Disorders of Sodium and Water Homeostasis PDF

**Disorders of Sodium and Water Homeostasis** KEY CONCEPTS I. Maintenance of normal blood volume and serum osmolality is essential for cellular function and is tightly regulated in the human body II. **[Water balance] determines [serum sodium conc]**, and **[Sodium balance] determines...

**Disorders of Sodium and Water Homeostasis** KEY CONCEPTS I. Maintenance of normal blood volume and serum osmolality is essential for cellular function and is tightly regulated in the human body II. **[Water balance] determines [serum sodium conc]**, and **[Sodium balance] determines [volume status]** III. TBW (total body water) range: **45% - 80% of body weight** - depending on sex, age, gestational age, and disease states - distributed into two compartments: 1. intracellular compartment/fluid (**ICF**) - **two-thirds \[67%\] of TBW** 2. extracellular compartment/fluid (**ECF**) - **one-third \[33%\] of TBW** IV. **Normal** serum sodium concentration: **135 to 145 mEq/L** V. Arginine Vasopressin (**AVP**) -- also known as antidiuretic hormone (ADH) - **synthesized** in the **hypothalamus** and **secreted** by **posterior pituitary** in **response** **to** both osmotic (**serum sodium greater than 135 mEq/L**) and non-osmotic regulators **[to maintain water balance]** VI. **HYPONATREMIA** - defined as serum **Na conc less than 135** mEq/L - **most common** electrolyte abnormality **with** significant **morbidity and mortality** in both adults and children - predominantly the **result of an excess of extracellular water** **relative to sodium** because of **impaired water excretion** - *Analogy*: Imagine adding extra water to a cup of salty soup---it doesn't reduce the amount of salt but dilutes its concentration. Similarly, in hyponatremia, sodium is diluted due to water retention. VII. **HYPOVOLEMIC HYPOTONIC HYPONATREMIA** - Common in pxs **taking thiazide diuretics** - *Analogy*: Imagine you have a water tank filled with saltwater (salt = sodium). Now, suppose there\'s a leak in the tank causing both salt and water to spill out, but more salt than water is lost. Over time, the amount of saltwater in the tank decreases (this represents hypovolemia, or reduced blood volume). However, since more salt than water is lost, the remaining water in the tank becomes diluted (this represents hypotonic hyponatremia, where sodium levels are low relative to water). - \*The leak = vomiting, diarrhea, or diuretic use, which cause both sodium and water loss. - \*The tank becoming less full = hypovolemia (low blood volume). - \*The diluted saltwater left in the tank = hyponatremia with low sodium relative to water. VIII. **EUVOLEMIC (ISOVOLEMIC) HYPOTONIC HYPONATREMIA** -- associated with: - normal or slightly decreased ECF sodium content - increased TBW and ECF volume - most often caused by the Syndrome of Inappropriate ADH Secretion (**SIADH**) - Analogy: Imagine a swimming pool filled with saltwater, where the salt represents sodium. Now, picture that the pool is being filled with fresh water (representing water retention in the body) but no significant amount of saltwater is added or lost. Over time, the salt concentration in the pool decreases because the fresh water is diluting the saltwater, but the total amount of water in the pool remains unchanged. The volume of water in the pool is normal (euvolemic), but the salt concentration is lower than normal (hypotonic), which mirrors euvolemic hypotonic hyponatremia. - \*The pool\'s volume stays the same, but excess fresh water dilutes the salt. - \*In the body, conditions like SIADH or certain medications cause water retention without a significant loss of sodium, resulting in normal blood volume (euvolemia) but dilution of sodium (hypotonic). - \*The sodium concentration is low, but the total fluid volume is normal---hence the term euvolemic IX. **Hyponatremia with [hypervolemia]** (ECF volume expansion) - occurs when sodium and water excretion is impaired such as **heart failure**, **cirrhosis**, or **nephrotic syndrome** X. **HYPERNATREMIA** - defined as a serum sodium concentration **greater than 145 mEq/L** - always associated with **hypertonicity** and **intracellular dehydration**, resulting from a **water deficit** **relative to ECF sodium content** XI. Brain's adaptation to chronic serum hypoosmolality or hyperosmolality **leads to neurologic symptoms** **when** either hyponatremia (hypoosmolality) or hypernatremia (hyperosmolality) is **corrected too rapidly**. XII. **Edema** - defined as a clinically detectable **increase in interstitial fluid volume** - due to **heart, kidney, or liver failure** or a combination of these conditions - edema can also develop with a rapid **decrease in serum albumin** concentration along with **excess fluid intake** such as seen in the setting of **burns or trauma** XIII. **Adequate blood volume is required** for effective **tissue perfusion** which is required to **deliver oxygen and nutrients** to and **remove metabolic waste products** from tissues. XIV. **[Serum osmolality]** -- **determined by serum Na conc** and **important determinant of ICF volume** - **normal ICF volume** is **important to be maintained** particularly in the **brain** which is **80% water**. **Alterations** or **rapid changes** will result in significant **dysfunction**, and even **death** XV. Homeostatic mechanisms - **for controlling blood volume**, **focus** is on **controlling sodium balance** - **for controlling serum osmolality** (serum sodium concentration), **focus** is on **controlling water balance** **SODIUM AND WATER HOMEOSTASIS** - **Excessive sodium intake** is a major **risk factor for HTN** as BP rises with increased sodium intake - **Kidney** - Proper functioning kidney **excrete excess sodium** to **maintain** the **serum Na conc** and **osmolality** **within** a tight **range** - can also **conserve sodium** during periods of **low sodium intake** or in the presence of **excessive losses** - Hyponatremia and Hypernatremia **both** have **altered serum tonicity** and **cell volume** that reflect a **change in the ratio of total exchangeable body sodium to TBW** - Serum (plasma) volume: \~ 17% of the ECF volume - **Sodium** contributes more than 90% of the **ECF osmolality** - **ICF osmolality** - primarily determined by the **ICF** **potassium** concentration - \*PISO - **extra- and intracellular Na and K concs** are **maintained by Na+-K+-ATPase pump** - Because most cell membranes are freely permeable to water, the free flow of water between compartments ensures that the ICF and ECF osmolalities remain equal. - **Effective osmoles** - kept in their respective compartments by the Na+-K+-ATPase pump - solutes that **cannot freely cross cell membranes** like **sodium and potassium** - **ECF concentration of effective osmoles determines** **[tonicity]** - **tonicity** of the ECF **controls the movement of water between the fluid compartments** - ex: If the ECF is more concentrated, water moves out of the cells into the ECF, causing cells to shrink. - If the ECF is less concentrated, water moves into the cells from the ECF, causing cells to swell. +-----------------------+-----------------------+-----------------------+ | **Addition of soln to | **effective ECF | **ICF volume** | | ECF** | osmolality** | | +=======================+=======================+=======================+ | Isotonic solution | **no change** in ECF | no change in ICF | | (eg, 0.9% NaCl) | osmolality | volume | +-----------------------+-----------------------+-----------------------+ | Hypertonic solution | change in ECF | **decrease** in ICF | | (eg, 3% NaCl) | osmolality | (cell) volume | | | | | | | | cell crenation | +-----------------------+-----------------------+-----------------------+ | Hypotonic solution | change in ECF | **increase** in ICF | | (eg, 0.45% NaCl) | osmolality | volume | | | | | | | | hemolysis | +-----------------------+-----------------------+-----------------------+ +-----------------------------------+-----------------------------------+ | Dextrose 5% in water | Hypotonic | +===================================+===================================+ | 0.2% NaCl \[quarter normal | Hypotonic | | saline\] | | +-----------------------------------+-----------------------------------+ | 0.45% NaCl \[half normal saline\] | Hypotonic | +-----------------------------------+-----------------------------------+ | 0.9% NaCl \[normal saline\] | Isotonic | +-----------------------------------+-----------------------------------+ | Lactated Ringer's / LR \[dextrose | Isotonic | | 5% LR\] | | +-----------------------------------+-----------------------------------+ | Plasma-Lyte A pH 7.4 | Isotonic | | | | | Plasma-Lyte 148 pH 5.5 | | +-----------------------------------+-----------------------------------+ | Normosol-R pH 6.6 | Isotonic | | | | | Normosol-R pH 7.4 | | +-----------------------------------+-----------------------------------+ | 3% NaCl | Hypertonic | +-----------------------------------+-----------------------------------+  - **Edelman's** equation - defines **serum sodium** (Nas) as a function of the **total exchangeable sodium and potassium** **in the** **body and the TBW** - abnormally **high glucose** and blood urea nitrogen (**BUN**) cons can also **may contribute in serum osmolality** - **Glucose is an effective osmole** but **BUN is not** - So **elevated osmolality** due to these two will have **differing effects** **Arginine Vasopressin** - When serum osmolality increases by as little as 1% to 2%, **AVP is released, binds to V2 receptor** (G protein-coupled receptor) on the basolateral membrane of principal cells lining the renal collecting duct - This will result in the insertion of water channels (aquaporin 2, AQP2) into both the apical cell membrane of the collecting duct principal cells and intracellular vesicles below the apical membrane **increasing permeability** - **Water can then pass through** the cell into the peritubular capillary space where it is reabsorbed into the systemic circulation - When the serum Na conc is 145 mEq/L (mmol/L) or above, a maximally concentrated urine (1,200 mOsm/L) will be formed - AVP release will also **stimulate thirst** (additional means to return serum osmolality to normal) - So, **decrease in serum osmolality** **happens** due to combination of: 1. **increased water intake (response to thirst)** 2. **decreased water excretion because of kidney's response to AVP** - Once restored to normal: - AVP secretion is inhibited - AQP2 water channels are retrieved - water permeability returns to the usual low state - renal excretion of solute-free water (aquaresis) occurs. - AVP secretion - **regulated primarily by osmolality** - Non-osmotic AVP release - occurs when the **brain's osmoreceptors detect** as little as a **6% to 10% reduction** in the **effective circulating volume** or **arterial BP** - **effective circulating volume** = **portion of the ECF** **responsible for organ perfusion** - a **decrease in this / Arterial BP** will **activates arterial baroreceptors** in the carotid sinus and glomerular afferent arterioles - results in **RAAS system stimulation** and increased **angiotensin II synthesis** - **Angiotensin II stimulates** both **non-osmotic AVP release** and **thirst** - can override osmotic AVP inhibition To understand treatment options, [differentiating between dehydration and hypovolemia is important] 1. **Dehydration** - refers to a **loss of TBW** producing **hypertonicity** 2. **Hypovolemia** (volume depletion) - a **symptomatic ECF volume deficit** - These two can **exist independently or concurrently** - they are different processes that [requires different types and rates of fluid replacement] **HYPONATREMIA** \- defined as a serum Na conc **less than 135** mEq/L (mmol/L) **Medication-induced hyponatremia** is a common type of hyponatremia: - [**thiazide** diuretics] - **[psychotropic] medications** Risk factors: - advancing age - increased intake of hypotonic fluids either orally or through enteral feedings or IV fluids. - ingestion of excessive volumes of hypotonic fluids (water, sports drinks) - can cause **exercise-associated hyponatremia** occurring during or up to 24 hours after prolonged physical activity - seen in **pregnancy**, frequently seen in **patients with hyperemesis gravidarum** and **preeclampsia** Associated with **significant morbidity and mortality** - **even in asymptomatic** pxs, **chronic** hyponatremia is associated with **decreased cognitive function** and **increased risk of** **frailty, falls, fractures, and bone loss**, especially in older adults - transient or permanent brain dysfunction can result from either acute effect of hypoosmolality or too rapid correction **Hyponatremia** is predominantly the result of an **excess of extracellular water relative to sodium because of impaired water excretion** - kidney normally can excrete large volumes of dilute urine after ingestion of a water load - but a **non-osmotic AVP release** can **lead to water retention** and a **decrease in the serum Na conc**, **despite a decrease in ECF and ICF osmolality** - **causes** of non-osmotic AVP release: - **hypovolemia** - **decreased effective circulating volume** (eg, **CHF, nephrotic syndrome, cirrhosis**) - **SIADH** -- common cause of hyponatremia - associated with some **cancers**, **CNS damage**, certain **lung conditions**, **medications**, and primary or psychogenic **polydipsia** **Pathophysiology: Hyponatremia** - can be associated with normal, increased, or decreased serum osmolality \[tonicity\], depending on its cause **ISOTONIC** Hyponatremia - **Normal (\~280 mOsm/L)** - [Hyponatremia (expected low osmolality]) with a [normal measured serum osmolality] (**osmol gap**) - can be **seen in hyperlipidemia** (markedly **elevated** serum **[lipids]**) or **hyperproteinemia, [multiple myeloma]** (**elevated [proteins]**) when **flame photometry** or **indirect potentiometry** is used to measure the sodium concentration - Elevated serum lipids or proteins result in a larger discrepancy between the volume of the sample and serum water, which leads to a falsely low measurement of the serum sodium concentration \[**Pseudohyponatremia**\] - This pseudohyponatremia is an artifact (**false/misleading result**) because elevated lipids or proteins account for a larger than usual proportion of the total sample volume, reducing the percentage of water in the serum - Meaning, blood is made up of water, proteins, lipids, and other components. Normally, water accounts for the majority of the volume. But when lipids or proteins increase, the water percentage decreases. Most lab machines measure sodium in the total blood volume, not just in the water portion. If lipids or proteins take up more space, it artificially lowers the measured sodium concentration, even though the sodium in the water (where it actually matters) is normal. - **Pseudohyponatremia is [not seen]** when measured via **[direct potentiometry] using [ion-selective] electrodes**\-\--most often done in current laboratory practice, including **[blood gas analyzers]**, because it does not involve sample dilution - Treatment of hyponatremia in a case of pseudohyponatremia can lead to serious consequences **HYPERTONIC** Hyponatremia - High **(\>280** mOsm/L) - Hypertonic (increased serum osmolality) hyponatremia - Occurs when there is presence of **excess effective osmoles (other than Na) in the ECF** - Most **frequent cause** - **significant [hyperglycemia ]**\[glucose attracts water\] - elevated serum glucose conc initially **cause water diffusion [from cells (ICF) into the ECF]** = decreasing the ICF volume, expanding the ECF volume, and **diluting the existing sodium** resulting in hyponatremia. - **Increased ECF volume** results in **increased urine output (polyuria**) that **triggering** thirst (**polydipsia**) - **If hyperglycemia** is **not corrected** and/or **extra fluid is not ingested**, **[HYPOVOLEMIA develops]** due to excessive urinary losses - **Mannitol** (another effective osmole) can also cause hypertonic hyponatremia - **If hypertonicity is present and glucose is normal**, the high osmolality must be due to something else---an **unmeasured osmole** - So, in pxs w/ **hypertonic hyponatremia**, a **normal glucose concentration**, and a **large osmolal gap**, look for hidden substances or toxins in the blood that are contributing to the increased osmolality. These unmeasured solutes are responsible for pulling water into the extracellular fluid, diluting sodium. **HYPOTONIC** Hyponatremia - Low **(\ A. **HYPOVOLEMIC** **Hypotonic** Hyponatremia - Pxs with fluid losses caused by **diarrhea, excessive sweating, and diuretics** - these people have ECF volume contraction and have lost fluids that are hypotonic relative to the serum - so, they can be transiently hypernatremic - this transient **hypernatremic hyperosmolality** **results** in **osmotic AVP release** and **thirst** - If sodium and water losses continue, it will result more to hypovolemia resulting in more AVP release - If they drink water (a hypotonic fluid) or who are given hypotonic IV fluids retain water, hyponatremia will develop - these patients will typically have: - concentrated urine - urine osmolality \ 450 mOsm/kg (reflecting AVP action) - urine Na conc: - less than 30 mEq/L - when sodium losses are extrarenal (eg, diarrhea, vomiting) - greater than 30 mEq/L with renal sodium losses (eg, thiazide diuretics, adrenal insufficiency); although, urine sodium concentration is also affected by solute intake - Explanation: - Fluid Loss and Hypernatremia: - When someone loses fluids through diarrhea, sweating, or diuretics, the fluids lost are usually hypotonic (less concentrated than blood) - This makes the blood temporarily hypernatremic (too much sodium) and hyperosmolar (too concentrated) - Body's Response: - The high sodium concentration triggers the release of a hormone called arginine vasopressin (AVP), which makes the body hold onto water. - It also makes the person feel thirsty to encourage drinking water. - Progression to Hyponatremia: - If the person continues losing sodium and water without adequate replacement, they develop hypovolemia (low blood volume). - The body releases even more AVP to conserve water. - If they drink a lot of water or receive hypotonic IV fluids (fluids less concentrated than blood), the added water dilutes the blood sodium further, causing hyponatremia (low blood sodium). - Urine Characteristics: - The urine will be very concentrated (osmolality \> 450 mOsm/kg) due to AVP making the kidneys conserve water. - The amount of sodium in the urine can help identify the cause: - Low urine sodium (\30 mEq/L): Sodium loss is from the kidneys (e.g., diuretics, adrenal problems). Key Idea: When fluids are lost, the body initially becomes sodium-rich and concentrated (hypernatremic). The body's response to conserve water and correct the imbalance can overshoot if too much water is added back, leading to low sodium (hyponatremia). The urine's sodium level helps pinpoint the underlying cause. - \[**Thiazide diuretic-induced hyponatremia**\] **Hypovolemic hypotonic hyponatremia** -- common in pxs taking thiazide diuretics - usually mild and relatively asymptomatic but can be severe - older women are at greater risk - develops w/in 2 weeks of initiation but can occur anytime especially when dosage increases or if other causes of hyponatremia are present - **does not alter medullary osmolality** because they act in the renal cortex - related to a balance of direct and indirect effects - Thiazide diuretics block sodium reabsorption in the distal tubules of the renal cortex, thereby increasing sodium and water removal from the body. The resultant decrease in effective circulating volume stimulates AVP release, resulting in increased free water reabsorption in the collecting duct, as well as increased water intake because of thirst stimulation. Hyponatremia develops when the net result of these effects is the loss of more sodium than water. - Explanation: - Thiazide diuretics and how they work: - Thiazide diuretics are medications that make your body lose sodium (salt) and water by blocking sodium absorption in a part of the kidney called the distal tubules. - This causes you to urinate out more sodium and water. - What happens next: - When the body loses too much sodium and water, the blood volume decreases (less fluid circulating in the body). - Body\'s response: - The body thinks it's dehydrated and releases a hormone called arginine vasopressin (AVP), which helps the kidneys reabsorb water to make up for the lost fluid. - At the same time, the brain tells you to drink more water because you feel thirsty. - How hyponatremia happens: - The diuretics cause you to lose more sodium than water through urine. - At the same time, the extra water you drink and reabsorb (because of AVP) dilutes the remaining sodium in your blood. - End result: - Your blood sodium level becomes low (hyponatremia) because there's more water relative to the amount of sodium in your body. - Loop diuretics - hyponatremia **infrequently** occurs due to: - **different site** of action - **decreases medullary osmolality** (less likely to cause hyponatremia because they **reduce the kidney\'s ability to reabsorb water**) - **shorter half-life** than thiazides (effects wear off quickly) so pxs usually replete the urinary sodium and water losses prior to taking the next dose, thereby minimizing AVP stimulation. - **Cerebral** (**renal) [salt wasting] syndrome** - results in **decreased ECF volume** due to a **profound natriuresis** (urinary sodium loss) - seen in pxs w/ **intracranial disorders** like **subarachnoid hemorrhage** and **traumatic brain injury** (TBI) or **after neurosurgical procedures**, but it **can occur in patients without CNS pathology** - Characteristics of cerebral salt wasting: - **high** **[urine] sodium, osmolality, and volume** - **high** **serum BUN** - **orthostatic hypotension** - **[low]** **central venous pressure** - **treatment** for severe cases: - IV volume repletion with **[0.9% NaCl]** - **[3% NaCl]** -- if serum Na conc is **less than 120** mEq/L - **For stable pxs**: - **Oral salt supplementation** **[and]** a mineralocorticoid like **fludrocortisone** - used **to augment serum sodium and intravascular volume** until resolved B. **EUVOLEMIC (isovolemic) Hypotonic** Hyponatremia - normal or slightly decreased ECF sodium content and increased TBW and ECF volume - its increase in **ECF volume is not sufficient to cause peripheral/pulmonary edema** or other signs of volume overload, so pxs will appear euvolemic - **Causes**: - **SIADH** - pxs with **kidney and adrenal insufficiency** or **hypothyroidism** - may develop even with more modest water intakes in individuals who ingest low-solute diets - **primary or psychogenic polydipsia** (water intoxication or compulsive water drinking) - more water (\> 20 L/day) is ingested than the kidneys can excrete as solute-free water - **unlike SIADH, [AVP secretion is suppressed]** = **urine osmolality is low (\< 100** mOsm/kg) - **urine sodium is low** with **\< 15** mEq/L **due to dilution** - SIADH -- most often cause - where water **intake exceeds** the kidney's capacity to **excrete** a water load, because of: - **increased AVP release** via nonosmotic and/or nonphysiologic processes or - **enhanced sensitivity of the kidney to AVP** - Values in pxs with SIADH: - urine osmolality - **greater than** 100 mOsm/kg (Concentrated Urine) - Why? - In SIADH, excess ADH causes the kidneys to reabsorb water. This water retention leaves urine highly concentrated, even when the body doesn't need to conserve water. - Normally, if the body has excess water, urine should become dilute. In SIADH, this doesn't happen because ADH keeps acting inappropriately. - **urine sodium** concentrations - **greater than 20 to 30** mEq/L (High Sodium in Urine) - Why? - The body detects the excess water from SIADH and tries to compensate by excreting more sodium in the urine. - Even though the blood sodium is diluted (hyponatremia), the kidneys continue excreting sodium because the body perceives slight volume expansion from water retention. - **serum osmolality** - less than 275 mOsm/kg due to ECF volume expansion (**Diluted Blood**) - Why? - Serum osmolality reflects the concentration of solutes (mainly sodium) in the blood. - In SIADH, the **retained water dilutes sodium and other solutes in the blood**, lowering serum osmolality (making it **hypotonic**). - This is a **hallmark of hypotonic hyponatremia** -- low serum osmolality - **Most common causes of SIADH**: a. certain **cancers** (eg, small cell lung \[SCLC\], pancreatic, brain) b. **CNS disorders** (eg, TBI, stroke, meningitis, pituitary surgery) c. **lung disease** (eg, TB, pneumonia, abscess, acute respiratory distress syndrome/ARDS) d. **medications** C. **HYPERVOLEMIC Hypotonic** Hyponatremia - **Hyponatremia** **with ECF [volume expansion]** (hypervolemia) - Occurs when both sodium and water excretion are impaired - Seen in in **HF, cirrhosis, or nephrotic syndrome**. Patients with these have **[expanded ECF volume and edema]** but a **decreased [effective arterial blood volume]** - The decrease in effective arterial blood volume results in: - **renal sodium retention** and eventual **ECF volume expansion** and **edema** - excess sodium retention will have **concomitant non-osmotic AVP stimulation** and **water retention** which perpetuates hyponatremia. Explanation: - What it is: - A condition where there's too much fluid (hypervolemia) in the body but the sodium level is low (hyponatremia). - It happens because the body can't get rid of both sodium and water properly. - Common causes: - Heart failure (HF): The heart doesn't pump blood well. - Cirrhosis: Liver scarring affects blood flow and fluid balance. - Nephrotic syndrome: Kidney problems lead to protein and fluid imbalance. - What's happening in the body: - These conditions cause the blood vessels to sense that there isn't enough blood circulating, even though there's actually too much fluid in the body. - The body reacts as if it's dehydrated, leading to: - Sodium retention: Kidneys hold onto sodium to increase blood flow. - Water retention: The hormone AVP (which makes the body hold water) is released to "fix" the perceived low blood volume. - The problem: - Both sodium and water are retained, but water retention is greater, causing the sodium level to dilute. This worsens hyponatremia (low sodium). - The result: - Too much fluid builds up (causing swelling and edema), but the sodium level stays low, making the blood hypotonic. In short: The body retains water and sodium due to miscommunication from the blood vessels, but water retention dominates, leading to low sodium levels despite having excess fluid in the body **CLINICAL PRESENTATION: HYPONATREMIA** - **Chronic Mild** **Hyponatremia** (**125-134** mEq/L): - Often asymptomatic and discovered incidentally during routine tests. - Symptoms may be subtle or go unnoticed, but can include: - - - - **Moderate** Hyponatremia (**115-124** mEq/L): - **Neurologic** symptoms **due to brain cell swelling**: - - **Severe** Hyponatremia (**110-114** mEq/L) or **Rapid Development**: - Life-threatening **CNS symptoms**: **seizures**, **coma, respiratory arrest, brainstem herniation, death** **Mechanism of Symptoms**: - Brain Adaptation: - - - - Role of Serum Sodium and Osmolality: - - Factors Influencing Hyponatremia Severity: - Age and Gender: - - Comorbidities: - - - **Risks of Rapid Correction**: **Osmotic Demyelination Syndrome** (ODS): - Symptoms may include, confusion, disorientation, dysarthria (difficulty speaking), dysphagia (difficulty swallowing), hyperreflexia, para-/quadriparesis, parkinsonism, locked-in syndrome (patient is aware but unable to move or speak), seizures, coma, and death within days. - **Risk factors** for ODS: - **Chronic hyponatremia** (sodium \ - **requires more aggressive therapy** to correct the hypotonicity - **initial** treatment goal - **increase serum tonicity** [just enough to control severe symptoms] - typically requires only a **small increase (5%) in the serum Na conc** - [once subsided], **continue** correction **at a slower**, more **controlled rate** - **asymptomatic** or who have only **mild to moderate** symptoms - [do not require rapid correction] - in all case -- avoid increase in serum Na conc: - more than 6-12 mEq/L in 24 hours (0.5 mEq/L per hour) or - 18 mEq/L (mmol/L) in any 48-hour period - correction rate of **no more than 6 to 8** mEq/L **in 24 hours** is [practical] **[to avoid ODS]** **ODS ([Osmotic Demyelination Syndrome])** is a preventable, rare but serious **neurological condition** caused by the **rapid correction of chronic hyponatremia** (low sodium levels). It leads to damage ([demyelination]) of nerve cells in certain areas of the brain, particularly the **pons**, which is part of the brainstem. +-----------------------------------------------------------------------+ | General Guidelines for Treatment of Hyponatremia | +=======================================================================+ | For both short- and long-term management | | | | - treat the underlying cause of hyponatremia, if possible | | | | treatment of **moderate-to-severe hypotonic hyponatremia** | | | | - requires **balancing the risks of hyponatremia vs the risk of | | ODS** | | | | Pxs who **acutely develop moderate-to-severe hyponatremia** and/**or | | who have severe symptoms** are at greatest risk | | | | - **benefit** most **from** more **rapid correction** of | | hyponatremia | | | | Correction of **hypovolemic** hypotonic hyponatremia | | | | - best accomplished with **[0.9% NaCl]**, as these | | patients [have both **sodium and water deficits**] | | | | **Active correction** of **euvolemic** and **hypervolemic** hypotonic | | hyponatremia in patients [who **do not require rapid | | correction**] | | | | - best accomplished by **[water restriction]** | | | | - **if** the initial response to **water restriction is not | | adequate** -- use **[Demeclocycline], [VRA, | | urea]**, or a **[loop diuretic]** | | | | Pxs with **[severe] symptoms** | | | | - **[3% NaCl]** - used initially to correct the | | hyponatremia [more rapidly] | | | | - A **[loop diuretic]** - administered | | **[simultaneously] with 3% NaCl** | | | | | | | | - will enhance the serum sodium correction by **[increasing free | | water excretion]** | | | | required for those whose **underlying cause** of hyponatremia | | **cannot be corrected** | | | | - **Long-term** management | | | | - Depending on the cause - [water restriction], | | [increasing sodium intake], **and/or** a | | [VRA] may be used | +-----------------------------------------------------------------------+ **[ACUTE OR SEVERELY SYMPTOMATIC] HYPOTONIC HYPONATREMIA** \- serum sodium is **less than 110-115** mEq/L - should receive a **small amount of 3% NaCl** until severe symptoms are resolved - While resolution of severe symptoms generally requires approximately a 5% increase in serum Na conc, some clinicians suggest that the initial safe target should be a serum sodium concentration of approximately 120 mEq/L Urine Na and K conc should be compared with those of the infusate (NaCl infusion) in planning a treatment regimen for patients with hypotonic hyponatremia - **for serum Na conc to increase** after administration of the infusion, **Na conc of the infusate must exceed the sum of the urinary Na and K concentrations** so that an effective net free-water excretion is produced - **[Na conc of infusion \ urine Na + K conc]** In **SIADH**, the urinary concentration of effective cations exceeds 154 mEq/L which is the Na conc of 0.9% NaCl, thus 0.9% NaCl administration could worsen hyponatremia - **Preferred: 3% NaCl** \[has a much higher concentration\-\--513 mEq/L than the urine in SIADH\] - **If urine osmolality in SIADH exceeds 300** mOsm/kg (mmol/kg) - administer an **IV loop diuretic** to: - increase solute-free water excretion - prevent volume overload (which can result from the administered NaCl) - to decrease urine osmolality to less than 150 mEq/L - **IV furosemide** 20 to 40 mg given every 6 hours or - **IV bumetanide** 0.5 to 1 mg given every 2-3 hours for several doses - If intermittent doses are not sufficient to manage volume overload - IV furosemide 20 to 40 mg **followed by a 10 to 40 mg/hr infusion** or - IV bumetanide 1 mg **followed by a 0.5 to 2 mg/hr infusion** Patients with **hypovolemic** hypotonic hyponatremia - should be treated initially with **0.9% NaCl** - reabsorption of Na occurs because effective circulating blood volume is decreased so urine Na conc usually is less (\ - 3% NaCl is usually given in small amounts to avoid overcorrecting sodium levels Patients with **acute** **hypervolemic** hypotonic hyponatremia \- particularly problematic to manage because the sodium and volume needed to minimize the risk of cerebral edema or seizures can worsen already compromised liver, heart, or kidney function - Treated initially with **[3% NaCl]** and **[water restriction]** - **Loop diuretic** or **Vasopressin receptor blocker (VRA)** therapy - often required to **facilitate urinary-free water excretion** **Determination of a NaCl Infusion Regimen** **Practical:** 3% NaCl 150 mL or 1 to 2 mL/kg of can be infused over 20 minutes If symptoms do not resolve - 3% NaCl 100 mL or 1 mL/kg of can be administered over 10 to 20 minutes every 30 minutes - until symptoms resolve and/or - target serum Na conc is reached, usually 5-8 mEq/L from baseline Within the first hour - serum Na should not increase by more than 5 mEq/L **After relief of symptoms - 0.9% NaCl is used to continue** the sodium correction **Another method:** [Calculate the sodium deficit] Then replace **one-third** of the deficit in the **first 6 hours** Then the **remaining two-thirds** over the **following 24 to 48 hours or longer** depending on how rapid the serum sodium conc have dropped Equation: Where: - Nad = goal serum Na w/c is usually no higher than 120-125 mEq/L. This is to avoid too rapid/overcorrection - Nas = px's current serum Na conc - TBW = patient's current TBW Advantages and disadvantages of 3% NaCl to patients with symptomatic hypotonicity: a. Advantage: 3% NaCl is more rapid correction of serum Na conc with a smaller infusion volume b. Disadvantage: 1. higher risk of too rapid correction of serum Na conc and ODS 2. high osmolality (1,026 mOsm/L) - result in **phlebitis** and significant tissue damage with extravasation when given via a peripheral IV catheter (\~7% complication rate with peripheral administration) - Central line administration is preferred but short-term peripheral administration is acceptable if infusion rate is low and large peripheral IV catheter is used The appropriate **infusion volume** - can be estimated using the amount of fluid needed to provide the calculated sodium deficit or the desired proportion of the estimated change that would result from a 1-L infusion Final step: calculate an appropriate **infusion rate** - Should increase the serum Na conc by **no more than 6 to 8** mEq/L in **24 hours** - **in high-risk patients** - Should increase the serum Na conc by **10 to 12 mEq/L** (mmol/L) in **24 hours** or **18 mEq/L** (mmol/L) in **48 hours** - **in others** In **pxs w/ severe** **hyponatremia** **[to minimize the risk of too rapid correction]** of hyponatremia - **Desmopressin** (1-4 mcg) and **free water replacement** [given along with] **3% NaCl** may be considered - [until] the serum sodium concentration **[reaches 128]** mEq/L **Assessment and Treatment of Euvolemic Hyponatremia**   Evaluation: - For pxs w/ severely symptomatic hypotonic hyponatremia - for **frequent** **monitoring of CNS symptoms** and **volume status** -- should be admitted to ICU - **Frequent** examination of the **heart, lungs, and neurologic status** during the **first 12 hour**s of therapy - **Measure** serum **Na conc** at least **every 2 to 4 hours** - **Measure urine** **sodium, potassium, and osmolality** **every 4 to 6 hours** during the **first 24 to 48 hours** of therapy - to **allow timely infusion rate adjustment** to avoid too rapid correction **[NONEMERGENT] [HYPOVOLEMIC] HYPOTONIC HYPONATREMIA** - patients are either **asymptomatic** or have **only mild-to-moderate** **symptoms** and **do not require rapid sodium correction** - many are **at high risk of developing ODS** if there is rapid correction because they have chronic hyponatremia and maximum compensation by the brain's osmotic adaptive mechanisms. - **correction of the underlying condition**, if possible - **[0.9% NaCl]** or **other isotonic soln** (eg, [lactated Ringer's, Plasma-Lyte®, Normosol-R®)] - to **correct the [hypovolemia]** - these will replace the existing sodium and water deficits while conveying a **lower risk of too rapid sodium correction** than 3% NaCl. **Assessment and Treatment of Hypotonic Hypovolemic Hyponatremia**  - If the patient's previous weight is unknown, ECF deficit can be roughly estimated based on clinical sxs - presence of hyponatremia = 5% ECF deficit - presence of orthostatic hypotension = at least 10% to 15% ECF deficit An isotonic solution - ideal to correct the patient's ECF volume deficit - because essentially 100% of it will remain in the ECF space Overriding initial treatment goal - to restore effective circulating volume so it may be needed to - administer an IV bolus over a period of 1 hour or less or - begin an IV infusion of the isotonic soln at 200 to 400 mL/hr until symptoms of hypovolemia improve Infusion rate - can then be decreased to 100 to 150 mL/hr (4-6 mL/ kg/hr in children) so that the serum Na conc does not increase too rapidly - Fluids should be given rapidly enough and in sufficient quantity - to restore and maintain adequate tissue perfusion without overloading the CV or pulmonary system - if the infusion rate is not adjusted appropriately, once hypovolemia is corrected, the serum sodium will increase rapidly 0.45% NaCl w/c is a hypoosmolar solution (154 mOsm/L), should not be infused alone - may result in red blood cell hemolysis - Dextrose 5%/0.45% NaCl -- infused to provide a relatively isotonic solution - Dextrose 5% provides 250 mOsm/L to the solution Potassium - Potassium depletion or repletion can also affect hyponatremia and its correction - 1 mEq of retained K = 1 mEq retained Na - so if hypokalemia is corrected at the same time as hyponatremia, the serum sodium may increase more rapidly Evaluation: - should be reexamined frequently during the initial few hours of therapy - urine output will often lag behind during fluid resuscitation - careful monitoring for pulmonary congestion is critical, especially in pxs with underlying heart, lung, or kidney dysfunction - serum sodium concentration should be measured every 2 to 4 hours - to allow timely adjustment of the rate and composition of IV fluids - to avoid too rapid increase of serum Na conc - pxs w/ hx of HF or kidney insufficiency - 0.9% NaCl is administered cautiously with frequent cardiopulmonary assessments so that the infusion rate can be adjusted at the earliest sign of pulmonary congestion **NONEMERGENT [EUVOLEMIC] HYPOTONIC HYPONATREMIA** - Long-term management - for patients when underlying cause is not readily correctable Treatment of SIADH - always involves **restricting water** and **correcting** the **underlying cause** - identify and discontinue medications that could be contributing \[if possible\] - **primary** treatment **goal**: to **induce a negative water balance** - by initially restricting water intake to 1,000 to 1,200 mL per day so that insensible water loss (skin and lung) plus obligate urine and stool loss exceed water intake \[meaning, it is to ensure the [body loses more water than it takes in]\] - additional goal: **maintain serum Na conc [close to 130 mEq/L]** to **reduce CNS symptoms** and **avoid iatrogenic hypovolemia** - water restriction may be needed but adherence is difficult - for those **with chronic SIADH** who are **unable to restrict water intake** sufficiently to maintain an acceptable serum Na conc - treated by [increasing solute intake] with [**NaCl supplementation** and/or **loop diuretic**] - NaCl supplementation - [increases the obligatory daily solute excretion], which [increases the kidney's capacity for water excretion] - Goal: to increase the daily solute intake and excretion to approximately 900 mOsm per day - expected adverse effect: **ECF volume expansion** - **loop diuretic** - administered concurrently to **[avoid volume overload and edema]** - it will also **[enhance water excretion]** by [limiting the formation] of the [medullary concentration gradient] **Vasopressin Receptor Antagonists** \- "vaptans" \- high-affinity [non]-peptide **blockers** of arginine vasopressin **V2** and **V1a receptors** - **additional** therapeutic **options** for both **euvolemic** and **hypervolemic** hypotonic hyponatremia X **contraindicated** in **hypovolemic** hyponatremia - V**1a** = predominant in **liver**, **CNS**, **cardiomyocytes** - V**1b** = **anterior pituitary**, **pancreas** - V**2** = **distal nephron** - Selective V2 receptor blockers - prevents AQP2 water channel transport to the apical surface, thereby **decreasing** AVP-dependent **water reabsorption** in the collecting duct - AVP inhibition = excretion of large water volumes, decreased urine osmolality, and an increase in the serum sodium concentration - called **aquaretics** - outcomes are achieved without significantly increasing electrolyte excretion Conivaptan and Tolvaptan - Conivaptan - **mixed V1 and V2** receptor **blocker** - **FDA-labeled** for treatment of **acute euvolemic and hypervolemic** hyponatremia in **hospitalized** pxs - Reason why use for **chronic hyponatremia is limited** - **only** available as **IV formulation** - FDA-labeled for up **to 4 days of use only** - **moderate CYP3A4 inhibitor** - **[not] FDA-labeled** for use in **pxs w/ HF** - Tolvaptan - oral and **selective V2 blocker** \[greater affinity for the V2 than endogenous AVP\] - oral bioavailability - 56% - peaks at 2 to 4 hours after a dose - primarily metabolized to inactive metabolites by CYP3A4 \[1% -metabolized unchanged in the urine\] - Inhibitor of P-gp - use with CYP inducers may not achieved benefits on usual dosages (eg, phenytoin, phenobarbital, St. John's Wort) - use with P-gp inhibitors and grapefruit juice = increased serum tolvaptan conc - **FDA-labeled** for tx of: - clinically significant (serum **Na conc \< 125** mEq/L) **euvolemic or hypervolemic** hyponatremia - **less marked symptomatic hyponatremia** that is **unresponsive to other therapy** in **pxs with HF, cirrhosis,** and **SIADH** - given alone = promotes aquaresis and modestly raises serum Na conc by 3.6 mEq/L at 4 days and 4.4 mEq/L (mmol/L) at 30 days - if used as **monotherapy**, tolvaptan is **superior** **to** either **furosemide** or **water restriction** - if given in **combination w/ furosemide** = **synergistic effects** **Patients with euvolemic** hypotonic hyponatremia are at **greater risk of overcorrection** of serum sodium **compared to hypervolemic** - **lower starting dosage** to **7.5 mg once daily** -- has equivalent efficacy and lower risk of overcorrection Critically ill neurological patients - often **require more aggressive care** to prevent long-term morbidity - a single tolvaptan dose -- effective to increase serum Na conc by 5 to 7.8 mEq/L and lasts for up to 96 hours \[multiple doses may be required\] - use of 15 mg = higher risk of overcorrection \[Na conc \ 6 to 12 mEq/L in 24 hours\] For pxs who cannot swallow tablets - tablets can be crushed, suspended in water, and the slurry administered orally or via a nasogastric tube During VRA therapy - **Avoid the water restriction within the first 24 to 48 hours** of initiation when active sodium correction is occurring - **After 24 hours**, **if a greater increase** in serum Na conc **is needed** - dosage may be **increased to 30 mg once daily**, and after another 24 hours, to a **maximum of 60 mg once daily** Reasons for therapeutic **resistance or failure to respond** to **VRA therapy** 1. **high** circulating **AVP concentrations** 2. **AVP-independent** **impaired urinary dilution** 3. **excessive water intake** 4. an activating **V2 -receptor** **mutation** causing nephrogenic SIADH **Contraindication** for **Tolvaptan** Therapy 1. who **needs rapid** serum sodium **correction** because it has 2- to 4-hour **delayed onset** 2. who is **unable to sense or respond** appropriately to **thirst** 3. pxs with **[hypo]volemic** hyponatremia 4. is taking **strong CYP3A4 inhibitors** \[eg, ketoconazole, clarithromycin, itraconazole, ritonavir\] 5. who are **anuric** \[produces very little or no urine\] Patients with **more profound hyponatremia** are more likely to **experience larger increases in serum Na conc** - Tolvaptan should be used cautiously with serum Na conc monitoring every 2 to 4 hours In pxs with CKD (stages 3, 4, 5) who are not receiving renal replacement therapy - Tolvaptan effectively produces aquaresis and increases serum sodium concentrations **VRA use** should be **avoided with hypertonic saline** (eg, **3% NaCl**) due to the - **risk of too rapid/overcorrection** of the serum Na conc Most common **ADRs** of VRA therapy: - Thirst, dry mouth, weakness, constipation, hyperglycemia, and urinary frequency Other Information for Tolvaptan: - FDA warning: avoid use for more than 30 days in anyone with chronic liver disease - Discontinued if any sign of liver injury occurs during therapy - Boxed warning: to reduce the ODS risk, tolvaptan therapy should begin or resume only in a hospital where the serum sodium concentration can be closely monitored When considering long-term VRA treatment - cost and potential liver toxicity must be weighed against benefits **Sodium-Glucose Co-Transporter-2 Inhibitors \[SGLT2-I\]** - has **cardiovascular and kidney benefits** - resulting **glucosuric effect** causes an **osmotic diuresis** and **increases free water excretion** - can be routinely recommended for treatment of **EUVOLEMIC hypotonic hyponatremia** **Demeclocycline** - semisynthetic tetracycline antibiotic - **option for some pxs with SIADH** whose serum Na conc is **not adequately controlled by water restriction** alone - essentially **causes nephrogenic diabetes insipidus** by - unpredictably inhibiting tubular AVP activity, which increases free water excretion - some may even develop polyuria and hypernatremia - has **delayed onset** (2-6 days) - **not used in acute mgt of severe hyponatremia** - dosage adjustments should be made no more frequently than every 3 to 4 days - **Photosensitivity with skin rash** may occur - **UV protection** during sun exposure - Contraindications: - has cirrhosis or compromised fluid intake - at high risk for demeclocycline-induced renal tubular toxicity and acute kidney failure - pregnant - younger than 8 years (unless absolutely necessary) - long-term use of demeclocycline can cause **tooth and bone development issues** **Urea** - osmotic agent - **increases** **urinary-free water excretion** - **decreases** **urinary sodium excretion** - **alternative** oral **tx for SIADH** and other hyponatremic disorders - Adherence to therapy -- a concern due to the **bitter taste** - FDA considers urea to be a medical food \[Rx is not required\] Evaluation - **When** the serum **sodium** has **increased by 6 to 8 mEq/L** (mmol/L) - **oral water or IV Dextrose 5% in water (D5W)** - given to replace urine output to minimize the risk of overcorrecting and ODS - **Volume status** - should also be assessed, particularly in patients who are being **treated with** **NaCl supplements and/or loop diuretics** - eg, BP, mucous membranes, skin turgor, heart, and lung examination **NONEMERGENT [HYPERVOLEMIC] HYPOTONIC HYPONATREMIA** \- asymptomatic or minimally symptomatic hypervolemic (expanded ECF volume) hypotonic hyponatremia - correction of the underlying cause, when possible - water restriction - combined daily losses (insensible water, urine, and stool) must exceed fluid intake - achieve negative water balance - minimizing rapid changes in brain cell volume until the serum Na conc is ≥ 125 mEq/L - dietary sodium intake should be restricted, depending on the degree of ECF volume expansion If only modest changes are seen over the first 5 days of fluid restriction can be due to poor adherence and frequent practice of sucking on ice chips to quench thirst. In moderately severe cases, other options should be considered if it does not improve in the first 24 to 48 hours Patients with hypervolemic hyponatremia caused by HF - treat w/ therapy that can potentially improve cardiac contractility and effective circulating volume, limiting non-osmotic AVP release - digitalis - afterload reduction with ACEI, ARBs, ARNI, SGLT2 inhibitors, or other vasodilators - only ACEI have proven benefit in partially correcting hyponatremia - dose limiting ADR: hyperkalemia and impaired kidney function Other potentially treatable causes of asymptomatic hypervolemic - **nephrotic syndrome** - **ACEI** - decreases proteinuria = **partial** **correction of hypoalbuminemia** and **decrease** in **non-osmotic AVP release** - **cirrhosis** - **temporary discontinuation of diuretics** - **fluid restriction** plus cautious **correction of hypokalemia** - administering potassium will enter the cells as intracellular sodium is exchanged in the opposite direction - consider that there will be an increase extracellular sodium, to avoid rapid overcorrection of hyponatremia - **if** hyponatremia **persists** - sh**ort-term hyper-oncotic albumin solutions** (20%-25%) - it will **increase urinary-free water clearance** following intravascular volume expansion - VRAs have also been used for the treatment of hypervolemic hypotonic hyponatremia in patients with HF or cirrhosis - Conivaptan - **Not an ideal** VRA of choice for patients with cirrhosis **due to its mixed blockade** - V1 blockade can: - worsen hypotension - increase bleeding risk - compromise kidney function - Tolvaptan - FDA issued a warning for pxs w/ impaired liver function for potential further injury of the liver Patients with advanced cirrhosis - may benefit from placement of a transjugular intrahepatic portosystemic shunt - which can increase the effective circulating volume and thus reduce non-osmotic AVP release - but this procedure can potentially exacerbate or precipitate hepatic encephalopathy, so it is not recommended in patients with a history of encephalopathy Tolvaptan may be considered in patients with end-stage liver disease awaiting liver transplantation to normalize serum sodium concentrations - The benefit of avoiding the need for rapid perioperative sodium correction outweighs the likely negligible effect of tolvaptan-related liver damage in these patients - It is also reasonable to continue treatment until liver transplantation even if the duration is longer than 30 days. In hyponatremic patients with HF - VRA treatment - reserved for refractory patients; does not adequately respond to other medical mgt strategies - tolvaptan use - decreases body weight, increases urine output, decreases left ventricular filling pressures, and decreases urine osmolality - guidelines recommend short-term use of a VRA - in hospitalized patients who have volume overload and persistent severe hyponatremia - who are at risk for or having cognitive symptoms despite fluid restriction and optimization of guideline-directed medical therapy - V1a receptor stimulation and V1a receptor dose-dependent activity - potential vascular and cardiac effects - oral V1a or nonselective VRA - would provide greater benefits - diagnostic utility for hyponatremia in HF - Various biological markers - Copeptin - the c-terminal segment of the precursor of provasopressin - Apelin - midregional proatrial natriuretic peptide (MR-proANP) Evaluation - on a daily basis - lung congestion, ascites, peripheral edema, and signs or symptoms of hyponatremia - If water restriction is started -- Na conc is measured daily and stabilized at 125 mEq/L or higher - If VRA therapy is used -- monitor Na conc every 4 hours to minimize the risk of overcorrection and ODS **HYPERNATREMIA** - serum Na conc **greater than 145** mEq/L - always associated with **hypertonicity** and **intracellular dehydration**, because of water deficit relative to ECF sodium content - hypertonic state - potent stimulus for AVP secretion and thirst - most commonly observed in pxs w/ an impaired thirst response or in those who cannot access water - In critically ill patients, majority are **iatrogenic** hypernatremia cases - result of too little free water and too much hypertonic solution along with increased renal water loss - Hypernatremia is often associated with a serious underlying illness, which likely contributes to the higher mortality rate Pathophysiology/Causes of Hypernatremia - water loss - either renal or extrarenal mechanisms - hypertonic or isotonic fluid administration or excess sodium ingestion - pxs can develop either of the 3 depending on the magnitude of sodium and water loss or gain caused by the underlying condition: 1. Hypovolemic hypernatremia 2. Hypervolemic hypernatremia, or 3. Euvolemic (isovolemic) hypernatremia  - Water loss - commonly happens in pxs deprived of water, resulting to insensible losses (evaporative water loss through the skin and lungs) - to replace insensible losses in hospitalized patients who are febrile or mechanically ventilated are treated with isotonic IV fluids w/c contain insufficient free water - pxs with hypotonic GI losses (eg, diarrhea, vomiting, gastric suctioning) - pxs who have been exposed to high temperatures who suffer large water losses from both sweat and insensible losses - Pxs with hyperaldosteronism - can also cause expanded ECF and mild hypernatremia - pxs with untreated DI excrete large volumes of dilute urine, resulting in hypernatremia - **water diuresis** can be caused by DI - central = decreased AVP secretion - nephrogenic = decreased kidney response to AVP - **most common cause** of acquired **nephrogenic** DI - **Lithium** - impairs AVP-mediated water transport Hypertonic NaCl administration - Causes **hypervolemic \[**expanded ECF volume**\]** hypernatremia - typically iatrogenic - excess sodium bicarbonate administration - hypertonic NaCl enemas - intrauterine injection of hypertonic NaCl Excessive isotonic infusions (0.9% NaCl, lactated Ringers) = sodium accumulation if dilute urine is excreted Common cause of hypernatremia in the ICU - sodium intake from IV and enteral fluids and medications - monitor sodium balance in critically ill patients to avoid iatrogenic hypernatremia **Clinical Presentation: Hypernatremia** - results in water **movement from the ICF to the ECF** - Central DI - Presents with sudden onset of polyuria - Nephrogenic DI - polyuria develop gradually - Symptoms - primarily neurological due to decreased brain cell volume - and like those seen with hyponatremia - mild-to-moderate hypernatremia (hypertonicity) - weakness, lethargy, restlessness, irritability, twitching, and confusion - severe or rapidly developing hypernatremia can lead to seizures, coma, and death - Brain cells adapt to ECF tonicity changes by decreasing or increasing the concentration of inorganic (K+, Cl-) and organic (glutamate, taurine, and myoinositol) osmolytes - ECF hypertonicity results in intracellular organic osmolyte generation within 24 hours of onset leading to an increase in ICF tonicity that then draws water into brain cells, limiting the decrease in cell volume - Thus, patients with chronic hypernatremia are less likely to be symptomatic than patients with acute hypernatremia - Explanation: - When there is hypernatremia (too much sodium in the blood), the fluid outside the brain cells (ECF) becomes very salty and concentrated (hypertonic). This can make water leave the brain cells, shrinking them, which could potentially harm the cells and cause symptoms. To protect themselves, brain cells adapt by making or keeping certain substances (osmolytes) like potassium, chloride, and small molecules like glutamate, taurine, and myoinositol. These osmolytes help balance the concentration inside the cells (ICF) with the salty environment outside. This draws water back into the cells, preventing them from shrinking too much. If hypernatremia happens slowly over time (chronic), the brain cells have enough time to adjust, so symptoms are less likely. However, if it happens suddenly (acute), the brain cells don't have time to adapt, and this can lead to more severe symptoms. - Hypernatremia is often associated with serious underlying illness and its sxs are often present - Pxs w/ hx of severe diarrhea or vomiting -- can present w/ ECF volume depletion - Older patients deprived of water after sustaining a stroke or hip fracture - often present with mental status changes and other signs of ECF volume depletion - ECF depletion is clinically detectable but may not be evident until the serum Na conc exceeds 160 mEq/L - because these patients primarily have water loss, two-thirds of which is derived from the ICF. - The urine will be concentrated (exceeding 450 mOsm/kg), because of osmotic and non-osmotic AVP release. - Explanation: - When someone loses a lot of water from their body, it primarily comes from inside the cells (ICF). This can lead to high sodium levels in the blood (hypernatremia). However, you might not notice signs of low body water outside the cells (ECF volume depletion) unless the sodium level gets very high, usually above 160 mEq/L. - When the body senses this water loss, it tries to hold onto as much water as possible. The kidneys make urine very concentrated (with an osmolality often above 450 mOsm/kg) due to the release of AVP, which helps the body conserve water. - The first step in the evaluation and treatment of hypernatremia is assessment of: 1. ECF and urine volume 2. serum and urine osmolality  - Pxs with sustained insensible water losses that exceed intake, as well as those with extrarenal losses of hypotonic fluids. - Those with contracted ECF volume and low urine output - In physical exam, they present: - postural hypotension - diminished skin turgor - delayed capillary refill - Lactic acidosis and low mixed venous oxygen saturation - indicates decreased tissue perfusion - daily urine output - typically \< 1 liter - All are common in older pxs with hypernatremia: - Hypotension - Tachycardia - dry oral mucosa - decreased skin turgor - recent changes in consciousness - presence of signs of dehydration are variable, with orthostatic hypotension and decreased subclavicular and forearm skin turgor present in at least 60% of pxs. **Osmotic Diuresis** In the presence of an ongoing osmotic diuresis, patients will have a urine volume greater than 3 L/day. - Excessive urinary excretion of glucose, sodium, urea, or an exogenously administered solute (eg, mannitol) can be identified either by history or by direct measurement of serum and urinary concentrations of the suspected solute, if possible. Patients with post-obstructive diuresis like bladder outlet obstruction caused by prostatic hypertrophy - are usually ECF volume expanded because of retained solute because of a reduction in GFR - The osmotic diuresis that follows resolution of the obstruction is appropriate in that it promotes excretion of the excess solute. Explanation: Sometimes, people urinate a lot (more than 3 liters a day) because their body is trying to get rid of extra substances in the blood, like **glucose (sugar), sodium, or urea**. This is called **osmotic diuresis**, and it can also happen if a medication like **mannitol** is given. Doctors can figure out the cause by looking at the patient's history or measuring these substances in the blood and urine. In some cases, like **bladder problems caused by prostate issues**, urine might get backed up and the body holds onto too much fluid (expanding the ECF volume). This happens because the kidneys aren't filtering properly (**reduced GFR**). Once the blockage is cleared, the body starts getting rid of the extra fluid and solutes through increased urination, which is normal and helps fix the imbalance. Patients with severe hyperglycemia may have a i. low measured serum sodium concentration (hyponatremia) but a ii. high corrected sodium concentration (hypernatremia) iii. present with signs of hypovolemia a. in this case, **diuresis is inappropriate** because it can further exacerbate the ECF volume contraction associated with hyperglycemia. As previously discussed, the estimated (or corrected) serum sodium concentration can be calculated by: - add 1.6 mEq/L (mmol/L) for every 100 mg/dL increase in the serum glucose conc before estimating the water deficit. Explanation: - When someone has very high blood sugar (severe hyperglycemia), it can make their sodium levels in the blood look lower than they really are (a condition called hyponatremia). This happens because the high sugar pulls water from the cells into the bloodstream, diluting the sodium. However, if you correct for this effect by using a formula, their actual sodium levels may turn out to be high (hypernatremia). - At the same time, high blood sugar causes the body to lose a lot of water through excessive urination (diuresis), which can make the dehydration (low ECF volume) worse. - To figure out the real sodium level, doctors use a calculation: - Add 1.6 mEq/L to the sodium level for every 100 mg/dL increase in blood sugar. This helps estimate how much water the person has lost and guides the treatment plan. **Diabetes Insipidus** Patients with DI - tend to maintain a normal ECF volume if they are conscious, can drink, and have access to water. Typical values in pxs w/ DI that have hypernatremia: - serum Na conc: 141-145 mEq/L - daily urine volumes: greater than 3 liters Water Deprivation Test - \[way to figure out why someone is urinating a lot\] - diagnostic test - aids in differential diagnosis - diagnostic value only for patients with polyuria and a **NORMAL** serum sodium concentration - Explanation: In people with excessive urination (polyuria) and high sodium levels (hypernatremia), the usefulness of a water deprivation test is questionable. Why? - Hypernatremia already makes the body release as much AVP (antidiuretic hormone) as it can. - Doctors can usually tell the difference between central diabetes insipidus (DI) and nephrogenic DI by measuring AVP levels in the blood and seeing how the urine responds to desmopressin, without needing the water deprivation test. - The water deprivation test is more helpful for diagnosing polyuria with normal sodium levels, where it's less obvious what's causing the problem. - test: depriving a patient with marked polyuria of water for 8 to 12 hours \[in a supervised setting to avoid severe hypernatremia and volume depletion\] - Why? This test checks if the body can concentrate urine properly. Normally, when you don\'t drink water, your body saves water by making urine more concentrated. If this doesn't happen, it could indicate a problem - Body weight and urine osmolality and volume are measured before and after administration of **desmopressin acetate** - After desmopressin administration: 1. patients with central DI a. will have a prompt increase in urine osmolality to approximately 600 mOsm/kg \[urine is more concentrated\] b. and decreased urine volume 2. In patients with nephrogenic DI c. urine osmolality will not increase above 300 mOsm/kg Explanation: - If the person has central DI (their body doesn't make enough ADH), the medicine will fix the problem - If the person has nephrogenic diabetes insipidus (DI) (their kidneys don't respond to ADH), the desmopressin won't help much **Sodium Overload** Pxs that are Volume expanded: - Pxs who have ingested a large amount of sodium \[\> 4 tbsp table salt \[1,400 mEq sodium\], or - Those who have received \> 5 liters of hypertonic fluids - Note that this volume may not always be clinically evident as edema Results of Volume expansion: - osmotic diuresis - polyuria - urine osmolality \> 300 mOsm/kg In patients with **normal perfusion and kidney function** - excess sodium will be excreted in the urine In patients with **organ dysfunction** - sodium excretion is compromised, and volume expansion occurs **TREATMENT: HYPERNATREMIA** Goal: 1. correcting the serum sodium concentration to between 145 and 150 mEq/L - at a rate that restores and maintains brain cell volume as close to normal as possible - while normalizing ECF volume, if indicated. Adverse effects associated with too rapid correction of hypernatremia - cerebral edema, seizures, neurologic damage, and death - careful titration of fluids and medications will minimize these - this occurs almost exclusively in young children with - chronic hypernatremia (at least 48 hours duration) - serum sodium concentrations greater than 150 mEq/L Necessary to prevent recurrence of hypernatremia a. Water replacement and dietary sodium restriction **Hypovolemic Hypernatremia (symptomatic)** Initial tx: - treated similarly to those with hypovolemic hyponatremia, w/c is - 0.9% NaCl or another isotonic fluid until hemodynamic stability is restored - Explanation: because in both cases, the primary issue is low blood volume (hypovolemia), which can lead to unstable blood pressure and poor circulation. Priority is to restore blood volume first. After intravascular volume is restored: - Infusion of 0.45% NaCl, D5W, or another hypotonic fluid -- to correct the water deficit In patients with **hypernatremia from \[pure\] water loss**, the ECF volume deficit can be estimated as follows  - Where: Nas = initial serum Na conc \[mEq/L\]; 140 = normal or goal serum Na conc Base the appropriate rate for correcting the water deficit on how rapid the hypernatremia developed - If less than 48 hours - initially corrected at a rate of \~ 1 mEq/L per hour - if more slowly - rate of 0.5 mEq/L per hour or less Sodium - should be lowered no more than 10 to 12 mEq/L (mmol/L) per day Hospitalized patients are often given fluids to keep them hydrated, and to avoid low sodium levels (hyponatremia), doctors recommend using isotonic fluids (like 0.9% saline). These fluids have the same salt concentration as the blood, so they help maintain balance. - However, giving **too much 0.9% saline** can cause problems: - It can **dehydrate the cells** (because too much salt can pull water out of cells). - It can cause **too much chloride** in the body, leading to metabolic acidosis (a condition where the blood becomes too acidic). To avoid these issues - **balanced electrolyte solutions like lactated Ringer's or Plasma-Lyte are often preferred** because they're **safer** for the body. Also, giving too much salt can lead to high sodium levels (hypernatremia) or fluid overload, especially in patients who are at risk, like those with kidney problems. In short, while isotonic fluids are useful, they should be given carefully, especially in patients who don't need extra fluids or have kidney issues. Monitoring sodium levels in IV fluids is important for all hospitalized patients **EUVOLEMIC HYPERNATREMIA** **CENTRAL DI**  Desmopressin dosage - should be adjusted to achieve adequate urinary concentration to control nighttime symptoms during sleep (nocturia), a daily urine volume of approximately 1.5 to 2 L, and a safe serum sodium concentration. To minimize the risk of a second episode in pxs experiencing water intoxication: - delay one desmopressin dose each week until polyuria and thirst develop, thus demonstrating the continued need for desmopressin therapy **NEPHROGENIC DI**  **Thiazide diuretics \"trick\" the kidneys into reabsorbing more water earlier in the kidney tubules to compensate for the excessive water loss. This ultimately reduces urine output in nephrogenic DI.** **What are Central DI and Nephrogenic DI?** 1. **Central DI (Diabetes Insipidus)**: - The brain (pituitary gland) **does not make enough ADH** (antidiuretic hormone). - ADH normally tells the kidneys to **keep water in the body**. Without enough ADH, the kidneys **lose too much water** by making large amounts of dilute urine. 2. **Nephrogenic DI**: - The kidneys **do not respond to ADH properly**, even if the brain makes enough of it. - This also leads to **water loss** in the form of large amounts of dilute urine. **How Do These Cause Euvolemic Hypernatremia?** - **Hypernatremia** means high sodium levels in the blood. - **Euvolemia** means normal blood volume (not dehydrated, but still losing water). Here's what happens step by step: 1. **Water Loss, Not Sodium Loss**: - In DI (both types), the kidneys **lose a lot of water** because they cannot hold onto it properly. - But sodium is **not lost** with this water; it stays in the blood. 2. **Blood Sodium Concentration Rises**: - Since you're losing water but not sodium, the sodium becomes more **concentrated** in the blood. This causes **hypernatremia**. 3. **Euvolemia** (Normal Volume Status): - Your body can still pull some water from cells to keep the blood volume normal (compensation). - This water shift helps you **avoid severe dehydration**, so you end up in a state of **euvolemic hypernatremia**---where sodium is high, but the blood volume is \"okay.\" **Key Difference Between Dehydration and Euvolemia:** - In **dehydration**: Both water **and sodium** are lost, causing **low blood volume**. - In **DI**: Mostly **water is lost**, but sodium stays, causing **high sodium (hypernatremia)** with normal blood volume (**euvolemia**). **Simple Analogy:** Imagine your blood is a soup: - Normally, the soup has the right balance of water (fluid) and salt (sodium). - In DI, you **lose water** (it evaporates), but the salt stays in the soup. Now the soup becomes too salty (hypernatremia). - Your body pulls water from its \"reserve\" (cells) to balance the soup\'s volume, so you don't become dehydrated, which keeps you **euvolemic**. **HYPERVOLEMIC HYPERNATREMIA (SODIUM AND WATER OVERLOAD)**   **D5W** adds water to correct the high sodium.  **Furosemide** removes the extra sodium and fluid from the body. **EDEMA** \- **clinically detectable increase in [interstitial] fluid volume** \- usually due to **heart, kidney, or liver failure** or a combination of these conditions \- can also happen when there is **rapid decrease in serum albumin** conc ((a protein in the blood that helps keep fluid inside blood vessels) combined with **too much fluid intake w/c is common in cases like burns or trauma (injuries).** \- increase of fluid, at least **2.5 to 3 L** in the interstitial volume **Pathophysiology: Edema** Develops when excess sodium is retained either as: a. primary **defect** in **renal sodium** **excretion** or i. Problem with the kidneys: If the kidneys are not properly getting rid of sodium, it builds up in the body. b. response to a decrease in the effective circulating volume (actually the BP resulting from that volume) despite a normal or expanded ECF volume ii. **Low blood pressure**: When there is not enough blood flow or pressure in the body (even if the total fluid in the body seems normal or high), the body may hold onto sodium in an attempt to increase blood pressure. This can also lead to swelling. - Under these conditions, the kidneys **retain** all the water and sodium ingested **until** the **effective circulating volume is restored** to near normal Homeostasis 1. Increase in intake of dietary sodium 2. Will cause increase in serum osmolality and thirst thereby increase in water intake 3. The resulting ECF volume increase increases kidney perfusion, thereby increasing transient GFR 4. Leads to sodium filtration and excretion - homeostatic mechanisms are crucial for maintaining sodium balance, as **retention of just a few milliequivalents of sodium per day** can eventually **lead** to an **expanded ECF volume** and **edema formation** - increase in the **capillary hydrostatic pressure** because of ECF volume expansion or an **increase in central venous pressure** also can lead to edema formation Can also cause edema formation: - increase in the capillary hydrostatic pressure because of ECF volume expansion - increase in central venous pressure - alteration in Starling forces within the capillary - rapid development in edema - happens in pxs with an **acute decompensation in myocardial contractility** - leads to an elevated pulmonary venous pressure transmitted back to the pulmonary capillaries, ultimately results in **acute pulmonary edema** - **Patients with nephrotic syndrome** - initially present with edema, primarily periorbital, labial/scrotal, and lower extremity - w/c may progress to pulmonary edema, ascites, and anasarca - 2 Theories: Edema in Nephrotic Syndrome A. **Underfill Hypothesis** - states that high-grade proteinuria leads to decreased oncotic pressure due to hypoalbuminemia (most pronounced with a serum albumin conc \< 2 g/dL - Decreased oncotic pressure leads to excess fluid movement from the intravascular space to the interstitial space (third spacing) causing hypovolemia, kidney hypoperfusion, activation of the RAAS, and secondary renal sodium retention - patients who are primarily underfilled will likely have worsening hypovolemia and an elevated serum creatinine requiring volume repletion after initially tolerating diuresis Explanation:\ When too much protein is lost in the urine (proteinuria), the blood doesn\'t have enough protein (hypoalbuminemia). This is more serious when albumin levels drop below 2 g/dL. Protein in the blood normally helps hold fluid inside blood vessels. When protein levels are low, fluid leaks from the blood vessels into surrounding tissues (this is called third spacing). This leads to: - Low blood volume (hypovolemia). - Poor blood flow to the kidneys (kidney hypoperfusion) In response to low blood volume, the body activates a system called RAAS, which makes the kidneys hold onto sodium and water. This is an attempt to restore blood volume, but it can worsen fluid retention.\ If this type of patient (underfilled) is treated with too many diuretics (to remove excess fluid), their blood volume can drop further, leading to worse hypovolemia and higher serum creatinine (a sign of kidney strain). These patients may need fluid replacement instead of more diuretics to stabilize them. B. **Overfill Hypothesis** - protein loss in the urine leads to primary renal sodium retention causing intravascular volume expansion, leading to fluid overflow into the interstitial space (edema) - **Patients with cirrhosis** - initially develop ascites because of splanchnic vasodilation resulting in an increase in the pressure in the portal circulation (portal hypertension) - combination of portal hypertension and splanchnic vasodilation increases capillary pressure and permeability and facilitates the accumulation of ascites (fluid in the abdominal cavity) - Ascites can cause a decrease in effective circulating volume and activation of the sympathetic nervous system and the RAAS, leading to secondary hyperaldosteronism. - Subsequent renal sodium retention leads to worsened ascites, edema, and hypervolemic hyponatremia **Clinical Presentation: Edema** \- described as "pitting" when a depression created by exerting pressure for several seconds over a bony prominence, such as the tibia, does not rapidly refill Usual first areas edema is detected: a. ambulatory patients - feet - periorbital area - pretibial area Edema severity: Rated on a semi-quantitative scale of 1+ to 4+ depending on the depth of the pit: - 1+ = 2 mm - 2+ = 4 mm - 3+ = 6 mm - 4+ = 8 mm Quantification of the extent of edema: according to areas involved - Pretibial edema - should be quantified according to how far it extends up the lower leg - limited to the ankles and feet = less severe edema than edema extending halfway up the lower legs - Pulmonary edema - increase in lung interstitial and alveolar water, is often evidenced by crackles (rales) upon auscultation - Rales - quantified according to how far the crackles extend from the dependent portion of the lung(s) - limited to the base of both lungs in an upright person = less severe than crackles throughout both lung fields. - Anasarca - a term for massive amount of edema generalized throughout the body **TREATMENT: EDEMA** Goal: 1\. minimize edema 2\. improve organ function 3\. relieve symptoms like **dyspnea**, **abdominal distention**, **extremity pain** Note that presence of edema does not always dictate the need for **diuretic therapy** Severe pulmonary edema - life-threatening = requires immediate pharmacologic treatment Other forms -- treated acutely \[comprehensive approach\] - Diuretics - sodium and water restriction - optimal treatment of the underlying disease In non-urgent cases, it's important to use diuretics carefully and slowly to avoid complications: - excessive diuresis, impaired perfusion, azotemia, impaired CO due to decreased left ventricular end-diastolic filling pressure, and electrolyte abnormalities Fluid removal - cautiously done in patients with cirrhosis and ascites but no peripheral edema - goal: 500 mL/day - safely mobilized in patients with isolated ascites - higher than that will: - decreased ECF volume and lead to elevated BUN and possibly hepatorenal syndrome **Diuretic Therapy** \- when edema is severe or tx of the underlying disease and sodium and water restriction are insufficient, diuretics is the primary pharmacologic therapy Category for diuretics: according to the site in the nephron where sodium reabsorption is inhibited a. Loop diuretics -- inhibit Na+--K+--2Cl-- carrier in the **loop of Henle** - The most potent type of diuretic class i. Furosemide ii. Bumetanide iii. Torsemide iv. Ethacrynic acid b. thiazide and thiazide-like \[longer DOA\] diuretics - inhibit the Na+--Cl-- carrier in the **distal tubule** v. Hydrochlorothiazide \[classic\] vi. Chlorothiazide \[classic\] vii. Chlorthalidone \[thiazide-like\] viii. Indapamide \[thiazide-like\] ix. Metolazone \[thiazide-like\] c. Potassium-sparing diuretics - inhibit the sodium channel in the cortical collecting duct either: - Directly - triamterene, amiloride - interfering with aldosterone activity - spironolactone, eplerenone d. Carbonic anhydrase inhibitor \[Acetazolamide\] - acts in the proximal convoluted tubule - used in patients with diuretic resistance Factors for Diuretic efficacy in patients with edema: - amount of filtered sodium normally reabsorbed at its site of action - amount of sodium reabsorbed distal to its site of action - adequate medication delivery to the site of action - amount of sodium reaching the site of action Large portion of the filtered sodium is reabsorbed in the proximal nephron, but efficacy of proximal-acting diuretics (acetazolamide) is limited by excess fluid and sodium reabsorption in the LoH. Sodium reabsorption by the distal tubule can compensate for reduced reabsorption in the loop of Henle when sodium intake is high - Explanation: - Proximal-acting diuretics (like acetazolamide) work in the first part of the kidney (called the proximal nephron) to block sodium reabsorption. - However, their effect is limited because the next parts of the kidney, like the loop of Henle, can reabsorb the sodium that escapes from the proximal nephron. - When sodium intake is high, the kidney\'s distal tubule (another part farther down the line) can also step in and absorb even more sodium to compensate. - This means the sodium-blocking effect of proximal-acting diuretics gets \"overridden\" by the kidney\'s ability to reabsorb sodium in other areas. Loop diuretics, except torsemide, have a rapid onset but short half-life requiring administration every 2 to 3 hours while thiazide diuretics have a longer half-life allowing for less frequent (once daily) dosing Patients with kidney insufficiency often require larger diuretic doses to achieve adequate medication concentrations at the site of action. The natriuretic response is decreased in patients with kidney insufficiency because the filtered sodium load falls proportionately as GFR declines - can be partially overcome by administering diuretics more frequently or by using a continuous infusion - Continuous delivery - will limit the effect of the post-diuresis sodium retention in the distal nephron - a method commonly employed in critically ill patients **Loop Diuretic Resistance**: A. **Pronounced sodium reabsorption in the distal nephron** when sodium absorption in the loop of Henle is blocked - If sodium intake is not restricted, distal sodium reabsorption can compensate entirely for loop diuretic-induced sodium loss - Patients with diuretic-resistant edema - treated with a loop diuretic and **metolazone**. - Metolazone - should be given first and allowed sufficient time to start blocking distal sodium reabsorption to maximize loop diuretic efficacy. Explanation: - Loop diuretic resistance happens when the kidneys can still reabsorb sodium in other parts of the kidney (the distal nephron) even after loop diuretics block sodium reabsorption in the loop of Henle. - If sodium intake is not limited, the kidney can make up for the loss of sodium caused by the loop diuretic by reabsorbing more sodium farther down the kidney. - This is why some people with diuretic-resistant edema (swelling) don't respond well to just loop diuretics. - To overcome this, **metolazone can be added to the treatment**. Metolazone blocks sodium reabsorption in the distal part of the kidney, helping the loop diuretic work better. - Metolazone should be given first and given enough time to act before the loop diuretic is taken, to make sure the loop diuretic works at its best. B. **Impaired diuretic delivery to the site of action** - **Patients with HF and a normal GFR** - have impaired oral **furosemide** absorption - increasing the frequency of diuretic administration - higher dose is also effective - **GI edema** and **delayed gastric emptying** -- can compromise absorption of oral loop diuretics - patients with **decompensated HF** or those with **decreased kidney perfusion** - decreased perfusion C. Due to **extensive albumin binding** (more than 95%), little of these agents reach the tubule lumen by filtration, and they are almost exclusively transported into the proximal tubule lumen by active secretion via the organic acid secretory pathway - When albumin binding is inhibited by concurrent sulfasoxazole administration = diuretic resistance persists - can be overcome by using higher diuretic doses to increase unbound medication delivery to the secretory site in the nephron D. Decreased intrinsic diuretic activity with repeated dosing **For pxs with Nephrotic syndrome**  - combination of a **loop diuretic with a distally acting diuretic** is generally necessary to promote a natriuresis that exceeds distal tubular sodium reabsorption in patients with nephrotic syndrome **For pxs with Cirrhosis** - secondary hyperaldosteronism from activation of the RAAS - plays a major role in the pathogenesis of edema - pxs are initially be treated with (in the absence of impaired GFR and hyperkalemia) - **aldosterone antagonist -- spironolactone** - for pxs with a creatinine clearance \> than 50 mL/min - Thiazides can be added - If px has diuretic-resistant edema - Loop is added instead of thiazide - Patients with impaired GFR \[CrCl \< 40 mL/min\] - will require a loop diuretic, with addition of a thiazide in those who do not achieve adequate diuresis ADRs of loop and thiazide - **HYPOkalemia** - at high risk: px with refractory edema treated with high-dose synergistic combinations - **HYPOvolemia/excess ECF volume loss** - **HYPOmagnesemia** - **metabolic alkalosis** - **HYPERuricemia** - **Sodium** imbalance is a concern with diuretic therapy - **hypo**natremia with **thiazides** - **hyper**natremia with **loops** - **Calcium** imbalance: - **hyper**calcemia with **thiazides** - more common in mild subclinical hyperparathyroidism - **hypo**calcemia with **loops** - hypercalciuria - can lead to bone disorders (osteopenia, osteoporosis), kidney stones, or nephrocalcinosis when used chronically ADR: K-sparing diuretic: - Chronic use - **mild metabolic acidosis** - **HYPERkalemia** - At high risk: pxs with moderate-to-severe kidney dysfunction or those receiving NSAIDs, ACEI,or ARBs - Spironolactone - reversible gynecomastia \[not in eplerenone\] Evaluation: - In patients with significant edema - volume status - monitored carefully to ensure adequate tissue perfusion - pxs are monitored by careful history and intermittent physical examination to detect sxs of edema as well as AEs - Physical examination includes: - measurement of BP and pulse - either supine or seated positions and - after standing for 2 to 3 minutes to assess for orthostasis - ECF volume - estimated based on: - height of the jugular venous pressure - extent of edema - heart and lung auscultation - skin turgor - Follow-up monitoring: - 10 to 14 days after therapy initiation - determinations of serum sodium, potassium, chloride, bicarbonate, magnesium, calcium, BUN, serum creatinine, and uric acid - A new steady-state balance will have developed over that time period and further fluctuations in ECF volume and electrolyte balance generally do not occur in the absence of a change in clinical status, diuretic dosage, or dietary intake