Therapeutics III

Sodium & Water Disorders

Manhal A. Amber MSc Clinical Pharmacy, BSc Pharmacy

Objectives
To understand water and sodium hemostasis

in the body
To know the relation between water, sodium and volume disorders To know the types of hyponatremia and hypernatremia T o know the Causes of hyponatremia and hypernatremia To understand the management of hyponatremia and hypernatremia

Introduction
The human body tightly regulates blood volume and plasma osmolality as both are essential for..? Blood volume determinant of tissue perfusion deliver O2 & nutrients + remove metabolic waste products from tissues. Plasma osmolality is an important determinant of ICV. Maintenance of normal intracellular volume is particularly critical in the brain, (prevent neural dysfunction & death).

Introduction
The homeostatic mechanisms for regulating blood volume and plasma osmolality involve control of sodium and water balance. Blood volume are controlled by sodium balance.

In contrast, the homeostatic mechanisms for controlling plasma osmolality, which is largely determined by serum sodium concentration, are focused on controlling water balance.
Sodium and water balance are closely related and are frequently considered together. T or F ?

Compartments Ions Distribution 95%

98%

Serum Osmolality Sosm.

S. Na conc. is tightly regulated ( 2% to 3% variation). (ADH), is released from the posterior pituitary when the plasma osmolality increases. An increase in serum osmolality sensed in the hypothalamus results not only in AVP release, but also in stimulation of thirst. The combination of an increase in water intake and a decrease in water excretion results in a decrease in the serum osmolality and inhibition of AVP secretion once the plasma osmolality is restored to normal.

Serum Sodium

CNS Symptoms

CV Symp & signs

Hyponatremia
Defined as sodium concentration < 135 mEq/L. Generally considered a disorder of water as opposed to disorder of salt. Results from increased water retention. Normal physiologic measures allow a person to excrete up to 10 liters of water per day which protects against hyponatremia. Thus, in most cases, some impairment of renal excretion of water is present.

Hyponatremai
Normal ADH response to low sodium is to be suppressed to allow maximally dilute urine to be excreted thereby raising serum sodium level Psuedohyponatremia High blood sugar (DKA) or protein level (multiple myeloma) can cause falsely depressed sodium levels Causes of Hyponatremia can be classified based on volume status and osmolality.
Hypovolemic, Euvolemic or Hypervolemic Hypertonic, hypotonic or normotonic

Hyponatremia
Serum OSM Low Normal
Marked hyperlipidemia Hyperproteinemia (Multiple myeloma)

High (Hypertonic hyponatremia)

Hyperglycemia Mannitol

Hypotonic Hyponatremia

ECFv Low Normal

Renal loss (UNa > 20) Diuretics Thiazide K-sparing ACE-I, ARB Extra-renal loss (UNa <10) Bleeding Burns GI (N/V, diarrhea) Pancreatitis

High
CHF Cirrhosis Nephrosis

Hypothyroidism SIADH Reset Osmostat Water Intoxication 1 Polydipsia

First step in Assessment: Are symptoms present?

Hyponatremia can be asymptomatic and found by routine lab testing It may present with mild symptoms such as nausea and malaise (earliest) or headache and lethargy

Or it may present with more severe symptoms such as seizures, coma or respiratory arrest

Presentation determines if immediate action is needed

If severe symptoms are present, hypertonic saline needs to be administered to prevent further decline If severe symptoms are not present, can start by initiating fluid restriction and determining cause of hyponatremia Oral fluid restriction is good first step as it will prevent further drop in sodium NOTE: This does not mean that you cant give isotonic fluids to someone who is truly volume depleted

Volume status helps predict cause

Hypovolemia (urine output, dry mucous membranes, sunken eyes)
True Volume Depletion Adrenal insufficiency Thiazide overdose Exercised induced hyponatremia

Euvolemia
SIADH Primary Polydipsia

Hypervolemia (Edema)
Cirrhosis and CHF

Diagnostic Tests
3 mandatory lab tests
Serum Osmolality Urine Osmolality Urine Sodium Concentration

Additional labs depending on clinical suspicion

TSH, cortisol (Hypothryoidism or Adrenal insufficiency) Albumin, BMP, triglycerides and SPEP (psuedohyponatremia, cirrhosis, MM)

Treatment is based on symptoms

Patients with serum sodium above 120 are generally asymptomatic Symptoms tend to occur at serum sodium levels lower than 120 or when a rapid decline in sodium levels occur Patients can have mild symptoms at sodium concentrations of 110-115 mEq/L when this level is reached gradually

Severe symptoms present

As stated earlier, symptoms dictate treatment If severe symptoms are present, starting bolus of 100 ml of 3% hypertonic saline which generally raise serum sodium level by 2-3 mEq/L Goals for correction:
1.5 to 2 mEq/L per hour for first 3-4 hours until symptoms resolve Increase by no more than 10 mEq/L in first 24 hrs Increase by no more than 18 mEq/L in first 48 hrs

What if little to no symptoms are present?

Oral fluid restriction is the first step
No more than 1500 mL per day NOTE: This only pertains to oral fluid, isotonic IV fluids do not count towards fluid intake

If volume depletion is present, isotonic (0.9%) saline can be given intravenously Careful monitoring should be used whether symptoms are present or not
Serum sodium levels should be drawn every 4-6 hours or more frequently if hypertonic saline is used

Rx Hyponatremia
Na deficit = 0.6 x wt(kg) x (desired [Na] - actual [Na]) (mmol)

When do you need to Rx quickly?

Acute (<24h) severe (< 120 mEq/L) Hyponatremia
Prevent brain swelling or Rx brain swelling

Symptomatic Hyponatremia (Seizures, coma, etc.)

Alleviate symptoms

Quickly: 3% NS, 1-2 mEq/L/h until:

Symptoms stop 3-4h elapsed and/or Serum Na has reached 120 mEq/L

Then SLOW down correction to 0.5 mEq/L/h with 0.9% NS or simply fluid restriction. Aim for overall 24h correction to be < 10-12 mEq/L/d to prevent myelinolysis

What if the sodium increases too fast?

The dreaded complication of increasing sodium too fast is Central Pontine Myelinolysis which is a form of osmotic demyelination Symptoms generally occur 2-6 days after elevation of sodium and usually either irreversible or only partially reversible Symptoms include: dysarthria, dysphagia, lethargy, coma or even seizures

Treatment Options (APPENDIX)

CPM is associated with poor prognosis Prevention is the key + Prevent complication. Small studies have shown that plasmapharesis done immediately after diagnosis may improve clinical outcomes

Summary of Hyponatremia
Hyponatremia has variety of causes Treatment is based on symptoms
Severe symptoms = Hypertonic Saline Mild or no symptoms = Fluid restriction

Overcorrection, more than 12 mEq increase in 24 hours must be avoided with monitoring Serum Osmolality, Urine Osmolality and Urine sodium concentration are initial tests to order

SIADH: Important concept to understand

Caused by various etiologies CNS disease tumor, infection, CVA, SAH Pulmonary disease TB, pneumonia, positive pressure ventilation Cancer Lung, pancreas, thymoma, ovary, lymphoma Drugs NSAIDs, SSRIs, diuretics, TCAs Surgery - Postoperative Idopathic most common

Main diagnostic criteria for SIADH

Clinical Euvolemia Hypotonic Hyponatremia Normal hepatic, renal and cardiac function Normal thyroid and adrenal function Urine osmolality greater than 100 mOsm/kg Urine sodium level greater than 20 mEq/L

SIADH
Treatment
Fluid Restriction < 1000-12000 ml/day Oral Salt, Hi-protein diet or Urea(30 g/d): promote solute diuresis Lasix 20 mg po od-bid: Loop direct Demeclocycline 300-600 mg bid Inhibit tubular AVP activity Delayed onst (3-6 day) so what? Cant be used in children (can be nephrotoxic) Vasopressin receptors antagonist, V1, Conivaptan V1V2 (only I.V.)

IV salt solution:

Rarely if ever needed (i.e. only if symptomatic with SZ/coma) Solution given must be of greater OSM than UOSM or in long run will just make hyponatremia worse (often IV NS not sufficient)

HYPERNATREMIA

Hypernatremia
Produced by either administration of hypertonic fluids or much more frequently, loss of thirst Because of extremely efficient regulatory mechanisms such as ADH and thirst, hypernatremia generally occurs only in people with prolonged lack of thirst mechanism Patients with loss of ADH (Diabetes Insipidus) usually can compensate with increased fluid intake

Causes of Hypernatremia
Insensible water losses GI losses (hypotonic) ex; NV Diabetes Insipidus (both central and nephrogenic) Osmotic Diuresis DKA Hypothalamic lesions which affect thirst function Causes include tumors, granulomatous diseases or vascular disease Sodium Overload Infusion of Hypertonic sodium bicarbonate for metabolic acidosis Salt ingestion

Symptoms of Hypernatremia
Initial symptoms include lethargy, weakness and irritability Can progress to seizures, obtundation or coma Resulting decrease in brain volume can lead to rupture of cerebral veins leading to hemorrhage Severe symptoms usually occur with rapid increase to sodium concentration of 158 mEq or more Sodium concentration greater than 180 mEq are associated with high mortality

Diagnosis of Hypernatremia
Same labs as workup for hyponatremia: Serum osmolality, urine osmolality and urine sodium Urine sodium should be lower than 25 mEq/L if water and volume loss are the cause. It can be greater than 100 mEq/L when hypertonic solutions are infused or ingested If urine osmolality is lower than serum osmolality then DI is present
Administration of AVP will differentiate
Urine osmolality will increase in central DI, no response in nephrogenic DI

TREATMENT OF HYPERNATREMIA
Goal is to restore normal volume & osmolality Slow correction over 48 hours Replace concomitant continuous losses Treat the cause of hypernatremia

Treatment of Hypernatremia
First, calculate water deficit Water deficit = CBW x ((plasma Na/desired Na level)-1) CBW = current body water assumed to be 50% of body weight in men and 40% in women So lets do a sample calculation:
60 kg woman with 168 mEq/L How much water will it take to reduce her sodium to 140 mEq/L

Calculation continued
Water deficit = 0.4 x 60 ([168/140]-1) = 4.8 L But how fast should I correct it? Same as hyponatremia, sodium should not be lowered by more than 12 mEq/L in 24 hours
Overcorrection can lead to cerebral edema which can lead to encephalopathy, seizures or death

So what does that mean for our patient?

Typical fluids given in form of D5 water

Treatment of DI
DI: Excessive urination and extreme thirst CDI or NDI Rx Dehydration
NS initially if ECFv contraction Then IV D5W or enteral free water to lower serum [Na]

AVP (Desmopressin)
Reduces U/O and therefore simplifies fluid therapy Long t: duration 8-12h, up to 24h AVP 1ug IV/SC x 1 Once nasal mucosa stable can switch to intranasal Also oral form DDAVP now available

AVP: 1ug IV/SC = 10 ug IN = 0.1 mg PO

AVP Analoge
Dose should be adjusted to prevent nocturia, Daily urine volume of approximately 1.5 to 2 L. Maintain the serum sodium conc. n in the 137 to 142 mEq/L range. Measure Na conc.d every 3 to 4 days during the initial dose titration period, and then every 2 to 4 months. SEs: water intoxication caused by excess water retention ( montor for signs and symptoms of hyponatremia and hypervolemia).

Treatment of DI
Chlorpropamide HTCZ Amiloride Indomethacin Clofibrate Tegretol

Summary of Hypernatremia
Loss of thirst usually has to occur to produce hypernatremia Rate of correction same as hyponatremia D5 water infusion is typically used to lower sodium level Same diagnostic labs used: Serum osmolality, Urine osmolality and Urine sodium Beware of overcorrection as cerebral edema may develop

Thank You