TREATMENT OF TREATMENT OF HYPOTONIC HYPOTONIC

HYPONATREMIAHYPONATREMIA

BSIM 2010 BSIM 2010 -- LeuvenLeuven

G. Decaux, MD, PhD (Erasme, Brussels, ULB)G. Decaux, MD, PhD (Erasme, Brussels, ULB)General Internal MedicineGeneral Internal Medicine

Na+e + K+

e

[ Na ] =

TBW

♂ 60 y BW 66 kg, TBW ± 33 L, SNa 140 mEq/L

TBW 1 L → SNa: 3% (or 4.2 mEq/L)

Retention or los of 33 mEq of Na+ or K+

→ SNa: 1 mEq/L

♀ 80 y BW 60 kg, TBW ± 25 L, SNa 140 mEq/L

TBW 1 L → SNa: 4% (or 5.6 mEq/L)

Retention or los of 25 mEq of Na+ or K+

→ SNa: 1 mEq/L

Data obtained from a rat model of SIADH

SNa (mEq/l)

90% survival

10% mortality

NaCl

24hr

24hr 72hr

NaCl

140

105

140

105

140

105

80-90% mortality (by ODS)

100% survival

100% survival

In rats increase of SNa by 15 mEq/l/d

is well tolerated (even acutely)

Re-induction of hyponatremia after overcorrection

reduces mortality particularly if rats are still

asymptomatic

NaCl

DDAVP

water

12580% survival

80-90% mortality

24hr 72hr

12-24hr

Soupart et al. Kidney Intern 1994; 45: 193-200

SNa 140 mEq/L

Na

x K+x

x

x

x

x

x

xx

xx

OO (organic osmolytes: Myo-

inositol, taurine,…)

Acute 20% dilution

x

x

x

x

x

x

x

xx

x

Brain volume expansion (skull tolerate 8-10%)

Nausea, emesis, headaches, coma, seizure

Risk of brain herniation, respiratory arrest and non

cardiogenic pulmonary oedema (hypoxemia)

H2O

H2O

x K+

(OO)

I

II

SNa 118 mEq/L Ventricular collapse

SNa 118 mEq/L

Na

x K+

x

x

xx

x

OO (Myo-inositol, taurine,…)

Rapid correction of SNa

SNa 140 mEq/LIntracellular hyperionisation and OO

depletion (5-7 days to reaccumulate)

Apoptose of the astrocytes

→ ODS (or CPM)

(Urea protect the cell from apoptosis)

48hr

H2O

Brain adaptation (24-48hr) by intracellular

solute depletion

Paucisymptomatic

xx

x

x

x

x

x x

x x

H2O

x

Na

I

ACUTE (< 48 hr) (usually < 125 mEq/l)

Generally hospital acquired

- Post operative

- Excessive IV hypotonic fluids with inappropriate antidiuresis

- Post-TURP syndrome (Uterine surgery with glycine irrigant, …)

- Oxytocine

- Recent thiazides prescription

- Polydypsia (acquired generally outside the hospital) (beer potomania)

- Exercise induced (acquired outside the hospital)

- Ecstasy

- Colonoscopy preparation (PEG plus excessive water intake)

- Desmopressin therapy for nocturnal enuresis

GENERALLY SYMPTOMATIC

Severe symptoms sometimes explosive in nature (coma, seizure)

- Hypertonic saline (NaCl 3%) furosemide (20-40 mg)

Rate of IV infusion: 1-2 ml/kg b.w./hr (increases the SNa by 1-2 mEq/l/hr and 2-4 mEq/l/hr if combined with

furosemide)

OR

- Bolus infusion of 150 ml of 3% NaCl repeat 10 min later if no improvement

- TARGET: interrupt correction when symptoms disappear

(rapid normalisation of the serum sodium usually safe but rarely necessary). Check SNa after 30 min, to be sure that

SNa is increasing (then each 2-4hr)

PROMPT CORRECTION MANDATORY

CHRONIC (> 48hr), subacute or unknown duration

Acquired outside the hospital

- Edema states

- SIADH

- Diuretics

- Digestive losses, excessive sweating, third space

- Salt losing nephropathy

- Cerebral salt wasting syndrome

- Polydypsia (often acute surimposed upon chronic hyponatremia)

- Endocrine (hypocorticism and hypoaldosteronism, hypothyroidism)

SYMPTOMATIC ASYMPTOMATIC

SYMPTOMATIC

- Obviously, electrolyte-free water intake must be

withheld

- NaCl 3% by controlled IV infusion

Rate of infusion 1-2 ml/kg b.w./hr during

4-5hr

OR

- 1 L NaCl 0.9%/12hr with urea (IV or by gastric

tube) 0.5 to 1 g/kg b.w. in one or two doses during

the first 24hr (except if volume depletion)

- TARGET: interrupt correction

if symptoms improvement and/or

- SNa > 10 mEq/l/24hr

INITIAL RAPID BUT LIMITEDCORRECTION

ASYMPTOMATIC

- Conservative measures:

. Withdrawal of causative factors(drugs, ...)

. Water restriction (SIADH, Edema states)

. Oral urea 0.5 gr/kg/24hr in one or two

doses (SIADH)

. Furosemide with salt supplements

(SIADH)

. Isotonic saline if salt depletion

. Captopril + Furosemide (heart failure)

. Dialysis (renal failure, cirrhosis)

. Hormonal substitution

. Fluorohydrocortisone (cerebral salt

wasting syndrome)

. V2 antagonist (Conivaptan; Tolvaptan)

NO NEED FOR RAPID CORRECTION

TABLE 2: RISK FACTORS FOR MYELINOLYSIS

• Major risk factors: daily magnitude of the SNa increase (SNa/24hr < 10-15 mEq/l)

• Hypokaliemia (SNa/24hr < 10 mEq/l/24hr)

• Alcoholism, malnutrition, cirrhosis… (SNa< 10 mEq/l)

• (most cases of myelinolysis: initial SNa < 115 mEq/l and SNa > 12 mEq/l/24hr)

• Isolated cases occurred after SNa of only 9 to10 mEq/l

General recommendations

- Salt depletion is treated by isotonic saline

- Initial rapid correction if severe symptoms

- Maximum SNa correction: 10-12 mEq/l/24hr and less than

8 mEq/l/24hr if associated risk factors for myelinolysis

(hypokalemia, malnutrition, alcoholism, liver disease, burns,

hypocorticism)

- Normalize kalemia before or during SNa correction

- Serum sodium must be initially monitored at least every 4 hours

- Administration of DDAVP if correction is too rapid

- Decrease SNa by DDAVP and “water” if necessary

Decaux G, Soupart A. Am J Med Sci 2003; 326(1): 25-30

Oya et al. Neurology 2001

Urea: intravenous* or by gastric tube 0.5 g/kg

b.w. (to max 1 g/kg b.w.) will increase osmolality

by 15 (to 30) mosm/kg H2O in 30 min

May be repeated if needed each 8-12hr

Urea protects against ODS

*Ureaphil (Abbott): bottle with 40 gm powder of sterile

urea to dilute with 105 ml of 5% glucose to obtain a final

volume of 135 ml of a 30% urea solution

ALTERNATIVE TREATMENTALTERNATIVE TREATMENTTO HYPERTONIC SALINETO HYPERTONIC SALINE

Javid M. Lancet 1961

Javid M. Surg. Clin. North Am. 1958, Aug, 38 (4): 907-928

Javid, Settlage. JAMA 1956, March 17; 160 (11): 943-949

Decreases rapidly brain edema

Increases SNa by osmotic diuresis and salt retention

No risk of inducing or increasing potassium deficit

(as with furosemide)

Easy to apply (electrolytes monitoring each 4hrs)

Decreases the risk of myelinolysis

USE OF UREA FOR TREATMENT OF USE OF UREA FOR TREATMENT OF SYMPTOMATIC HYPONATREMIASYMPTOMATIC HYPONATREMIA

Decaux G. et al. JAMA 1982; 247: 471-474

100

105

110

115

120

125

130

135

0 1 2

Days

SN

A (

mE

q/L

)

Isotonic saline

(1 or 2 L/day)

Urea

(0.5-1 g/kg/day)

-1 0 1 2

Days

0 4 hr 8 hr

Days

90

60

30

Urea (mg/dl)

1 L/12 hr

isotonic saline

urea(0.5 g/kg)

Figure 2

(

)A

(n = 35)

C(n = 10)

B(n = 12)

*

*

*

*

**

*

*

*

Decaux et al. Critical Care 2010; 14: R184

Easy formula: 1 ml/kg/hr of 3% NaCl will increase

SNa by 1 mmol/l/hr (assuming no renal

excretion !)

Example: - 60 kg woman with SIADH and a SNa of

110 mEq/l and and intended increase of 8 mEq/l

We will need to infuse 480 ml NaCl 3%

- or TBW (30 L) x 8 mEq/l = 240 mEq Na

or 240/513 = 0.468 l Na Cl 3%

CAUTION WITH HYPERTONICCAUTION WITH HYPERTONICSALINE (NACL 3%) INFUSIONSALINE (NACL 3%) INFUSION

Effect of diuresis and urine composition on SNa during

hypertonic saline infusion in the same patient

UNa + K Uosm Water excreted (WE) NTBW SNa

for 468 ml NaCl 3% (TBW + 0.46 - WE)

75 220 240/75 = 3.2 l 27.26 11

170 510 240/170 = 1.41 l 29.05 3.6

300 900 240/300 = 0.8 l 29.6 1

Decaux G., Soupart A. Am J Med Sci 2003; 326 (1): 25-30

Frequently spontaneous correction secondary to high

dilute urine output combined with water restriction

Often mixed disorder (solute depletion component)

1 or 2 of isotonic saline + KCl 30 mmol/l over 24hr

If SNa very low (< 110 mEq/l) likely SNa increase of no

more than 10-15 mEq/l/24hr

HYPONATREMIA RELATED TO HYPONATREMIA RELATED TO POLYDYPSIA OR BEER DRINKERSPOLYDYPSIA OR BEER DRINKERS

Most frequently elderly women

High risk of myelinolysis

Slow correction: 1 or 2 L isotonic saline with 40 mmol KCl/l

DIURETIC RELATED HYPONATREMIADIURETIC RELATED HYPONATREMIA

Excess NaCl administration

Potassium supplementation (SNa = Nae + Ke / H2O)

Unexpected increase in electrolyte free water

excretion (due to spontaneous hypoosmotic

polyuria, ADH inhibition by volume expansion, or

high solute output)

OVERCORRECTION OF OVERCORRECTION OF HYPONATREMIAHYPONATREMIA

Asymptomatic or early symptomatic

Decrease rapidly SNa (DDAVP + electrolyte

free water) so that SNa/24hr stay under 10 mEq/l

Other therapeutic options in myelinolysis:

- Thyreotropin releasing hormone (?)

- Immunoglobulins (?)

- Plasmapheresis (?)

- Corticosteroids (?)

- Minocycline (data obtained in rats)

OVERCORRECTION OF SNAOVERCORRECTION OF SNA

Is asymptomatic hyponatremia really

asymptomatic?

x

y

Posture and Gait Evaluation

• RSScan International® Platform

• Thousands of Pressure Sensors

• Measure displacement of the Pressure Center of the patient in different conditions

Renneboog B., Musch W. et al. Am J Med 2006

Response Time (RT)

Median RT in Hyponatremia: 673±182 msec.

Median RT in Normonatremia: 615±184 msec.

Difference = 58 msec (p<0.001)

ATTENTION TESTS

MEDIAN RESPONSE LATENCIES

0

100

200

300

400

500

600

700

800

900

1000

128 138

MEAN NATREMIA (mEq/L)

LA

TE

NC

Y (

ms

ec

)

Visual Vigilance

Digit Span

GO/NOGO

Intermodal Comparison

Divided Attention (sounds)

Divided Attention

(sounds+squares)

Phasic Alert 1-4

Phasic Alert 2-3

Renneboog B., Musch W. et al. Am J Med 2006

Renneboog B., Musch W. et al. Am J Med 2006

Table 1 : Baseline characteristics of patients and controls and site of bone fracture in patients.

Cases

Controls

SNa < 135

n = 76

SNa > 135

n = 446

Overall

n = 522

SNa < 135

n = 21

SNa> 135

n = 501

Overall

n = 522

Mean age (yrs) 81 ± 9 81± 8 80 ± 8 85 ± 6 81± 7 81 ± 7

Male/ Female 18/58 117/329 135 / 387 9 / 12 126/375 135 / 387

Mean SNa (mEq/L) 131. 3 ± 2.9 140.1 ± 3.2 138.8 ± 4.4 131. 4 ± 3.2 140.8 ± 7.7 140.43± 3.4

Hip and femoral fractures 44 242 286 NA*

Upper Limb Fractures 20 139 159

Fracture of other sites 12 65 77

* NA: Non applicable

Table 3: Prevalence of hyponatremia in patients and controls and Odds ratios

for bone fracture associated with hyponatremia

Patients (%)

n = 522

Controls (%)

n = 522

Unadjusted OR (CI) Adjusted OR (CI)

Hyponatremia 76 (14.55) 21 (4.23) 3.89 (2.35 - 6.45)* 4.12 (2.34 -7.59)*

OR: Odds ratio. CI: 95% confidence interval; * P< 0.001

Gankam Kengne F. et al. QJM 2008; 101: 583-588

Decaux G., Soupart A., Vassart G.Lancet 2008

Decaux G., Soupart A., Vassart G.Lancet 2008

Decaux G., Soupart A., Vassart G.Lancet 2008

W. Schrier, et al. N. Engl. J. Med. 2006; 355: 2099-2112

Table: Effect of urea in hypothetical case of inappropriate secretion of antidiuretic hormone compared with normal person receiving same intake of food and fluid

(Food intake shown as amount of solute of excretion in urine)

Daily intake Urinary composition

Urine volume (L/day)

Water balance (L/day)

Normal 500 mmol solute; 2 L Water*

250 mmol/L 2 0

Inappropriate secretion of hormone

500 mmol solute; 2 L Water*

500 mmol/L 1 + 1

Inappropriate secretion of hormone treated with 30 g urea daily

500 mmol solute; 500 mmol urea;2 L Water

500 mmol/L 2 0

*Intake minus insensible loss. Conversion: SI to traditional units – Intake and urinary composition:1 mmol = 1 mOsmol

Decaux G. et al. Br Med J 1981; 283: 1081-1083

Decaux G.Am J Med 2001; 110 (7): 582-584

CONSEQUENCES OF CHRONIC (>48hr) CONSEQUENCES OF CHRONIC (>48hr) HYPONATREMIAHYPONATREMIA

Mild to moderate chronic hyponatremia (HN) generally

considered « asymptomatic »: symptoms subtle and

difficult to detect

HN associated with

– Attention and posture deficit, gait instability

– Increased falls (> elderly)

– Bone fracture (non-vertebral > vertebral) (e.g. odds ratio BF/HN

4.1, mean SNa 131 mEq/l)

– Role of chronic HN in induction of osteoporosis (?)

THERAPEUTIC OPTIONS IN SIADHTHERAPEUTIC OPTIONS IN SIADH

Fluid restriction (< 1-1.5 l/day)

Furosemide + oral NaCl supplement (+ K sparing

diuretics)

Urea oral (15-30 g/day)

Demeclocycline

Vaptans (AVP-V2 receptor antagonists)

– Conivaptan* (IV, V1a/V2) (Vaprisol®)

– Tolvaptan* (oral, V2) (Samsca®)

– Satavaptan (oral, V2)

– Lexivaptan (oral, V2) (in development)

*FDA approved

Decaux G., Musch W., Soupart A. Acta Clin Belgica 2010

40mg Furosemide

NaCl 3g P.O.

115

120

125

130

135

140

-2 -1 0 1 2

Days

SN

A (

mE

q/L

)

Urea (mg/dl) 100

90

80

70

60

50

40

30

20

(

) *

* *

Isotonic saline or halfIsotonic saline

Urea(15-120 g/d)

Decaux et al. Critical Care 2010; 14: R184

Evolution of SNa and blood urea in 50 patients before and after urea therapy in ICU

Months0 2 4 6 8 10 12 0 2 4 6 8 10 12

140

135

130

125

SNa

(mEq/l) VAPTANS UREADRUG

HOLIDAY

8 DAYS

Figure 1

N = 12

Soupart A., Decaux G. Submitted

TOLERANCE TO VAPTANS AND UREA (1)TOLERANCE TO VAPTANS AND UREA (1)

Vaptans (about 10-20% failure)

– Thirst

– Orthostatic hypotension

– Nausea

– Polyuria

– Hypernatremia (≈ 5%) or overcorrection

(> 8 mEq/l/24hr) (≈ 10%)

Urea

– Poor palatal taste (decreases with time), gastric intolerance:

withdrawal (≈ 15%)

Take after meal + orange juice

– Contraindications

• Gastric ulcer, hemorrhage

• Renal failure

• Liver failure, hepatic encephalopathy

TOLERANCE TO VAPTANS AND UREA (2)TOLERANCE TO VAPTANS AND UREA (2)

Both treatments well tolerated, no major side effects

Vaptans

– One patient stopped Tolvaptan for excessive thirst

Urea

– One episode of hypernatremia (155 mEq/l) at admission for

pneumonia

Complete recovery

Drug holiday

– One patient falled during dry holiday period (Satavaptan) with wrist

fracture (SNa 123 mEq/l)

Second fall after urea withdrawal with a hip fracture (SNa 126 mEq/l)

CONCLUSIONSCONCLUSIONS

Urea shows similar efficacy than vaptans for

treatment of chronic hyponatremia due to

SIADH

Tolerance is good in both groups

Vaptan will likely be particularly useful for

hyponatremia associated with cirrhosis and

cardiac failure