This is a 70kg man. Water makes up 60% of a man’s body weight and 50% of a woman’s body weight.Water diffuses freely in response to solute concentration gradients. Therefore, the amount of water in different compartments depends entirely on the quantity of solute in that compartment. The major solute in the ECF is sodium; potassium is the major intracellular solute. The maintenance of this distribution is fulfilled by active transport through the Na+,K+-ATP– dependent pumps on the cell membrane, and this determines the relative volume of different compartments. Because sodium is the predominant extracellular solute, the ECF is determined primarily by the sodium content of the body and the mechanisms responsible for maintaining it. The amount of sodium is therefore very tightly regulated by modulation of renal retention and excretion in situations of deficient and excess ECF, respectively.Fluid movement between the intravascular and interstitial compartments of the ECF occurs across the capillary wall and is governed by the Starling forces, namely, the capillary hydrostatic pressure and colloid osmotic pressure
Circulatory stability depends on a meticulous degree of ECF homeostasis. The operative homeostatic mechanisms include an afferent sensing limb comprising several volume and stretch detectors distributed throughout the vascular bed and an efferent effector limb. Adjustments in the effector mechanisms occur in response to afferent stimuli by sensing limb detectors with the aim of modifying circulatory parameters. Disorders of either sensing or effector mechanisms can lead to failure of adjustment of sodium handling by the kidney with resultant hypertension or edema formation in the case of positive sodium balance or hypotension and hypovolemia in the case of negative sodium balance.PGE2 is stimulated by Ang II and has vasodilatory properties secondary to total blood volume or EABV contraction. Increased level of Ang II, AVP, and catecholamines stimulates synthesis of prostaglandins, which in turn act to dilate the renal vasculature, to inhibit sodium and water reabsorption, and further to stimulate renin release. By doing so, renal prostaglandins serve to dampen and counterbalance the physiologic effects of the hormones that elicit their production and so maintain renal function. Inhibition of prostaglandins by nonsteroidal anti-inflammatory drugs (NSAIDs) leads to magnification of the effect of vasoconstricting hormones and unchecked sodium and water retention. AVP is a polypeptide synthesized in supraoptic and paraventricular nuclei of the hypothalamus and is secreted by the posterior pituitary gland. Besides osmotic control of AVP release, a nonosmotic regulatory pathway sensitive to EABV exists.2 AVP release is suppressed in response to ECF volume overload sensed by increased afferent impulses from arterial baroreceptors and atrial receptors, whereas decreased ECF volume has the opposite effect. AVP release leads to antidiuresis and, in high doses, to systemic vasoconstriction through the V1 receptors. 3 The antidiuretic action of AVP is the result of the effect on the principal cell of the collecting duct through activation of the V2 receptor. AVP increases the synthesis and provokes the insertion of aquaporin 2 water channels into the luminal membrane, thereby allowing water to be reabsorbed down the favorable osmotic gradient. AVP may also lead to enhanced reabsorption of sodium and the secretion of potassium. AVP appears to have synergistic effects with aldosterone on sodium transport in the cortical collecting duct.4 AVP stimulates potassium secretion by the distal nephron, and this serves to preserve potassium balance during ECF depletion, when circulatinglevels of vasopressin are high and tubular delivery of sodium and fluid is reduced.
The juxtaglomerular apparatus (JGA) is located between the afferent arteriole and the returning distal convoluted tubule of the same nephron. It is responsible for regulating both intrarenal (tubuloglomerular feedback) and extrarenal (renin-angiotensin-aldosterone) mechanisms necessary to maintain both renal and entire body volume status.The three components of the JGA are the following:(1) the juxtaglomerular cells of the afferent arteriole, synthesize and store renin, which is secreted in response to specific stimuli (e.g., low blood flow, decreased NaCl delivery). The juxtaglomerular cells could be considered the "effector arm" of the renin-angiotensin-aldosterone axis.(2) the macula densa, a region of the distal convoluted tubule characterized by tubular epithelial cells which are more densely-packed than in other regions of the nephron (and thereby leading to its characteristic appearance on light microscopy). The macula densa can be considered the "sensory arm" of the renin-angiotensin-aldosterone axis in that these are the cells which sense decreased Na Cl delivery which determines downstream function. They are also involved in the mechanism of tubuloglomerular feedback “solute delivery to the macula densa is also an important determinant of renin release by way of the tubuloglomerular feedback mechanism; an increase in chloride passage through the macula densa results in inhibition of renin release, whereas a decrease in concentration results in enhanced secretion of renin. Renal nerve stimulation through activation of β-adrenergic receptors of the juxtaglomerular apparatus cells directly stimulates renin release.”(3) mesangial cells, which form connections via actin and microtubules which allow for selective vasoconstriction/vasodilation of the renal afferent and efferent arterioles with mesangial cell contraction.
Renin formation by the juxtaglomerular apparatus increases in response to the aforementioned ECF homeostatic afferent limb stimuli. Renin converts angiotensinogen to angiotensin I, which is then converted to Ang II by the action of angiotensin-converting enzyme; Ang II can subsequently affect circulatory stability and volume homeostasis. It is an effective vasoconstrictor and modulator of renal sodium handling mechanisms at multiple nephron sites. Ang II preferentially increases the efferent arteriolar tone and hence affects the glomerular filtration rate (GFR) and filtration fraction by altering Starling forces across the glomerulus, which leads to enhanced proximal sodium and water retention. Ang II also augments sympathetic neurotransmission and enhances the tubuloglomerular feedback mechanism. In addition to these indirect mechanisms, Ang II directly enhances proximal tubular volume reabsorption by activating apical membrane sodium-hydrogen exchangers. In addition to a nephron effect, Ang II enhances sodium absorption by stimulating the adrenal gland to secrete aldosterone, which in turn increases sodium reabsorption in the cortical collecting tubule
In volume-contracted states, this ratio may significantly increase because of an associated differential increase in urea reabsorption in the collecting duct. Upper gastrointestinal hemorrhage and administration of corticosteroids increase urea production, and hence the BUN/ creatinine ratio increases. Malnutrition and underlying liver disease diminish urea production, and thus the ratio is less helpful to support volume depletion in such clinical settings.U osm and sp gravity low but may be altered by an underlying renal disease that leads to renal sodium wasting, concomitant intake of diuretics,or a solute diuresisHypovolemia normally promotes avid renal sodium reabsorption, resulting in low urine sodium concentration and low fractional excretion of sodium. Urine chloride follows a similar pattern because sodium and chloride are generally reabsorbed together. Volume depletion with metabolic alkalosis (e.g., with vomiting) is an exception because of the need to excrete the excess bicarbonate in conjunction with sodium to maintain electroneutrality; in that case, the urine chloride concentration is a better index of sodium avidity. Elevated (>1) FENa is most helpful in the diagnosis of acute kidney injury; FENa of less than 1% is consistent with volume depletion.
Studies have not shown an advantage for colloid-containing solutions in the treatment of hypovolemic states. A meta-analysis of 55 studies showed no outcome difference between critically ill patients who received albumin and those who received crystalloids.7 Furthermore, a large multicenter trial that randomized medical and surgical critical patients to receive fluid resuscitation with 4% albumin or normal saline showed similar mortality, measured morbidity parameters, and hospitalization rates in the two groups.8 Consequently, timely administration of a sufficient quantity of intravenous fluids is more important than the type of fluid chosen. However, because of the higher cost of colloids, these are best reserved for hemodynamically unstable patients in whom rapid correction is needed, such as trauma and burns victimsHypovolemic shock may be accompanied by lactic acidosis due to tissue hypoperfusion. Fluid resuscitation restores tissue oxygenation and will decrease the production of lactate. Correction of acidosis with sodium bicarbonate has the potential for increasing tonicity, expanding volume, worsening intracellular acidosis from increased carbon dioxide production, and not improving hemodynamics compared with isotonic saline. Use ofsodium bicarbonate for correction of cardiac contractility coexisting with lactic acidosis has not been well documented by clinical studies. Therefore, its use to manage lactic acidosis in the setting of volume depletion is not recommended (unless the arterial pH is below 7.1).It has been suggested, that severe acidemia may contribute to continued tissue hypoperfusion by decreasing cardiac contractility via a reduction in myocardial cell pH.The infusion of sodium bicarbonate can lead to a variety of problems in patients with lactic acidosis, including fluid overload, a postrecovery metabolic alkalosis (as the excess lactate is converted back to bicarbonate), and hypernatremia. Furthermore, studies in both animals and humans suggest that alkali therapy may only transiently raise the plasma bicarbonate concentration.This finding appears to be related in part to the carbon dioxide generated as the administered bicarbonate buffers excess hydrogen ions. This carbon dioxide is normally eliminated via the lungs. However, patients with severe circulatory failure or cardiac arrest often have a marked reduction in pulmonary blood flow. As a result, the newly formed carbon dioxide accumulates in the venous system [5,6]. Mixed venous PCO2 will continue to rise until the product of the greater than normal mixed venous PCO2 and the less than normal pulmonary blood flow is sufficient to eliminate the CO2 that is produced. It has been proposed that the rise in PCO2 in the venous blood that is perfusing the tissues may then exacerbate the intracellular acidosis, leading to an impairment in both hepatic lactate utilization and cardiac contractility
Decreased cardiac output with arterial underfilling leads to reduced stretch of arterial baroreceptors. This results in increased sympathetic discharge from the CNS and resultant activation of the RAAS. Adrenergic stimulation and increased Ang II both activate receptors on the proximaltubular epithelium that enhance sodium reabsorption. The renal vasoconstriction of the glomerular efferent arteriole by Ang II in CHF also alters net Starling forces in the peritubular capillary in a direction to enhance sodium reabsorption.13 Thus, angiotensin and α-adrenergic stimulation increase sodium reabsorption in the proximal tubule by a direct effect on the proximal tubule epithelium and secondarily by renal vasoconstriction.This subsequently leads to decreased sodium delivery to the collecting duct, which is the major site of action of aldosterone and the natriuretic peptides. CHF patients experience renal resistance to natriuretic effects of atrial and ventricular peptides.
The chief factor contributing to ascites is splanchnic vasodilatation. Increased hepatic resistance to portal flow due to cirrhosis causes the gradual development of portal hypertension, collateral-vein formation, and shunting of blood to the systemic circulation. As portal hypertension develops, local production of vasodilators, mainly nitric oxide, increases, leading to splanchnic arterial vasodilatation. In the early stages of cirrhosis, splanchnic arterial vasodilatation is moderate and has only a small effect on the effective arterial blood volume, which is maintained within normal limits through increases in plasma volume and cardiac output. In the advanced stages of cirrhosis, splanchnic arterial vasodilatation is so pronounced that the effective arterial blood volume decreases markedly, and arterial pressure falls. As a consequence, arterial pressure is maintained by homeostatic activation of vasoconstrictor and antinatriuretic factors, resulting in sodium and fluid retention. The combination of portal hypertension and splanchnic arterial vasodilatation alters intestinal capillary pressure and permeability, facilitating the accumulation of retained fluid within the abdominal cavity. As the disease progresses, there is marked impairment in renal excretion of free water and renal vasoconstriction — changes that lead to dilutional hyponatremia and the hepatorenal syndrome, respectively
Unlike CHF and liver cirrhosis, in which the kidneys are structurally normal, the nephrotic syndrome is characterizes by diseased kidneys that are often functionally impaired. Nephrotic patients typically have a higher arterial blood pressure, higher GFR, and less impairment of sodium and water excretion than do patients with CHF and cirrhosis. Whereas edema is recognized as a major clinical manifestation of the nephrotic syndrome, its pathogenetic mechanism remains less clearly defined. Two possible explanations are the underfill and the overfill theories
Dihydropyridine calcium channel blockers may cause peripheral edema, which is related to redistribution of fluid from the vascular space into the interstitium, possibly induced by capillary afferent sphinctericvasodilation in the absence of an appropriate microcirculatory myogenic reflex. This facilitates transmission of the systemic pressure to the capillary circulation.
As a group, most diuretics reach their luminal transport sites through tubular fluid secretion. All but osmotic agents have a high degree of protein binding, which limits glomerular filtration, traps them in the vascular spaces, and allows them to be delivered to the proximal convoluted tubule for secretion. Diureticbraking, and its mechanism includes activation of the sympathetic nervous and RAAS systems, decreased systemic and renal arterial blood pressure, hypertrophy of the distal nephron cells with increased expression of epithelial transporters, and perhaps alterations in natriuretic hormones such as ANPThe most serious adverse effects of diuretics are electrolyte disturbances. By blocking sodium reabsorption in the loop of Henle and the distal tubule, loop and thiazide diuretics cause natriuresis and increased distal sodium delivery. The resultant negative sodium balance activates the RAAS. The effect of aldosterone to enhance distal potassium and hydrogen excretion can lead to hypokalemia and metabolic alkalosis.
1/4 teaspoon salt = 600 mg sodium1/2 teaspoon salt = 1,200 mg sodium3/4 teaspoon salt = 1,800 mg sodium1 teaspoon salt = 2,300 mg sodiumTable salt is sodium chloride (NaCl). Molecular weight equals the sum of the atomic weights of the atoms in the molecule. For NaCl, the atomic weight of sodium is 23, of chlorine is 35 and a molecule contains one sodium and one chlorine, so 23 + 35 = 58, the molecular weight of NaCl.The atomic weight of Sodium (Na) = 22.99 The atomic weight of Chlorine (Cl) = 35.45 Read more: http://wiki.answers.com/Q/How_many_grams_of_salt_does_a_teaspoon_hold#ixzz1RsH80JAD
2.3 g of sodium 6 g of sodium chloride 1 teaspoon of table salt
Extracellular fluid homeostasis
Disorders of ECF Homeostasis<br />Waleed Ali<br />Division of Renal Diseases and Hypertension<br />University of Colorado<br />Denver, USA<br />
Effective Arterial Blood Volume<br />“The blood volume that is detected by the sensitive arterial baroreceptors in the arterial circulation”<br /> The EABV can change independently of the total ECF volume and can explain the sodium and water retention in different health and disease clinical situations<br />
Lab Evaluation of ECF Volume Depletion<br />Hemoconcentration and hyperalbuminemia<br />BUN/creatinine >10 (mg/dl) or 40 (mmol/l)<br />↑Urine osm and specific gravity<br />↓ Urine Na and FeNa<br />FENa = [UNa × Pcreat Ucreat × PNa ] ×100<br />
Therapy for Extracellular Volume Contraction<br />Replace deficit + ongoing losses with similar fluids<br />Assess clinically &/or invasively<br />Replacement fluid:<br />Crystalloids: 1/3, 2/3<br />Human albumin (5% and 25%) and hetastarch (6% hydroxyethyl starch)<br />Remain within the vascular compartment (if transcapillary barrier not disrupted by capillary leak states (MOF, SIRS)<br />Outcome difference? <br />
Therapy for Extracellular Volume Contraction<br />Crystalloids or colloids?*<br />High, normal or low serum Na?<br />Sodium chloride or bicarbonate?<br />*Wilkes et al. Ann Intern Med. 2001;135:149-164.<br />*Finfer et al. N Engl J Med. 2004;350:2247.<br />
A 34 yom presents to the ER with a few days duration of severe nausea, vomiting and watery diarrhea. Physical exam reveals a sick patient with PR of 110/BP of 106/56, and dry axillae. What is the initial replacement fluid of choice:<br />D5W<br />Isotonic sodium bicarbonate<br />Hetastarch 6% (hydroxyethyl starch)<br />Isotonic (normal) saline<br />
A 56 yof with presents to the ER with a few days duration of RUQ abd pain, fever and lethargy. Physical exam reveals an obtunded patient with Temp of 39.6, PR of 120, BP of 84/40, with general abdominal tenderness. Lab studies show Na 130, K 4.6, Cl 100, HCO3 12, BUN 68, Cr 2.1. ABG: 7.23/100/36/14 on 40% FiO2<br />What is the initial replacement fluid of choice:<br />Isotonic (normal) saline<br />Isotonic sodium bicarbonate<br />D5W<br />Hetastarch 6% (hydroxyethyl starch)<br />
ECF volume expansion refers to excess fluid accumulation in the ECF compartment. <br />Generalized edema results when an apparent increase in the interstitial fluid volume takes place. <br />It may occur in disease states most commonly in response to cardiac failure, cirrhosis with ascites, and the nephrotic syndrome.<br />
Drug-Induced Edema<br />Thiazolidinediones: <br />Can cause fluid retention and CHF exacerbation <br />Activation of peroxisomeproliferator- activated receptor γ (PPARγ) -> stimulation of ENac<br />NSAIDs:<br />↓ vasodilatory prostaglandins of the afferent arteriole.<br />Guan et al. Thiazolidinediones expand body fluid volume through PPARγ stimulation of ENaC-mediated renal salt absorption. Nat Med. 2005;11:861<br />
TherapeuticApproaches<br />Recognizing and treating the underlying cause <br />Attempting to achieve negative sodium balance, judiciously:<br />Dietary sodium restriction<br />Diuretics<br />Specific measures:<br />Cirrhosis: large-volume paracentesis with albumin, TIPS<br />Ultrafiltration<br />
A 72 yom with known CHF 2/2 ischemic CM is seen at the clinic. He had noticed ↑SOB and ↓exercise tolerance over the past few weeks. O/E distended neck vein and bibasilar crackles, and +1 LEE. Labs: Na: 132, K 5.1, BUN 38, s. Cr 1.9. The initial diuretic of choice in this case:<br />Eplerenone<br />Chlorthalidone<br />Bumetanide<br />Mannitol<br />
Management<br />Achieve negative sodium balance:<br />Restrict Na to <100 meq/day!! <br />Use diuretics<br />
What does “Na to <100 meq/day” mean?!! <br />Calculate the molecular weight of NaCl<br />Na = 23<br />Cl = 35<br />NaCl= 58<br />Therefore: 40% of NaCl is Na<br />I Mole of NaCl = 58 grams<br />1Equivalent of NaCl = 58 grams<br />1mMole = 58 mg<br />1 meqNaCl = 58 mg; this provides 1 meq Na and 1 meqCl<br />100 meqNaCl ~ 6000 mg, 40% of which is Na ~ 2300 mg ~ I teaspoon of table salt<br />
Practically, how do you advise low salt diet?!<br />Avoid processed and prepared foods/eat fresh fruits and vegetables!<br />
Diuretics<br />Diuretic tolerance<br />Decreased action 2/2 distal nephron hypertrophy and enhanced Na reabsorption proximally<br />Diuretic resistance<br />edema that is or has become refractory to a given diuretic<br />CKD<br />Arterial underfilling -> ↑ RAAS (↑proximal Na reabsorption -> ↓ distal delivery)<br />NSAIDs (↓ PG-mediated ↑ in RBF, ↑ expression of Na-K-2Cl cotransporters in TAL)<br />
Loopdiuretics<br />Most potent since block absorption of loop where 25% of Na reabsorption occurs<br />Short elimination T ½ , -> dosing interval needs to be short to maintain adequate levels (avid Na reabsorption may result in post diuretic retention)<br />“Threshold drugs”<br />
Distal Convoluted Tubule Diuretics<br />Inhibit Na/Cl absorption in DCT, 5% of filtered load is reabsorbed ->less potent than loop diuretics. <br />Have long T ½ -> can be administered QD/BID<br />
Collecting Duct Diuretics (K-sparing)<br />Amiloride, triamterene (ENaC blockers), and spironolactone and eplerenone (aldosterone antagonists) <br />Are weak diuretics because they block only a small part (3%) of the filtered Na -> most commonly used in combinations to augment diuresis or to preserve potassium<br />Are considered 1st-line agents in in liver cirrhosis with ascites and amiloride in the treatment of Liddle syndrome.<br />
Proximal Tubule Diuretics<br />Acetazolamide is a blocker of Na-H+ -> sodium<br />bicarbonate excretion. <br />Are weak since the loop has a large reabsorptive capacity that captures most of the Na/Cl escaping<br />Generates a hyperchloremic metabolic acidosis particularly with prolonged use. <br />Rarely used as a single agent, this diuretic is most commonly used:<br />in combination with other diuretics<br />In the treatment of metabolic alkalosis accompanied by edematous states, and in chronic obstructive pulmonary disease<br />
Approaches to manage resistance<br />Restricting dietary salt<br />Increasing the dose<br />Administering more frequent doses<br />Using combination therapy to sequentially block more than one site in the nephron <br />Ultrafiltration<br />