author at the Department of Translational Medicine, Università del Piemonte Orientale - Via Solaroli 17 28100 Novara, Italy; Tel: +39 0321 373 3097; E-mail:
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Bouchat J, Couturier B, Marneffe C, Gankam-Kengne F, Balau B, De Swert K, Brion JP, Poncelet L, Gilloteaux J, Nicaise C. Regional oligodendrocytopathy and astrocytopathy precede myelin loss and blood-brain barrier disruption in a murine model of osmotic demyelination syndrome. Glia 2017; 66:606-622. [DOI: 10.1002/glia.23268] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 11/06/2017] [Accepted: 11/07/2017] [Indexed: 12/28/2022]
Affiliation(s)
| | - Bruno Couturier
- Department of General Medicine; Erasme Hospital, Université Libre de Bruxelles; Bruxelles Belgium
- Laboratory of Histology, Neuroanatomy and Neuropathology; Université Libre de Bruxelles; Bruxelles Belgium
| | | | - Fabrice Gankam-Kengne
- Laboratory of Histology, Neuroanatomy and Neuropathology; Université Libre de Bruxelles; Bruxelles Belgium
- Department of Nephrology; EpiCURA Ath; Ath Belgium
| | - Benoît Balau
- URPhyM - NARILIS, Université de Namur; Namur Belgium
| | | | - Jean-Pierre Brion
- Laboratory of Histology, Neuroanatomy and Neuropathology; Université Libre de Bruxelles; Bruxelles Belgium
| | - Luc Poncelet
- Laboratory of Anatomy, Biomechanics and Organogenesis; Université Libre de Bruxelles; Bruxelles Belgium
| | - Jacques Gilloteaux
- URPhyM - NARILIS, Université de Namur; Namur Belgium
- Department of Anatomical Sciences; St George's University School of Medicine, Newcastle upon Tyne; United Kingdom
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Gankam-Kengne F, Couturier BS, Soupart A, Brion JP, Decaux G. Osmotic Stress-Induced Defective Glial Proteostasis Contributes to Brain Demyelination after Hyponatremia Treatment. J Am Soc Nephrol 2017; 28:1802-1813. [PMID: 28122966 DOI: 10.1681/asn.2016050509] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 11/18/2016] [Indexed: 01/17/2023] Open
Abstract
Adequate protein folding is necessary for normal cell function and a tightly regulated process that requires proper intracellular ionic strength. In many cell types, imbalance between protein synthesis and degradation can induce endoplasmic reticulum (ER) stress, which if sustained, can in turn lead to cell death. In nematodes, osmotic stress induces massive protein aggregation coupled with unfolded protein response and ER stress. In clinical practice, patients sustaining rapid correction of chronic hyponatremia are at risk of osmotic demyelination syndrome. The intense osmotic stress sustained by brain cells is believed to be the major risk factor for demyelination resulting from astrocyte death, which leads to microglial activation, blood-brain barrier opening, and later, myelin damage. Here, using a rat model of osmotic demyelination, we showed that rapid correction of chronic hyponatremia induces severe alterations in proteostasis characterized by diffuse protein aggregation and ubiquitination. Abrupt correction of hyponatremia resulted in vigorous activation of both the unfolded protein response and ER stress accompanied by increased autophagic activity and apoptosis. Immunofluorescence revealed that most of these processes occurred in astrocytes within regions previously shown to be demyelinated in later stages of this syndrome. These results identify osmotic stress as a potent protein aggregation stimuli in mammalian brain and further suggest that osmotic demyelination might be a consequence of proteostasis failure on severe osmotic stress.
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Affiliation(s)
- Fabrice Gankam-Kengne
- Faculty of Medicine, Research Unit on Hydromineral Metabolism, .,Faculty of Medicine, Laboratory of Histology and Neuroanatomy and Neuropathology, and.,Service de Néphrologie, EpiCURA Ath, Ath, Belgium; and
| | - Bruno S Couturier
- Faculty of Medicine, Research Unit on Hydromineral Metabolism.,Faculty of Medicine, Laboratory of Histology and Neuroanatomy and Neuropathology, and.,Hopital Erasme, Service de Médecine Interne générale, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Alain Soupart
- Faculty of Medicine, Research Unit on Hydromineral Metabolism.,Service de Médecine Interne Générale, Hopitaux Iris Sud site Molière, Bruxelles, Belgium
| | - Jean Pierre Brion
- Faculty of Medicine, Laboratory of Histology and Neuroanatomy and Neuropathology, and
| | - Guy Decaux
- Faculty of Medicine, Research Unit on Hydromineral Metabolism, .,Hopital Erasme, Service de Médecine Interne générale, Université Libre de Bruxelles, Bruxelles, Belgium
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Sterns RH, Silver S, Kleinschmidt-DeMasters BK, Rojiani AM. Current perspectives in the management of hyponatremia: prevention of CPM. Expert Rev Neurother 2014; 7:1791-7. [DOI: 10.1586/14737175.7.12.1791] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH, Thompson CJ. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med 2013; 126:S1-42. [PMID: 24074529 DOI: 10.1016/j.amjmed.2013.07.006] [Citation(s) in RCA: 630] [Impact Index Per Article: 52.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hyponatremia is a serious, but often overlooked, electrolyte imbalance that has been independently associated with a wide range of deleterious changes involving many different body systems. Untreated acute hyponatremia can cause substantial morbidity and mortality as a result of osmotically induced cerebral edema, and excessively rapid correction of chronic hyponatremia can cause severe neurologic impairment and death as a result of osmotic demyelination. The diverse etiologies and comorbidities associated with hyponatremia pose substantial challenges in managing this disorder. In 2007, a panel of experts in hyponatremia convened to develop the Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations that defined strategies for clinicians caring for patients with hyponatremia. In the 6 years since the publication of that document, the field has seen several notable developments, including new evidence on morbidities and complications associated with hyponatremia, the importance of treating mild to moderate hyponatremia, and the efficacy and safety of vasopressin receptor antagonist therapy for hyponatremic patients. Therefore, additional guidance was deemed necessary and a panel of hyponatremia experts (which included all of the original panel members) was convened to update the previous recommendations for optimal current management of this disorder. The updated expert panel recommendations in this document represent recommended approaches for multiple etiologies of hyponatremia that are based on both consensus opinions of experts in hyponatremia and the most recent published data in this field.
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12
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Filippatos TD, Elisaf MS. Hyponatremia in patients with heart failure. World J Cardiol 2013; 5:317-328. [PMID: 24109495 PMCID: PMC3783984 DOI: 10.4330/wjc.v5.i9.317] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2013] [Revised: 07/30/2013] [Accepted: 08/17/2013] [Indexed: 02/06/2023] Open
Abstract
The present review analyses the mechanisms relating heart failure and hyponatremia, describes the association of hyponatremia with the progress of disease and morbidity/mortality in heart failure patients and presents treatment options focusing on the role of arginine vasopressin (AVP)-receptor antagonists. Hyponatremia is the most common electrolyte disorder in the clinical setting and in hospitalized patients. Patients with hyponatremia may have neurologic symptoms since low sodium concentration produces brain edema, but the rapid correction of hyponatremia is also associated with major neurologic complications. Patients with heart failure often develop hyponatremia owing to the activation of many neurohormonal systems leading to decrease of sodium levels. A large number of clinical studies have associated hyponatremia with increased morbidity and mortality in patients hospitalized for heart failure or outpatients with chronic heart failure. Treatment options for hyponatremia in heart failure, such as water restriction or the use of hypertonic saline with loop diuretics, have limited efficacy. AVP-receptor antagonists increase sodium levels effectively and their use seems promising in patients with hyponatremia. However, the effects of AVP-receptor antagonists on hard outcomes in patients with heart failure and hyponatremia have not been thoroughly examined.
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Abstract
In this review three major issues of sodium homeostasis are addressed. Specifically, volume-dependent (salt-sensitive) hypertension, sodium chloride content of maintenance fluid and clinical evaluation of hyponatremia are discussed. Regarding volume-dependent hypertension the endocrine/paracrine systems mediating renal sodium retention, the relationship between salt intake, plasma sodium levels and blood pressure, as well as data on the dissociation of sodium and volume regulation are presented. The concept of perinatal programming of salt-preference is also mentioned. Some theoretical and practical aspects of fluid therapy are summarized with particular reference to using hypotonic sodium chloride solution for maintenance fluid as opposed to the currently proposed isotonic sodium chloride solution. Furthermore, the incidence, the aetiological classification and central nervous system complications of hyponatremia are presented, too. In addition, clinical and pathophysical features of hyponatremic encephalophathy and osmotic demyelinisation are given. The adaptive reactions of the brain to hypotonic stress are also described with particular emphasis on the role of brain-specific water channel proteins (aquaporin-4) and the benzamil-inhibitable sodium channels. In view of the outmost clinical significance of hyponatremia, the principles of efficient and safe therapeutic approaches are outlined. Orv. Hetil., 2013, 154, 1488–1497.
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Affiliation(s)
- Endre Sulyok
- Pécsi Tudományegyetem Egészségtudományi Kar Pécs Vörösmarty u. 4. 7621
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Ismail FY, Szóllics A, Szólics M, Nagelkerke N, Ljubisavljevic M. Clinical semiology and neuroradiologic correlates of acute hypernatremic osmotic challenge in adults: a literature review. AJNR Am J Neuroradiol 2013; 34:2225-32. [PMID: 23413245 DOI: 10.3174/ajnr.a3392] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The complex interplay between hypernatremic osmotic disturbances and cerebral lesions is yet to be clarified. In this review, we discuss, on the basis of the reported data of hypernatremic CNS challenge in the adult population, the clinical and radiologic features of the condition. Our search captured 20 case studies and 1 case series with 30 patients in total who acquired acute hypernatremia due to different etiologies and developed CNS lesions. We explored the associations between premorbid conditions, clinical presentation, hypernatremic state, correction rate, and radiologic appearance, including the localization of brain lesions and the outcomes. The results revealed that altered mental status was the most commonly reported symptom and osmotic demyelination syndrome in the form of extrapontine myelinolysis was the prevailing radiologic pattern. Finally, we contrasted, when appropriate, clinical and experimental data related to hypernatremic and hyponatremic osmotic insults to aid the understanding of the pathophysiology of CNS osmotic brain injury.
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Gankam Kengne F, Nicaise C, Soupart A, Boom A, Schiettecatte J, Pochet R, Brion JP, Decaux G. Astrocytes are an early target in osmotic demyelination syndrome. J Am Soc Nephrol 2011; 22:1834-45. [PMID: 21885671 DOI: 10.1681/asn.2010111127] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Abrupt osmotic changes during rapid correction of chronic hyponatremia result in demyelinative brain lesions, but the sequence of events linking rapid osmotic changes to myelin loss is not yet understood. Here, in a rat model of osmotic demyelination syndrome, we found that massive astrocyte death occurred after rapid correction of hyponatremia, delineating the regions of future myelin loss. Astrocyte death caused a disruption of the astrocyte-oligodendrocyte network, rapidly upregulated inflammatory cytokines genes, and increased serum S100B, which predicted clinical manifestations and outcome of osmotic demyelination. These results support a model for the pathophysiology of osmotic brain injury in which rapid correction of hyponatremia triggers apoptosis in astrocytes followed by a loss of trophic communication between astrocytes and oligodendrocytes, secondary inflammation, microglial activation, and finally demyelination.
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Affiliation(s)
- Fabrice Gankam Kengne
- Erasme University Hospital, Department of General Internal Medicine, Research Unit on Hydromineral Metabolism, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
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Cascales Campos P, Ramirez P, Gonzalez R, Pons J, Miras M, Sanchez Bueno F, Robles R, Parrilla P. Central Pontine and Extrapontine Myelinolysis: A Rare and Fatal Complication after Liver Transplantation. Transplant Proc 2011; 43:2237-8. [PMID: 21839243 DOI: 10.1016/j.transproceed.2011.06.052] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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Velasco Cano MV, Runkle de la Vega I. [Current considerations in syndrome of inappropriate secretion of antidiuretic hormone/syndrome of inappropriate antidiuresis]. ACTA ACUST UNITED AC 2011; 57 Suppl 2:22-9. [PMID: 21130959 DOI: 10.1016/s1575-0922(10)70019-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The syndrome of inappropriate secretion of antidiuretic hormone (SIADH)/syndrome of inappropriate antidiuresis is characterized by a hypotonic hyponatremia, with an insufficiently diluted urine given the plasmatic hypoosmolality, in the absence of hypovolemia (with or without a third space), hypotension, renal or heart failure, cirrhosis of the liver, hypothyroidism, adrenal insufficiency, vomiting, or other non-osmotic stimuli of ADH secretion. The response of ADH to the infusion of hypertonic saline divides SIADH into 4 different types. In type D, there is no alteration in ADH secretion. Rather, the defect is the maintained permeability of kidney aquaporin-2 channels to water. Activating mutations of the V2 receptor have been identified. The most frequent cause of SIADH is the use of drugs that induce secretion of the hormone. Old age is per se a risk factor for its development. SIADH is underdiagnosed, and hospitalization often worsens the clinical situation, due to an iatrogenic excess in the use of oral and i.v. liquids, often hypotonic, together with a reduction in salt intake. Treatment is directed towards normalization of natremia when possible, together with the avoidance of both hyponatremic encephalopathy as well as the osmotic demyelinization syndrome. Cases of "appropriate" secretion of ADH with normovolemic hyponatremia and high mortality rates should be treated with the same urgency as SIADH--such is the case of post-surgical hyponatremia.
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Affiliation(s)
- M V Velasco Cano
- Servicio de Endocrinología, Metabolismo y Nutrición, Hospital Clínico San Carlos, Madrid, Spain
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Abstract
UNLABELLED Hyponatremia with cerebral symptoms is a medical emergency in which treatment delay may prove fatal. However, controversy prevails over which treatment is the best. This paper presents a practical and unified approach based on a literature study of the physiology of plasma [Na(+) ], the brain's response and clinical and experimental studies. Experimental and clinical studies were thoroughly reviewed. The literature was identified through MESH and free text search in the databases PubMed, Embase and Cochrane, and references in the literature. Cerebral water homeostasis is pivotal in hyponatremia. Prompt, repeated boluses of 2 ml/kg 3% saline constitute a rational treatment of symptomatic hyponatremia. After the initial correction, concern is mainly with avoiding overcorrection and osmotic demyelination. Plasma [Na(+)] is determined by the external balances of water and cations. The water balance must therefore be carefully monitored to counter the dramatic increase in plasma [Na(+)] that may result from brisk diuresis. Definitive treatment of hyponatremia should be directed toward its etiology. This can be challenging and the clinical application of traditional classifications based on hydration is difficult. Therefore, a practical approach is proposed based on the mechanisms of impaired urine dilution. CONCLUSIONS The conflict between previously opposing standpoints is gradually giving way to an emerging consensus: Prompt bolus treatment of symptomatic hyponatremia with hypertonic saline. After the initial treatment, overcorrection must be avoided. Definitive treatment should be directed toward the nature of the underlying disorder. An approach based on the mechanism governing the impaired urine dilution has been proposed.
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Brain volume regulation: osmolytes and aquaporin perspectives. Neuroscience 2010; 168:871-84. [DOI: 10.1016/j.neuroscience.2009.11.074] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2009] [Revised: 11/13/2009] [Accepted: 11/25/2009] [Indexed: 02/08/2023]
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Abstract
The osmotic demyelination syndrome (ODS) has been a recognized complication of the rapid correction of hyponatremia for decades. However, in recent years, a variety of other medical conditions have been associated with the development of ODS, independent of changes in serum sodium. This finding suggests that the pathogenesis of ODS may be more complex and involve the inability of brain cells to respond to rapid changes in osmolality of the interstitial (extracellular) compartment of the brain, leading to dehydration of energy-depleted cells with subsequent axonal damage that occurs in characteristic areas. Features of the syndrome include quadriparesis and neurocognitive changes in the presence of characteristic lesions found on magnetic resonance imaging of the brain. Although slow correction of hyponatremia seems to be the best way to prevent development of the syndrome, there are new data that suggest reintroduction of hyponatremia in those patients who have undergone inadvertent rapid correction of the serum sodium and corticosteroids may play a role in prevention of ODS.
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Overgaard-Steensen C, Stødkilde-Jørgensen H, Larsson A, Broch-Lips M, Tønnesen E, Frøkiaer J, Ring T. Regional differences in osmotic behavior in brain during acute hyponatremia: an in vivo MRI-study of brain and skeletal muscle in pigs. Am J Physiol Regul Integr Comp Physiol 2010; 299:R521-32. [PMID: 20445159 DOI: 10.1152/ajpregu.00139.2010] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Brain edema is suggested to be the principal mechanism underlying the symptoms in acute hyponatremia. Identification of the mechanisms responsible for global and regional cerebral water homeostasis during hyponatremia is, therefore, of utmost importance. To examine the osmotic behavior of different brain regions and muscles, in vivo-determined water content (WC) was related to plasma sodium concentration ([Na(+)]) and brain/muscle electrolyte content. Acute hyponatremia was induced with desmopressin acetate and infusion of a 2.5% glucose solution in anesthetized pigs. WC in different brain regions and skeletal muscle was estimated in vivo from T(1) maps determined by magnetic resonance imaging (MRI). WC, expressed in gram water per 100 g dry weight, increased significantly in slices of the whole brain [342(SD = 14) to 363(SD = 21)] (6%), thalamus [277(SD = 13) to 311(SD = 24)] (12%) and white matter [219(SD = 7) to 225(SD = 5)] (3%). However, the WC increase in the whole brain and white mater WC was less than expected from perfect osmotic behavior, whereas in the thalamus, the water increase was as expected. Brain sodium content was significantly reduced. Muscle WC changed passively with plasma [Na(+)]. WC determined with deuterium dilution and tissue lyophilzation correlated well with MRI-determined WC. In conclusion, acute hyponatremia induces brain and muscle edema. In the brain as a whole and in the thalamus, regulatory volume decrease (RVD) is unlikely to occur. However, RVD may, in part, explain the observed lower WC in white matter. This may play a potential role in osmotic demyelination.
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Norenberg MD. Central pontine myelinolysis: historical and mechanistic considerations. Metab Brain Dis 2010; 25:97-106. [PMID: 20182780 DOI: 10.1007/s11011-010-9175-0] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2009] [Accepted: 01/28/2010] [Indexed: 02/06/2023]
Abstract
Central pontine myelinolysis (CPM) is a demyelinating condition affecting not only the pontine base, but also involving other brain areas. It usually occurs on a background of chronic systemic illness, and is commonly observed in individuals with alcoholism, malnutrition and liver disease. Studies carried out 25-30 years ago established that the principal etiological factor was the rapid correction of hyponatremia resulting in osmotic stress. This article reviews progress achieved since that time on its pathogenesis, focusing on the role of organic osmolytes, the blood-brain, barrier, endothelial cells, myelinotoxic factors triggered by osmotic stress, and the role of various factors that predispose to the development of CPM. These advances show great promise in providing novel therapeutic options for the management of patients afflicted with CPM.
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Affiliation(s)
- Michael D Norenberg
- Departments of Pathology, University of Miami School of Medicine, PO Box 016960, Miami, FL 33101, USA.
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25
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Kacprowicz RF, Lloyd JD. Electrolyte complications of malignancy. Emerg Med Clin North Am 2009; 27:257-69. [PMID: 19447310 DOI: 10.1016/j.emc.2009.01.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
A thorough working knowledge of the diagnosis and treatment of life-threatening electrolyte abnormalities in cancer patients, especially hyponatremia, hypoglycemia, and hypercalcemia, is essential to the successful practice of emergency medicine. Although most minor abnormalities have no specific treatment, severe clinical manifestations of several notable electrolytes occur with significant frequency in the setting of malignancy. The treatment of life-threatening electrolyte abnormalities is reviewed here. Promising future treatments directed at the underlying physiology are also introduced.
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Affiliation(s)
- Robert F Kacprowicz
- San Antonio Uniformed Services Health Education Consortium Residency in Emergency Medicine, San Antonio, TX, USA.
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27
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Baslow MH, Guilfoyle DN. Are Astrocytes the Missing Link Between Lack of Brain Aspartoacylase Activity and the Spongiform Leukodystrophy in Canavan Disease? Neurochem Res 2009; 34:1523-34. [DOI: 10.1007/s11064-009-9958-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2008] [Accepted: 03/09/2009] [Indexed: 10/21/2022]
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29
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Weant KA, Cook AM. Pharmacologic Strategies for the Treatment of Elevated Intracranial Pressure. Adv Emerg Nurs J 2008. [DOI: 10.1097/01.tme.0000311542.95656.92] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med 2007; 120:S1-21. [PMID: 17981159 DOI: 10.1016/j.amjmed.2007.09.001] [Citation(s) in RCA: 332] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Although hyponatremia is a common, usually mild, and relatively asymptomatic disorder of electrolytes, acute severe hyponatremia can cause substantial morbidity and mortality, particularly in patients with concomitant disease. In addition, overly rapid correction of chronic hyponatremia can cause severe neurologic deficits and death, and optimal treatment strategies for such cases are not established. An expert panel assessed the potential contributions of aquaretic nonpeptide small-molecule arginine vasopressin receptor (AVPR) antagonists to hyponatremia therapies. This review presents their conclusions, including identification of appropriate treatment populations and possible future indications for aquaretic AVPR antagonists.
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Affiliation(s)
- Joseph G Verbalis
- Division of Endocrinology and Metabolism, Department of Medicine, Georgetown University Medical Center, Washington, District of Columbia 20007, USA.
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31
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Abstract
Hyponatremia is a common clinical problem in hospitalized patients and nursing home residents. It also may occur in healthy athletes after endurance exercise. The majority of patients with hyponatremia are asymptomatic and do not require immediate correction of hyponatremia. Symptomatic hyponatremia is a medical emergency requiring rapid correction to prevent the worsening of brain edema. How fast we should increase the serum sodium levels depends on the onset of hyponatremia and still remains controversial. If the serum sodium levels are corrected too rapidly, patients may develop central pontine myelinolysis, but if they are corrected too slowly, patients may die of brain herniation. We review the epidemiology and mechanisms of hyponatremia, the sensitivity of women to hyponatremic injury, the adaptation and maladaptation of brain cells to hyponatremia and its correction, and the practical ways of managing hyponatremia. Because the majority of hyponatremia is caused by the non-osmotic release of vasopressin, the recent approval of the vasopressin receptor antagonist conivaptan for euvolemic hyponatremia may simplify hyponatremia management. However, physicians should be aware of the risk of rapid correction of hyponatremia, hypotension, and excessive fluid intake.
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Affiliation(s)
- Yeong-Hau H Lien
- University of Arizona Health Sciences Center, Tucson, Ariz, USA.
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Abstract
Hyponatremia exerts most of its clinical effects on the brain. An acute onset (usually in <24 hours) of hyponatremia causes severe, and sometimes fatal, cerebral edema. Given time, the brain adapts to hyponatremia, permitting survival despite extraordinarily low serum sodium concentrations. Adaptation to severe hyponatremia is critically dependent on the loss of organic osmolytes from brain cells. These intracellular, osmotically active solutes contribute substantially to the osmolality of cell water and do not adversely affect cell functions when their concentration changes. The adaptation that permits survival in patients with severe, chronic (>48 hours' duration) hyponatremia also makes the brain vulnerable to injury (osmotic demyelination) if the electrolyte disturbance is corrected too rapidly. The reuptake of organic osmolytes after correction of hyponatremia is slower than the loss of organic osmolytes during the adaptation to hyponatremia. Areas of the brain that remain most depleted of organic osmolytes are the most severely injured by rapid correction. The brain's reuptake of myoinositol, one of the most abundant osmolytes, occurs much more rapidly in a uremic environment, and patients with uremia are less susceptible to osmotic demyelination. In an experimental model of chronic hyponatremia, exogenous administration of myoinositol speeds the brain's reuptake of the osmolyte and reduces osmotic demyelination and mortality caused by rapid correction.
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Affiliation(s)
- Richard H Sterns
- Department of Medicine, Rochester General Hospital, University of Rochester School of Medicine and Dentistry, Rochester, New York 14621, USA.
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Silver SM, Schroeder BM, Sterns RH, Rojiani AM. Myoinositol Administration Improves Survival and Reduces Myelinolysis After Rapid Correction of Chronic Hyponatremia in Rats. J Neuropathol Exp Neurol 2006; 65:37-44. [PMID: 16410747 DOI: 10.1097/01.jnen.0000195938.02292.39] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
When chronic hyponatremia is rapidly corrected, reaccumulation of brain organic osmolytes is delayed and brain cell shrinkage occurs, leading to the osmotic demyelination syndrome (ODS). We hypothesized that treatment with myoinositol, a major organic osmolyte, could prevent ODS. Severe hyponatremia was induced in adult male rats by administration of arginine vasopressin and intravenous infusion of dextrose and water. Sixty-four hours after induction of hyponatremia, all animals underwent rapid correction of hyponatremia with infusion of hypertonic saline over 4 hours, increasing the serum sodium from 105 to 135 mM; half of the animals were also given myoinositol intravenously beginning 20 minutes before correction and continuing for 28 hours. Serum sodium concentrations were equivalent in both groups at all time points. At 7 days, 7 of 8 animals that received myoinositol survived compared with one of the 9 control animals (p < 0.01). In a second study, sodium was reduced to 106 mM over 64 hours in 24 animals and then corrected by 20 mM over 4 hours with concomitant loading and infusion of either mannitol (control) or myoinositol. Animals were killed 96 hours after correction of hyponatremia was begun. Myoinositol-treated animals had significantly fewer demyelinating lesions than mannitol (2.25 +/- 1.1 versus 6.42 +/- 1.4 lesions/brain, p < 0.03). We conclude that myoinositol administration improves survival and reduces myelinolysis after rapid correction of chronic hyponatremia in rats.
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Affiliation(s)
- Stephen M Silver
- Department of Medicine, Rochester General Hospital, University of Rochester School of Medicine, Rochester, New York, NY 14621, USA.
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Sugimura Y, Murase T, Takefuji S, Hayasaka S, Takagishi Y, Oiso Y, Murata Y. Protective effect of dexamethasone on osmotic-induced demyelination in rats. Exp Neurol 2005; 192:178-83. [PMID: 15698632 DOI: 10.1016/j.expneurol.2004.10.018] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2004] [Revised: 10/08/2004] [Accepted: 10/20/2004] [Indexed: 12/17/2022]
Abstract
Central pontine myelinolysis (CPM) is a serious demyelination disease commonly associated with the rapid correction of hyponatremia. Although its pathogenesis remains unclear, the disruption of the blood-brain barrier (BBB) as a consequence of a rapid increase in serum sodium concentration is considered to play a critical role. Since glucocorticoids are known to influence BBB permeability and prevent its disruption as a result of hypertension or hyperosmolarity, we investigated whether dexamethasone (DEX) could protect against osmotic demyelination in an animal model of CPM. Hyponatremia was induced in rats by liquid diet feeding and dDAVP infusion. Seven days later, the animals' hyponatremia was rapidly corrected by injecting a bolus of hypertonic saline intraperitoneally. Rats subjected to this treatment displayed serious neurological impairment and 77% died within 5 days of rapid correction of their hyponatremia; demyelinative lesions were observed in various brain regions in these animals. On the other hand, rats that were treated with DEX (2 mg/kg, 0 and 6 h after hypertonic saline injection) exhibited minimal neurological impairment and all were alive after 5 days. Demyelinative lesions were rarely seen in the brains of DEX-treated rats. A marked extravasation of endogenous IgG was observed in the demyelinative lesions in the brains of rats that did not receive DEX, indicating disruption of the BBB, but was not observed in DEX-treated rats. Furthermore, Evans blue injection revealed a significant reduction in staining in the brains of DEX-treated rats (P < 0.05). These results indicate that early DEX treatment can prevent the BBB disruption that is caused by the rapid correction of hyponatremia and its associative demyelinative changes, and suggest that DEX might be effective in preventing CPM.
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Affiliation(s)
- Yoshihisa Sugimura
- Department of Teratology and Genetics, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
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35
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Schwahn B, Laryea M, Chen Z, Melnyk S, Pogribny I, Garrow T, James S, Rozen R. Betaine rescue of an animal model with methylenetetrahydrofolate reductase deficiency. Biochem J 2005; 382:831-40. [PMID: 15217352 PMCID: PMC1133958 DOI: 10.1042/bj20040822] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2004] [Revised: 06/16/2004] [Accepted: 06/24/2004] [Indexed: 11/17/2022]
Abstract
MTHFR (methylenetetrahydrofolate reductase) catalyses the synthesis of 5-methyltetrahydrofolate, the folate derivative utilized in homocysteine remethylation to methionine. A severe deficiency of MTHFR results in hyperhomocysteinaemia and homocystinuria. Betaine supplementation has proven effective in ameliorating the biochemical abnormalities and the clinical course in patients with this deficiency. Mice with a complete knockout of MTHFR serve as a good animal model for homocystinuria; early postnatal death of these mice is common, as with some neonates with low residual MTHFR activity. We attempted to rescue Mthfr-/- mice from postnatal death by betaine supplementation to their mothers throughout pregnancy and lactation. Betaine decreased the mortality of Mthfr-/- mice from 83% to 26% and significantly improved somatic development from postnatal day 1, compared with Mthfr-/- mice from unsupplemented dams. Biochemical evaluations demonstrated higher availability of betaine in suckling pups, decreased accumulation of homocysteine, and decreased flux through the trans-sulphuration pathway in liver and brain of Mthfr-/- pups from betaine-supplemented dams. We observed disturbances in proliferation and differentiation in the cerebellum and hippocampus in the knockout mice; these changes were ameliorated by betaine supplementation. The dramatic effects of betaine on survival and growth, and the partial reversibility of the biochemical and developmental anomalies in the brains of MTHFR-deficient mice, emphasize an important role for choline and betaine depletion in the pathogenesis of homocystinuria due to MTHFR deficiency.
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Affiliation(s)
- Bernd C. Schwahn
- *Departments of Pediatrics, Human Genetics and Biology, McGill University–Montreal Children's Hospital, Montreal, Canada
- †Clinic for General Pediatrics, University Children's Hospital, Düsseldorf, Germany
| | - Maurice D. Laryea
- †Clinic for General Pediatrics, University Children's Hospital, Düsseldorf, Germany
| | - Zhoutao Chen
- *Departments of Pediatrics, Human Genetics and Biology, McGill University–Montreal Children's Hospital, Montreal, Canada
| | - Stepan Melnyk
- ‡Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, U.S.A
| | - Igor Pogribny
- §Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR, U.S.A
| | - Timothy Garrow
- ∥Department of Food Science and Human Nutrition, University of Illinois, Urbana, IL, U.S.A
| | - S. Jill James
- ‡Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, U.S.A
| | - Rima Rozen
- *Departments of Pediatrics, Human Genetics and Biology, McGill University–Montreal Children's Hospital, Montreal, Canada
- To whom correspondence should be addressed: Montreal Children's Hospital, 4060 Ste. Catherine West, Room 200, Montreal, Canada H3Z 2Z3 (email )
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36
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Abstract
MTHFR (methylenetetrahydrofolate reductase) catalyses the synthesis of 5-methyltetrahydrofolate, the folate derivative utilized in homocysteine remethylation to methionine. A severe deficiency of MTHFR results in hyperhomocysteinaemia and homocystinuria. Betaine supplementation has proven effective in ameliorating the biochemical abnormalities and the clinical course in patients with this deficiency. Mice with a complete knockout of MTHFR serve as a good animal model for homocystinuria; early postnatal death of these mice is common, as with some neonates with low residual MTHFR activity. We attempted to rescue Mthfr-/- mice from postnatal death by betaine supplementation to their mothers throughout pregnancy and lactation. Betaine decreased the mortality of Mthfr-/- mice from 83% to 26% and significantly improved somatic development from postnatal day 1, compared with Mthfr-/- mice from unsupplemented dams. Biochemical evaluations demonstrated higher availability of betaine in suckling pups, decreased accumulation of homocysteine, and decreased flux through the trans-sulphuration pathway in liver and brain of Mthfr-/- pups from betaine-supplemented dams. We observed disturbances in proliferation and differentiation in the cerebellum and hippocampus in the knockout mice; these changes were ameliorated by betaine supplementation. The dramatic effects of betaine on survival and growth, and the partial reversibility of the biochemical and developmental anomalies in the brains of MTHFR-deficient mice, emphasize an important role for choline and betaine depletion in the pathogenesis of homocystinuria due to MTHFR deficiency.
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37
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Kiyoshima A, Kudo K, Goto Y, Tobimatsu S, Ikeda N. Cerebral concentrations of myo-inositol in rats with induced brain death. Leg Med (Tokyo) 2005; 7:110-2. [PMID: 15708334 DOI: 10.1016/j.legalmed.2004.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2004] [Revised: 07/20/2004] [Accepted: 08/05/2004] [Indexed: 11/28/2022]
Abstract
In anaesthetized, mechanically ventilated rats with brain death induced by epidural balloon inflation, we assessed the levels of cerebral myo-inositol in three brain areas 4 h after brain death had been confirmed. The levels were measured using HPLC, along with the water content. Myo-inositol levels were significantly increased in the cerebellum (P<0.05) and decreased in the brainstem (P<0.001), compared to findings in controls. Such changes can serve as hallmarks of brain death.
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Affiliation(s)
- Akiko Kiyoshima
- Department of Forensic Pathology and Sciences, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashu-ku, Fukuoka 812-8582, Japan
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Moritani T, Smoker WRK, Sato Y, Numaguchi Y, Westesson PLA. Diffusion-weighted imaging of acute excitotoxic brain injury. AJNR Am J Neuroradiol 2005; 26:216-28. [PMID: 15709116 PMCID: PMC7974100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/01/2023]
Affiliation(s)
- Toshio Moritani
- Department of Radiology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA
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Bilić I, Kovac Z. Macromolecular oxidation in anisotonic suspensions of mouse spleen cells. Cell Biochem Funct 2005; 24:201-7. [PMID: 15672412 DOI: 10.1002/cbf.1207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Macromolecular oxidative alterations have been analysed in vitro in anisotonic suspensions of mouse splenocytes. Both hypertonicity and hypotonicity induced the generation of thiobarbituric acid reactive species (TBARS) and carbonylation of the proteins, which took place along with cell death. Addition of antioxidants partially inhibited oxidative changes in isotonic and hypotonic suspensions. Anisotonic shock of mouse splenocytes proved to be an inducer of oxidative stress. The oxidative macromolecular alterations might contribute to pathogenesis of cell death caused by osmotic stress.
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Affiliation(s)
- Ivan Bilić
- Department of Pathophysiology, Medical School, University of Zagreb, Zagreb, Croatia.
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Moreno-Torres A, Pujol J, Soriano-Mas C, Deus J, Iranzo A, Santamaria J. Age-related metabolic changes in the upper brainstem tegmentum by MR spectroscopy. Neurobiol Aging 2004; 26:1051-9. [PMID: 15748785 DOI: 10.1016/j.neurobiolaging.2004.09.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2004] [Revised: 08/02/2004] [Accepted: 09/22/2004] [Indexed: 11/21/2022]
Abstract
Several neurodegenerative disorders have a profound metabolic and structural impact on the brainstem. MR spectroscopy provides metabolic information non-invasively and has the potential to characterize the changes associated with normal aging and differentiate them from neurodegenerative alterations. The present work was aimed at studying the upper brainstem tegmentum at the midbrain and pontine levels in 57 adult normal volunteers, aged 23-79 years, with long-echo time proton MR spectroscopy to evaluate possible regional differences and the effect of age. Higher ratios of N-acetyl aspartate (NAA)/total creatine (Cr) and choline-containing compounds (Cho)/Cr were observed in the pons compared to the midbrain, resulting from higher net NAA and Cho content. In the midbrain, there was a linear decline of NAA and Cho with age in subjects over 50, most probably related to neuronal tissue loss. In the pons, such an aging effect was not observed, with subjects over 50 showing higher Cr and Cho than the under-50 subjects. Our findings provided evidence of regional differences and suggest different effects of age on the two studied brainstem segments, hitherto undescribed.
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Affiliation(s)
- Angel Moreno-Torres
- Research Department, Centre Diagnòstic Pedralbes, 08950, Esplugues de Llobregat, Spain.
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Yu J, Zheng SS, Liang TB, Shen Y, Wang WL, Ke QH. Possible causes of central pontine myelinolysis after liver transplantation. World J Gastroenterol 2004; 10:2540-3. [PMID: 15300900 PMCID: PMC4572157 DOI: 10.3748/wjg.v10.i17.2540] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To sum up the clinical characteristics of patients with central pontine myelinolysis (CPM) after orthotopic liver transplantation (OLT) and to document the possible causes of CPM.
METHODS: Data of 142 patients undergoing OLT between January 1999 to May 2003 were analyzed retrospectively. Following risk factors during perioperation were analyzed in patients with and without CPM: primary liver disease, preoperative serum sodium level, magnesium level and plasma osmolality, fluctuation degree of serum sodium concentration, and immunosuppressive drug level, etc.
RESULTS: A total of 13 (9.2%) neurologic symptoms appeared in 142 patients post-operation including 5 cases (3.5%) with CPM and 8 cases (5.6%) with cerebral hemorrhage or infarct. Two patients developing CPM after OLT had a hyponatremia history before operation (serum sodium < 130 mmol/L), their mean serum sodium level was 130.6 ± 5.54 mmol/L. The serum sodium level was significantly lower in CPM patients than in patients without neurologic complications or with cerebral hemorrhage/infarct (P < 0.05).The increase in serum sodiumduring perioperative 48 h after OLT in patients with CPM was significantly greater than that in patients with cerebral hemorrhage/infarct but without neurologic complications (19.5 ± 6.54 mmol/L, 10.1 ± 6.43 mmol/L, 4.5 ± 4.34 mmol/L, respectively, P < 0.05). Plasma osmolality was greatly increased postoperation in patients with CPM. Hypomagnesemia was noted in all patients perioperation, but there were no significant differences between groups. The duration of operation on patients with CPM was longer than that on others (492 ± 190.05 min, P < 0.05). Cyclosporin A (CsA) levels were normal in all patients, but there were significant differences between patients with or without neurologic complications (P < 0.05).
CONCLUSION: CPM may be more prevalent following liver transplantation. Although the diagnosis of CPM after OLT can be made by overall neurologic evaluations including magnetic resonance imaging (MRI) of the head, the mortality is still very high. The occurance of CPM may be associated with such factors as hyponatremia, rapid rise of serum sodium concentration, plasma osmolality increase postoperation, the duration of operation, and high CsA levels.
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Affiliation(s)
- Jun Yu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Zhejiang University,Hangzhou 310003, Zhejiang Province, China
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Massieu L, Montiel T, Robles G, Quesada O. Brain amino acids during hyponatremia in vivo: clinical observations and experimental studies. Neurochem Res 2004; 29:73-81. [PMID: 14992265 DOI: 10.1023/b:nere.0000010435.06586.e2] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Hyponatremia is a highly morbid condition, present in a wide range of human pathologies, that exposes patients to encephalopathic complication and the risk of permanent brain damage and death. Treating hyponatremia has proved to be difficult and still awaits safe management, avoiding the morbid sequelae of demyelinizing and necrotic lesions associated with the use of hypertonic solutions. During acute and chronic hyponatremia in vivo, the brain extrudes the excessive water by decreasing its content of electrolytes and organic osmolytes. At the cellular level, a similar response occurs upon cell swelling. Among the organic osmolytes involved in both responses, free amino acids play a prominent role because of the large intracellular pools often found in nerve cells. An overview of the changes in brain amino acid content during hyponatremia in vivo is presented and the contribution of these changes to the adaptive cell responses involved in volume regulation discussed. Additionally, new data are provided concerning changes in amino acid levels in different regions of the central nervous system after chronic hyponatremia. Results favor the role of taurine, glutamine, glutamate, and aspartate as the main amino acid osmolytes involved in the brain adaptive response to hyponatremia in vivo. Deeper knowledge of the adaptive overall and cellular brain mechanisms activated during hyponatremia would lead to the design of safer therapies for the hyponatremic patient.
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Affiliation(s)
- Lourdes Massieu
- Departamento de Neurociencias, Instituto de Fisiología Celular, Universidud Nacional Autónoma de México, México, DF
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Abstract
Inadequate treatment of severe hyponatremia (<120 mEq/L) can be associated with severe neurological damage. In acute (<48 hours) hyponatremia, usually observed in the postoperative period, prompt treatment with hypertonic saline (3%) can prevent seizures and respiratory arrest. For patients with chronic (>48-72 hours) symptomatic hyponatremia, correction must be rapid during the first few hours (to decrease brain edema) followed by a slow correction limited to 10 mmol/L over 24 hours to avoid the development of osmotic demyelinating syndrome. In patients with asymptomatic hyponatremia, slow correction is the appropriate approach. When patients are overtreated, neurologic damage can be prevented by relowering the serum sodium (SNa) so that the daily increase in SNa remains below 10 mmol/L/24 hours. Frequent measurements of SNa during the correction phase of SNa are mandatory to avoid overcorrection. The use of urea to treat hyponatremia represents an advantageous alternative to hypertonic saline.
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Affiliation(s)
- Guy Decaux
- Hôpital Universitaire Erasme, Bruxelles, Belgium.
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44
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Ceremuga TE, Yao XL, Xia Y, Mukherjee D, McCabe JT. Osmotic stress increases cullin-5 (cul-5) mRNA in the rat cerebral cortex, hypothalamus and kidney. Neurosci Res 2003; 45:305-11. [PMID: 12631466 DOI: 10.1016/s0168-0102(02)00228-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Cullin-5 (cul-5), a member of the cullin gene family, may have a role in proteolysis and cell cycle regulation. Our recent study demonstrated that cul-5 mRNA is ubiquitously expressed in the central nervous system and many peripheral organs. The present study used quantitative realtime polymerase chain reaction to measure changes in cul-5 mRNA expression as a consequence of osmotic stress in vivo. Cul-5 mRNA levels were significantly increased in the rat cerebral cortex, hypothalamus and kidney following 48 h of water deprivation. Water deprivation for a shorter time period (24 h) or rehydration (24 h access to water following 48 h of water deprivation) also elevated kidney cul-5 mRNA levels. Water deprivation did not significantly alter cul-5 mRNA levels in the brainstem, cerebellum, hippocampus, lung or liver. Since cul-5 appears to be linked to proteosome-mediated protein degradation, it may have a role in protein regulation under conditions of osmotic stress.
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Affiliation(s)
- Thomas E Ceremuga
- Graduate Program in Neuroscience, F. Edmund Hébert School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, 20814, Bethesda, MD, USA.
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45
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Soupart A, Silver S, Schroöeder B, Sterns R, Decaux G. Rapid (24-hour) reaccumulation of brain organic osmolytes (particularly myo-inositol) in azotemic rats after correction of chronic hyponatremia. J Am Soc Nephrol 2002; 13:1433-41. [PMID: 12039971 DOI: 10.1097/01.asn.0000017903.77985.cd] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
It was recently demonstrated that renal failure and exogenous urea prevent myelinolysis induced by rapid correction of experimental hyponatremia. To determine why elevated blood urea levels favorably affect brain tolerance to osmotic stress, the changes in brain solute composition that occur when chronic hyponatremia is rapidly corrected were studied in rats with or without mercuric chloride-induced renal failure. After 48 h of hyponatremia, the brains of azotemic and nonazotemic animals became depleted of sodium, potassium, and organic osmolytes. Twenty-four hours after rapid correction of hyponatremia, the brains of animals without azotemia remained depleted of organic osmolytes, with little increase in myo-inositol or taurine contents above those observed in animals with uncorrected hyponatremia; brain electrolytes were rapidly reaccumulated, increasing the brain sodium content to a level 17% higher than values for normonatremic control animals. In contrast, within 2 h after correction of hyponatremia, brain myo-inositol contents in azotemic rats returned to control levels and brain taurine levels were significantly higher than those in azotemic animals with uncorrected hyponatremia (16.5 versus 9 micromol/g dry weight). There was no "overshooting" of brain sodium and water contents after rapid correction in the azotemic animals. Rapid reaccumulation of brain organic osmolytes after correction of hyponatremia could explain why azotemia protects against myelinolysis.
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Affiliation(s)
- Alain Soupart
- Department of Internal Medicine, Jolimont/Tubize-Nivelles Hospital, Tubize-Nivelles, Belgium.
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46
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Silver SM, Schroeder BM, Sterns RH. Brain uptake of myoinositol after exogenous administration. J Am Soc Nephrol 2002; 13:1255-1260. [PMID: 11961013 DOI: 10.1681/asn.v1351255] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
An acute increase in plasma tonicity results in an adaptive increase in brain organic osmolyte content, but this process requires several days to occur. Slow reaccumulation of brain organic osmolytes may contribute to osmotic demyelination. It was investigated whether administration of intravenous myoinositol in rats could speed entry of the osmolyte into the brain. Two groups of animals were studied: normonatremic animals and animals with hyponatremia (105 mmol/L) of 3-d duration. Animals were intravenously administered either 1 M NaCl to induce a 25 to 28 mM increase in serum sodium concentration over 200 min or an infusate that maintained serum sodium concentration. In some animals, myoinositol was administered intravenously over the same time period to raise plasma myoinositol levels by 5 to 10 mM. Brain myoinositol, electrolyte, and water contents were determined at the end of the infusions. In both normonatremic and hyponatremic rats, infusion of hypertonic saline without myoinositol or infusion of myoinositol without hypertonic saline did not increase brain myoinositol levels above control levels. In normonatremic animals, concurrent infusion of hypertonic saline and myoinositol increased brain myoinositol levels by about 50% above control levels. Brain myoinositol content in animals with uncorrected hyponatremia was about 50% of that found in normonatremic controls; concurrent infusion of hypertonic saline and myoinositol increased brain myoinositol to levels similar to those found in normonatremic controls. Intravenous infusion of myoinositol did not alter brain water content compared with animals not infused with myoinositol. In conclusion, systemic infusion of myoinositol can rapidly increase brain myoinositol content, but only when plasma tonicity is concomitantly increased.
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Affiliation(s)
- Stephen M Silver
- Department of Medicine, Rochester General Hospital, University of Rochester School of Medicine, Rochester, New York
| | - Barbara M Schroeder
- Department of Medicine, Rochester General Hospital, University of Rochester School of Medicine, Rochester, New York
| | - Richard H Sterns
- Department of Medicine, Rochester General Hospital, University of Rochester School of Medicine, Rochester, New York
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47
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Affiliation(s)
- P Gross
- Universitätsklinikum Carl Gustav Carus, Dresden, Federal Republic of Germany.
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48
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Doyle JA, Davis DP, Hoyt DB. The use of hypertonic saline in the treatment of traumatic brain injury. THE JOURNAL OF TRAUMA 2001; 50:367-83. [PMID: 11242309 DOI: 10.1097/00005373-200102000-00030] [Citation(s) in RCA: 119] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- J A Doyle
- Department of Emergency Medicine, University of California at San Diego, 200 West Arbor Drive, San Diego, CA 92103-8676, USA
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49
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Soupart A, Penninckx R, Stenuit A, Decaux G. Azotemia (48 h) decreases the risk of brain damage in rats after correction of chronic hyponatremia. Brain Res 2000; 852:167-72. [PMID: 10661508 DOI: 10.1016/s0006-8993(99)02259-3] [Citation(s) in RCA: 48] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Brain myelinolysis complicates excessive correction of chronic hyponatremia in man. Myelinolysis appear in rats for correction levels deltaSNa) > 20 mEq/l/24 h. We previously showed in rats that when chronic hyponatremia was corrected with urea, the incidence and the severity of brain lesions were significantly reduced compared to hypertonic saline. In man, hyponatremia is frequently associated with azotemia and hemo-dialysis usually corrects rapidly the serum sodium (SNa) but only few patients apparently develop demyelination. We hypothesize that uremic state protects brain against myelinolysis. This hypothesis was evaluated in rats developing azotemia by administration of mercuric chloride (HgCl2, 1.5 mg/kg). Severe (SNa < 120 mEq/l) hyponatremia (3 days) was induced by S.C. AVP and i.p. 2.5% D-glucose for 3 days. HgCl2 was injected on day 2. Hyponatremia was corrected on day 4 by i.p. injections of 5% NaCl in order to obtain a correction level largely above the toxic threshold for brain (deltaSNA approximately 30 mEq/l/24 h). Surviving rats were decapitated on day 10 for brain analysis. In the group with renal failure (Group I, n = 15, urea 59 mmol/l) the outcome was remarkably favourable with only three rats (3/15) dying before day 10 and only one of them (1/3) presenting myelinolysis-related neurologic symptoms. The 12 other rats (80%) survived in Group I without symptoms and brain analysis was normal in all of them despite large correction level (deltaSNa: 32 mEq/l/24 h). On the contrary in nine rats in which HgCl, did not produce significant azotemia (control 1, n = 9, urea: 11 mmol/l), all the rats developed severe neurologic symptoms and eight of them died before day 10. Similar catastrophic outcome was observed in the non-azotemic controls (control 2, no HgCl2 administration, n = 15, urea: 5 mmol/l). All of them developed myelinolysis-related neurologic symptoms and only four of them survived with severe brain lesions (survival 12/15 in Group I vs. 5/24 in pooled controls 1 and 2, p < 0.001). In conclusion, we showed for the first time that chronic hyponatremic rats with azotemia (48 h) tolerated large increases in SNa (approximately 30 mEq/l/24 h) without significant brain damage.
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Affiliation(s)
- A Soupart
- Research Unit for the Study of Hydromineral Metabolism, Erasmus University Hospital, Free University of Brussels, Belgium
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50
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Miller TJ, Hanson RD, Yancey PH. Developmental changes in organic osmolytes in prenatal and postnatal rat tissues. Comp Biochem Physiol A Mol Integr Physiol 2000; 125:45-56. [PMID: 10779730 DOI: 10.1016/s1095-6433(99)00160-9] [Citation(s) in RCA: 66] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
At high osmotic pressures, mammalian kidney medulla, heart, lens, and brain utilize organic osmolytes to regulate cell volume. However the types and proportions of these solutes vary among tissues in patterns and for non-osmotic roles not fully elucidated. To clarify these, we analyzed osmolyte-type solute contents in rat tissues at 7 and 2 days prenatal and at 0, 7, 14, 21 (weaning), 35 (juvenile) and 77 (adult) days postnatal. Placentas were dominated by betaine, taurine, and creatine, which decreased between the prenatal times. Fetuses were dominated by glutamate and taurine, which increased between the times. In cerebrum, hindbrain and diencephalon, taurine dominated at early stages, but dropped after postnatal day 7, while myo-inositol, glutamine, creatine and glutamate increased after birth, with the latter two dominating in adults. In olfactory bulb, taurine content declined gradually with age and was equal to glutamate in adults. In all brain regions, glycerophosphorylcholine (GPC) reached a peak in juveniles. In postnatal renal medulla, urea, sodium, GPC, betaine, and taurine increased sharply at day 21. Thereafter, most increased, but taurine decreased. In heart, taurine dominated, and increased with age along with creatine and glutamine, while glutamate decreased after postnatal day 7. In lens, taurine dominated and declined in adults. These patterns are discussed in light of hypotheses on non-osmotic and pathological roles of these solutes.
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Affiliation(s)
- T J Miller
- Department of Biology, Whitman College, Walla Walla, WA 99362, USA
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