Workshop CME 22 mars Pr Alain SOUPART Service de Médecine Interne Général Cliniques Universitaires Erasme, Bruxelles

Transcription

1 Workshop CME 22 mars 2013 Pr Alain SOUPART Service de Médecine Interne Général Cliniques Universitaires Erasme, Bruxelles

2 Overcorrection of chronic hyponatremia

3 CASE REPORT I (1) Female 71 year Altered mental status < 5 days (bradypsychia) Nausea Vomiting Weakness gait disturbances Thiazide < 10 days for arterial hypertension Admission: confused, disoriented normal BP Laboratory data: - SNa 106 meq/l - SK meq/l Brain CT Scan normal

4 CASE REPORT I (2) Treatment Normal Saline 0.9% 1500 ml/24h KCl 80 meq/24h Evolution Serum Na Symptoms SNa (0) 106 mrq/l Normalization (24h) 125 meq/l +21 meq/l neurological status SK meq/l

5 CASE REPORT I (3) On Day 3: SNa 131 meq/l Confusional state Pyramidal syndrome Generalized hyperactive deep tendon reflexes, clonus and bilaterally upgoing toes Diagnosis? What to do now?

6 CASE REPORT I (4) : Brain myelinolysis (Osmotic Demyelination Syndrome) suspected Rescue Treatment Reinduction of hyponatremia: DDAVP 4 µg S.C. Oral water 1 l/1h then 1 l/4h + IV 5% DGlucose 1 l/24h SNa = -6 meq/2h -16 meq/14h SNa = 115 meq/l Brain MRI (30 days): normal

7 Soupart A, et al. Clin Nephrol 1999

8 Synopsis 1. Case reports (2) 2. Rationale for serum sodium re-lowering Mechanisms of brain adaptation to an osmotic stress ODS: risk factors ODS: pathogenesis 3. Situations at risk for overcorrection 4. Overcorrection is a medical emergency Sodium re-lowering: experimental data Sodium re-lowering: clinical experience 5. ODS prevention 6. ODS treatment 7. ERBP recommandations 8. Future

9 CASE REPORT II (1) Male 76 year Few days: General malaise Lethargic Disorientation On admission: SNa 106 meq/l K meq/l Brain CT scan large mass sella turcica pituitary apoplexy + adrenocortical insufficiency

10 CASE REPORT II (2) Treatment Hormone replacement Hydrocortisone 20 mg/day Thyroxin 50 µg/day Correction of hyponatremia IV Saline 0.9% (aim 10 meq/l/24h) Evolution Serum Na Symptoms SNa (0) 106 meq/l (12h) 111 meq/l (24h) 118 meq/l 12 meq/l/24h improvement consciousness (48h) 129 meq/l 11 meq/l/24h fully oriented

11 CASE REPORT II (3) On day 4: SNa 132 meq/l deterioration of consciousness rapidly comatous quadriparesis bilateral hyperreflexia Brain CT: normal : brain myelinolysis (ODS) suspected Rescue Treatment Reinduction of hyponatremia DDAVP (intranasal desmopressin) + 5% glucose IV 2 L/12h SNa -12 meq/l/12h SNa 120 meq/l Brain MRI (day 20): normal

12 Changes of serum sodium concentration and neurologic status Oya, S. et al. Neurology 2001;57:1931

13 Rationale for serum sodium re-lowering

14 ACUTE (< 48 hr) HYPONATREMIA

15 CHRONIC (> 48 hr) HYPONATREMIA Intracellular hyperionisation and OO depletion (5-7 days to reaccumulate) Apoptose of the astrocytes and oligodendrocytes degeneration ODS (or CPM) (Urea protect the cell from apoptosis)

16 BRAIN ELECTROLYTES Brain NaCl overshooting BRAIN ORGANIC OSMOLYTES

17 Osmotic Demyelination Syndrome (ODS) Major risk factors: Rate of correction of SNa in chronic hyponatremia > 10 meq/l/24h Incidence? Probably 30% but correlated with the magnitude of SNa above limit (experimental studies) Isolated cases after correction < 10 meq/l/24h Virtually all cases occurring in patients with initial SNa < 120 meq/l

18 Osmotic Demyelination Syndrome (ODS) Additional risk factors: Hypokalemia Thiazide use (female) Alcoholism Denutrition, anorexia nervosa Cirrhosis, liver transplantation (? Cyclosporine) Hypophosphoremia (?)

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21 Osmotic Demyelination Syndrome (ODS) Pathogenesis? Excessive brain dehydratation related to slow recovery of solutes lost initially (adaptative response overwhelmed by rapid correction) Shrinkage of brain cells Increased BBB permeability: secondary phenomenoninflammatory response to osmotic insult Toxicity of brain intracellular hyperionisation observed after treatment with NaCl, or water restriction/diuresis and Vaptans (Conivaptan, Satavaptan) but not with urea

22 Risk factors of overcorrection of hyponatremia (1) Excess NaCl administration: Caution with hypertonic saline use Potassium supplementation (SNa = Nae + Ke / H2O) Unexpected increase in electrolyte free water excretion (reversible impairment of renal water excretion) - Spontaneous hypoosmotic polyuria - ADH inhibition by volume expansion - High solute input

23 Risk factors of overcorrection of hyponatremia (2) Examples:. Hypovolemia. Beer potomania, tea and toast diet (increase solute intake). Diuretic withdrawal. Interruption of drugs causing SIADH (SSRI ). Potomania (acute + chronic HN), schizophrenia. Hormonal replacement (glucocorticoid deficiency). Discontinuation of DDAVP use (enuresia, incontinence)! Check urinary output

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25 REINDUCTION OF HYPONATREMIA IN ASYMPTOMATIC RATS AFTER OVERCORRECTION OF CHRONIC HYPONATREMIA SNa (meq/l) ASYMPTOMATIC OUTCOME SNa (24h) Symptoms Mortality Brain lesions (ODS) 32 (n = 26) 100% 80% 100% 25 (n = 8) 75% 38% 90% 15 (n = 22) 4% 4% 9% DAYS 0h HYPONA 1h 12h 14h 24h Time (hours) NaCl 3% DDAVP Hypotonic fluids Soupart A, et al. Kidney Int 1994 Soupart A, et al. J Neuropathol Exp Neurol 1996 Gankam F, et al. Kidney Int 2009

26 REINDUCTION OF HYPONATREMIA IN SYMPTOMATIC RATS AFTER OVERCORRECTION OF CHRONIC HYPONATREMIA SNa (meq/l) SYMPTOMATIC OUTCOME SNa (24h) Symptoms Mortality Brain lesions (ODS) 28 (n = 13) 100% 92% 100% (n = 15) 100% 53% 30% 100 Neurologic symptoms 95 3 DAYS 0h HYPONA 1h 12h 18h 24h Time (hours) NaCl 3% DDAVP Hypotonic fluids at time symptoms arise Soupart A, et al, J Neuropathol Exp Neurol 1996

27 SODIUM RE-LOWERING IN HYPONATREMIC PATIENTS WITH OVERCORRECTION ( SNA < 10 meq/l/24hr) WITHOUT PRE-EXISTENT NEUROLOGIC SYMPTOMS

28 SODIUM RE-LOWERING IN HYPONATREMIC PATIENTS WITH OVERCORRECTION ( SNA < 10 meq/l/24hr) AND PRE-EXISTENT NEUROLOGIC SYMPTOMS

29 ODS Prevention (1) Major points: Maintain SNa < 10 meq/l/24hr Close monitoring of SNa Strategy for controlled correction rate: combination of saline with DDAVP (ongoing study) Additional: Treatment of hyponatremia with Urea protects brain against ODS (mortality 13% vs 87% with NaCl) Large clinical experience. No cases of ODS reported Soupart et al. Clin Sci 1991; Soupart et al. JASN 2002; Soupart et al. Nephrol Dial Transpl 2007; Soupart et al. CJASN 2012 Dexamethasone (experimental studies) starting before NaCl (T0, T6h) Reduction neurological manifestations No effect of mortality Gankam et al. Kidney Int 2009

30 ODS Prevention (2) Additional: Minocycline (experimental studies) starting before NaCl (T12h) Reduction of mortality (80% 48%) Gankam et al. JASN 2010; Suzuki et al. JASN 2010 Infusion (IV) of Myo-Inositol (organic osmolyte) (experimental studies) Concomittant Myo-Inositol and NaCl infusion for 28 hours Reduction of mortality (87% 11%) Silver et al. J Neuropathol Exp Neurol 2006

31 µg/g dry brain weight µg/g dry brain weight µg/g dry brain weight Brain organic osmolytes content after correction of chronic hyponatremia with NaCl in normal rats (A), azotemic rats (B) or with urea (C) 30 NaCL: Mortality 80% 25 A MYO-I TAUR Gln ASP BET PEA Azotemia + NaCL: Mortality 20% B MYO-I TAUR Gln ASP BET PEA Urea: Mortality 13% C MYO-I (**) TAUR(**) Gln (**) ASP (**) BET (*,**) PEA (*,**) Soupart et al, JASN 2002

32 TREATMENT OF ODS Serum sodium re-lowering (highly efficient) No other available options - Gammaglobulins? (case report) - Plasmapheresis? (case report)

33 ERBP recommendations Reverse overshooting of a correction > 10 mmol/l/day Discontinue ongoing active treatment DDAVP 2 µg IV + 10 ml/kg/bw of free water over one hour Repeat DDAVP after 8 hours SNa measurement after 2 hours Adjust infusion of free water according to evolution of SNa and urine output Call for an expert

34 Serum Sodium re-lowering in patients after overcorrection of hyponatremia: prospective study (ongoing) (1) Indication: serum sodium re-lowering when: Goal: - SNa > 12 meq/l at any time during the first 24 hours of correction - and/or development of neurological signs or symptoms consistent with ODS - Reduce the level of correction ( SNa) under the critical level (< 10 meq/l/24h) considering the initial (before correction) SNa value - Maintain this safe SNa level during the next hours till the end of the first 24 hours of correction - Correction rate during the subsequent day(s) must remain lower than 10 meq/l/24h

35 Serum Sodium re-lowering in patients after overcorrection of hyponatremia: prospective study (ongoing) (2) Method: - Stop ongoing treatment of hyponatremia - Administration of DDAVP 4 µg s.c. or IV, one dose Second dose after 8 hours as appropriate - Administration of oral water 1 liter in 1 hour (it decreases the SNa from approximately 5 meq/l under DDAVP) Must be adapted to level of overcorrection (value of SNa about safe limit of 10 meq/l/24h) - Then 1 liter oral water or IV D-glucose 5% in water in 4 hours and - Then 1 liter IV D-glucose 5% in water during 24 hours to maintain the required level of natremia

36 Serum Sodium re-lowering in patients after overcorrection of hyponatremia: prospective study (ongoing) (3) Additional comments: - Volume administered will depend on initial level of overcorrection and kinetic of serum sodium - Monitoring of SNa 2 hours, 4 hours and 24 hours after starting re-lowering * * *