SATURDAY PRESENTATIONS

Transcription

1 Carolinas Chapter - American Association of Clinical Endocrinologists SATURDAY PRESENTATIONS 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

2 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 1

3 Joseph G. Verbalis: disclosures consultant: Cumberland, Ferring, Otsuka advisory board: Corcept, Otsuka data safety board: Ferring grant support: NIA, NCATS 2

4 hyponatremia: association with adverse outcomes 3

5 relationship between hospital admission serum [Na + ] and in-hospital mortality 0.20 Predicted Probability of In-Hospital Mortality St. Elizabeth s MC n = 53, Admission Serum [Na + ] Concentration (meq/l) Wald et al. Arch Intern Med 170: ,

6 hyponatremia on admission is associated with increased subsequent 30-day and 1-year mortality (279,508 acutely hospitalized patients in Denmark ) Holland-Bill et al. Eur J Endocrinol 173:71-81,

7 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,

8 hyponatremia: brain adaptation to hyponatremia 7

9 acute hyponatremia is associated with high morbidity and mortality acute chronic patients duration < 12 hrs 3 days serum [Na + ] 112 ± ± 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) 8

10 acute hyponatremia can cause death from cerebral edema and brain herniation normal brain hyponatremic brain Gross, Kidney Int 60: ,

11 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. 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. p[na + ] = 122 mmol/l drank Lucozade /Marathon-victim-died-drinking-MUCH-water.html 10

12 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 11

13 chronic hyponatremia is associated with much less severe symptomatology acute chronic patients duration < 12 hrs 3 days serum [Na + ] 112 ± ± 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) 12

14 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: ,

15 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: ,

16 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: , 1993 THIS IS NOT A NORMAL BRAIN! 15

17 hyponatremia: brain deadaptation: osmotic demyelination syndrome 16

18 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: ,

19 osmotic demyelination syndrome: clinical manifestations tremor incontinence hyperreflexia, pathological reflexes quadriparesis, quadriplegia dysarthria, dysphagia cranial nerve palsies mutism, locked-in syndrome 18

20 C3d immunohistochemical staining normonatremic rat hyponatremic rat, 24 hours after rapid correction 19

21 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,

22 patients at high risk of ODS Verbalis et al, Am J Med 126:S1-42,

23 lower [Na + ] and BUN levels predict greater rates of correction of hyponatremia with tolvaptan Morris et al, AJKD 71:772, 2018 n=28 patients with SIADH) 22

24 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,

25 guidelines for managing excessive corrections of hyponatremia to decrease risk of ODS Verbalis et al, Am J Med 126:S1-42,

26 hyponatremia: symptom-based treatment recommendations 25

27 treatments for hyponatremia isotonic saline infusion hypertonic saline infusion vaptan (conivaptan, tolvaptan) fluid restriction demeclocycline furosemide + NaCl mineralocorticoids urea vaptan (tolvaptan) short-term long-term 26

28 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 27

29 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

30 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: 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 29

31 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

32 hyponatremia can be caused by dilution from retained water, or by depletion from electrolyte losses in excess of water 31

33 U-Na+ excretion for identification of EABV with diuretics without diuretics Fenske W. et al, JCEM 92: ,

34 X Nielsen et al., JASN 10: ,

35 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 34

36 tolvaptan: SALT studies and SALT-WATER open label extension study Berl et al. J Am Soc Nephrol 4: ,

37 SALT: mean increases in serum [Na + ] after 30 d in patients with cirrhosis, HF, and SIADH Delta increase in serum Sodium (mmol/l) Control Tolvaptan * *P<.05 * * X cirrhosis HF SIADH Schrier et al. NEJM 355: ,

38 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: ,

39 7.4.3 Patients with SIAD Spasovzki G et al. Nephrol Dial Transplant 29:Suppl 2:i1-i39,

40 urea increases [Na + ] via an osmotic diuresis Sterns et al. Kidney Int 87:268-70,

41 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,

42 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 41

43 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 42

44 choice of appropriate initial therapy Verbalis et al, Am J Med 126:S1-42,

45 use of urine electrolytes to predict stringency of fluid restriction urine/plasma electrolyte ratio recommended fluid consumption >1.0 0 ml Up to 500 ml <0.50 Up to 1 L Furst H et al. Am J Med Sci 319: ,

46 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,

47 hyponatremia: effects of treatment on outcomes 46

48 hyponatremia improvement is associated with reduced risk of mortality Corona et al. PLOSone 10(4) Apr 23,

49 update of hyponatremia treatment guidelines first published in 2007 Verbalis et al, Am J Med 126:S1-42,

50 49