Michael F. Michelis, M.D., F.A.C.P., F.A.S.N.Director, Division of Nephrology

Lenox Hill Hospital, New York

Clinical Professor of MedicineNew York University School of Medicine

Conventional and Novel Therapy

TREATMENT OF ACUTE HYPONATREMIA

Hyponatremia is the most common electrolyte disorder seen

in hospitalized patients.

Hyponatremia 21 %

Hypokalemia 12 %

Hyperkalemia 10 %

Hypernatremia 5 %

LECTURE GOALLECTURE GOAL

UNDERSTANDING UNDERSTANDING HYPONATREMIC HYPONATREMIC ENCEPHALOPATHY (HE) ENCEPHALOPATHY (HE)

•• Risk factorsRisk factors

•• Signs and symptomsSigns and symptoms

•• TherapyTherapy

Anatomy of Hyponatremia

Glomerulus – Filtration

Proximal Tubule – Na Reabsorption

Loop of Henle – Na K 2 Cl Transport

Distal Nephron – AVP

DeFronzo RA, Arieff AI. Fluid Elec, A-B,pg 259, Churchill Livingstone, 1995

AVP RELEASE

Hypothalamus

Osmo Supraoptic &

Receptors Paraventricular nuclei

axonal flow to

Posterior pituitary ( or release)

AVP RELEASE

Baroreceptors and volume receptors

Volume Aortic arch, carotid sinus and atria

Receptors Parasympathetic afferent pathway

back to

Hypothalamus ( or release)

(can override osmolar)

Regulate Vascular Tone

Regulate H2 OReabsorption by the Kidney

AVP (ADH)

V1a Receptors V2 Receptors

RISK FACTORS FOR HERISK FACTORS FOR HE

•• PostPost--operative stateoperative state

•• Cortisol deficiencyCortisol deficiency

•• Nausea, emesis, pain, stressNausea, emesis, pain, stress

•• Female sex steroids Na/K/ATPaseFemale sex steroids Na/K/ATPase

•• HypoxiaHypoxia--limits adaptationlimits adaptation

•• CNS disease or surgeryCNS disease or surgery

•• Children < 16 yearsChildren < 16 yearsMoritz M. Ped Nephrol 2010; 25: 1225Moritz M. Ped Nephrol 2010; 25: 1225--12381238

SYMPTOMS AND SIGNS OF HESYMPTOMS AND SIGNS OF HE

HeadacheHeadache

Nausea and Nausea and vomitingvomiting

LethargyLethargy

WeaknessWeakness

ConfusionConfusion

AgitationAgitation

SeizuresSeizures

ComaComa

ApneaApnea

Pulmonary edemaPulmonary edema

PapilledemaPapilledema

Cardiac arrhythmiasCardiac arrhythmias

CHILDREN VS ADULTSCHILDREN VS ADULTS

Average serum sodium in children with Average serum sodium in children with hyponatremic encephalopathy is 120 mEq/L hyponatremic encephalopathy is 120 mEq/L vs adults is 111 mEq/L.vs adults is 111 mEq/L.

A childA child’’s brain reaches adult size by 6 years of s brain reaches adult size by 6 years of age but the skull does not reach adult size age but the skull does not reach adult size until 16 years of age. until 16 years of age.

Therefore, herniation occurs at higher serum Therefore, herniation occurs at higher serum sodium levels in children.sodium levels in children.

ACUTE HYPONATREMIA/TRAUMA ACUTE HYPONATREMIA/TRAUMA (CEREBRAL EDEMA) (CEREBRAL EDEMA)

VSVS

CHRONIC HYPONATREMIA (CHRONIC HYPONATREMIA (BRAIN BRAIN ADAPTATION, LOSS OF ELECTROLYTES ADAPTATION, LOSS OF ELECTROLYTES AND OSMOLYTES. MAY LEAD TO CPM AND OSMOLYTES. MAY LEAD TO CPM

SECONDARY TO DEHYDRATION IF SECONDARY TO DEHYDRATION IF OVERCORRECTION OCCURS)OVERCORRECTION OCCURS)

Diagnostic Approach for the Syndrome of Inappropriate Antidiuretic Hormone Release

Diagnostic CriteriaDecreased extracellular fluid effective osmolality(<270 mOsm/kg H2O)

Inappropriate urinary concentration(>100 mOsm/kg H2O)

Clinical euvolemia

Elevated urinary sodium concentration underconditions of a normal salt and water intake

Absence of adrenal, thyroid, pituitary, or renalinsufficiency or diuretic use

Diagnostic Criteria for SIADH

Supplemental

Abnormal H2O load test

Plasma AVP level inappropriately high relative to plasma osmolality

No significant correction of plasma [Na+] with volume expansion, but improvement after fluid restriction

SIADH=syndrome of inappropriate antidiuretic hormone secretionJanicic N et al. Endocrinol Metab Clin N Am. 2003;23:459-481Kumar S et al. In: Atlas of Diseases of the Kidney. 1999:1.1-1.21

CASE 1CASE 1Healthy 3 year old brought to ER with 1 day Healthy 3 year old brought to ER with 1 day

history N&V. Blood pressure 85/60 mm Hg. history N&V. Blood pressure 85/60 mm Hg. ExamExam--dry. Chemistries normal except dry. Chemistries normal except increased BUN. Child received 2 boluses of increased BUN. Child received 2 boluses of normal saline IV. Child admitted and then normal saline IV. Child admitted and then treated with treated with ““2/3 and 1/32/3 and 1/3”” at 130 mL per hr IV. at 130 mL per hr IV. The child voided about 110 mL urine and The child voided about 110 mL urine and received 1.5 liters IV fluid. The child received 1.5 liters IV fluid. The child developed lethargy, incontinence and serum developed lethargy, incontinence and serum sodium now 120 mEq/L. Seizures developed, sodium now 120 mEq/L. Seizures developed, and mannitol and saline were given prior to and mannitol and saline were given prior to demise. What went wrong? Therapy?demise. What went wrong? Therapy?Koczmara C. CJHP 2009; 62: 512Koczmara C. CJHP 2009; 62: 512--515515

CASE 2CASE 2

A 7 year old girl with cloacal exstrophy presented A 7 year old girl with cloacal exstrophy presented with 2 large bladder stones in association with with 2 large bladder stones in association with cutaneous fistulae after a prior gastriccutaneous fistulae after a prior gastric--ileal ileal augment, bladderaugment, bladder--neck reconstruction. During neck reconstruction. During the 35 minute procedure to remove the stones, the 35 minute procedure to remove the stones, a total of 2 liters of sterile water was used for a total of 2 liters of sterile water was used for bladder irrigation for stone fragment removal. bladder irrigation for stone fragment removal. Postoperatively, she was extubated but Postoperatively, she was extubated but became lethargic and irritable prior to became lethargic and irritable prior to respiratory arrest. Serum sodium 120 mEq/L. respiratory arrest. Serum sodium 120 mEq/L. CT showed massive cerebral edema. What CT showed massive cerebral edema. What went wrong? Therapy?went wrong? Therapy?Walker MR. JP Urol. 2008; 4:231Walker MR. JP Urol. 2008; 4:231--233233

SEVERE CEREBRAL EDEMA

SODIUM AND WATER SAMPLE SODIUM AND WATER SAMPLE CALCULATIONCALCULATION

18 L X 140 mEq/L 18 L X 140 mEq/L = 133 mEq/L= 133 mEq/L

19 L19 L

CASE 3CASE 3

13 year old boy admitted with depressed level of 13 year old boy admitted with depressed level of consciousness secondary to severe consciousness secondary to severe hyponatremia of 116 mEq/L. At age 3 months hyponatremia of 116 mEq/L. At age 3 months nasofrontal encephalocele repaired with nasofrontal encephalocele repaired with subsequent DI, hypothyroidism and AI. Treated subsequent DI, hypothyroidism and AI. Treated with corticosteroids, thyroid and DDAVP. with corticosteroids, thyroid and DDAVP. Following admission, serum sodium increased Following admission, serum sodium increased during 48 hours to 176 mEq/L. Neurologic during 48 hours to 176 mEq/L. Neurologic status worsened and MRI demonstrated status worsened and MRI demonstrated changes consistent with extrapontine changes consistent with extrapontine myelinolysis. What went wrong? Therapy?myelinolysis. What went wrong? Therapy?

Ranger A. Ped Neurosurg. 2010; 46:318Ranger A. Ped Neurosurg. 2010; 46:318--323323

AVOIDANCE OF AND MANAGEMENT AVOIDANCE OF AND MANAGEMENT OF DYSNATREMIASOF DYSNATREMIAS

Frequent monitoring and measurement Frequent monitoring and measurement of serum sodium levels in at risk of serum sodium levels in at risk patientspatients

Infusion of 3% saline for hyponatremic Infusion of 3% saline for hyponatremic encephalopathyencephalopathy

THREE PERCENT SALINE AND THREE PERCENT SALINE AND TRANSPORT (n=101)TRANSPORT (n=101)

Mean age 5.9 yMean age 5.9 y

Mean weight 27.6 kgMean weight 27.6 kg

MVA (n) 23MVA (n) 23

Hyponatremia (n) 6Hyponatremia (n) 6

Mean dose 5.3 mL/kg (1.2Mean dose 5.3 mL/kg (1.2--24)24)

Sodium change 135 Sodium change 135 --> 143 mEq/L> 143 mEq/L

range (115range (115--152) 152) --> (127> (127--183)183)

Access Peripheral line (central, osseous)Access Peripheral line (central, osseous)Luu JL. Ped Emerg Care. 2011; 27: 113Luu JL. Ped Emerg Care. 2011; 27: 113--117117

OUTLINE FOR USE OF 3% SALINE OUTLINE FOR USE OF 3% SALINE IN HEIN HE

•• 2 mL/kg of 3% NaCl over 10 minutes. 2 mL/kg of 3% NaCl over 10 minutes. Maximum 100 ccMaximum 100 cc

•• Repeat bolus 1Repeat bolus 1--2 times as needed until 2 times as needed until symptoms improve. Goal 5symptoms improve. Goal 5--6 mEq/L increase6 mEq/L increase

•• Recheck SNa following second bolus or Recheck SNa following second bolus or

Q 2 HQ 2 H

•• HE is unlikely if no improvementHE is unlikely if no improvement

•• Stop therapy if either symptom free or SNa Stop therapy if either symptom free or SNa increases > 10 mEq/Lincreases > 10 mEq/L

Moritz M. Ped Nephrol 2010; 25: 1225Moritz M. Ped Nephrol 2010; 25: 1225--12381238

Avoidance of Overcorrectionof Hyponatremia

R.H. Sterns et al. Kidney Int 2009;76:587-589

Goal: 4 - 6 mEq/L

Remedy: 5% D/W at 6 ml/kg over 1 - 2 Hr

DDAVP 2 µg q 6 - 8 Hrs

Change in serum sodium concentration

Infusate sodium concentration –Patient Serum Na concentration

with 1L of infusate = Total body water + 1

Adrogué-Madias. Intensive Care Med 1997;23:309-316

Adrogué-Madias Formula

H.K. Mohmand et al. Clin JASN 2007;2:1110-1117

VAPTANSVAPTANS

The safety and effectiveness of The safety and effectiveness of vaptans in pediatric patients have vaptans in pediatric patients have not been studied.not been studied.

SERUM SODIUM RESPONDERS

B. Metzger, M. DeVita, M. Michelis. Int Urol Nephrol 2008;40:725-730

Day 0 Day 1

Serum Na

mEq/L

115

120

125

130

135

SERUM SODIUM RESPONDERS

B. Metzger, M. DeVita, M. Michelis. Int Urol Nephrol 2008;40:725-730

Day 0 Day 1

Urine Osm

mOsm/kg

100

200

300

400

500

600

CHF VS SIADHCHF VS SIADH

R. R. VaghasiyaVaghasiya, M. , M. DeVitaDeVita, M. Michelis. , M. Michelis. IntInt UrolUrol NephrolNephrol .2012; .2012; 44: 86544: 865--871871

TOLVAPTAN IN A SIX YEAR OLDTOLVAPTAN IN A SIX YEAR OLD

Ten kg male with CHF treated with furosemide,Ten kg male with CHF treated with furosemide,

thiazide and spironolactone gained weight andthiazide and spironolactone gained weight and

serum sodium decreased to 118 mEq/L. serum sodium decreased to 118 mEq/L.

Treated with tolvaptan 2Treated with tolvaptan 2--33--44--5 mg per day over5 mg per day over

30 days. Serum sodium increased to 13330 days. Serum sodium increased to 133

mEq/L and Uosm decreased to 216 mOsm/kg.mEq/L and Uosm decreased to 216 mOsm/kg.

Body weight decreased by 1.5 kg. Body weight decreased by 1.5 kg.

Horibate, et al. Card in the Young. 2013: 1Horibate, et al. Card in the Young. 2013: 1--33

HYPONATREMIA THERAPY HYPONATREMIA THERAPY SUMMARY:SUMMARY:

Boluses or infusions of 3% saline are Boluses or infusions of 3% saline are the most effective therapies for acute or the most effective therapies for acute or severe hyponatremic encephalopathysevere hyponatremic encephalopathy

Chronic hyponatremia with limited Chronic hyponatremia with limited symptoms and mild/moderate symptoms and mild/moderate decreases in serum sodium can be decreases in serum sodium can be managed by traditional and/or newer managed by traditional and/or newer therapeutic approachestherapeutic approaches

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