Ebook Clinical physiology of acid - base and electrolyte disorders (5th edition): Part 2

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Editors: Rose, Burton David; Post, Theodore W Title: Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th Edition C opyright ©2001 McGraw-Hill > Table of Contents > Part Three - Physiologic Approach to Acid-Base and Electroltye Disorders > Chapter Thirteen - Meaning and Application of Urine Chemistries Chapter Thirteen Meaning and Application of Urine Chemistries As is discussed in the ensuing chapters, measurement of the urinary electrolyte concentrations, osmolality, and pH plays an important role in the diagnosis and management of a variety of disorders This chapter briefly reviews the meaning of these parameters and the settings in which they may be helpful (Table 13-1) It is important to emphasize that there are no fixed normal values, since the kidney varies the rate of excretion to match net dietary intake and endogenous production Thus, interpretation of a given test requires knowledge of the patient's clinical state As an example, the urinary excretion of 125 meq of Na + per day may be appropriate for a subject on a regular diet, but represents inappropriate renal Na + wasting in a patient who is volume-depleted In addition to being clinically useful, these tests are simple to perform and widely available In most circumstances, a random urine specimen is sufficient, although a 24-h collection to determine the daily rate of solute excretion is occasionally indicated When K + depletion is due to extrarenal losses, for example, the urinary K + excretion should fall below 25 meq/day In some patients, however, random measurement may be confusing If the urine output is only 500 mL/day because of associated volume depletion, then the appropriate excretion of only 20 meq of K + per day will be associated with an apparently high urine K + concentration of 40 meq/L (20 meq/day÷ 0.5 L/day=40 meq/L) Table 13-1 Clinical application of urine chemistries Parameter Na+ excretion Uses Assessment of volume status Diagnosis of hyponatremia and acute renal failure Dietary compliance in patients with hypertension Evaluation of calcium and uric acid excretion in stone formers Cl excretion Similar to that for Na+ excretion Diagnosis of metabolic alkalosis Urine anion gap K+ excretion Diagnosis of hypokalemia Osmolality or specific gravity Diagnosis of hyponatremia, hypernatremia, and gravity acute pH Diagnosis of renal tubular acidosis Efficacy of treatment in metabolic alkalosis and uric acid stone disease - SODIUM EXCRETION The kidney varies the rate of Na + excretion to maintain the effective circulating volume, a response that is mediated by a variety of factors, including the renin-angiotensin-aldosterone system and perhaps atrial natriuretic peptide and related peptides (see C hap 8) As a result, the urine Na + concentration can be used as an estimate of the patient's volume status In particular, a urine Na + concentration below 20 meq/L is generally indicative of hypovolemia This finding is especially useful in the differential diagnosis of both hyponatremia and acute renal failure The two major causes of hyponatremia are effective volume depletion and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) The urine Na + concentration should be low in the former, but greater than 40 meq/L in the SIADH, which is characterized by water retention but normal Na + handling (i.e., output equal to intake; see C hap 23) Similar considerations apply to acute renal failure, which is most often due to volume depletion or acute tubular necrosis.1 The urine Na + concentration usually exceeds 40 meq/L in the latter, in part because of the associated tubular damage and a consequent inability to maximally reabsorb Na + 1,2 and Measuring the fractional excretion of Na + and the urine osmolality also can help to differentiate between these conditions (see below) In normal subjects, urinary Na + excretion roughly equals average dietary intake Thus, measurement of urinary Na + excretion (by obtaining a 24-h collection) can be used to check dietary compliance in patients with essential hypertension Restriction of Na + intake is frequently an important component of the therapeutic regimen,4,5 and adequate adherence should result in the excretion of less than 100 meq/day The concurrent use of diuretics does not interfere with the utility of this test as long as drug dose and dietary intake are relatively constant A thiazide diuretic, for example, initially increases Na + and water excretion by reducing Na + transport in the distal tubule However, the diuresis is attenuated over a period of days, because the ensuing volume depletion enhances Na + reabsorption both in the collecting tubules (via aldosterone) and in the proximal tubule (in part via angiotensin II).6,7 The net effect is the establishment within week of a new steady state in which the plasma volume is somewhat diminished, but Na + excretion is again equal to intake (see Fig 15-2).8 Measurement of urinary Na + excretion is also important when evaluating patients with recurrent kidney stones A 24-h urine collection is typically obtained in this setting to determine if calcium or uric acid excretion is increased, both of which can predispose to stone formation.9,10 However, the tubular reabsorption of both calcium and uric acid is indirectly linked to that of Na + (see C hap 3) Thus, the increased Na + reabsorption in hypovolemia can mask the presence of underlying hypercalciuria or hyperuricosuria.11 In general, Na + excretion above 75 to 100 meq/day indicates that volume depletion is not a limiting factor for calcium or uric acid excretion Limitations Despite its usefulness, there are some pitfalls in relying upon the measurement of Na + excretion as an index of volume status A low urine Na + concentration, for example, may be seen in normovolemic patients who have selective renal or glomerular ischemia due to bilateral renal artery stenosis or acute glomerulonephritis.2,12 On the other hand, a defect in tubular Na + reabsorption can lead to a high rate of Na + excretion, despite the presence of volume depletion This can occur with the use of diuretics,* in aldosterone deficiency, or in advance renal failure.13 The urine Na + concentration can also be influenced by the rate of water reabsorption This can be exemplified by central diabetes insipidus, a disorder in which a deficiency of antidiuretic hormone (ADH) can lead to a urine output exceeding 10 L/day In this setting, the daily excretion of 100 meq of Na + will be associated with a urine Na + concentration of 10 meq/L or less, incorrectly suggesting the presence of volume depletion C onversely, a high rate of water reabsorption can raise the urine Na + concentration and mask the presence of hypovolemia To remove the effect of water reabsorption, the renal handling of Na + can be evaluated directly by calculating the fractional excretion of Na + (FENa) Fractional Excretion of Sodium The FENa can be calculated from a random urine specimen:2,3,14 The quantity of Na + excreted is equal to the product of the urine Na + concentration (UNa) and the urine flow rate (V); the quantity of Na + filtered is equal to the product of the plasma Na + concentration (P Na) and the glomerular filtration rate (or creatinine clearance, which is equal to Ucr × V/P cr) Thus, The primary use of the FENa is in patients with acute renal failure As described above, a low urine Na + concentration favors the diagnosis of volume depletion, whereas a high value points toward acute tubular necrosis However, a level between 20 and 40 meq/L may be seen with either disorder.2,3 This overlap, which is due in part to variations in the rate of water reabsorption, can be minimized by calculating the FENa.2,3,14 Na + reabsorption is appropriately enhanced in hypovolemic states, and the FENa is usually less than percent; i.e., more than 99 percent of the filtered Na + has been reabsorbed In contrast, tubular damage leads to a FENa in excess of to percent in most patients with acute tubular necrosis There are, however, exceptions to this general rule, as the FENa may be less than percent when acute tubular necrosis is superimposed upon chronic effective volume depletion (as occurs in cirrhosis, heart failure, and burns) or when it is induced by radiocontrast media or heme pigment deposition.1,15,16 and 17 The mechanism by which this occurs is uncertain, although tubular function may be better preserved in these disorders.14 Limitations The major limitation in the use of the FENa is that it is dependent upon the amount of Na + filtered, and therefore the dividing line between volume depletion and normovolemia is not always percent This can be best appreciated in patients with normal renal function If the glomerular filtration rate (GFR) is 180 L/day (125 mL/min) and the plasma Na + concentration is 150 meq/L, then 27,000 meq of Na + will be filtered each day As a result, the FENa will always be under percent as long as daily Na + intake is in the usual range of 125 to 250 meq Since patients with relatively normal renal function should be able to lower daily Na + excretion to less than 20 meq/day in the presence of volume depletion, the FENa should be less than 0.2 percent in this setting A FENa of 0.5 percent is indicative of normovolemia, not volume depletion, in such a patient unless there is renal salt wasting In comparison, a FENa of 0.5 percent does reflect volume depletion in advanced renal failure, a condition in which the GFR and therefore the filtered Na + load are markedly reduced If, for example, the GFR is only 10 percent of normal, then the filtered Na + load is 2700 meq/day; 0.5 percent of this quantity is equal to only 14 meq of Na + excreted per day The FENa and the UNa are difficult to interpret with concurrent diuretic therapy, since the ensuing natriuresis will raise these values even in patients who are hypovolemic Although not widely available, measurement of the fractional clearance of endogenous lithium (which is present in trace amounts) may circumvent this problem Lithium is primarily reabsorbed in the proximal tubule, which has two important consequences: Proximal reabsorption is increased and therefore lithium excretion is reduced in hypovolemic states, and lithium excretion is not significantly increased by loop diuretics The fractional excretion of lithium (FELi) is approximately 20 percent in healthy controls In one report of patients with acute renal failure, a value below 15 percent (and usually below 10 percent) was highly suggestive of prerenal disease, independent of diuretic therapy.18 In comparison, the mean FELi was 26 percent in acute tubular necrosis (ATN) Given the usual lack of ability to measure trace lithium, other markers for proximal function have been evaluated Uric acid handling occurs almost entirely in the proximal tubule, and the fractional excretion of uric acid is not affected by loop diuretic therapy In the study noted above, values below 12 percent were suggestive of prerenal disease (sensitivity 68 percent, specificity 78 percent), while values above 20 percent were suggestive of ATN (sensitivity 96 percent, specificity only 33 percent).18 CHLORIDE EXCRETION C hloride is reabsorbed with sodium throughout the nephron (see C haps 3,4 and 5) As a result, the rate of excretion of these ions is usually similar, and measurement of the urine C l- concentration generally adds little to the information obtained from the more routinely measured urine Na + concentration However, as many as 30 percent of hypovolemic patients have more than a 15-meq/L difference between the urine Na + and C lconcentrations.19 This is due to the excretion of Na + with another anion (such as HC O - or carbenicillin) or to the excretion of C l- with another cation (such as NH+ in metabolic acidosis.19,20 Thus, it may be helpful to measure the urine C l- concentration in a patient who seems to be volume-depleted but has a somewhat elevated urine Na + concentration This most often occurs in metabolic alkalosis, in which acid-base balance can be restored by urinary excretion of the excess HC O - as NaHC O (see C hap 18) Many of these patients, however, are volume-depleted due to vomiting or diuretic use To the degree that the hypovolemic stimulus to Na + retention predominates, there will be low Na + and HC O - levels in the urine and persistence of the alkalosis If, on the other hand, there is a relatively mild volume deficit as compared to the severity of the alkalosis, some NaHC O will be excreted, thereby elevating the urine Na + concentration (in some cases to over 100 meq/L) In comparison, the urine C lconcentration will remain appropriately low (unless some diuretic effect persists), since there is no defect in the reabsorption of NaC l Another setting in which measurement of the urine C l- concentration may be helpful is in patients with a normal anion gap metabolic acidosis (see C hap 19).21,22 In the absence of renal failure, this problem is most often due to diarrhea or to one of the forms of renal tubular acidosis (RTA) The normal response to acidemia is to increase urinary acid excretion, primarily as NH+ When urine NH+ levels are high, the urine anion gap, Figure 13-1 Relationship between the specific gravity and osmolality of the urine from normal subjects who have neither glucose nor protein in the urine For comparison, the relationship between the specific gravity and osmolality for glucose solutions is included (Adapted from Miles B, Paton A, deWardener H, Br Med J 2:904, 1954 By permission of the British Medical Journal.) will have a negative value, since the C l- concentration will exceed the concentration of Na + and K + by the approximate amount of NH+ in the urine Thus, the urine C l- concentration may be inappropriately high in diarrhea-induced hypovolemia because of the need to maintain electroneutrality as NH+ excretion is enhanced.20 In comparison, urinary acidification is impaired in RTA, leading to a low level of NH+ excretion and a positive value for the urine anion gap.21 The urine pH also will be inappropriately high (>5.3) in this setting POTASSIUM EXCRETION Potassium excretion varies appropriately with intake, a response that is mediated primarily by aldosterone and a direct effect of the plasma K + concentration (see C hap 12) If K + depletion occurs, urinary K + excretion can fall to a minimum of to 25 meq/day.23 As a result, measurement of K + excretion can aid in the diagnosis of unexplained hypokalemia An appropriately low value suggests either extrarenal losses (usually from the gastrointestinal tract) or the use of diuretics (if the collection has been obtained after the diuretic effect has worn off) In comparison, the excretion of more than 25 meq of K + per day indicates at least a component of renal K + wasting Measurement of K + excretion is less helpful in patients with hyperkalemia If K + intake is increased slowly, normal subjects can take in and excrete more than 40 meq of K + per day without a substantial elevation in the plasma K + concentration (normal daily intake is 40 to 120 meq).24,25 Thus, chronic hyperkalemia must be associated with a defect in urinary K + excretion, since normal renal function would result in the rapid excretion of the excess K + As a result, the urine K + concentration will be inappropriately low in this setting, most often as a result of renal failure or hypoaldosteronism (see C hap 28) URINE OSMOLALITY Variations in the urine osmolality (Uosm) play a central role in the regulation of the plasma osmolality (P osm) and Na + concentration This response is mediated by osmoreceptors in the hypothalamus that influence both thirst and the secretion of ADH (see C hap 9) After a water load, for example, there is a transient reduction in the P osm, leading to suppression of ADH release This diminishes water reabsorption in the collecting tubules, resulting in the excretion of the excess water in a dilute urine Water restriction, on the other hand, sequentially raises the P osm, ADH secretion, and renal water reabsorption, resulting in water retention and the excretion of a concentrated urine These relationships allow the Uosm to be helpful in the differential diagnosis of both hyponatremia and hypernatremia (see C haps 23 and 24) Hyponatremia with hypoosmolality should virtually abolish ADH release As a result, a maximally dilute urine should be excreted, with the Uosm falling below 100 mosmol/kg If this is found, then the hyponatremia is probably due to excess water intake at a rate that exceeds normal excretory capacity (a rare disorder called primary polydipsia) Much more commonly, the Uosm is inappropriately high and the hyponatremia results from an inability of the kidneys to excrete water normally Lack of suppression of ADH release, due to volume depletion or the syndrome of inappropriate ADH secretion, is the most common cause of this problem In contrast, hypernatremia should stimulate ADH secretion, and the Uosm should exceed 600 to 800 mosmol/kg If a concentrated urine is found, then extrarenal water loss (from the respiratory tract or skin) or the administration of Na + in excess of water is responsible for the elevation in the plasma Na + concentration On the other hand, a Uosm below that of the plasma indicates primary renal water loss due to lack of or resistance to ADH The Uosm (in addition to the FENa) also may be helpful in distinguishing volume depletion from postischemic ATN as the cause of the acute renal failure ADH levels tend to be elevated in both disorders, because hypovolemia is a potent stimulus to the release of ADH (see page 176) However, tubular dysfunction in acute tubular necrosis impairs the response to ADH, leading to the excretion of urine with an osmolality that is generally less than 400 mosmol/kg.1,3 In comparison, the Uosm may exceed 500 mosmol/kg with hypovolemia alone if there is no underlying renal disease Thus, a high Uosm essentially excludes the diagnosis of ATN The finding of an isosmotic urine, however, is less useful diagnostically It is consistent with ATN but does not rule out volume depletion, since there may be a concomitant impairment in concentrating ability, a common finding in the elderly or in patients with severe reductions in glomerular filtration rate.26,27 Urine Specific Gravity The solute concentration of the urine (or other solution) also can be estimated by measuring the urine specific gravity, which is defined as the weight of the solution compared with that of an equal volume of distilled water Plasma is approximately 0.8 to 1.0 percent heavier than water and therefore has a specific gravity of 1.008 to 1.010 Since the specific gravity is proportional to the weight, as well as the number, of particles in the solution, its relationship to osmolality is dependent upon the molecular weights of the solutes As illustrated in Fig 13-1, the specific gravity varies with osmolality in a relatively predictable way in normal urine, which contains primarily small solutes such as urea, Na + , C l(-), K + , NH+ 4, and H2PO 4- In this setting, each 30 to 35 mosmol/kg raises the specific gravity by approximately 0.001 Thus, a specific gravity of 1.010 usually represents urine osmolality between 300 and 350 mosmol/kg However, there will be a disproportionate increase in the specific gravity as compared with the osmolality if larger molecules, such as glucose, are present in high concentrations C linical examples of this phenomenon include glucosuria in uncontrolled diabetes mellitus, and the administration of radiocontrast media (mol wt approximately 550) or high doses of the antibiotic carbenicillin In these settings, the specific gravity can exceed 1.040 to 1.050, even though the urine osmolality may be about 300 mosmol/kg, similar to that of the plasma.28 URINE PH The urine pH generally reflects the degree of acidification of the urine and normally varies with systemic acid-base balance The major clinical use of the urine pH occurs in patients with metabolic acidosis The appropriate response to this disorder is to increase urinary acid excretion, so that the urine pH falls below 5.3 and usually below 5.0.21 Values above 5.3* in adults and 5.6 in children usually indicate abnormal urinary acidification and the presence of renal tubular acidosis; the urine anion gap also tends to have a positive value in this setting, since NH+ excretion is impaired.21 Distinction between the various types of renal tubular acidosis can then be made by measurement of the urine pH and the fractional excretion of HC O - at different plasma HC O - concentrations (see C hap 19) Monitoring the urine pH is also helpful in assessing the efficacy of treatment in metabolic alkalosis and uric acid stone disease As described above, HC O - reabsorption is often increased in metabolic alkalosis due to concomitant volume depletion The net effect is that the urine pH is inappropriately acid (≤6.0), since virtually all of the filtered HC O - is reabsorbed This defect can typically be reversed by NaC l administration; as normovolemia is restored, the excess HC O - can be excreted, resulting in an elevation in the urine pH to above 7.0 A persistently low urine pH usually indicates inadequate volume repletion A persistently acid urine is also an important factor in many patients with uric acid stone disease A high H+ concentration will drive the reaction to the right The ensuing elevation in the uric acid concentration is physiologically important, since uric acid is much less soluble than urate.29 Administering alkali, on the other hand, can reverse this problem The efficacy of therapy can be assessed by monitoring the urine pH, which should be above 6.0 to 6.5 REFERENCES Rose BD Pathophysiology of Renal Disease, 2d ed New York, McGraw-Hill, 1987, p 82 Miller TR, Anderson RJ, Linas SL, et al Urinary diagnostic indices in acute renal failure: A prospective study Ann Intern Med 89:47, 1978 Espinel C H, Gregory AW Differential diagnosis of acute renal failure Clin Nephrol 13:73, 1980 C utler JA, Follmann D, Alexander PS Randomized trials of sodium reduction: An overview Am J Clin Nut 65(suppl): 643S, 1997 Law MR, Frost C D, Wald NJ By how much does dietary salt reduction lower blood pressure I An analysis of observational data among populations; III Analysis of data of salt reduction Br Med J 302:811,819, 1991 Wilcox C S, Guzman NJ, Mitch WE, et al Na + , K + and BP homeostasis in man during furosemide: Effects of prazosin and captopril Kidney Int 131:135, 1987 Bock HA, Stein JH Diuretics and the control of extracellular fluid volume: Role of counterregulation Semin Nephrol 8:264, 1988 Maronde R, Milgrom M, Vlachakis ND, C han L Response of thiazide-induced hypokalemia to amiloride JAMA 249:237, 1983 C oe FL, Parks JH, Asplin JR The pathogenesis and treatment of kidney stones N Engl J Med 327:1141, 1992 10 Parks JH, C oe FL A urinary calcium-citrate index for the evaluation of nephrolithiasis Kidney Int 30:85, 1986 11 Muldowney FP, Freaney R, Moloney MF Importance of dietary sodium in the hypercalciuric syndrome Kidney Int 22:292, 1982 12 Besarab A, Brown RS, Rubin NT, et al Reversible renal failure following bilateral renal artery occlusive disease: clinical features, pathology, and the role of surgical revascularization JAMA 235:2838, 1976 13 Danovitch GM, Bourgoignie JJ, Bricker NS Reversibility of the “salt-losing” tendency of chronic renal failure N Engl J Med 296:15, 1977 14 Steiner RW Interpreting the fractional excretion of sodium Am J Med 77:699, 1984 15 Planas M, Wachtel T, Frank H, Henderson LW C haracterization of acute renal failure in the burned patient Arch Intern Med 142:2087, 1982 16 Diamond JR, Yoburn DC Nonoliguric acute renal failure associated with a low fractional excretion of sodium Ann Intern Med 96:597, 1982 17 Fang LST, Sirota RA, Ebert TH, Lichtenstein NS Low fractional excretion of sodium with contrast media–induced acute renal failure Arch Intern Med 140:531, 1980 18 Steinhaulin F, Burnier M, Magnin JL, et al Fractional excretion of trace lithium and uric acid in acute renal failure J Am Soc Nephrol 4:1429, 1994 19 Sherman RA, Eisinger RP The use (and misuse) of urinary sodium and chloride measurements JAMA 247:3121, 1982 20 Kamel KS, Ethier JH, Richardson RMA, et al Urine electrolytes and osmolality: When and how to use them Am J Nephrol 10:89, 1990 21 Batlle DC , Hizon M, C ohen E, et al The use of the urine anion gap in the diagnosis of hyperchloremic metabolic acidosis N Engl J Med 318:594, 1988 22 Goldstein MB, Bear R, Richardson RMA, et al The urine anion gap: A clinically useful index of ammonium excretion Am J Med Sci 292:198, 1986 23 Squires RD, Huth EJ Experimental potassium depletion in normal human subjects I Relation on ionic intakes to the renal conservation of potassium J Clin Invest 38:1134, 1959 24 Talbott JH, Schwab RS Recent advances in the biochemistry and therapeusis of potassium salts N Engl J Med 222:585, 1940 25 Rabelink TJ, Koomans HA, Hené RJ, Dorhout Mees EJ Early and late adjustment to potassium loading in humans Kidney Int 38:942, 1990 26 Sporn IN, Lancestremere RG, Papper S Differential diagnosis of oliguria in aged patients N Engl J Med 267:130, 1962 27 Levinsky NG, Davidson DG, Berliner RW Effects of reduced glomerular filtration and urine concentration in presence of antidiuretic hormone J Clin Invest 38:730, 1959 28 Zwelling LA, Balow JE Hypersthenuria in high-dose carbenicillin therapy Ann Intern Med 89:225, 1978 29 C oe FL Uric acid and calcium oxalate nephrolithiasis Kidney Int 24:392, 1983 Footnotes * Although chronic diuretic use does not prevent attainment of a new steady state, urinary Na + excretion that is equal to intake is still inappropriately high in a hypovolemic patient † The diagnostic use of the urine pH requires that the urine be sterile Infection with any of the urinary pathogens that produce urease results in the metabolism of urinary urea into ammonia NH3) The excess NH3 directly elevates the urine pH according to the Henderson-Hasselbalch equation (see C hap 10): Editors: Rose, Burton David; Post, Theodore W Title: Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th Edition C opyright ©2001 McGraw-Hill > Table of Contents > Part Three - Physiologic Approach to Acid-Base and Electroltye Disorders > Chapter Fourteen - Hypovolemic states Chapter Fourteen Hypovolemic states In variety of clinical disorders, fluid losses lead to depletion of the extracellular fluid This problem, if severe, can cause a potentially fatal decrease in tissue perfusion Fortunately, early diagnosis and treatment can restore normovolemia in almost all cases ETIOLOGY True volume depletion occurs when fluid is lost from the extracellular fluid at a rate exceeding net intake These losses may occur from the gastrointestinal tract, skin, or lungs; in the urine; or by acute sequestration in the body in a “third space” that is not in equilibrium with the extracellular fluid (Table 14-1) When these losses occur, two factors tend to protect against the development of hypovolemia First, dietary Na + and water intake are generally far above basal needs Thus, relatively large losses must occur unless intake is concomitantly reduced (as with anorexia or vomiting) Second, the kidney normally minimizes further urinary losses by enhancing Na + and water reabsorption The adaptive renal response explains why patients given a diuretic for hypertension not develop progressive volume depletion Although a thiazide diuretic inhibits NaC l reabsorption in the distal tubule, the initial volume loss stimulates the renin-angiotensin-aldosterone system (and possibly other compensatory mechanisms), resulting in increased proximal and collecting tubule Na + reabsorption.1,2 This balances the diuretic effect, resulting in the attainment within to weeks of a new steady state in which there has been some fluid loss, but, in which Na + intake and excretion are again equal (see Fig 15-2).3 Table 14-1 Etiology of true volume depletion Gastrointestinal losses Gastric: vomiting or nasogastric suction Intestinal, pancreatic, or biliary: diarrhea, fistulas, ostomies, or tube drainage Bleeding Renal losses Salt and water: diuretics, osmotic diuresis, adrenal insufficiency, or salt-wasting nephropathies Water: central or nephrogenic diabetes insipidus Skin and respiratory losses Insensible losses from skin and respiratory tract Sweat Burns Other: skin lesions, drainage and reformation of large pleural effusion, or bronchorrhea Sequestration into a third space Intestinal obstruction or peritonitis Crush injury of skeletal fractures Acute pancreatitis Bleeding Obstruction of a major venous system Gastronintestinal Losses Each day approximately to liters of fluid is secreted by the stomach, pancreas, gallbladder, and intestines into the lumen of the gastrointestinal tract Almost all this fluid is reabsorbed, with only 100 to 200 mL being lost in the stool However, volume depletion may ensue if reabsorption is decreased (as with external drainage) or secretion is increased (as with diarrhea) Acid-base disturbances frequently occur with gastrointestinal losses, depending upon the site from which the fluid is lost Secretions from the stomach contain high concentrations of H+ and C l- As a result, vomiting and nasogastric suction are generally associated with metabolic alkalosis In contrast, intestinal, pancreatic, and biliary secretions are relatively alkaline, with high concentrations of HC O - Thus, the loss of these fluids due to diarrhea, laxative abuse, fistulas, ostomies, or tube drainage tends to cause metabolic acidosis Hypokalemia is also commonly associated with these disorders, since K + is present in all gastrointestinal secretions Acute bleeding from any site in the gastrointestinal tract is another common cause of volume depletion Electrolyte disturbances usually not occur in this setting (except for shock-induced lactic acidosis), since it is plasma, not gastrointestinal secretions, that is lost Renal Losses Under normal conditions, renal Na + and water excretion is adjusted to match intake In a normal adult, approximately 130 to 180 liters is filtered across the glomerular capillaries each day More than 98 to 99 percent of the filtrate is then reabsorbed by the tubules, resulting in a urine output averaging to L/day Thus, a small (1 to percent) reduction in tubular reabsorption can lead to a 2- to 4liter increase in Na + and water excretion, which, if not replaced, can result in severe volume depletion NaCl and water loss A variety of conditions can lead to excessive urinary excretion of NaC l and water (Table 14-1) Diuretics, for example, inhibit active Na + transport at different sites in the nephron, resulting in an increased rate of excretion (see C hap 15) Although they are frequently given to remove fluid in edematous patients, diuretics can produce true hypovolemia if used in excess The presence of large amounts of nonreabsorbed solutes in the tubule also can inhibit Na + and water reabsorption, resulting in an osmotic diuresis The most common clinical example occurs in uncontrolled diabetes mellitus, in which glucose acts as the osmotic agent With severe hyperglycemia, urinary losses can contribute to a net fluid deficit of as much as to 10 liters (see C hap 25) Variable degrees of Na + wasting are also present in many renal diseases Most patients with renal insufficiency [glomerular filtrate rate (GFR) less than 25 mL/min] are unable to maximally conserve Na + if acutely placed on a low-sodium diet These patients may have an obligatory Na + loss of 10 to 40 meq/day, in contrast to normal subjects, who can lower Na + excretion to less than meq/day.4,5 This degree of Na + wasting is usually not important, since normal Na + balance is maintained as long as the patient is on a regular diet In rare cases, a more severe degree of Na + wasting is present in which obligatory urinary losses may exceed 100 meq of Na + and liters of water per day In this setting, hypovolemia will ensue unless the patient maintains a high Na + intake This picture of a severe salt-wasting nephropathy is most often seen in tubular and interstitial diseases, such as medullary cystic kidney disease.6,7 Three factors are thought to contribute to this variable salt wasting: the osmotic diuresis produced by increased urea excretion in the remaining functioning nephrons; direct damage to the tubular epithelium, which, in severe cases, can impair the response to aldosterone; and, probably most important in chronic renal disease, an inability to acutely shut off natriuretic forces.5,6,8 Patients with renal insufficiency tend to have a decreased number of functioning nephrons If Na + intake remains normal, they must be able to augment Na + excretion per functioning nephron to maintain Na + balance This requires a fall in tubular Na + reabsorption that may be mediated at least in part by a natriuretic hormone, such as atrial natriuretic peptide Thus, the salt wasting that occurs when Na + intake is abruptly lowered could represent persistent activation of these natriuretic forces C onsistent with this hypothesis is the observation that apparent salt wasters (with acute obligatory losses of as much as 300 meq/day) can maintain Na + balance on an intake of only meq/day if intake is gradually reduced over a period of weeks rather than acutely.5 Therapy of renal salt wasting must be directed toward establishing the level of Na + intake required to maintain Na + balance This can usually be determined empirically, as most patients will tolerate a daily intake above 1.5 to g (60 to 80 meq) It should not be assumed, however, that a patient with salt wasting has a normal ability to excrete a Na + load Some patients with renal insufficiency who become hypovolemic with Na + restriction may retain Na + and develop edema and hypertension if placed on a high-sodium diet In these patients, the range of Na + intake compatible with the maintenance of Na + balance is relatively narrow The increase in urine output following relief of bilateral urinary tract obstruction is often considered to represent another example of renal salt wasting This postobstructive diuresis, however, is in almost all cases appropriate in that it represents an attempt to excrete the fluid retained during the period of obstruction.9,10 Thus, quantitative replacement of the urine output will lead to persistent volume expansion and a urine output that can exceed 10 L/day Although the diuresis is largely appropriate, some fluid therapy is required (e.g., 50 to 75 mL/h of half-isotonic saline), since there is often a mild sodium-wasting tendency, the severity of which is limited by the concurrent reduction in glomerular filtration rate and a modest concentrating defect due to downregulation of water channels.11 Although the risk of volume depletion is minimal with this regimen, the patient should be monitored for signs such as hypotension, decreased skin turgor, or a rise in the blood urea nitrogen (BUN) Water loss Volume depletion can also result from a selective increase in urinary water excretion This is due to decreased water reabsorption in the collecting tubules, where antidiuretic hormone (ADH) promotes the reabsorption of water but not Na + As a result, an impairment in either ADH secretion (central diabetes insipidus) or the renal response to ADH (nephrogenic diabetes insipidus) may be associated with the excretion of relatively large volumes (over 10 L/day in severe cases) of dilute urine (see C hap 24) This water loss is usually matched by an equivalent increase in water intake, since the initial elevation in the plasma osmolality and Na + concentration stimulates thirst However, water loss, hypovolemia, and persistent hypernatremia will ensue in infants, comatose patients (neither of whom have ready access to water), or those with a defective thirst mechanism Skin and Respiratory Losses Each day, approximately 700 to 1000 mL of water is lost by evaporation from the skin and respiratory tract (see C hap 9) Since heat is required for the evaporation of water, these insensible losses play an important role in thermoregulation, allowing the dissipation of some of the heat generated from body metabolism When external temperatures are high or metabolic heat production is increased (as with fever or exercise), further heat can be lost by the evaporation of sweat (a “sensible” loss) from the skin Although sweat (Na + concentration equals 30 to 50 meq/L) production is low in the basal state, it can exceed to L/h in a subject exercising in a hot, dry climate.12* Negative water balance due to these insensible and sensible losses is usually prevented by the thirst mechanism, similar to that in diabetes insipidus However, the cumulative sweat Na + losses can lead to hypovolemia In addition to its role in thermoregulation, the skin acts as a barrier that prevents the loss of interstitial fluid to the external environment When this barrier is interrupted by burns or exudative skin lesions, a large volume of fluid can be lost This fluid has an electrolyte composition similar to that of the plasma and contains a variable amount of protein Thus, the replacement therapy in a burn patient differs from that in a patient with increased insensible or sweat losses Although rare, pulmonary losses other than those by evaporation can lead to volume depletion This most often occurs in patients who have either continuous drainage of an active, usually malignant pleural effusion or an alveolar cell carcinoma with a marked increase in bronchial secretions (Bronchorrhea) Sequestration into a Third Space Volume depletion can be produced by the loss of interstitial and intravascular fluid into a third space that is not in equilibrium with the extracellular fluid For example, a patient with a fractured hip may lose 1500 to 2000 mL of blood into the tissues adjacent to the fracture Although this fluid will be resorbed back into the extracellular fluid over a period of days to weeks, the acute reduction in blood volume, if not replaced, can lead to severe volume depletion Other examples of this phenomenon include intestinal obstruction, severe pancreatitis, crush injuries, bleeding (as with trauma or a ruptured abdominal aortic aneurysm), peritonitis, and obstruction of a major venous system The main difference between these disorders and, for example, the development of ascites in cirrhosis is the rate of fluid accumulation C irrhotic ascites develops relatively slowly, allowing time for renal Na + and water retention to replenish the effective circulating volume (see C hap 16) As a result, cirrhotic patients typically have symptoms of edema rather than those of hypovolemia HEMODYNAMIC RESPONSES TO VOLUME DEPLETION Volume depletion induces a characteristic sequence of compensatory hemodynamic responses The initial volume deficit results in decreases in the plasma volume and venous return to the heart The latter is sensed by the cardiopulmonary receptors in the atria and pulmonary veins, leading to sympathetically mediated vasoconstriction in skin and skeletal muscle.13 This effect, which shunts blood toward the more important cerebral and coronary circulations, is mediated by partial removal of the tonic inhibition of sympathetic tone normally induced by these receptors More marked volume depletion leads to a reduction in cardiac output From the relationship between mean arterial pressure, cardiac output, and systemic vascular resistance,† Mean arterial pressure = cardiac output × systemic vascular resistance the fall in cardiac output lowers the systemic blood pressure This hemodynamic change is sensed by the carotid sinus and aortic arch baroreceptors, which induce a more generalized increase in sympathetic activity that now involves the splanchnic and renal circulations The net effect is relative maintenance of cerebral and coronary perfusion and return of the arterial pressure toward normal The latter is mediated by increases in venous return (mediated in part by active venoconstriction), cardiac contractility, and heart rate (all of which act to elevate the cardiac output) and increases in vascular resistance due both to direct sympathetic effects and to enhanced secretion of renin from the kidney, resulting in the generation of angiotensin II.13 If the volume deficit is small (about 10 percent of the blood volume, which is equivalent to donating 500 mL of blood), these sympathetic effects return the cardiac output and blood pressure to normal or near normal, although the heart rate is likely to be increased.14 In contrast, a marked fall in blood pressure will ensue if the sympathetic response does not occur—for example, because of autonomic insufficiency.15,16 With more severe hypovolemia (16 to 25 percent of the blood volume), there is more pronounced sympathetic and angiotensin II– mediated vasoconstriction Although this may maintain the blood pressure when the patient is recumbent, hypotension can occur when the upright position is assumed, leading to postural dizziness At this point, the compensatory sympathetic responses are maximal, and any further fluid loss will induce marked hypotension, even in recumbency, and eventually shock (see below).14,17 SYMPTOMS Three sets of symptoms can occur in hypovolemic patients: those related to the manner in which fluid loss occurs, such as vomiting, diarrhea, or polyuria; those due to volume depletion; and those due to the electrolyte and acid-base disorders that can accompany volume depletion The symptoms induced by hypovolemia are primarily related to the decrease in tissue perfusion The earliest complaints include lassitude, easy fatigability, thirst, muscle cramps, and postural dizziness More severe fluid loss can lead to abdominal pain, chest pain, or lethargy and confusion as a result of mesenteric, coronary, or cerebral ischemia These symptoms usually are reversible, although tissue necrosis may develop if the low-flow state is allowed to persist Symptomatic hypovolemia most often occurs in patients with isosmotic Na + and water depletion in whom most of the fluid deficit comes from the extracellular fluid In contrast, in patients with pure water loss due to insensible losses or diabetes insipidus, the elevation in plasma osmolality (and Na + concentration) causes water to move down an osmotic gradient from the cells into the extracellular fluid The net result is that about two-thirds of the water lost comes from the intracellular fluid C onsequently, these patients are likely to exhibit the symptoms of hypernatremia (produced by the water deficit) before those of marked extracellular fluid depletion A variety of electrolyte and acid-base disorders also may occur, depending upon the composition of the fluid that is lost (see below) The more serious symptoms produced by these disturbances include muscle weakness (hypokalemia and hyperkalemia); polyuria and polydipsia (hypokalemia and hyperglycemia); and lethargy, confusion, seizures, and coma (hyponatremia, hypernatremia, and hyperglycemia) An additional symptom that appears to occur only in primary adrenal insufficiency is extreme salt craving Approximately 20 percent of patients with this disorder give a history of heavily salting all foods (including those not usually salted) and even eating salt that they have sprinkled on their hands.18 The mechanism responsible for this appropriate increase in salt intake is not known EVALUATION OF THE HYPOVOLEMIC PATIENT The evaluation of the patient with suspected hypovolemia includes a careful history for a source of fluid loss, the physical examination, and appropriate laboratory studies In many patients in whom the history does not provide a clear etiology, a common presumption, particularly in the elderly, is that unreplaced insensible losses are responsible Evaporative and sweat losses are hypotonic and therefore must produce an elevation in the plasma Na + concentration if they are solely responsible for volume depletion The presence of a normal plasma sodium indicates proportionate salt and water loss if the patient is truly hypovolemic These observations also help to avoid the common mistake of assuming that dehydration and volume depletion (or hypovolemia) are synonymous.19 Volume depletion refers to extracellular volume depletion of any cause, most often due to salt and water loss In contrast, dehydration refers to the presence of hypernatremia due to pure water loss; such patients are also hypovolemic Physical Examination Although relatively insensitive and nonspecific,20 certain findings on physical examination may suggest volume depletion A decrease in the interstitial volume can be detected by examination of the skin and mucous membranes, while a decrease in the plasma volume can lead to reductions in systemic blood pressure and in venous pressure in the jugular veins Among patients with hypovolemia due to severe bleeding, the most sensitive and specific findings are severe postural dizziness (preventing measurement of upright vital signs) and/or a postural pulse increment of 30 beats/min or more.20 Among patients with mild to moderate blood loss or other causes of hypovolemia (vomiting, diarrhea, decreased intake), few findings have proven predictive value, and laboratory confirmation of the presence of volume depletion is typically required.20 Skin and mucous membranes If the skin and subcutaneous tissue on the thigh, calf, or forearm is pinched in normal subjects, it will immediately return to its normally flat state when the pinch is released This elastic property, called turgor, is partially dependent upon the interstitial volume of the skin and subcutaneous tissue Interstitial fluid loss leads to diminished turgor, and the skin flattens more slowly after the pinch is released In younger patients, the presence of decreased skin and subcutaneous tissue turgor is a reliable indicator of volume depletion However, elasticity diminishes with age, so that reduced turgor does not necessarily reflect hypovolemia in older patients (more than 55 to 60 years old) In these patients, skin elasticity is usually best preserved on the inner aspect of the thighs and the skin overlying the sternum Decreased turgor at these sites is suggestive of volume depletion Although reduced skin turgor is an important clinical finding, normal turgor does not exclude the presence of hypovolemia This is particularly true with mild volume deficits, in young patients whose skin is very elastic, and in obese patients, since fat deposits under the skin prevent the changes in subcutaneous turgor from being appreciated In addition to having reduced turgor, the skin is usually dry; a dry axilla is particularly suggestive of the presence of hypovolemia.20 The tongue and oral mucosa may also be dry, since salivary secretions are commonly decreased in this setting Examination of the skin also may be helpful in the diagnosis of primary adrenal insufficiency The impaired release of cortisol in this disorder leads to hypersecretion of adrenocorticotropic hormone (AC TH), which can result in increased pigmentation of the skin, especially in the palmar creases and buccal mucosa Arterial blood pressure As described above, the arterial blood pressure changes from near normal with mild hypovolemia to low in the upright position and then, with progressive volume depletion, to persistently low regardless of posture Postural hypotension leading to dizziness may be the patient's major complaint and is strongly suggestive of hypovolemia in the absence of an autonomic neuropathy or the use of sympatholytic drugs for hypertension, or in elderly subjects, in whom postural hypotension is common in the absence of hypovolemia An important change that can occur with marked fluid loss is that the secondary neurohumoral vasoconstriction leads to decreased intensity of both the Korotkoff sounds (when the blood pressure is being measured with a sphygmomanometer) and the radial pulse.17,21 As a result, a very low blood pressure suggested by auscultation or palpation may actually be associated with a near-normal pressure when measured directly by an intraarterial catheter It is important to appreciate that the definition of normal blood pressure in this setting is dependent upon the patient's basal value Although 120/80 is considered “normal,” it is actually low in a hypertensive patient whose usual blood pressure is 180/100 Venous pressure The reduction in the vascular volume seen with hypovolemia occurs primarily in the venous circulation (which normally contains 70 percent of the blood volume), leading to a decrease in venous pressure As a result, measurement of the venous pressure is useful both in the diagnosis of hypovolemia and in assessing the adequacy of volume replacement.22 In most patients, the venous pressure can be estimated with sufficient accuracy by examination of the external jugular vein, which runs across the sternocleidomastoid muscle The patient should initially be recumbent, with the trunk elevated at 15 to 30 degrees and the head turned slightly away from the side to be examined The external jugular vein can be identified by placing the forefinger just above the clavicle and pressing lightly This will occlude the vein, which will then distend as blood continues to enter from the cerebral circulation The external jugular vein usually can be seen more easily by shining a beam of light obliquely across the neck At this point, the occlusion at the clavicle should be released and the vein occluded superiorly to prevent distention by continued blood flow The venous pressure can now be measured, since it will be approximately equal to the vertical distance between the upper level of the fluid column within the vein and the level of the right atrium (estimated as being to cm posterior to the sternal angle of CHAPTER 8-1 a An acute myocardial infarction will initially diminish the effective circulating volume (because of the fall in cardiac output) and therefore urinary Na + excretion, without affecting either the plasma volume or total extracellular volume b A high-Na + diet will expand the plasma, extracellular, and effective circulating volumes and increase urinary Na + excretion c The retention of ingested water will also expand the plasma, extracellular, and effective circulating volumes and increase urinary Na + excretion 8-2 Diuretic-induced hypovolemia enhances the release of renin The ensuing increase in the formation of angiotensin II will tend to raise the blood pressure, thereby minimizing the hypotensive effect of the diuretic.3 8-3 (d) The rate of urinary Na + excretion is generally the best estimate of the effective circulating volume, since it reflects the physiologic assessment of the kidney's systemic hemodynamics A low rate of Na + excretion (urine Na + concentration below 25 meq/L in the absence of marked polyuria) is generally diagnostic of volume depletion unless there is selective renal ischemia due to bilateral renal artery stenosis or acute glomerular disease The cardiac output, plasma volume, and systemic blood pressure are less accurate For example, a fall in blood pressure may be prevented by the compensatory rise in sympathetic tone On the other hand, the cardiac output may be misleadingly elevated if there are arteriovenous fistulas or vasodilatation, as occurs in hepatic cirrhosis 8-4 In the steady state, Na + intake and excretion are equal even in a patient on diuretic therapy In this setting, the natriuretic effect of the diuretic is counteracted by enhanced Na + reabsorption, which may be induced by the compensatory increases in angiotensin II, aldosterone, and norepinephrine production The new steady state is generally attained within weeks, as long as diuretic dose and dietary Na + intake remain relatively constant (see page 453) 8-5 a Isotonic saline will expand volume without affecting osmolality Thus, ANP will rise, aldosterone will fall, and ADH will be unaffected The net effect is that the excess Na + will appropriately be excreted in a relatively isosmotic urine b A water load will be rapidly excreted, as the ensuing fall in P osm will diminish ADH release This will lead to a fall in Uosm with little change in the rate of Na + excretion (although the urine Na + concentration will fall by dilution) c A Na + load without water will cause both volume expansion and an elevation in the plasma Na + concentration and P osm, thereby activating both the volume regulatory and osmoregulatory systems As a result, ANP and ADH levels will rise and aldosterone secretion will fall In this setting, both the urine Na + concentration and Uosm will be elevated, allowing the excretion of the excess Na + with little water loss d Half-isotonic saline will cause volume expansion and hypoosmolality Therefore, ANP and Na + excretion will rise, while aldosterone, ADH, and the Uosm will fall The net effect is that the excess Na + will appropriately be excreted in a dilute urine CHAPTER 9-1 The loss of isosmotic diarrheal fluid will (a) reduce the effective circulating volume, (b) diminish urinary Na + excretion, (c and d) have no direct effect on the P osm or the plasma Na + concentration, and (e and f) increase ADH release and therefore the Uosm The ingestion of water in this setting will result in water retention (because of the high ADH levels) and hyponatremia 9-2 The Na + +K + concentration in the fluid that is lost is less than that in the plasma in this example As a result, water is being lost in excess of effective solute Since the plasma Na + concentration is generally determined by the plasma Na + concentration will rise 9-3 There is no predictable relationship between the plasma Na + concentration (which is regulated by the osmoregulatory pathway) and urinary Na + excretion (which is determined by changes in the effective circulating volume) 9-4 Two factors contribute to the inability to excrete water normally in volume depletion: increased release of ADH and reduced fluid delivery to the diluting segment in the ascending limb of the loop of Henle because of enhanced proximal Na + and water reabsorption 9-5 The minimum Uosm is unaffected by beer drinking However, the C H2O is also dependent upon the rate of solute excretion Since Na + , K + , and urea excretion are low in a subject ingesting only beer, solute excretion will also be low Suppose, for example, that the Uosm can be lowered to 75 mosmol/kg and that the P osm is 300 mosmol/kg The maximum urine output in this setting will be 10 liters in a normal subject excreting 750 mosmol of solute per day, but only liters in a beer drinker excreting 225 mosmol of solute The respective C H2O will be as follows: 9.6 a Although the Uosm is the same in both examples, there are important differences in the rate of electrolyte-free water reabsorption: In the patient with the syndrome of inappropriate ADH secretion, Thus, there is no electrolyte free water reabsorption in this setting In comparison, in the patient with heart failure, b At similar levels of water intake, the patient with heart failure will be less likely to retain water and become hyponatremic because the kidney is excreting 540 mL of free water each day (a minus value for free water reabsorption represents free water excretion) CHAPTER 10 10-1 Buffers minimize changes in the free H+ concentration by appropriately taking up (H+ +Buf- →HBuf) or releasing (HBuf→H+ +Buf- ) H+ ions The efficacy of a buffer is determined by the quantity of buffer present and the relation of the pK a of the buffer to the pH of the solution In addition, the ability to excrete C O increases the effectiveness of the HC O - 3-C O buffer system 10-2 The fall in the plasma HC O - concentration is due to the different rates with which the administered HC O - enters the different fluid compartments The added HC O - is initially limited to the vascular space, resulting in a large increase in the plasma HC O - concentration The HC O - then equilibrates throughout the total extracellular fluid (within 15 min) and subsequently with the cell buffers (a process that reaches completion within to h) Both of these processes reduce the plasma HC O - concentration toward the baseline level As discussed in C hap 11, acid-base balance is restored in this setting by the excretion of the excess HC O - in the urine This time-related effect of exogenous HC O - becomes clinically important when HC O - is given to treat metabolic acidosis (see C hap 19) The increment in the plasma HC O - concentration and therefore in the extracellular pH will be greater if measured within 15 than after equilibration with the cell buffers has occurred at to h Thus, it should not be assumed that early measurements (which will overestimate the true elevation in the plasma HC O - concentration) represent the steady-state condition 10-3 The quantity of available extracellular and intracellular buffers will determine how much of a reduction in pH will occur Buffering capacity is best estimated from the initial plasma HC O - concentration Patients with a low baseline level due to preexisting metabolic acidosis are more prone to a major reduction in pH following an acid load CHAPTER 11 11-1 The primary adaptive response of the kidney to an acid load is increased NH+ production and excretion As a result, reduced titratable acid excretion will have little effect on acid-base balance, since enhanced NH+ excretion can compensate for this defect In comparison, the ability to augment titratable acid excretion is limited Thus, a marked decline in NH+ excretion (as occurs in advanced renal failure) will lead to H+ retention and metabolic acidosis 11-2 The buffering of HC l and H2SO by NaHC O results in the respective generation of NaC l and Na 2SO When the NaC l is presented to the distal nephron, the reabsorption of Na + will be followed by that of C l- In comparison, SO 2- is a nonreabsorbable anion; thus, the distal reabsorption of Na + creates a greater lumen-negative potential difference that promotes the luminal accumulation of H+ The relatively low luminal C l- concentration in this setting also may contribute by generating a more favorable gradient for C l- to be cosecreted with H+ The net effect is increased acid excretion and therefore a lesser degree of metabolic acidosis when H2SO is given.4 11-3 a Net acid excretion is equal to the following: b In comparison, total H+ secretion is equal to Note that net acid excretion is appropriately increased in metabolic acidosis even though total H+ secretion is actually reduced as a result of the marked reduction in the filtered HC O - load 11-4 At a urine pH of 5.80 with 60 mmol of phosphate, In the filtrate, however, the initial pH was 7.40, similar to that in the plasma Thus Thus, 42.55 mmol of HPO 2- (48-5.45) has been converted to H2PO - by buffering; this is the quantity of titratable acidity excreted as H2PO - Titratable acidity is measured by the number of milliequivalents of NaOH that must be added to an acid urine to return the pH to 7.40 NH+ excretion is not included in this titration, since the pK a of the NH3-NH+ system is 9.0 Thus, raising the urine pH from 5.80 to 7.40 will have little effect on the NH3/NH+ ratio 11-5 The metabolic alkalosis persists in this setting because both volume and C l- depletion enhance HC O - reabsorption, thereby preventing the excretion of the excess HC O - (see C hap 18) CHAPTER 12 12-1 Aldosterone deficiency initially decreases urinary K + excretion The ensuing rise in the plasma K + concentration, however, is a direct stimulus to distal K + secretion, eventually leading to a new steady state in which intake and output are again equal (see Fig 1210) 12-2 Increasing Na + intake will enhance distal flow, resulting in augmented K + secretion and hypokalemia in patients with primary hyperaldosteronism.5 K + wasting does not occur in normal subjects, because the high Na + diet suppresses the release of aldosterone.5 12-3 Urinary K + excretion should be helpful in this setting, being less than 25 meq/day with extrarenal losses (or with a diuretic when the drug effect has worn off) but above this level with renal K + wasting 12-4 Spontaneous K + wasting and hypokalemia not occur with effective volume depletion, because the decline in distal flow counteracts the stimulatory effect of secondary hyperaldosteronism If, however, distal flow is augmented with a loop or thiazide-type diuretic, then urinary K + losses will increase and the plasma K + concentration may fall 12-5 (a, c, and possibly e) A converting enzyme inhibitor diminishes the release of aldosterone; a β -adrenergic blocker impairs the entry of K + into the cells after a K + load; and glucose can, in diabetics, raise the plasma K + concentration by elevating both the plasma glucose concentration and plasma osmolality (see Fig 12-7) 12-6 There will be little direct effect on K + excretion, since the stimulatory effect of the high distal flow is counteracted by removal of ADH, which normally promotes K + secretion In some patients, however, K + wasting can occur because the urine K + concentration cannot be reduced below to 10 meq/L Thus, a urine output of 10 L/day can lead to obligatory K + losses of 50 to 100 meq/day.6 CHAPTER 14 14-1 a The shock state is probably due to the sequestration of fluid in the infarcted bowel b Fluid replacement should proceed with isotonic saline Blood is not necessary initially, since the hematocrit of 53 percent suggests hemoconcentration due to loss of fluid from the vascular space c The high urine Na + concentration indicates that this is a Na + diuresis, not a water diuresis as in diabetes insipidus (see C hap 24 for a discussion of the approach to the polyuric patient) In this patient who had a positive balance of liters prior to surgery, it is likely that the diuresis represents an appropriate attempt to excrete the excess Na + ; true Na + wasting of this degree is extremely rare d The correct therapy is to administer replacement fluids (such as half-isotonic saline at 50 to 100 mL/h), while allowing the patient to develop negative fluid balance If the diuresis is appropriate, it will cease spontaneously without the patient developing any of the signs of volume depletion, such as diminished skin turgor or hypotension 14-2 For each liter of water lost, about 60 percent comes from the cells and 40 percent from the extracellular fluid Although the water is initially lost from the extracellular fluid, the ensuing rise in the P osm pulls a proportionate volume of water out of the cells In comparison, each liter of isotonic Na + loss comes entirely from the extracellular fluid, producing a greater reduction in the extracellular volume and possibly also in the arterial blood pressure 14-3 There is no role for the use of pure dextrose solutions in the treatment of hypovolemic shock, since only 40 percent of the fluid will remain in the extracellular space In addition, the retention of free water can lead to symptomatic hyponatremia Isotonic saline is the solution of choice; this applies even to patients who are hypernatremic, since isotonic saline will still be hypoosmotic to plasma, thereby tending to lower the plasma Na + concentration toward normal 14-4 a Volume repletion is responsible for the increases in Na + excretion and urine output b The central venous pressure alone is not an adequate determinant of volume status, since the normal range is to cmH2O Thus, cmH2O is normal in some subjects and low in others c The elevation in BUN on admission represents urea accumulation over 10 days as a result of reduced urea excretion Although normovolemia was restored over 18 h, a longer period is required for the renal excretion of the excess urea 14.5 a The patient is depleted of Na + and water (physical findings) and K + In addition, the hypernatremia indicates that water has been lost in excess of solute Thus, the replacement fluid should be hypotonic and contain Na + and K + ; for example, quarter-isotonic saline to which 20 to 40 meq of K + per liter has been added This solution can be safely given at an initial rate of 100 mL/h (The formula for calculating the rate of correction of hypernatremia is derived on page 776.) 14-6 a Any definition of hypotension must be made in relation to the patient's baseline blood pressure Although 110/70 appears normal, it is probably low in this patient with a past history of hypertension b Volume depletion from unreplaced insensible losses must be accompanied by a rise in the plasma Na + concentration, since relatively solute-free water has been lost The normal plasma Na + concentration in this patient indicates that Na + and water have been lost in proportion and therefore that a source of Na + loss must be present In this case, the history of hypertension and the concurrent hypokalemia and metabolic alkalosis suggest that diuretic therapy is the likely cause CHAPTER 15 15-1 (c) The thiazides are the treatment of choice for hypercalciuric stone disease, since they lower calcium excretion both by increasing distal C a 2+ reabsorption and, via volume depletion, by increasing proximal Na + and secondary C a 2+ reabsorption (d) Spironolactone is preferred in cirrhosis, occasionally being more effective than a loop diuretic (since it does not require secretion into the tubular lumen) and protecting against the development of hypokalemic alkalosis, which can precipitate hepatic coma in some cases 3.(a) Acetazolamide will cause preferential loss of NaHC O 3, thereby correcting both the metabolic alkalosis and fluid overload (b) Loop diuretics directly increase C a 2+ excretion by diminishing passive C a 2+ reabsorption in the loop of Henle (b) A loop diuretic is also helpful in hyponatremic patients, who tend to have high ADH levels and therefore inappropriate water retention By interfering with loop NaC l reabsorption, the medullary accumulation of solute and therefore concentrating ability and the degree of water retention are diminished 15-2 a Hypoalbuminemia limits the degree of protein-binding, resulting in a wider extravascular distribution of the diuretic and therefore a slower rate of delivery to the kidney b Both angiotensin II and aldosterone enhance Na + reabsorption (in the proximal and collecting tubules, respectively), directly impairing the natriuretic response to the diuretic c Hypotension, via the pressure natriuresis phenomenon, increases Na + reabsorption, thereby counteracting the effect of the diuretic CHAPTER 16 16-1 (a and d) Tissue perfusion may fall after the appropriate use of diuretics in heart failure and cirrhosis With mild hypoalbuminemia or renal failure, on the other hand, there is primary renal Na + retention, and removal of the excess fluid will lower the effective circulating volume from a high level down toward normal (b) A reduction in the effective circulating volume will lead sequentially to increased proximal Na + and water reabsorption, enhanced passive proximal urea reabsorption, and a rise in the BUN The urine Na + concentration is already low (in the absence of diuretics) in most patients with heart failure and cirrhosis, and a small further reduction is hard to detect 16-2 a The oliguria and azotemia are due to effective volume depletion resulting from either overdiuresis or a primary fall in cardiac output following the myocardial infarction b No Patients with diastolic dysfunction have a normal ejection fraction but a low output due to impaired diastolic filling Furthermore, a moderately reduced ejection fraction does not necessarily mean that cardiac output is reduced, since cardiac dilatation may allow a normal stroke volume to be maintained despite the impaired contractility c No Primary left ventricular damage may be associated with normal right ventricular function Remember that a low jugular venous pressure may be normal (normal range equals to cmH2O) d The extracellular volume in this previously healthy man was normal on admission and then must have declined after fluid removal with the diuretic e Therapy should be aimed at increasing the effective circulating volume toward normal If there is no evidence of pulmonary congestion, overdiuresis may be the primary problem, and cautious liberalization of Na + intake may restore normal tissue perfusion If this is ineffective or if pulmonary congestion is present, then treatment must be aimed at increasing cardiac function and therefore renal perfusion with vasodilators or digitalis CHAPTER 17 17-1 a 26 nanoeq/L (40× 0.8× 0.8) b The H+ concentration is 63 nanoeq/L at a pH of 7.20 (40× 1.25× 1.25) and 80 nanoeq/L at a pH of 7.10 (63× 1.25) Thus, the H+ concentration at a pH of 7.15 is 72 nanoeq/L [63+0.5× (80-63)] c The H+ concentration at a pH of 7.30 is 50 nanoeq/L (40× 1.25) Thus, at a pH of 7.24, the H+ concentration is 59 nanoeq/L [50+0.6× (63-50)] 17-2 a Metabolic acidosis—low pH, low HC O - concentration, compensatory reduction in P CO2 b C hronic respiratory alkalosis—high pH, low P CO2, compensatory reduction in HC O - concentration Note that a low HC O - concentration does not necessarily reflect a metabolic acidosis c C ombined respiratory and metabolic acidosis—low pH, high P CO2, low HC O - concentration d Metabolic alkalosis—high pH, high HC O - concentration, compensatory elevation in P CO2 17-3 a This patient has a pure metabolic acidosis b If the P CO2 remains constant, the plasma HC O - concentration must be raised to meq/L to increase the pH to 7.20 (H+ concentration equals 63 nanoeq/L): c At a P CO2 of 18 mmHg, These examples illustrate that in patients who are able to hyperventilate in response to metabolic acidosis, only a small elevation in the plasma HC O - concentration is initially required to get the patient out of danger CHAPTER 18 18-1 a The acute metabolic alkalosis is due to the citrate load from the multiple blood transfusions b The urine Na + should be less than 15 meq/L and the urine pH acid (due to maximum NaHC O reabsorption), since effective volume depletion persists It is possible, however, that HC O - reabsorptive capacity may not be sufficiently increased to reabsorb all of the marked increment in the filtered HC O - load In this setting, the urine Na + concentration and pH may be elevated because of the obligatory NaHC O excretion A low urine C l- concentration will still be present, because the patient remains hypovolemic c Acetazolamide is the preferred therapy, both to remove the excess fluid and to cause a preferential NaHC O diuresis Saline loading is not indicated, since it will result in a marked increase in ascites formation 18-2 a This patient is both volume- and K + -depleted Thus, treatment should consist of half-isotonic saline to which 40 meq of K + (as KC l) should be added b C orrection of volume and C l- depletion will allow the excess HC O - to be excreted Thus, the anion gap between the high urine (Na + +K + ) concentration and low urine C l- concentration is due primarily to HC O - If, for example, the urine pH is 7.8 (H+ concentration equals 16 nanoeq/L) and the urine P CO2 is 46 mmHg (similar to the renal venous P CO2), then Note that the urine C l- concentration is still low in this patient, indicating the need for further fluid and C l- replacement; the urine Na + concentration is not an accurate estimate of volume status in this setting because the excretion of HC O - obligates Na + loss 18-3 a The differential diagnosis of unexplained hypokalemia, urinary K + wasting, and metabolic alkalosis includes surreptitious diuretic use or vomiting (during the phase of HC O - excretion in which both Na + and K + excretion are increased; see page 565) or some form of primary hyperaldosteronism The normal blood pressure in this patient excludes all of the causes of the last condition other than Bartter's syndrome b The urine C l- concentration should be measured next A value below 25 meq/L is highly suggestive of vomiting (which was present in this case), whereas a higher value is consistent with diuretic use or Bartter's syndrome The last two conditions can usually be distinguished by a urinary assay for diuretics CHAPTER 19 19-1 a No The extracellular pH has not been measured, so the patient may have chronic respiratory alkalosis with an appropriate compensatory reduction in the plasma HC O - concentration b Yes Although the pH is relatively well maintained, this occurs only by marked hyperventilation (P CO2 equals 14 mmHg) that is probably symptomatic The administration of NaHC O will partially correct the acidemia and therefore the stimulus to ventilation 19-2 a This patient has a combined respiratory and high anion gap metabolic acidosis, most likely due to seizure-induced lactic acidosis b No C essation of the seizure will allow the excess lactate to be metabolized back to HC O - c There is likely to be no change, since neither lactic acidosis nor its correction seems to affect the internal distribution of K + 19-3 a Type RTA in adults is associated with a progressive but slow decline in the plasma HC O - concentration as some of the dietary H+ load is retained each day b Type RTA in infants is associated with a more rapid fall in the plasma HC O - concentration because the higher urine pH also obligates a fixed degree of HC O - loss c The plasma HC O - concentration falls rapidly in type RTA and then stabilizes once the reduced level of HC O - reabsorptive capacity has been reached At a near-normal plasma HC O - concentration following HC O - administration, these disorders can be distinguished by calculating the fractional excretion of HC O - 3: less than percent in type RTA in adults, to 10 percent in infantile type RTA, and greater than 15 percent in type RTA (see Fig 19-6) 19-4 a Hypoaldosteronism is associated with hyperkalemia, an acid urine pH, but a positive urine anion gap, since hyperkalemia impairs NH+ production and excretion b Diarrhea can lead to hypokalemia, which raises both NH3 production and excretion, thereby elevating the urine pH This disorder can be distinguished from RTA since NH+ excretion is appropriately increased, as evidenced by the negative urine anion gap c The high urine pH and positive urine anion gap are suggestive of type RTA The degree of metabolic acidosis is more severe than is typically seen with type RTA, which can induce all of the other findings in this example 19-5 a This patient has a mixed metabolic and respiratory acidosis, since a P CO2 of 40 mmHg is inappropriately high in a patient with a plasma HC O - concentration of meq/L The expected value is about 22 mmHg, since the P CO2 normally falls by about 1.2 mmHg for every meq/L reduction in the plasma HC O - concentration b The H+ concentration at a pH of 7.20 is 63 meq/L Thus, c At this degree of acidemia, the initial distribution of the excess acid is 50 to 70 percent of lean body weight Thus, d The above formula is dependent upon the presence of a steady state Since this patient is losing liter of diarrheal fluid per hour, there is continuing HC O - loss that is not being replaced e Body K + stores are probably markedly reduced This is masked as the marked acidemia promotes K + movement out of the cells, thereby accounting for the initially normal plasma K + concentration 19-6 a The metabolic acidosis in renal failure is primarily due to reduced NH+ excretion, which prevents the urinary excretion of all of dietary acid load b The second arterial pH was measured only 30 after the administration of NaHC O 3, before equilibration with the intracellular buffers had occurred Thus, the later reductions in the plasma HC O - concentration and pH probably reflected the effect of intracellular buffering; in addition, continued acid retention also may have played a contributory role CHAPTER 20 20-1 It is easiest to answer this problem by first determining the acid-base disorders represented by the three sets of blood values: a The low pH and high P CO2 indicate a respiratory acidosis The P CO2 is 25 mmHg above normal; in chronic respiratory acidosis, this should be associated with a plasma HC O - concentration of approximately 33 meq/L (3.5 meq/L increase in the plasma HC O - concentration for each 10 mmHg elevation in the P CO2) Thus, the HC O - concentration of 37 meq/L represents a superimposed metabolic alkalosis b At a P CO2 of 60 mmHg, the plasma HC O - concentration should be roughly 26 meq/L in acute respiratory acidosis (1 meq/L increase per 10 mmHg elevation in the P CO2) and 31 meq/L in chronic respiratory acidosis Therefore, the measured HC O - concentration of 26 meq/L can reflect either uncomplicated acute respiratory acidosis or chronic respiratory acidosis with a superimposed metabolic acidosis (which lowers the HC O - concentration from 31 to 26 meq/L) c Uncomplicated chronic respiratory acidosis or acute respiratory acidosis with a superimposed metabolic alkalosis (raising the HC O - concentration from 26 to 32 meq/L) The correct diagnosis can be made only by correlating the history with the laboratory values: C hronic bronchitis plus diarrhea suggests chronic respiratory acidosis with a superimposed metabolic acidosis, or (b) Marked obesity suggest chronic hypercapnia, or (c) Severe acute asthma suggests acute respiratory acidosis, or (b) C hronic bronchitis plus diuretic therapy suggests chronic respiratory acidosis with superimposed metabolic alkalosis, or (a) 20-2 a From the history and laboratory values, the probable diagnosis is acute superimposed upon chronic respiratory acidosis (see Fig 20-6) b Patients with chronic hypercapnia rely on the hypoxemic drive to ventilation This is removed by the administration of oxygen, resulting in further hypoventilation and a rise in the P CO2 c The patient cannot tolerate the administration of oxygen, nor can he tolerate the P O2 on 30 mmHg of room air Thus, some form of mechanical ventilation and probably endotracheal intubation are required d Rapid normalization of the P CO2 will lead to a posthypercapnic alkalosis, since the elevated plasma HC O - concentration will persist e C orrection of the posthypercapnic alkalosis requires the urinary excretion of the excess HC O - as NaHC O In the presence of volume depletion (low urine Na + concentration), however, HC O - excretion will not occur until normovolemia is restored 20-3 a Metabolic alkalosis, with the elevated P CO2 reflecting the appropriate respiratory compensation b The (A–a) O gradient is 13 mmHg, making underlying lung disease and chronic hypercapnia unlikely CHAPTER 22 22-1 a The P osm can be calculated from b No The effective P osm is actually reduced at 256 mosmol/kg, since the contribution of the ineffective osmole urea must be excluded 22-1 a The administration of isotonic fluids to a patient who can excrete only an isosmotic urine will lead to hyperosmolality and a rise in the plasma Na + concentration, since no free water is given to replace insensible losses from the skin and respiratory tract b Half-isotonic saline plus 77 meq/L of KC l is also an isosmotic fluid and therefore will have the same osmotic effect as isotonic saline At first glance, it may seem that the addition to the extracellular fluid of a solution with a Na + concentration less than that of the plasma (and extracellular fluid) should lower the plasma Na + concentration However, not all of this fluid remains in the extracellular space This can be appreciated if each liter of the added fluid is viewed as having two components: 500 mL of isotonic NaC l, which stays in the extracellular fluid, and 500 mL of isotonic KC l, which must either enter the cells or be excreted in the urine to prevent fatal hyperkalemia Thus, the osmotic effect of this solution is similar to that of isotonic saline In comparison, the administration of half-isotonic saline alone will lower the P osm and the plasma Na + concentration, since it is a hypotonic fluid These concepts are clinically important, since the osmotic contribution of K + in intravenous fluids is frequently ignored CHAPTER 23 23-1 All of these factors contributed to the hyponatremia Hydrochlorothiazide induced volume depletion (physical findings plus low urine Na + concentration), which enhanced ADH release (high Uosm of 540 mosmol/kg), resulting in water retention and hyponatremia The loss of K + also played a contributory role via a transcellular K + -Na + exchange Therapy should include the administration of Na + and K + in a hypertonic solution, such as 40 meq of KC l added to each liter of isotonic saline There is little justification for water restriction, since the patient is volume-depleted In view of the metabolic alkalosis, KC l, not potassium citrate, is indicated (since citrate is metabolized into HC O - 3) Half-isotonic saline should also be avoided, because it is a hypotonic solution that will further lower the plasma Na + concentration 23-2 The hyponatremia in this patient is due to volume depletion, probably induced by diuretic therapy for hypertension The physical findings suggestive of hypovolemia, hypokalemia, and high plasma HC O - concentration are all compatible with this diagnosis Pseudohyponatremia due to mannitol is not present, since the measured P osm is low and is similar to the calculated value [C alculated P osm = 2× 120+(125/18) + (15/2.8) = 252 mosmol/kg] SIADH due to the stroke also cannot account for the hyponatremia; the hyponatremia must have preceded the stroke, since the patient subsequently received only 100 mL of water, a quantity that is insufficient to lower the plasma Na + concentration 23-3 (b) This edematous patient is both water- and sodium-overloaded, and should be treated with both water and sodium restriction (f) The combination of marked hyponatremia and a very concentrated urine should be treated with hypertonic saline plus a loop diuretic (such as furosemide) to lower the Uosm (d) True volume depletion with mild hyponatremia is best treated with isotonic saline (c) No therapy is required for pseudohyponatremia (normal P osm) (b) This edematous patient, like the one with renal failure, is both water- and sodium-overloaded (a or e) Either water restriction alone or the use of hypertonic saline is reasonable in this patient with presumed SIADH and asymptomatic hyponatremia A loop diuretic is not necessary, since the Uosm is only 290 mosmol/kg 23-4 a The most likely diagnosis is SIADH due to the oat cell carcinoma b Hypertonic saline should be given initially in view of the marked hyponatremia and neurologic symptoms The approximate Na + deficit that must be corrected to raise the plasma Na + concentration to a safe value of 120 meq/L can be estimated from This requires approximately 1200 mL of 3% saline, which should be given at the rate of 40 mL/h over 30 h to raise the plasma Na + concentration by 0.5 meq/L/h Furosemide will enhance the efficacy of this regimen by lowering Uosm, thereby increasing free-water excretion 23-5 Volume depletion increases the proximal reabsorption of Na + and secondarily that of uric acid (see page 90) The result is an increase in the plasma uric acid concentration In comparison, SIADH is associated with initial volume expansion, thereby increasing Na + and uric acid excretion Thus, the plasma uric acid concentration is typically below mg/dL in this disorder.7 CHAPTER 24 24-1 a Polydipsia and polyuria with a dilute urine is due either to primary polydipsia or to central or nephrogenic diabetes insipidus Sarcoidosis can produce each of these conditions: the first two by hypothalamic infiltration and nephrogenic diabetes insipidus by hypercalcemia.8 The only clue to the correct diagnosis is the low plasma Na + concentration and P osm, suggesting water overload due to primary polydipsia b The diagnosis can be established by the water-restriction test followed by the administration of dDAVP or aqueous vasopressin after the maximum Uosm has been achieved or the P osm reaches 295 mosmol/kg 24-2 (b and e) Insensible water losses that were not replaced as a result of decreased thirst were the major factors responsible for the hypernatremia in this patient The diarrhea also may have made a contribution, if it was an osmotic diarrhea in which the (Na + +K + ) concentration in the diarrheal fluid was less than that in the plasma (see page 293) In this setting, water would be lost in excess of effective solute (thereby promoting the development of hypernatremia), even though the diarrheal fluid was isosmotic to plasma The low urine Na + concentration in this patient is indicative of volume depletion There is no predictable relationship between the plasma Na + concentration (a measure of osmolality) and the urine Na + concentration (which varies with the effective circulating volume) (d) The water deficit can be approximated from This deficit should be repaired gradually over 68 h (34 meq/L reduction in the plasma Na + concentration at a rate of 0.5 meq/L per h); thus, fluid should be given at the approximate rate of 75 mL/h C ontinuing insensible losses of 40 mL/h must also be replaced, leading to a total of 115 mL/h of free water In addition, this patient is also Na + -depleted from diuretic therapy and diarrhea Thus, initial fluid therapy should probably be given as quarter-isotonic saline This fluid, however, is only three-quarters free water Therefore, 150 mL/h [(4/3)× 115] must be given to provide the necessary free water 24-3 a The diagnosis of central diabetes insipidus can be confirmed by the administration of dDAVP or aqueous vasopressin, which should raise the Uosm and lower the urine volume There is no need to the water-restriction test, since the P osm is already 350 mosmol/kg b The water deficit can be estimated from c This deficit should be replaced gradually over 56 h at the rate of 125 mL/h Another 50 mL/h should be added to replace continuing insensible losses Thus, 175 mL/h can be given as dextrose in water There is no history of Na + loss and therefore no requirement for saline administration d The late development of hyponatremia is probably due to SIADH The administration of vasopressin tannate in oil results in nonsuppressible plasma ADH levels, which can lead to water retention if too much water is taken in CHAPTER 25 25-1 a The patient has both diabetic ketoacidosis and a superimposed metabolic alkalosis due to vomiting Notice that the anion gap is 28 meq/L (16 meq/L above normal), which should be associated with a reduction in the plasma HC O - concentration to about 10 meq/L The substantially high value in this case is indicative of the underlying metabolic alkalosis b Dehydration undoubtedly is responsible for much of the decline in renal function In addition, acetoacetate is measured as creatinine in the standard assay, resulting in a further apparent elevation in the plasma creatinine concentration c The major electrolyte problems in this patient are hypokalemia and volume depletion The hyperglycemia and metabolic acidosis are relatively mild; immediate correction of these disturbances with insulin is not necessary and may be deleterious by driving K + into the cells, possibly inducing arrhythmias Thus, the initial therapy should consist of isotonic or half-isotonic saline to which 40 meq/L of KC l is added This regimen will correct the hypokalemia and volume depletion and will slowly ameliorate the hyperglycemia, both by dilution and by improving renal function, thereby enhancing glucose excretion The patient should also be started on antimicorbial therapy for presumed acute pyelonephritis This infection was probably responsible for the loss of diabetic control 25-2 a The acidemia is due to retention of H+ ions from the ketoacids; the associated anions (β -hydroxybutyrate and acetoacetate) were presumably excreted in the urine, resulting in only a minor elevation in the anion gap b The patient should be given insulin with glucose This will correct the ketoacidosis without the risk of hypoglycemia CHAPTER 26 26-1 a C orrection of the acidemia will drive K + into the cells, further reducing the plasma K + concentration In this setting, in which the acidemia is not severe, alkali therapy should be withheld until K + supplements have partially corrected the hypokalemia b Hypocalcemia protects against the effects of hypokalemia via an uncertain mechanism Thus, treatment of the hypokalemia should precede correction of the hypocalcemia It should be noted that, for the same reasons, hypokalemia protects against the neuromuscular effects of hypocalcemia Thus, increasing the plasma K + concentration in this setting may precipitate hypocalcemic tetany.9 However, this risk is generally less serious than the potentially fatal cardiac arrhythmias that can be induced by severe hypokalemia CHAPTER 27 27-1 a The differential diagnosis of unexplained hypokalemia, urinary K + wasting, and metabolic alkalosis includes surreptitious diuretic use or vomiting (during the phase of HC O - excretion in which both Na + and K + excretion are increased; see page 566) or some form of primary hyperaldosteronism The normal blood pressure in this patient excludes all of the causes of the last condition other than Bartter's syndrome b These disorders can be distinguished by viewing this as a diagnostic problem of metabolic alkalosis and measuring the urine C lconcentration (see C hap 18) A value below 25 meq/L is highly suggestive of vomiting (which was present in this case), whereas a higher value is consistent with diuretic use or Bartter's syndrome The last two conditions can usually be distinguished by a urinary assay for diuretics 27-2 a The low Uosm is consistent with primary water overload, which shuts off ADH secretion Although the urine K + concentration is appropriately reduced, the urine volume is probably very high, resulting in an inappropriately high absolute level of K + excretion b The major clue suggesting hypomagnesemia is the presence of hypocalcemia c Metabolic acidosis with a high urine pH and positive urine anion gap (see C hap 19) is diagnostic of renal tubular acidosis d Metabolic acidosis with a normally acid urine pH, an appropriately negative urine anion gap (reflecting the adaptive increase in NH+ excretion), and a low urine K + concentration is compatible with extrarenal losses of K + and HC O - 3, as occurs with laxative abuse CHAPTER 28 28-1 a The underlying renal insufficiency, superimposed volume depletion (due to Na + wasting after the acute institution of a low-Na + diet), and metabolic acidosis all may play a contributory role However, many patients have these problems without lifethreatening hyperkalemia Therefore, the patient should be questioned about increased K + intake; this patient gave a history of using large quantities of KC l-containing salt substitute b By definition, pseudohyperkalemia produces no symptoms or signs of K + intoxication c The patient has both severe muscle weakness and electrocardiographic changes Therefore, therapy should be initiated with calcium gluconate, followed by glucose, insulin, and NaHC O to temporarily drive K + into the cells For example 500 mL of 10% dextrose in saline plus 10 units of regular insulin plus 45 meq of NaHC O infused over 30 will lower the plasma K + concentration, raise the plasma Na + concentration, and produce volume expansion Sodium polystyrene sulfonate should be given orally and repeated as necessary to remove the excess K + Dialysis should not be required, since the patient does not have severe renal failure d Mild asymptomatic hyperkalemia can be treated solely with sodium polystyrene sulfonate 28-2 a By definition, patients with chronic hyperkalemic have a defect in renal K + excretion, since normal subjects would rapidly excrete the excess K + in the urine Thus, the urine K + concentration of 34 meq/L is inappropriately low The transtubular K + gradient (TTKG) can be calculated in this patient to assess the degree of aldosterone effect: where 275 represents the calculated P osm The TTKG is low in this patient, a finding that is consistent with some form of mineralocorticoid deficiency or resistance b The findings of low blood pressure, increased skin pigmentation, a low TTKG, and hypoglycemia after the administration of glucose and insulin all point to the probable diagnosis of primary adrenal insufficiency c Acutely, sodium polystyrene sulfonate can be given to lower the plasma K + concentration C hronically, both glucocorticoid and mineralocorticoid replacement will be required because of the persistent adrenal dysfunction REFERENCES Jacobsen HR, Klahr S C hronic renal failure: Pathophysiology; management Lancet 338:419, 423, 1991 Epstein FH, Kleeman C R, Pursel S, Hendrikx A The effect of feeding protein and urea on the renal concentrating process J Clin Invest 36:635, 1957 Vaughan ED Jr, C arey RM, Peach MJ, et al The renin response to diuretic therapy: A limitation of antihypertensive potential Circ Res 42:376, 1978 DeSousa RC , Harrington JT, Ricanati ES, et al Renal regulation of acid-base equilibrium during administration of mineral acid J Clin Invest 53:465, 1974 George JM, Wright L, Bell NH, Bartter FC The syndrome of primary aldosteronism Am J Med 48:343, 1970 Hariprasad MK, Eisinger RP, Nadler IM, et al Hyponatremia in psychogenic polydipsia Arch Intern Med 140:1639, 1980 Beck LH Hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone N Engl J Med 301:528, 1979 Stuart C A, Neelon FA, Lebovitz HE Disordered control of thirst in hypothalamic-pituitary sarcoidosis N Engl J Med 303:1078, 1980 Engel FL, Martin SP, Taylor H On the relation of potassium to the neurologic manifestations of hypocalcemic tetany Bull Johns Hopkins Hosp 84:295, 1949 Editors: Rose, Burton David; Post, Theodore W Title: Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th Edition C opyright ©2001 McGraw-Hill > Table of Contents > Part Three - Physiologic Approach to Acid-Base and Electroltye Disorders > Chapter Thirty - Summary of equations and formulas Chapter Thirty Summary of equations and formulas UNITS OF MEASUREMENT where n=number of dissociable particles per molecules TUBULAR FUNCTION Variations in tubular reabsorption are the major way in which the kidneys alter solute and water excretion There are, however, no absolute normal values for the urine Na + or K + concentration, osmolality, or pH, since these parameters vary with intake For example, the urine Na + concentration should be less than 10 to 15 meq/L with volume depletion but may exceed 100 meq/L after a Na + load Similarly, the Uosm may fall below 100 mosmol/kg after a large water load but should exceed 800 mosmol/kg after water restriction has led to a rise in the plasma Na + concentration above 145 meq/L Thus, a Uosm of 300 mosmol/kg is inappropriately low in the latter setting, suggesting either lack of or resistance to antidiuretic hormone ACID-BASE Conversion of pH into Hydrogen Concentration For each 0.1-unit increase in pH, multiple [H+ ] by 0.8: pH of 7.60 = 40× 0.8×0.8 [H+ ] = 26 nanoeq/L For each 0.1 unit fall in pH, multiply [H+ ] by 1.25: pH of 7.30 =40×1.25 [H+ ] = 50 nanoeq/L Renal and Respiratory Compensations in Acid-Base Disorders Metabolic acidosis: 1.2-mmHg fall in P CO2 per 1-meq/L decrease in plasma [HC O - 3] Metabolic alkalosis: 0.6-mmHg rise in P CO2 per 1-meq/L elevation in plasma [HC O - 3] Respiratory acidosis: Acute: 1-meq/L increase in plasma [HC O - 3] per 10-mmHg rise in P CO2 C hronic: 3.5-meq/L elevation in plasma [HC O - 3] per 10-mmHg increase in P CO2 Respiratory alkalosis: Acute: 2-meq/L fall in plasma [HC O - 3] per 10-mmHg decrease in P CO2 C hronic: 4-meq/L reduction in plasma [HC O - 3] per 10-mmHg fall in P CO2 Estimation of Bicarbonate Deficit and Excess In severe metabolic acidosis with a plasma HC O - concentration below 10 meq/L: HC O - deficit (meq) [congruent] 0.7×lean body weight (kg)× (10-plasma [HC O - 3]) This formula applies only when the plasma HC O - concentration is very low and the cell and bone buffers are responsible for almost all buffering of excess H+ ions Once the plasma HC O - concentration is above 10 meq/L, however, there is more extracellular buffering and the apparent space of distribution of HC O - falls to 0.5 times the lean body weight In metabolic alkalosis OSMOLALITY AND THE PLASMA SODIUM CONCENTRATION Plasma Sodium Concentration in Hyperglycemia For each 62-mg/dL increment in the plasma glucose concentration, there will be a reciprocal 1-meq/L reduction in the plasma Na + concentration because of the osmotic movement of water from the cells into the extracellular fluid Thus, hyperglycemia results in a dissociation between the P osm (which is increased) and the plasma Na + concentration (which may be reduced) Hyponatremia This formula estimates the amount of Na + required to raise the plasma Na + concentration back up to 140 meq/L It may not represent the total Na + deficit, however, since there may be an additional isosmotic Na + and water loss (due, for example, to diuretics or diarrhea) Hypernatremia MISCELLANEOUS Alveolar-Arterial Oxygen Gradient Plasma Calcium Concentration and Hypoalbuminemia For every 1-g/dL fall in the plasma albumin concentration, there will be less bound C a 2+ leading to an 0.8 mg/dL reduction in the plasma C a 2+ concentration This does not represent true hypocalcemia, however, since there is no change in the physiologically important free (or ionized) C a 2+ concentration ... Title: Clinical Physiology of Acid- Base and Electrolyte Disorders, 5th Edition C opyright 20 01 McGraw-Hill > Table of Contents > Part Three - Physiologic Approach to Acid- Base and Electroltye Disorders. .. Thiazide-sensitive Na + entry in the distal nephron is mediated by neutral Na + -C l- cotransport.3 ,26 Both a Na + -C l- cotransporter27 ,28 and 29 and, to a lesser degree, parallel Na + -H+ and C l-... Henderson-Hasselbalch equation (see C hap 10): Editors: Rose, Burton David; Post, Theodore W Title: Clinical Physiology of Acid- Base and Electrolyte Disorders, 5th Edition C opyright 20 01 McGraw-Hill