uzma mehdi, m.d, ms nephrology. case patient presentation in er; 68-year-old female smoker malaise...
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UZMA MEHDI, M.D, MSNEPHROLOGY
Case Patient presentation in ER; 68-year-old female smoker Malaise Poor appetite Mild neurologic symptoms Physical Exam; 130/75 mmHg, 88, no orthostatic changes. Lab results serum Na: 124, K: 3.2, Cl: 94, Hco3: 26; Bun: 16,
Creatinine 0.6 Posm:249, Uosm:415; UNa: 48, uric acid : 1.8, Normal thyroid function test and am cortisol level. Diagnostic imaging CT scan showed right lung nodule Diagnosis Hyponatremia SIADH secondary to lung mass
Hyponatremia
Hyoponatremia Approach to the pt. AVP Siadh Treatment strategies of SIADH Non-peptide AVP receptor antagonist Salt Trial Samsca
Hyponatremia Hyponatremia defines as serum sodium
concentration <135meq/L.
Most frequent electrolyte abnormality in the hospitalized pt.
Essentially common in critical care units. In addition to being a potentially life-threatening condition, hyponatremia is an independent predictor of death among intensive care unit and geriatric patients and those with heart failure, and cirrhosis.
(Arief at al 1976; Terian et al 1994; Borroni et al 2000; Lee et al 2000, Bennani et al 2003; Goldberg et al 2004: Ruf et la 2005).
Hyponatremia Changes in serum sodium concentration
results from derangements in water balance.
Low serum sodium concentration denotes a relative deficit of sodium and /or a relative excess of water.
As seen in the formula, hyponatremia may result from either a decrease in the numerator or an increase in the denominator.
Serum sodium = total body sodium total body water
Approach to the patient with Hyponatremia
Check serum osmolality. increased or decreased.
Increased osmolality----- ---mannitol, glyceine or hyperglycemia ---movement of water from ICF to ECF
compartment. It causes translocational hyponatremia.
Decreased osmolality can be due to other causes.
Approach to the pt with hyponatremia Decreased serum osmolality --
check volume status. It could be:
Hypovolumeic, Hypervolumeic or Euvolumeic.
Approach to the patient with Hyponatremia Hypovolumeic Hyponatremia
(Dehydartion) Decrease Sodium Decrease water
Causes Diarrhea Diuretic use Mineralcorticoid defeciency Osmotic diuresis like
mannitol
Approach to the patient with Hyponatremia
Hypervolumeic Hyponatremia
Sodium content unchanged Increase water
Causes Heart Failure Cirrhosis Nephrotic syndrome
Approach to the patient with Hyponatremia
Euvolumeic Hyponatremia
Sodium content unchanged Relative increase in water
Cause Syndrome of inappropriate diuretic
hormone (SIADH)
Approach to the patient with Hyponatremia
Hyponatremia with decreases serum osmolality
ECF volume ECF volume ECF volume
decreased normal (euvolumic) increased (edema)
Renal Extrarenal SIADH CHFDiuretics GI losses
Cirrhosis
Nephrotic syndrome
Urine Na Urine Na Urine Na Urine Na
TB Na TB water
TB Na TB water
TB Na TB water
Arginine vasopressin( AVP) aka Antidiuretic hormone (ADH) Major hormone that controls the
water balance Release from pituitary glands Three receptors V1a V1b V2
AVP
Increase plasma osmolality
Decrease Intravascular volume
V1a receptors
V2 receptors
Regulate vascular tone
Regulate water reabsorption in kidney
Vasopressin receptors V1A receptors smooth muscle cells of blood vessels vasoconstrictive action
V1B receptors anterior pituitary Regulate pituitary ACTH secretion
V2 Receptors collecting duct cells antidiuretic effects of vasopressin
Vasopressin Action
After binding of AVP to V2 receptors --- c-Amp is formed--- increased expression of AQP2 and AQP3 – insertion into cell membrane.
Increase driving force for water reabsorption.
Increased water flow in collecting duct.
Collecting duct Cell
Luminal surface Basolateral surface
Aquaporin 3
Aquaporin 4
V2 repceptors fpr ADH
Recycling vesicles for
AQP-2 ADH
Without ADH
collecting duct is
impermeable to water.
Collecting duct cell
Luminal surfaceBasolateral surface
Aquaporin 3
Aquaporin 4
V2 repceptors for ADH
AQP-2
ADH
In Presence of ADH
collecting duct is
permeable to
water.
SIADH
Inappropriate release of ADH causes siadh.
It is diagnosed by checking : Serum sodium <135 Serum osmolality <280 Urine osmolality >100 Urine sodium >30 also low serum uric acid <4.0
Causes of SIADH Central nervous system; meningitis, brain abcess, stroke, acute psycosis
Pulmonary pneumonia, lung abcess, tuberculosis
Endocrine Addison's disease, hypothyroidisim , hypopituitarism
Neoplastic pancreatic or lung cancers.
Drugs induced SIADH
Increased ADH ADH potentiation Anti-depressant carbamazepine
anti-psycotics chlopropamide
carbamazepine cyclophosphamide
platinum alkaloids Nsaids
alkylating agents ADH like activity
interferon vasopressin levimasole ddavp oxytocin
Drugs induced Siadh
Common drugs
SSRI’s Ectasy Carbamazepine ddavp
Clinical manifestation of siadhAcute: (<48 hours) Stupor/coma Convulsions Treatment
with Respiratory arrest 3% NaCl
Chronic; (>48 hours) Headache Irritability Treat with
medicines Nausea & vomiting like Vaptans Confusion & Disorientation Gait disturbance
Correcting hyponatremia
traditional approach;
add to the numerator
Serum sodium = Total body sodium
Total body water
Correcting hyponatremia
Current approach;
Serum sodium = Total body sodium Total body
water
Subtract from the the denominator
Treatment strategies for Acute hyponatremic emergencies 3% NaCl: 100ml bolus for severe
symptoms. 3% NaCl@1 to 2ml/kg/hr for 2 to 4
hours plus furosemide. Goal: correction by 4 to 6 mEq/L in
first few hours. Monitor closely to avoid excessive
correction.
Treatment strategies for chronic hyponatremia
Treatment Mechanism
Advantages Limitations
Fluid restriction (0.5- 1 liter/day)
Water intake Effective, inexpensive
Poor compliance
Demeclocycline(600-1200mg/d)
Inhibits action of adh
Easily available
3-4 days for onset,nephrotoxicity
Urea(30mg/d)
Osmotic diuresis
Decreased risk Poor palatability, Avoid in ckd
Lithium(up to 900mg/d)
Inhibits action of adh
Easily available
Slow onset,toxicity
Rate of correction
Acute symptomatic : 4 to 6 mEq/L in first 4 hours Target <12 mEq/L in first 24 hours.
Chronic: Target correction at <8 mEq/L in first 24
hours
Goal not to exceed; 12 mEq/L in first 24 hr 18 mEq/L in first 48 hr
Importance of appropriate serum sodium correction Too-rapid correction of hyponatremia (e.g.,
>12 mEq/L/24 hours) can cause osmotic demyelination syndrome (ODS) resulting in:
dysarthria, dysphagia,
seizures, coma and death
spastic quadriparesis.
Risk factors for ODS: severe malnutrition, alcoholism, advanced liver disease
The ideal therapy
Water excretion without electrolyte excretion (Na+ and K+) Aquresis.
Prompt but safe correction in 24-48 hours; <12mEq/L in first 24 hr < 18mEq/L in first 48 hr
Eliminates fluid restriction.
Predictable and reliable action
Sustained effect and titratable
No unexpected side effects/toxicities.
Non-peptide AVP receptor antagonist (Vaptans) Aquaretic nonpeptide arginine
vasopressin receptor (AVPR) antagonists are safe and effective hyponatremia therapies.
Varbalis,JG at al, Hyponatremia treatment guidelines 2007, Am J of Med, 2007 Nov;120(11 Suppl 1):S1-21
Vaptans lead to aquaresis, an electrolyte-sparing excretion of free water, that results in the correction of serum sodium concentration.
Vasopressin antagonists in treatment of hyponatremia; Olszewski,W; Pol Arch MED Wewn, 2007 Aug:117(8)
Non-peptide AVP receptor antagonist
tolvaptan
lixivaptan satavaptan conivaptan
Receptor V2 V2 V2 V1a/V2
Route of administration
oral
oral
oral
IV
Urine volume
Urine osmolality
Na excretion/24 hours
Low dose High Dose
Non-peptide AVP receptor antagonist
tolvaptan
lixivaptan satavaptan conivaptan
Receptor V2 V2 V2 V1a/V2
Route of administration
oral
oral
oral
IV
Urine volume
Urine osmolality
Na excretion/24 hours
Low dose High Dose
Not available in United states
SALT Trial Multicenter randomized, placebo-controlled,
double-blind phase 3 studies (Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2) [SALT-1 and SALT-2]
225 pts with hyponatremia due to SIADH, cirrhosis or CHF vs 223 controls.
Serum Na <135 without neurological symptoms.
R.W.Schrier et al; Tolvaptan,a selective oral vasopressin v2 receptor antagonist, for hyponatremia. New Eng JM, vol 355, no 20.Nov 16,2006
SALT Trial Pt were randomly assigned to placebo vs
15mg of tolvaptan Dose of tolvaptan was increased to 30mg
and then to 60mg if necessary.
Primary end points; Change in serum sodium from baseline to
day 4 and day 30. Serum sodium a week after
discontinuation of drug.
SALT Trial
Significant increase in as early as 8 hours :
7% of tolvaptan-treated patients had an increase in serum sodium greater than 8 mEq/L
vs 1% of placebo-treated patients
Results consistent among patients with heart failure, cirrhosis, and SIADH
The average rates of serum sodium correction during the treatment initiation (first 24 hours) were
3.83 mEq/L for SAMSCA (15 mg) and 0.30 mEq/L for placebo
SALT Trial
Serum Sodium
tolavaptan placebo
Baseline 128.5 4.5 128.7 4.1
Day 4 133.9 4.8 129.7 4.9
Day 30 135.7 5.0 131.0 6.2
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Results of SALT
Results of SALT
In the SALT trials on Day 4, SAMSCA increased serum sodium concentration by 4.8 mEq/L vs 0.2 mEq/L for placebo.
On Day 30, SAMSCA increased serum sodium concentration by 7.4 mEq/L vs 1.5 mEq/L for placebo.
Results of SALT
SALT Trial
None of the patients in these studies had evidence of osmotic demyelination syndrome (ODS) or related neurologic sequel.
In patients receiving SAMSCA who develop too-rapid rise in serum sodium, discontinue or interruption of treatment with SAMSCA and administration of hypotonic fluid was considered.
Results of SALT Reduced need for fluid restriction Fluid restriction during the first 24
hours of therapy with SAMSCA may increase the likelihood of overly rapid correction of serum sodium and should be avoided.
Results of SALT Significant effect on fluid balance With SAMSCA, urine output is greater than
fluid intake, which results in a net negative fluid balance.
Samsca
SAMSCA is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L ) in heart failure, cirrhosis, and SIADH.
It is available in 15mg, 30mg and 60mg tablets.
Samsca SAMSCA is contraindicated in the
following conditions: Urgent need to raise serum sodium
acutely Inability of the patient to sense or
appropriately respond to thirst Hypovolemic hyponatremia Concomitant use of strong CYP 3A
inhibitors Anuric patients
Samsca
SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely.
Too rapid correction of serum sodium (e.g., >12 mEq/L/24 hours) can cause serious neurologic sequel, including osmotic demyelination syndrome (ODS).
Promise of Vasopressin Antagonist Management of hyponatremia Prompt, Reliable and Controlled Permits out pt management