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Dysnatremia: A Clear and Present Risk for Surgery
EDITORIAL
Dysnatremia: A Clear and Present Risk for Surgery SEE RELATED ARTICLE p. 877
Serum sodium (Na) levels have been increasingly valued in medical practice. Dysnatremia is associated with increased mortality and morbidity in patients in medical wards, intensive care units, and nursing homes.1,2 In this issue of the Journal, Leung et al3 report for the first time that preoperative hypernatremia is associated with increased perioperative complications. Together with their sister article on preoperative hyponatremia and perioperative complications using the same cohort data from the American College of Surgeons National Surgical Quality Improvement Program, the authors convincingly demonstrate that both hyponatremia and hypernatremia, even in mild form, are associated with increased 30-day mortalities, postoperative major coronary events, and pneumonia (Figure 1).3,4 These studies involved 300 academic and community hospitals nationwide, with data drawn from approximately 1 million patients. The statistical power is exceptionally strong compared with similar articles in the surgical field. Overall, approximately 2% and 0.2% patients had mild and moderate-severe hypernatremia and 6.9% and 0.9% had mild and moderate-severe hyponatremia, respectively. Of note, both crude rate (Figure 1A) and adjusted odds ratio (Figure 1B) against preoperative serum level show an approximately symmetric U shape for all 3 events. The crude mortality rate is 4.1% and 18.2% for mild and moderate-severe hypernatremia and 4.6% and 9.6% for mild and moderate-severe hyponatremia, respectively (Figure 1A). These high mortality rates in part are due to the fact that those with dysnatremia tend to be older, sicker, and more functionally dependent. After adjusting confounding factors, the risk of postoperative death is 1.31 and 2.03 for mild and moderate-severe hypernatremia and 1.38 and 1.72 for mild and moderate-severe hyponatremia, respectively (Figure 1B).3,4 Needless to say, these 2 articles provide important scientific bases for surgeons to discuss surgical
risks with patients with dysnatremia. Furthermore, the information derived from these studies can be incorporated into a comprehensive score system for better estimation of surgical risk for individual patients. Why do patients with dysnatremia have a poorer prognosis when they go to the operation room? Are serum Na levels directly related to surgical risk or simply a biomarker for overall sickness? Kleinewietfeld et al5 recently reported that NaCl induces interleukin-17 producing helper T (TH17) cells, the key T cells that mediate tissue inflammation, autoimmunity, and host defense. They found that adding NaCl 10-40 mmol/L to cultured media increased TH17 cells in a dose-dependent fashion. NaCl does not increase other helper T cells, such as TH1 and TH2 cells. Furthermore, the induction of TH17 is via the transcription factor, nuclear factor of activated T cells 5, also named “tonicity responsive element binding protein.” The tonicity responsive element binding protein was initially identified by Miyakawa et al6 while investigating transcription stimulated by hypertonicity. Subsequently, the nuclear factor of activated T cells 5 was cloned and found to be identical to tonicity responsive element binding protein.7 The NaCl effects on TH17 cells
Funding: None. Conflict of Interest: None. Authorship: The author is solely responsible for the content of this manuscript.
Figure 1 Dysnatremia is associated with an increased crude rate (A) and odds ratio (B) in surgical patients. Data are taken from 2 articles by Leung3 and Leung et al.4
0002-9343/$ -see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2013.04.023
850
The American Journal of Medicine, Vol 126, No 10, October 2013
are demonstrated in vivo with the experimental autoimmune encephalomyelitis, a mouse model of human multiple sclerosis. When mice are fed a high salt diet, there are more TH17 cells in both the central nervous system and the spleen, and they develop more severe diseases.5 It is too early to link the induction of TH17 cells to the poor prognosis associated with hypernatremia. However, we may entertain the idea that the tonicity responsive element binding protein/nuclear factor of activated T cells 5 could be the missing link for the poor outcomes due to dysnatremia. This transcription factor has been demonstrated in a variety of cells, including renal epithelial cells, T cells, neurons, cardiomyocytes, vascular smooth muscle cells, and others. It can be regulated by tonicity-dependent or independent fashions. Its activation induces various physiologic or pathophysiologic events.8,9 Like a double-edged sword, the tonicity responsive element binding protein/nuclear factor of activated T cells 5 activation may do harm or good to the body. For example, although it induces heat shock protein 70, which protects cells from apoptosis,8 its triggering of TH17 cells causes tissue damage and autoimmunity.5 Furthermore, there are still unidentified biological reactions regulated by this transcription factor. Therefore, theoretically, depending on situations and individuals, activation of tonicity responsive element binding protein/nuclear factor of activated T cells 5 by hypernatremia or its inactivation by hyponatremia could be detrimental. Further studies are needed to test this hypothesis. Regardless of the pathogenesis of dysnatremia-associated perioperative complications, given the significant surgical risks, it is reasonable to identify the cause of dysnatremia and attempt to correct it before surgery, if time allows.
Yeong-Hau H. Lien, MD, PhDa,b a
Department of Medicine College of Medicine University of Arizona Tucson b Arizona Kidney Disease and Hypertension Center Tucson
References 1. Lien YH, Shapiro JI. Hyponatremia: clinical diagnosis and management. Am J Med. 2007;120:653-658. 2. Adrogue HJ, Madias NE. Hypernatremia. N Engl J Med. 2000;342: 1493-1499. 3. Leung AA, McAlister FA, Finlayson SRG, Bates DW. Preoperative hypernatremia predicts increased perioperative morbidity and mortality. Am J Med. 2013;126:877-886. 4. Leung AA, McAlister FA, Rogers SO Jr, Pazo V, Wright A, Bates DW. Preoperative hyponatremia and perioperative complications. Arch Intern Med. 2012;172:1474-1481. 5. Kleinewietfeld M, Manzel A, Titze J, et al. Sodium chloride drives autoimmune disease by the induction of pathogenic T17 cells. Nature. 2013;496:518-522. 6. Miyakawa H, Woo SK, Dahl SC, Handler JS, Kwon HM. Tonicityresponsive enhancer binding protein, a rel-like protein that stimulates transcription in response to hypertonicity. Proc Natl Acad Sci U S A. 1999;96:2538-2542. 7. Lopez-Rodriguez C, Aramburu J, Rakeman AS, Rao A. NFAT5, a constitutively nuclear NFAT protein that does not cooperate with Fos and Jun. Proc Natl Acad Sci U S A. 1999;96:7214-7219. 8. Jeon US, Kim JA, Sheen MR, Kwon HM. How tonicity regulates genes: story of TonEBP transcriptional activator. Acta Physiol (Oxf). 2006;187: 241-247. 9. Halterman JA, Kwon HM, Wamhoff BR. Tonicity-independent regulation of the osmosensitive transcription factor TonEBP (NFAT5). Am J Physiol Cell Physiol. 2012;302:C1-C8.
Dysnatremia: A Clear and Present Risk for Surgery SEE RELATED ARTICLE p. 877
Serum sodium (Na) levels have been increasingly valued in medical practice. Dysnatremia is associated with increased mortality and morbidity in patients in medical wards, intensive care units, and nursing homes.1,2 In this issue of the Journal, Leung et al3 report for the first time that preoperative hypernatremia is associated with increased perioperative complications. Together with their sister article on preoperative hyponatremia and perioperative complications using the same cohort data from the American College of Surgeons National Surgical Quality Improvement Program, the authors convincingly demonstrate that both hyponatremia and hypernatremia, even in mild form, are associated with increased 30-day mortalities, postoperative major coronary events, and pneumonia (Figure 1).3,4 These studies involved 300 academic and community hospitals nationwide, with data drawn from approximately 1 million patients. The statistical power is exceptionally strong compared with similar articles in the surgical field. Overall, approximately 2% and 0.2% patients had mild and moderate-severe hypernatremia and 6.9% and 0.9% had mild and moderate-severe hyponatremia, respectively. Of note, both crude rate (Figure 1A) and adjusted odds ratio (Figure 1B) against preoperative serum level show an approximately symmetric U shape for all 3 events. The crude mortality rate is 4.1% and 18.2% for mild and moderate-severe hypernatremia and 4.6% and 9.6% for mild and moderate-severe hyponatremia, respectively (Figure 1A). These high mortality rates in part are due to the fact that those with dysnatremia tend to be older, sicker, and more functionally dependent. After adjusting confounding factors, the risk of postoperative death is 1.31 and 2.03 for mild and moderate-severe hypernatremia and 1.38 and 1.72 for mild and moderate-severe hyponatremia, respectively (Figure 1B).3,4 Needless to say, these 2 articles provide important scientific bases for surgeons to discuss surgical
risks with patients with dysnatremia. Furthermore, the information derived from these studies can be incorporated into a comprehensive score system for better estimation of surgical risk for individual patients. Why do patients with dysnatremia have a poorer prognosis when they go to the operation room? Are serum Na levels directly related to surgical risk or simply a biomarker for overall sickness? Kleinewietfeld et al5 recently reported that NaCl induces interleukin-17 producing helper T (TH17) cells, the key T cells that mediate tissue inflammation, autoimmunity, and host defense. They found that adding NaCl 10-40 mmol/L to cultured media increased TH17 cells in a dose-dependent fashion. NaCl does not increase other helper T cells, such as TH1 and TH2 cells. Furthermore, the induction of TH17 is via the transcription factor, nuclear factor of activated T cells 5, also named “tonicity responsive element binding protein.” The tonicity responsive element binding protein was initially identified by Miyakawa et al6 while investigating transcription stimulated by hypertonicity. Subsequently, the nuclear factor of activated T cells 5 was cloned and found to be identical to tonicity responsive element binding protein.7 The NaCl effects on TH17 cells
Funding: None. Conflict of Interest: None. Authorship: The author is solely responsible for the content of this manuscript.
Figure 1 Dysnatremia is associated with an increased crude rate (A) and odds ratio (B) in surgical patients. Data are taken from 2 articles by Leung3 and Leung et al.4
0002-9343/$ -see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2013.04.023
850
The American Journal of Medicine, Vol 126, No 10, October 2013
are demonstrated in vivo with the experimental autoimmune encephalomyelitis, a mouse model of human multiple sclerosis. When mice are fed a high salt diet, there are more TH17 cells in both the central nervous system and the spleen, and they develop more severe diseases.5 It is too early to link the induction of TH17 cells to the poor prognosis associated with hypernatremia. However, we may entertain the idea that the tonicity responsive element binding protein/nuclear factor of activated T cells 5 could be the missing link for the poor outcomes due to dysnatremia. This transcription factor has been demonstrated in a variety of cells, including renal epithelial cells, T cells, neurons, cardiomyocytes, vascular smooth muscle cells, and others. It can be regulated by tonicity-dependent or independent fashions. Its activation induces various physiologic or pathophysiologic events.8,9 Like a double-edged sword, the tonicity responsive element binding protein/nuclear factor of activated T cells 5 activation may do harm or good to the body. For example, although it induces heat shock protein 70, which protects cells from apoptosis,8 its triggering of TH17 cells causes tissue damage and autoimmunity.5 Furthermore, there are still unidentified biological reactions regulated by this transcription factor. Therefore, theoretically, depending on situations and individuals, activation of tonicity responsive element binding protein/nuclear factor of activated T cells 5 by hypernatremia or its inactivation by hyponatremia could be detrimental. Further studies are needed to test this hypothesis. Regardless of the pathogenesis of dysnatremia-associated perioperative complications, given the significant surgical risks, it is reasonable to identify the cause of dysnatremia and attempt to correct it before surgery, if time allows.
Yeong-Hau H. Lien, MD, PhDa,b a
Department of Medicine College of Medicine University of Arizona Tucson b Arizona Kidney Disease and Hypertension Center Tucson
References 1. Lien YH, Shapiro JI. Hyponatremia: clinical diagnosis and management. Am J Med. 2007;120:653-658. 2. Adrogue HJ, Madias NE. Hypernatremia. N Engl J Med. 2000;342: 1493-1499. 3. Leung AA, McAlister FA, Finlayson SRG, Bates DW. Preoperative hypernatremia predicts increased perioperative morbidity and mortality. Am J Med. 2013;126:877-886. 4. Leung AA, McAlister FA, Rogers SO Jr, Pazo V, Wright A, Bates DW. Preoperative hyponatremia and perioperative complications. Arch Intern Med. 2012;172:1474-1481. 5. Kleinewietfeld M, Manzel A, Titze J, et al. Sodium chloride drives autoimmune disease by the induction of pathogenic T17 cells. Nature. 2013;496:518-522. 6. Miyakawa H, Woo SK, Dahl SC, Handler JS, Kwon HM. Tonicityresponsive enhancer binding protein, a rel-like protein that stimulates transcription in response to hypertonicity. Proc Natl Acad Sci U S A. 1999;96:2538-2542. 7. Lopez-Rodriguez C, Aramburu J, Rakeman AS, Rao A. NFAT5, a constitutively nuclear NFAT protein that does not cooperate with Fos and Jun. Proc Natl Acad Sci U S A. 1999;96:7214-7219. 8. Jeon US, Kim JA, Sheen MR, Kwon HM. How tonicity regulates genes: story of TonEBP transcriptional activator. Acta Physiol (Oxf). 2006;187: 241-247. 9. Halterman JA, Kwon HM, Wamhoff BR. Tonicity-independent regulation of the osmosensitive transcription factor TonEBP (NFAT5). Am J Physiol Cell Physiol. 2012;302:C1-C8.