Carolinas Chapter - American Association of Clinical Endocrinologists SATURDAY HANDOUTS 2018 Annual Meeting September 7-9, 2018 Kiawah Island Golf Resort Kiawah Island, SC This continuing medical education activity is jointly provided by the Carolinas Chapter-AACE and Southern Regional Health Education Center
recent advances in the evaluation and treatment of hyponatremia Joseph G. Verbalis, MD Professor of Medicine and Physiology Chief, Endocrinology and Metabolism Director, Georgetown-Howard Universities Center for Clinical and Translational Science Georgetown University Washington, DC USA Joseph G. Verbalis: disclosures consultant: Cumberland, Ferring, Otsuka advisory board: Corcept, Otsuka data safety board: Ferring grant support: NIA, NCATS hyponatremia: association with adverse outcomes 1
relationship between hospital admission serum [Na + ] and in-hospital mortality 0.20 Predicted Probability of In-Hospital Mortality 0.15 0.10 0.05 St. Elizabeth s MC 2000-2007 n = 53,236 110 115 120 125 130 135 140 145 Admission Serum [Na + ] Concentration (meq/l) Wald et al. Arch Intern Med 170:294-302, 2010 hyponatremia on admission is associated with increased subsequent 30-day and 1-year mortality (279,508 acutely hospitalized patients in Denmark 2006-2011) Holland-Bill et al. Eur J Endocrinol 173:71-81, 2015 chronic hyponatremia is also associated with increased adverse outcomes increased mortality over a 12-year period of outpatient follow-up significantly increased risk of fracture Hoorn et al. J Bone Mineral Res 26:1822-8, 2011 2
hyponatremia: brain adaptation to hyponatremia acute hyponatremia is associated with high morbidity and mortality acute chronic patients 14 52 duration < 12 hrs 3 days serum [Na + ] 112 ± 2 118 ± 1 stupor or coma 100% 6% seizures 29% 4% mortality 50% 6% low [Na + ] deaths 36% 0% Arieff et al. Medicine 56:121, 1976 (hospital consults in one year; [Na + ]<128 mmol/l) acute hyponatremia can cause death from cerebral edema and brain herniation normal brain hyponatremic brain Gross, Kidney Int 60:2417-27, 2001 3
London marathon, April 22, 2007 A 22-year-old man died after completing his first London Marathon because he drank too much water. David Rogers collapsed at the end of the race and died yesterday in Charing Cross Hospital. p[na + ] = 122 mmol/l drank Lucozade Today it emerged the fitness instructor from Milton Keynes died from hyponatraemia, or water intoxication. This is when there is so much water in the body that it dilutes vital minerals such as sodium down to dangerous levels. It can lead to confusion, headaches and a fatal swelling of the brain. http://www.dailymail.co.uk/news/article- 450341/Marathon-victim-died-drinking-MUCH-water.html Hew-Butler et al. Br J Sports Med 49:1432, 2015 recommendations: drink only to thirst, no forced hydration or take USATF sweat test to gauge true fluid requirements decrease water/sport drink stops at endurance events point of care electrolyte testing at medical tent chronic hyponatremia is associated with much less severe symptomatology acute chronic patients 14 52 duration < 12 hrs 3 days serum [Na + ] 112 ± 2 118 ± 1 stupor or coma 100% 6% seizures 29% 4% mortality 50% 6% low [Na + ] deaths 36% 0% Arieff et al. Medicine 56:121, 1976 (hospital consults in one year; [Na + ]<128 mmol/l) 4
brain volume regulation 1. true loss of brain solute 2. can reduce or eliminate brain edema despite severe hypoosmolality 3. time dependent process Gullans & Verbalis Ann Rev Med 44:289-301, 1993 brain electrolyte and osmolyte losses after 7d of sustained hyponatremia nearly 1/3 of brain volume regulation occurs as a result of losses of organic osmolytes Gullans & Verbalis, Annu Rev Med 44:289-301, 1993 brain volume regulation 1. true loss of brain solute 2. can reduce or eliminate brain edema despite severe hypoosmolality 3. time dependent process Gullans & Verbalis Ann Rev Med 44:289-301, 1993 THIS IS NOT A NORMAL BRAIN! 5
hyponatremia: brain deadaptation: osmotic demyelination syndrome central pontine myelinolysis: white areas in the middle of the pons indicate massive demyelination of descending axons (corticobulbar and corticospinal tracts) Wright, Laureno & Victor Brain 102:361-385, 1979 osmotic demyelination syndrome: clinical manifestations tremor incontinence hyperreflexia, pathological reflexes quadriparesis, quadriplegia dysarthria, dysphagia cranial nerve palsies mutism, locked-in syndrome 6
C3d immunohistochemical staining normonatremic rat hyponatremic rat, 24 hours after rapid correction differentiating goals from limits of correction of hyponatremia re-lowering of serum [Na + ] is only recommended in patients with high risk of ODS Verbalis et al, Am J Med 126:S1-42, 2013 patients at high risk of ODS Verbalis et al, Am J Med 126:S1-42, 2013 7
lower [Na + ] and BUN levels predict greater rates of correction of hyponatremia with tolvaptan n=28 patients with SIADH) Morris et al, AJKD 71:772, 2018 rapid correction of hyponatremia occurs frequently, but ODS occurs rarely increase in [Na + ] >8 mmol/l/24h: 606/1490 = 41% osmotic demyelination by MRI: 8/1490 = 0.5% George et al, CJASN 13:984-92, 2018 guidelines for managing excessive corrections of hyponatremia to decrease risk of ODS Verbalis et al, Am J Med 126:S1-42, 2013 8
hyponatremia: symptom-based treatment recommendations treatments for hyponatremia isotonic saline infusion hypertonic saline infusion vaptan (conivaptan, tolvaptan) short-term fluid restriction demeclocycline furosemide + NaCl mineralocorticoids urea vaptan (tolvaptan) long-term symptomatic hyponatremia: neurological manifestations headache irritability nausea / vomiting mental slowing unstable gait / falls confusion / delerium disorientation stupor / coma convulsions respiratory arrest symptomatic but less impaired; usually chronic the degree of symptomatology is a surrogate for the duration of hyponatraemia life-threatening; usually acute 9
hyponatremia treatment algorithm based on neurological symptoms LEVEL 3 SEVERE SYMPTOMS: coma, obtundation, seizures, respiratory distress, vomiting ALL: hypertonic NaCl 1, followed by fluid restriction ± vaptan 2 1 some authors recommend simultaneous treatment with desmopressin to limit speed of correction. 2 no active therapy should be started within 24 hrs of hypertonic saline to decrease the chance of overly rapid correction of [Na + ] and risk of ODS. 28 hypertonic saline correction choose desired correction rate of plasma [Na + ] (e.g., 1.0 meq/l/h) obtain or estimate patient s weight (e.g., 70 kg) multiply weight X desired correction rate and infuse as ml/h of 3% NaCl (e.g., 70 kg X 1.0 meq/l/h = 70 ml/h infusion) OR: 100-200 ml bolus infusion (5-10 min) of 3% NaCl, repeat every 30 min until goal reached FOR ALL SALINE CORRECTIONS: follow serum [Na + ] and urine output every 2-4 hrs during the active correction hyponatremia treatment algorithm based on neurological symptoms LEVEL 3 SEVERE SYMPTOMS: coma, obtundation, seizures, respiratory distress, vomiting LEVEL 2 MODERATE SYMPTOMS: altered mental status, disorientation, confusion, unexplained nausea, gait instability ALL: hypertonic NaCl 1, followed by fluid restriction ± vaptan 2 HYPOVOLEMIC: solute repletion (isotonic NaCl iv or oral sodium replacement) 3 EUVOLEMIC: vaptan, limited hypertonic NaCl, or urea, followed by fluid restriction HYPERVOLEMIC: vaptan, followed by fluid restriction 1 some authors recommend simultaneous treatment with desmopressin to limit speed of correction. 2 no active therapy should be started within 24 hrs of hypertonic saline to decrease the chance of overly rapid correction of [Na + ] and risk of ODS. 3 with isotonic NaCl infusion, serum [Na+] must be followed closely to prevent overly rapid correction and risk of ODS due to secondary water diuresis. 30 10
hyponatremia can be caused by dilution from retained water, or by depletion from electrolyte losses in excess of water U-Na+ excretion for identification of EABV with diuretics without diuretics Fenske W. et al, JCEM 92:2991-2997, 2008 X Nielsen et al., JASN 10:647-663, 1999 11
diuresis: increased excretion of urine by the kidney; includes water and typically increased solute excretion as well aquaresis: increased excretion of water by the kidney without increased solute, i.e., electrolyte-sparing excretion of free water by the kidney tolvaptan: SALT studies and SALT-WATER open label extension study Berl et al. J Am Soc Nephrol 4:705-712, 2010 SALT: mean increases in serum [Na + ] after 30 d in patients with cirrhosis, HF, and SIADH Delta increase in serum Sodium (mmol/l) 8 7 6 5 4 3 2 1 0 Control Tolvaptan * *P<.05 * * X cirrhosis HF SIADH Schrier et al. NEJM 355:2099-2112, 2006 12
osmotic demyelination syndrome (ODS) one case of CPM has been reported following correction of hyponatremia using a vaptan as monotherapy in >5,000 patients to date; two cases of ODS have been reported with combined use of tolvaptan and hypertonic (3%) NaCl Wright, Laureno & Victor. Brain 102:361-385, 1979 7.4.3 Patients with SIAD Spasovzki G et al. Nephrol Dial Transplant 29:Suppl 2:i1-i39, 2014 urea increases [Na + ] via an osmotic diuresis Sterns et al. Kidney Int 87:268-70, 2015 13
hyponatremia (HN) registry: initial therapies utilized in patients with a clinical diagnosis of SIADH salt tabs utilized in 8% Greenberg et al. Kidney Int 88:167-77, 2015 salt tablets can also increase [Na + ] via an osmotic diuresis urea: 30g = 500 mosmols NaCl tabs: 1g = 34 mosmols how many salt tablets does it take to equal the osmotic diuresis of 30g of urea? 500/34 = 15g of NaCl hyponatremia treatment algorithm based on neurological symptoms LEVEL 3 SEVERE SYMPTOMS: coma, obtundation, seizures, respiratory distress, vomiting LEVEL 2 MODERATE SYMPTOMS: altered mental status, disorientation, confusion, unexplained nausea, gait instability ALL: hypertonic NaCl 1, followed by fluid restriction ± vaptan 2 HYPO: solute repletion (isotonic NaCl iv or oral sodium replacement) 3 EU: vaptan, limited hypertonic NaCl, or urea, followed by fluid restriction HYPER: vaptan, followed by fluid restriction ALL: fluid restriction LEVEL 1 NO OR MINIMAL SYMPTOMS: difficulty concentrating, irritability, altered mood, depression, unexplained headache 42 14
choice of appropriate initial therapy Verbalis et al, Am J Med 126:S1-42, 2013 use of urine electrolytes to predict stringency of fluid restriction urine/plasma electrolyte ratio recommended fluid consumption >1.0 0 ml 0.5 1.0 Up to 500 ml <0.50 Up to 1 L Furst H et al. Am J Med Sci 319:240-244, 2000 success rates in treating hyponatremia by physicians in the HN Registry diagnosis & treatment Δ[Na + ] 5 mmol/l [Na + ] 130 mmol/l [Na + ] 135 mmol/l SIADH, no rx (n=168) 41% 45% 20% SIADH, FR (n=625) 44% 29% 10% SIADH, NS (n=384) 36% 20% 4% SIADH, tolvaptan (n=183) 78% 74% 40% SIADH, 3% NaCl (n=78) 60% 25% 13% at discharge, serum [Na + ] was <135 mmol/l in 75% of patients, and 130 mmol/l in 43% of patients Verbalis et al. Am J Med 129(5):537.e9-537.e23, 2016 15
hyponatremia: effects of treatment on outcomes hyponatremia improvement is associated with reduced risk of mortality Corona et al. PLOSone 10(4) Apr 23, 2015 update of hyponatremia treatment guidelines first published in 2007 Verbalis et al, Am J Med 126:S1-42, 2013 16
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