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Régulation de la natrémie : des concepts physiopathologiques à la pratique clinique Bertrand Souweine, Clermont-Ferrand.

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Présentation au sujet: "Régulation de la natrémie : des concepts physiopathologiques à la pratique clinique Bertrand Souweine, Clermont-Ferrand."— Transcription de la présentation:

1 Régulation de la natrémie : des concepts physiopathologiques à la pratique clinique Bertrand Souweine, Clermont-Ferrand

2 Concepts physiopathologiques

3 NATREMIE Taux de sodium dans le sang (Larousse, 1997) Natrémie est mesurée habituellement dans le sérum Natrémie exprimée en millimol/L Raisonnement : / Kg H 2 O plasmatique en milliosmol

4 Rappels physiopathologiques Osmolarité : nb osmol / kg de plasma Osmolalité : nb osmol / kg deau Aquaporines Prix Nobel de chimie 2003

5 H 2 O Na

6 Rappels physiopathologiques Leau diffuse librement entre les compartiments Leau diffuse librement à travers la plupart des membranes Certaines molécules (urée éthanol) diffusent également librement Tonomoles : molécules non librement diffusibles Les tonomoles induisent un gradient osmotique transfert deau

7 Eau diffuse pour égaliser [molécules] pression osmotique A léquilibre, la pression osmotique est partout identique H2OH2O Tonomoles A, B, AB, C N=12 A B B B A AB A B C A A A 4 tonomoles dans compartiment 2 (C2) 8 tonomoles dans compartiment 1 (C1) Nb Tonomole C1 /Vol C1 = Nb Tonomole C2 / Vol C2 8 / Vol C1 = 4 / Vol C2 Vol C1 / Vol C2 = 2 H2OH2O Transfert deau entre C1 et C2 [tonomole] C1 = [tonomole] C2

8 Eau diffuse pour égaliser [molécules] A léquilibre, la pression osmotique est partout identique A B B B A AB A B C A A A H2OH2O 4 tonomoles / unité de volume Urée N=12 Urée Osmolalité = 8 / unité de volume

9 60% Poids Extra cellulaire 1/3 Intra cellulaire 2/3 Secteur interstitiel 3/4 Secteur vasculaire 1/4 Secteur Cellulaire Compartiments hydriques Eau : 2/3 du poids de lorganisme

10 Verbalis 2003 Schematic representation of body fluid compartments in man a 70-kg adult

11 Osmolalité Na e + K e = H 2 O totale Osmolalité Solutés EC + Soluté IC = H 2 O totale = 285 mosmol/kgH 2 O Na + > 90% Solutés EC K + > 90% Solutés IC Osmolalité 2 x (Na e + K e ) = H 2 O totale A léquilibre, losmolalité est partout identique P Osmol = Interstitiel osmol = Cell osmol P Na reflète losmolalité

12

13 Si numérateur constant [2x(Na e +K e )] osmolalité inverse du dénominateur H 2 O totale Osmolalité reflète lhydratation cellulaire P Na reflète lhydratation cellulaire Si P Osmol (P NA ) ; et 2x(Na e +K e )= constant ; H 2 O totale Hypernatrémie reflète une deshydratation cellulaire Osmolalité reflète H 2 O totale Si P Osmol (P NA ) ; et 2x(Na e +K e )= constant ; H 2 O totale Hyponatrémie reflète une hyperhydratation cellulaire

14 Si Osmolalité constante toute osm EC // de VEC Osmolalité reflète H 2 O totaleCapital Na reflète VEC osm EC 2 x Na ; capital Na reflète VEC Si osm EC [capital Na] et P osmol = Constant VEC

15 Shiau YF, Ann Intern Med 1985 Les sorties de Na de K et deau sont réglées au niveau du rein Adaptation du capital Na pour maintenir la volémie Adaptation de la tonicité pour maintenir le volume cellulaire

16 Proximal convoluted tubule Short loop nephron: absence of thin ascending limb 70-80% of human nephrons Long loop nephron Distal convoluted tubule Connecting tubule Collecting duct Thin descending limb Thick ascending limb Thin ascending limb

17 apical basal Réabsorption tubulaire NaCl

18 Proximal tubule Isoosmotic to plasma: water is isoosmotically reabsorbed Na+is the major driving force Fluid volume entering the bend: upper limit of the urine flow if no further water reabsorpsion occurs Thick ascending limb: diluting segment: separation of solutes from water Na + /K + /2Cl - Impermeable for water: osmolality decreases along the lenght Ascending limbs: impermeable for water Thin decending limb permeable for water (AQP1) solute impermeable

19 From fish to philosopher: the story of our environment Smith H 1953 The early provertebrates resided in a salt water environementwhose composition was similar to that of their own extracellular fluid. Therefore these animals could ingest salt water freely without altering the composition of their miluieu interieur

20 As early vertebrates migrated into freshwater streams the development of a more water impermeable tegument was necessary to avoid fluid dilution by the hypoosmotic fresh water environement

21

22 the concentrating capacity of the mammalian kidney contributed to the evolution of various biologic species including man. the glomerulus developed enabling the fish to filtrate excess fluid from the blood the subsequent development of the tubule in vertebrates was seminal for preservation of sodium and excretion af excess solute-free water

23 Mécanisme de concentration à contre courant daprès Rose BD

24 The water permeability of the collecting tubules is extremely low but increases in the presence of AVP daprès Rose BD

25 Basolateral membrane Urin e Apical membrane San g Distal tube of the nephron V2 Gs cAMPATP PKA Adenylate cyclate C-terminus phosphorylation of AQP-2 AQP-2 insertion Cytosolic storage vesicles AVP H2O H2O

26

27 Thick ascending limb Reabsorption of Na + /K + /Cl - Increase in interstitium tonicity Delivery of hypotonic fluid to distal tube Urea poorly reabsorbed and retained in the tubule Under vasopressin, tubular fluid equlibrates with the hypertonic interstitium low urea permeability allow its concentration to increase Urea is reabsorbed and constitutes a significant component of the medullar interstitial tonicity The increase in interstitial tonicity creates the obsmotic gradient that abstracts water from the descending limb [Na] in the tubular > interstitium passive reabsorption of NaCl in the water impermeable thin ascending limb Model of urinary concentration

28 Cl - /Na + Generation of medullary hypertonicity by normal functioning of thick ascending limb urea delivery normal medullar blood flow Mechanisms of urine concentration Cl - /Na + reabsorption Loop diuretics, osmotic diuretics, interstitial disease H 2 O Na + /Cl - Glomerular filtration by age, renal disease delivery of water determined by glomerular filtration rate, proximal tubule H 2 O and solute reabsorption H2OH2O Na + /Cl - Thiazide: no impact on concentrating capacity ureamembranes permeable to urea [urea] medullary urea movement into the medulla dietary intake of protein AVP release/action: nephrogenic or central diabetes insipidus vasopressinH2OH2O

29 Mechanisms of urine dilution Cl - /Na + Cl - /Na + reabsorption loop diuretics, osmotic diuretics, interstitial disease Collecting duct impermeable to water in absence of vasopressin or other antidiuretic substances water permeability by AVP, drugs age, volume depletion, CHF, cirrhosis, nephrotic syndrome Glomerular filtration H 2 O Na + /Cl - delivery of water determined by glomerular filtration rate, proximal tubule H 2 O reabsorption and Na + /Cl - reabsorption Thiazide diuretics Na + /Cl - reabsorption alter diluting capacity not concentrating capacity Na + /Cl -

30 Adaptation de la tonicité 1% de osmolalité mécanisme dadaptation Contrôle des entrées : soif Contrôle des sorties : excrétion rénale H 2 O régie par lADH Sécrétion dADH : 2 stimuli Hypovolémie et Hypotension indépendamment de la tonicité Hypertonie plasmatique Rein : réabsorption/sécrétion H 2 O et Na indépendamment 50 mosmol/L

31 daprès Robertson GL AVP secretion in response to increases in plasma osmolality versus decreases in blood volume or blood pressure in human subjects

32 daprès Robertson GL Relationship between plasma AVP concentrations and plasma osmolality under conditions of varying blood volume and pressure

33 1.11 Plasma water sodium : [Na+] pw [Na+] pw = 1.11(Na e + K e )/TBW

34 Total body water osmolality = plasma water osmolality [Na + ] pw = 1.11(Na e + K e )/TBW G/ Ø = slope [Na + ] pw = G/ Ø(Na e + K e )/TBW - y-intercept = Nguyen, AmJ Physiol Ren Physiol 2004

35 [Na + ] pw = 1.11(Na e + K e )/TBW [Na + ] pw = G/ Ø.(Na e + K e )/TBW - Ø: effectiveness of ions as independent osmotically active particles Osmotic coefficient for NaCl = 0.93 and for NaHCO 3 = 0.96 [104/128 x 0.93] + [24/128 x 0.96] Ø = 0.94 Nguyen, AmJ Physiol Ren Physiol 2004

36 Both K e and [K + ] pw must independently affect [Na + ] pw ECFICF K e in a 70-kg man, TBW = 42 liters, K ICF = 3,750 mmol (150 mmol/l x 25 liters) K ISF = 62 mmol (4.4 mmol/l x 14 liters) K Pl = 14 mmol (4.6 mmol/l x 3 liters) Quantitatively, K e will have a net incremental effect on the [Na + ] pw K e and [K + ] PW Nguyen, AmJ Physiol Ren Physiol 2004

37 y-intercept = Nguyen, AmJ Physiol Ren Physiol 2004

38 Titze J, AJKD 2002 do not contribute to the distribution of water between the EC and IC spaces failure to consider osmotically inactive Na e and K e will result in an overestimation of [Na + ] pw Nguyen, AmJ Physiol Ren Physiol 2004

39 Osmol ECF = osmotically active, extracellular non-Na + and non-K + osmoles Osmol ICF = osmotically active, intracellular non-Na + and non-K + osmoles osmol ICF will tend to increase [Na + ] pw osmol Pl tend to lower [Na + ] pw osmol ECF + osmol ICF will tend to increase [Na + ] pw V Pl = 1/5 de VEC osmol ECF will tend to increase [Na + ] pw Nguyen, AmJ Physiol Ren Physiol 2004

40 Plasma water non-Na + and non-K + osmoles: glucose, Ca 2+, Mg 2+, Cl - … Plasma water non-Na + and non-K + osmoles: glucose, Ca 2+, Mg 2+, Cl - … will have a dilutional effect by obligating the retention of water in the plasma space Nguyen, AmJ Physiol Ren Physiol 2004

41 Physiological parameters that determine [Na + ] PW Parameter G/Ø (Na e + K e )/TBW (Na osm inactive + K osm inactive )/TBW (osmol ECF + osmol ICF )/TBW [K + ] PW osmol PW /V PW Effect of increase in the parameter on [Na + ] PW Kurt I, Kidney int 2005

42 Quantification of renal water excretion C osmol = osmolar clairance volume needed to excrete solutes at the the concentration of solutes in the plasma C water = volume of free-solute water that had been added or subtracted from the isotonic portion of the urine (C osmol ) to create either hypotonic or hypertonic urine V = urine volume U osmol osmol urine = U osmol x V P osmol C osmol = Volume of urine Isotonic to plasma C water = free solute water

43 Quantification of renal water excretion C water = V x (1-U osmol /P osmol ) V = C osmol + C water C water = V - C osmol C osmol = (U osmol x V)/P osmol C water = V - (U osmol x V)/P osmol = V x (1-U osmol /P osmol ) Hypotonic urine = U osmol 0 Isotonic urine = U osmol = P osmol and C water = 0 Hypertonic urine = U osmol > P osmo l and C water < 0 Excretion of free water in a polyuric patient without water intake: the patient become hypernatremic Failure to ecrete free water in settings of increase water intake: the patient become hyponatremic

44 Quantification of renal water excretion U urea is a major component of U osmol urea crosses cell membrane readily urea do not influence P Na and vasopressin release

45 P osmol = 310 mosmolKg, P Na = 144 mmol/L U osmol = 620 mosmol, U Na = 5 mmol/L, U K = 43 mmol/L Diurèse = 1 L Osmol U V C water = V x (1-U osm /P osm ) = 1 x (1-620/310) = 1 x (1-2) = -1 litre Réponse rénale est-elle vraiment adéquate ? C water (e)= V x (1-[U Na +U K /P Na] ) C water (e)= 1 x (1-[5+43/144]) = 1x (1-0.33) = litre La réponse rénale est inadéquate = Posmol C osmol = +C water +

46 Quantification of renal water excretion C water (e)= V x (1-[U Na +U K ] / P Na )

47 Plasma osmol mOsmol/KgH 2 O Decrease Suppression of thirst Suppression of vasopressin Increase Stimulation of thirst Stimulation of vasopressin Dilute urine Disorder involving urine dilution with water intake Hyponatremia Disorder involving urine concentration with water intake Hypernatremia Concentrated urine Parikh C

48 Dysnatrémie en pratique clinique

49 Palewsky PM Ann Intern Med 1996 P Na >150 mmol/L in 0.2% of the 7836 patients admitted to a general hospital during a 3-month study period Hypernatremia P Na > 144 (?)

50 Primary Diagnoses for Patients with Hypernatremia P Na >150 mmol/L Palewsky PM Ann Intern Med 1996

51

52 Outcome Data Palewsky PM Ann Intern Med 1996 In 14 patients (14%), hypernatremia was judged to have contributed to associated morbidity and decreased functional status at hospital discharge

53 Polderman KH CCM 1999 P Na > 149 mmol/L 8.7%5.7% Dans cette étude, pas dimpact pronostique de lhypernatrémie présente à ladmission SAPS II P Na >144 1 point !

54 Hypernatremia Assess volume status Euvolemia (no edema) total body water no change in total body Na Hypovolemia total body water ++ total body Na Hypervolemia total body water total body Na ++ U Na analysis < 20 mmol/L variable > 20 mmol/L

55 Extra renal losses Vomiting Diarrhea Excess sweating Fistulae < 20 mmol/L Hypernatremia Renal losses Osmotic or loop diuretics Postobstruction Intrinsic renal disease Assess volume status Hypovolemia total body water ++ total body Na U Na analysis > 20 mmol/L Parikh C Hypervolemia total body water total body Na ++ > 20 mmol/L Sodium gains Primary hyper- aldosteronism Cushing Hypertonic dialysis fluid infusion Euvolemia (no edema) total body water no change in total body Na Renal losses Diabetes insipidus Hypodypsia variable Extra renal losses Respiratory dermal

56 Hyponatrémie P Na <136 mmol/L, Adrogué HJ, NEJM 2000 P Na <134 mmol/L, Yeates KE, CMAJ 2004

57 Relationship between P Na and [Na + ] PW Y intercept Na osm active volemia (hypovolemia, euvolemia, hypervolemia) C water (e) measure U Na

58 Relationship between P Na and [Na + ] PW

59 Idem avec triglycérides, mannitol, éthanol, méthanol, éthylène glycol… Isotonic hyponatremia

60 Isotonic fluid isotonic mannitol… Retention of large amounts of isotonic fluid Occurrence without any transmembrane shift in water

61 Hypertonic hyponatremia H2OH2O Solutes confined to the extracellular compartment: hyperglycemia, hypertonic mannitol… Shift of water from inside cells to the extracellular space

62 Sick cell syndrome Flear and Singh 1973 Solutés Hyponatrémie avec TO élargi Guglielminotti, CCM 2002 Guglielminotti CCM 2003 Gill, Clin Biochem patients consécutifs avec P Na <130 mmol/L ; 22/55 TO élargi 23 opérations du genou consécutives, G1 (N=19) Na > -2 mmol/L et Posmol + G2 (N=14) Na < -2 mmol/L EFW non différents entre G1 et G2 19 patients consécutifs PNa 7 mosmol/kg Anomalies mb lymphocytaire sans // avec osmol

63 Hoorn NDT 2006

64 Aux urgences (St Antoine) sur passages en 2001, (Offenstadt 2003) P Na <130 mmol/L, 1.5% P Na <120 mmol/L, 0.2% Aux urgences (Lee 2000) sur 3784 P Na < 130 mmol/L, 0.4% En réanimation (St Antoine) sur 865 admissions en 2001, (Offenstadt 2003) P Na <130 mmol/L, 14.8% P Na <120 mmol/L, 2.1% Cub-Réa ; patients, 1332 (1.4%) P Na <121 mmol/L Hyponatrémie, incidence

65 4123 patients de gériatrie (Terzian 1994) Hyponatrémie : 16% de décès hospitalier vs 8% (RR=1.95) 184 patients avec (Ellis SJ, 1995) P Na < 120 mmol/L Coma : 11% ; DC attribuable : 4.3% 435 insuffisants cardiaques (Chin 1996) P Na < 135 mmol/L, OR décès hospitalier : 2.2 [ ] ; DDS allongée 171 insuffisants cardiaques (Krumholz 1999) DDS allongée 168 patients (Nzerue 2003) P Na < 115 mmol/L 52.9% symptomatiques 4031 patients avec insuf card (Lee Jama 2003) P NA < 136 mmol/L décès à J30 OR=1.53[ ] ; à 1 an OR=1.46[ ] Hyponatrémie : Pronostic ?

66 Scores génériques SAPS II, P Na <125 mmol/L 5 points cf GCS ou PAS entre MPM : non APACHE III, P Na 55%) Scores de défaillances viscérales P Na généralement absente Hyponatrémie : Pronostic ?

67 Incidence = 1.4%

68 Verbalis 2004

69 Hyponatremia Assess volume status Hypovolemia total body water total body Na Hypervolemia total body water ++ total body Na Euvolemia* (no edema) total body water no change in total body Na > 20 mmol/L< 20 mmol/L > 20 mmol/L < 20 mmol/L U Na analysis Parikh C *The presence of normal or low BUN or serum uric acid levels are helpful laboratory correlates of normal ECF volume

70 Extra renal losses Vomiting Diarrhea Third spacing of fluids pancreatitis burns < 20 mmol/L Euvolemia (no edema) total body water no change in total body Na Glucocorticoid deficiency Hypothyroidism Stress Drugs SIADH > 20 mmol/L Hyponatremia Renal losses Diuretic excess Mineralocorticoid deficiency Salt loss nephropathy Renal tubular acidosis Ketonuria Osmotic diuresis Cerebral salt wasting Assess volume status Hypovolemia total body water total body Na U Na analysis > 20 mmol/L Hypervolemia total body water ++ total body Na > 20 mmol/L Acute or Chronique Renal failure < 20 mmol/L Nephrotic syndrome Cirrhosis Cardiac Failure Parikh C

71 Extra renal losses Vomiting Diarrhea Third spacing of fluids pancreatitis burns < 20 mmol/L Euvolemia (no edema) total body water no change in total body Na Glucocorticoid deficiency Hypothyroidism Stress Drugs SIADH > 20 mmol/L Hyponatremia Renal losses Diuretic excess Mineralocorticoid deficiency Salt loss nephropathy Renal tubular acidosis Ketonuria Osmotic diuresis Cerebral salt wasting Assess volume status Hypovolemia total body water total body Na U Na analysis > 20 mmol/L Hypervolemia total body water ++ total body Na > 20 mmol/L Acute or Chronique Renal failure < 20 mmol/L Nephrotic syndrome Cirrhosis Cardiac Failure < 20 mmol/L Primary polydipsia Poor dietary intake

72 Hyponatremia Assess volume status U Na analysis Extra renal losses Vomiting Diarrhea Third spacing of fluids pancreatitis burns < 20 mmol/L Renal losses Diuretic excess Mineralocorticoid deficiency Salt loss nephropathy Renal tubular acidosis Ketonuria Osmotic diuresis Cerebral salt wasting Hypovolemia total body water total body Na > 20 mmol/L Hypervolemia total body water ++ total body Na < 20 mmol/L Nephrotic syndrome Cirrhosis Cardiac Failure Sécrétion dADH « volodépendante » Absence dADH < 20 mmol/L Primary polydipsia Poor dietary intake Euvolemia (no edema) total body water no change in total body Na Glucocorticoid deficiency Hypothyroidism Stress Drugs SIADH > 20 mmol/L Sécrétion dADH non « volodépendante » > 20 mmol/L Acute or Chronique Renal failure Réduction néphronique

73 Principes thérapeutiques Traitement symptomatique des conséquences de lhyponatrémie Traitement étiologique / éviction du facteur déclenchant Traitement de lhyponatrémie proprement dite

74 Principes thérapeutiques 1) Ce qui est simple Traitement symptomatique des conséquences de lhyponatrémie Coma : protection des voies aériennes / ventilation mécanique Convulsions : traitement anti-comitial Traitement étiologique / éviction du facteur déclenchant Hypovolémie absolue : apports de cristalloïdes relative : diurétiques +/- albumine (Ascite / S Néphrotique) Déficit hormonal : substitution Éviction du médicament / toxique

75 Traitement de lhyponatrémie proprement dite Domaine de la médecine non factuelle… « eminence based medicine or common sense medicine » Hyponatrémie symptomatique ou non symptomatique (?) Hyponatrémie aiguë ou chronique (?)

76 Sterns 1990 Treatement of hyponatremia

77 Prompt correction of serum Na may significantly improve survival N=168 P Na < 115 mmol/L à H48 : Survivants : P NA =127 mmol/L vs DC : P Na =119 mmol/L (P=0.0016) FDR indépendant du caractère symptomatique ou non de lhyponatrémie Nzerue 2003 Treatement of hyponatremia

78 Licata 2003 HSS : 150 mL ( %) twice a day NYHA Stage IV, EF <35% Furosemide in both groups 500mg-1000mg twice a day Death rate : 24/53 vs 47/54 ; p <0.001 Treatement of hyponatremia

79 The outcome in both group 1 and 2 patients, who were treated with intravenous sodium chloride therapy, was significantly better (P<.01) than that in group 3 patients, who were treated with fluid restriction. Arieff 1999 G1, IV sodium chloride before the onset of repisatory insuficiency, G2, IV sodium chloride after respiratory insuficiency N=17 N=22 N= mmol/L0.8 mmol/L0.1 mmol/L mmol/L per hour

80 At present there is no consensus regarding the optimal treatment of symptomatic hyponatremia Horacio Adrogué

81 Current recommendations suggest the pace of correction be sufficient to reverse the manifestations of hypotonicity but not so rapid as to create significant risk for osmotic demyelination. The rate of correction should be 8 mEq/l/day; for patients with severe symptoms, the initial rate should be 1–2 mEq/l/h. These limits may be exceeded with caution when the risks associated with continued hypotonicity are greater than those of osmotic demyelination. Thus, although the benefits of prompt and aggressive treatment of hyponatremia have been demonstrated, it is important to remember that overly rapid correction of symptomatic hyponatremia can lead to osmotic demyelination and significant permanent neurologic deficits Adrogué 2005

82 Enfant 15 ans, Poids 40 kg / 1m70 P Na = 105 mmol/L, U urée = 15 mmol/L, U Na = 10 mmol/L, U K = 10 mmol/L P osmol = 220 milliosmol/KgH 2 O Diurèse 1200 mL/h U osmol = [15 + 2x(10+10)] = 55 mmol/L,, H 2 O = 0,6 x P x [(140/P Na ) – 1] = 11 L, C water = /220 = +740 mL/L Traitement : 9% NaCL : 2 L en 12 heures (600 mmol NaCl ) Elimination de la charge hydrique en 9 h Furosémide 20 mg U osmol = P osmol inhibition de C water positive Si la dilution urinaire est adéquate le furosémide inhibe le pouvoir de dilution des urines et soppose à lexcrétion deau libre

83 Hoorn Nephrol Dial Transplant 2006

84 T0,H 2 O = 0,6 x P 42L et P Na = 110 mmol/L Na tot = H 2 O x P Na = 4400 mmol H12,[H 2 0 = 42L + H 2 O (1L)] = 43L Na tot = 4400 (euvolémie) P Na = 4400/43 = 102 mmol/L En cas dhyponatrémie avec dilution urinaire inadéquate, si lhyperADH nest pas volodépendant, des apports isotoniques au plasma mais hypotoniques aux urines aggravent lhyponatrémie Homme 70 kg, SIADH, (euvolémique) P Na = 110 mmol/L, U urée = 440 mmol/L, U Na = 60 mmol/L, U K = 20 mmol/L U osmol [ x(60+20)] = 600 mmol/L Traitement : 2 L de NaCl 9% en 12 heures soit 600 mmol NaCl SIADH en euvolémie élimination des 600 mmol [U osmol = 600 mmol/L] élimination des 600 mmol dans 1 litre de diurèse Apports = 2 L gain net H 2 O = (2L - 1L) = 1L

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