Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

PART ONE – Basic Principles in Pediatric Anesthesia

Chapter 4 – Regulation of Fluids and Electrolytes in Infants and Children

Demetrius Ellis



Overview of Anatomy and Physiology, 109



Anatomy, 109



Renal Blood Flow, 109



Renal Physiology, 110



Glomerular Filtration, 110



Overview of Tubular Function, 112



Kidney and Antidiuretic Hormone, 113



Renin-Angiotensin-Aldosterone System,114



Kidney and Atrial Natriuretic Peptide, 115



Body Fluid Compartments, 115



Maturation of Renal Function, 117



Fluid and Electrolyte Needs in Healthy Infants and Children, 118



Parenteral and Oral Fluids and Electrolytes,118



Dehydration in Infants and Children, 119



Assessment of Dehydration,119



Treatment of Dehydration, 119



Perioperative Parenteral Guidelines of Fluids and Electrolytes, 120



Perioperative Fluid Management of Premature and Term Neonates,121



Fluid Management of Children Undergoing Renal Transplantation,123



Disorders of Sodium Metabolism, 124



Hyponatremia, 124



Hypernatremia, 126



Disorders of Potassium Metabolism, 128



Potassium Homeostasis,128



Hypokalemia, 129



Hyperkalemia, 132



Diuretic Therapy, 135



Classification of Diuretics and Site of Action,135



Anesthetic Agents and the Kidney, 137



Disorders of Divalent Ion Metabolism, 138



Calcium, 138



Magnesium, 142



Phosphorus, 144



Summary, 148

Concentrations of minerals and electrolytes in extracellular fluid (ECF) are maintained nearly constant despite large day-to-day variations in the dietary intake of salt and water. Such homeostasis is governed primarily by the kidneys through an array of intricate processes that may be influenced by intrarenal and extrarenal vasoactive substances and hormones. Although the basic tenants governing nephron function and homeostasis of body fluid composition have changed little over the past decade, major advances stemming from genetic research have greatly elucidated the structure and function of many renal tubular electrolyte transporters in both health and disease. A major objective of the present treatise is to enhance the understanding of electrolyte (and fluid) pathophysiology based on such newer information.



The kidneys are retroperitoneal paired organs located on each side of the vertebral column. A normal adult kidney measures 11 to 12 cm in length, 5 to 7.5 cm in width, and 2.5 to 3.0 cm in thickness. In the adult male it weighs 125 to 170 g, and in the adult female, it weighs 115 to 155 g. Beneath its fibrous capsule lies the cortex, which contains the glomeruli, the convoluted proximal tubules, the distal tubules, and the early portions of the collecting tubules. The remainder of the tissue, the medulla, contains the pars recta, the loop of Henle, and the middle and distal portions of the collecting duct. The inner medulla borders the renal pelvis, where urine is received from the collecting ducts. The ducts and loops are arranged into cone-shaped bundles called pyramids, whose tips project into the renal pelvis and form papillae. The pelvis drains into the ureter, which in the adult human descends a distance of 28 to 34 cm to open into the fundus of the bladder. The walls of the pelvis and ureters contain smooth muscles that contract in a peristaltic manner to propel urine to the bladder.


Despite accounting for only 0.5% of body weight, the kidneys receive about 25% of the cardiac output with a blood flow of approximately 4 mL/min per g of kidney tissue. Renal plasma flow (RPF) in women is slightly lower than in men, even when normalized for body surface area, averaging 592 ± 153 mL/min per 1.73 m2 and 654 ± 163 mL/min per 1.73 m2, respectively ( Smith, 1943 ). In children between the ages of 6 months and 1 year, normalized RPF is half that of adults but increases progressively to reach adult levels at about 3 years of age ( McCrory, 1972 ). After the age of 30 years, renal blood flow (RBF) decreases progressively; by the age of 90 years, it is approximately half of the value present at 20 years ( Davies et al., 1950 ). This generous supply provides not only for the basal metabolic needs of the kidneys but also for the high demands of ultrafiltration.

The basic arterial supply of the kidney is a single renal artery that divides into large anterior and posterior branches and subsequently into segmental or interlobar arteries. The latter form the arcuate and interlobular arteries. These blood vessels are end-arteries and therefore predisposed to tissue infarction in the presence of emboli. The arcuate arteries are short, large-caliber vessels supplying blood to the afferent arterioles of the glomeruli at a mean pressure of 45 mm Hg, which is higher than that found in most capillary beds. This high hydraulic pressure and large endothelial pore size lead to enhanced glomerular filtration ( Brenner et al., 1978 ).

Glomerular capillaries have many anastomoses but recombine to form the efferent arteriole. The latter subdivide into an extensive peritubular capillary network. This arrangement allows solute and water to move between the tubular lumen and blood. These networks rejoin to form the venous channels by which blood exits the kidney.

Ninety percent of RBF goes to the cortex, which accounts for 75% of the renal weight, whereas the medulla and the rest of the kidney receive 25% of the RBF. Although cortical blood flow is 5 to 6 mL/g per min, outer medullary blood flow decreases to 1.3 to 2.3 mL/g per min, and the flow to the papilla is as low as 0.22 to 0.42 mL/g per min ( Dorkin et al., 1991 ). The unevenness in the distribution of RBF between the cortex and the medulla is necessary to develop and maintain the medullary gradient of osmotically active solutes that drive the countercurrent exchange/multiplier, which is essential for the elaboration of concentrated urine. Outer medullary blood flow may preferentially supply Henle's loop, thereby accounting for the striking influence of loop diuretics in that region. Furthermore, papillary blood flow is far greater than the metabolic needs of the renal parenchyma and is well adapted to the countercurrent concentrating mechanism characteristic of this region.

RBF remains almost constant over a range of systolic blood pressures from 80 to 180 mm Hg, a phenomenon known as autoregulation. Consequently, glomerular filtration is also constant over this range of pressures ( Selkurt et al., 1949 ) as a result of adaptations in the renal vascular resistance ( Gertz et al., 1966 ). Because the changes in resistance that accompany graded reductions in renal perfusion pressure occur in both denervated and isolated perfused kidneys ( Thurau, 1964 ), autoregulation appears not to depend on extrinsic neural or hormonal factors. According to the “myogenic hypothesis,” first proposed by Bayliss (1902) , the stimulus for vascular smooth muscle contraction in response to increasing intraluminal pressure is either the transmural pressure itself or the increase in the tension of the vascular wall. An increase in perfusion pressure, which initially distends the vascular wall, is followed by a contraction of the resistance vessels and a return of blood flow to basal levels.

There are only a few studies of autoregulation of RBF in developing animals. Aortic constriction in adult animals reduces renal perfusion by 30% but has minimal effects on RBF and glomerular filtration rate, compared with the significant changes observed in 4- to 5-week-old rats ( Yared and Yoskioka, 1989 ). Furthermore, it has been demonstrated that autoregulation of RBF in young rats occurs at renal perfusion pressures between 70 and 100 mm Hg, compared with pressures of 100 to 130 mm Hg in the adult ( Chevalier and Kaiser, 1985 ). A similar increase in the pressure set point for autoregulation has been found in dogs ( Jose et al., 1975 ). It appears that autoregulation of RBF occurs in the very young and is sufficient to maintain blood flow constant over a wide range of perfusion pressures that are physiologically adequate for the age. No such human studies are available.

Several substances have been proposed to participate in the autoregulation of RBF, including vasoconstrictor and vasodilator prostaglandins ( Herbacznska-Cedro and Vane, 1973 ), kinins ( Maier et al., 1981 ), adenosine, vasopressin ( Osswald et al., 1978 ), the renin-angiotensin-aldosterone system ( Schnermann et al., 1984 ), endothelin, and endopeptidases. Nitric oxide (NO), previously known as endothelium-derived relaxing factor (EDRF), has also been shown to play an important role in regulating renal vascular tone, through its vasodilatory action. Bradykinin, thrombin, histamine, serotonin, and acetylcholine act on endothelial receptors to activate phospholipase C, which in turn results in the formation of inositol triphosphate and diacylglycerol, resulting in the release of intracellular calcium (Marsden and Brenner, 1991 ; Luscher et al., 1992 ). This, in turn, stimulates the synthesis of NO from L-arginine. Other factors that stimulate the formation of NO include hypoxia, calcium ionophores, and mechanical stimuli to the endothelium. NO increases RBF by decreasing efferent arteriolar vascular resistance, while glomerular filtration remains unchanged ( Marsden and Brenner, 1991 ).

Because in the mature kidney autoregulation is lost at arterial pressures less than 80 mm Hg, the lower physiologic pressures prevailing in the newborn period may be expected to limit this important control mechanism. There is evidence both to support ( Kleinman and Lubbe, 1972 ) and to refute ( Jose et al., 1975 ) this conclusion.


The glomerulus is a specialized capillary cluster arranged in loops that functions as a filtering unit. The capillary walls may be viewed as a basement membrane lined by a single layer of cells on either side. In contact with blood are endothelial cells, which contain many fenestrations, whereas podocytes, with their foot processes, line the other side of the basement membrane.

The route by which water and other solutes are filtered from the blood is not fully understood, but it appears that plasma ultrafiltrate traverses the large fenestrations of the glomerular capillary endothelium and penetrates the basement membrane and the slit pores located between the podocyte foot processes. Filtration of large molecules is greatly influenced by the size and charge of the specific molecule, as well as by the integrity and charge of the glomerular basement membrane. Abnormalities in various structural proteins of the slit pore diaphragm such as nephrin, podocin, and α-actinin may be responsible for several proteinuric disorders ( Mundel and Shankland, 2002 ). In general, the endothelium and the lamina rara interna of the glomerular basement membrane slow the filtration of circulating polyanions such as albumin ( Ryan and Karnovsky, 1976 ), and the lamina rara externa and the slit pores slow the filtration of cationic macromolecules such as lactoperoxidase ( Graham and Kellermeyer, 1968 ). Neutral polymers such as ferritin are not filtered because of their large molecular size and shape ( Farauhar et al., 1961 ). Molecules with a radius of 4.2 nm or more are excluded from the glomerular filtrate. In practical terms, red cells, white cells, platelets, and most proteins are restricted to the circulation.


Among the main functions performed by the kidney is the process of glomerular filtration. The glomerulus is primarily responsible for the filtration of plasma. The glomerular filtration rate (GFR) is the product of the filtration rate in a single nephron and the number of such nephrons, which range from 0.7 to 1.4 million in each kidney ( Keller et al., 2003 ). Clearance, which is defined as the volume of plasma cleared of a substance within a given time, provides only an estimate or approximation of GFR.

Although tubular reabsorption and tubular secretion may influence the blood level of numerous medications and endogenously produced substances such as urea, creatinine, and uric acid, the degree of elimination of such substances depends largely on GFR. Hence, in individuals with renal impairment, estimation or measurement of GFR is crucial in determining the dosage adjustment and choice of medications needed to achieve effectiveness while avoiding toxicity. GFR is also a major factor that affects electrolyte composition and volume of body fluids, as well as acid-base homeostasis.

Glomerular filtration is driven by hydrostatic pressure, which forces water and small solutes across the filtration barrier. In healthy individuals, changes in hydrostatic pressure rarely affect single-nephron GFR because autoregulatory mechanisms sustain or maintain a constant glomerular capillary pressure over a large range of systemic blood pressure ( Robertson et al., 1972 ). Hydrostatic pressure is opposed by the oncotic pressure produced by plasma proteins and the hydrostatic pressure within Bowman's capsule. Mathematically, this relation can be expressed by the following equation:

where SNGFR is the single-nephron glomerular filtration rate; K f is the glomerular ultrafiltration coefficient; P and p are the average hydraulic and osmotic pressure differences, respectively; and PUF is the net ultrafiltration pressure. As plasma water is filtered, the proteins within the capillaries become more concentrated, so oncotic pressure increases at the distal end of the glomerular capillary loop and the rate of filtration ceases at the efferent capillary ( Blantz, 1977 ). Under normal conditions, about 20% of the plasma water that enters the glomerular capillary bed is filtered; this quantity is referred to as the filtration fraction.

Renal blood flow (RBF) has the greatest influence on GFR. Renal parenchymal disorders interfere with autoregulation of RBF such that GFR may fall even with low normal mean arterial blood pressure (MABP). Still more pronounced changes in GFR may occur with hypotension or hypertension, which may accelerate ischemic or hypertensive injury.

Clearance of a molecule may serve as an indicator of GFR only if the assayed molecule is biologically inert and freely permeable across the glomerular capillary, if it remains unchanged after filtration, and if it is neither reabsorbed nor secreted by the tubule. The exogenous filtration marker inulin (a fructose polymer) has all of these attributes and is the ideal, or “gold standard,” for measuring GFR. However, inulin clearance measurement is rarely used clinically because it is an expensive and cumbersome method. Instead, measurement of an endogenous small molecule such as serum creatinine (molecular weight, 0.113 kDa), which is derived from muscle metabolism at a relatively constant rate and is freely filtered at the glomerulus, is a practical, rapid, and inexpensive means for estimating GFR, and thereby aiding clinical decisions. Thus, in the steady state, creatinine production and urinary creatinine excretion are equal even when GFR is reduced.

Serum creatinine concentrations vary by age and gender. In 1-year-old girls values are 0.35 ± 0.05 mg/dL (mean ± SD) and rise gradually to 0.7 ± 0.02 mg/dL (mean ± SD) by 17 years of age; boys have corresponding mean values that are 0.05 mg/dL higher until 15 years of age and 0.1 mg/dL higher subsequently (Schwartz et al., 1976). Expected creatinine excretion rates in 24-hour urine collections are often used to validate such collections. Values range from 8 to 14 mg/kg per day in neonates and up to 1 year of age, with an increase to about 22 ± 7 mg/kg per day (mean ± SD) in preadolescent children of either gender ( Hellerstein et al., 2001 ). Subsequently, creatinine excretion in boys is 27 ± 3.4 mg/kg per day.

In healthy children with proportional height and weight, GFR can be estimated by creatinine clearance (CrCl) as calculated by the Schwartz formula, which does not rely on measurement of urinary creatinine or timed urine collections:

where height is in centimeters, PCR is the plasma creatinine concentration in mg/dL, and k is a constant proportion to muscle mass. The value of k is 0.45 in full-term newborns and until 1 year of age, 0.55 in children 2 years of age and older and in adolescent girls, and 0.70 in adolescent boys ( Schwartz et al., 1987 ). Normal CrCl ranges from 90 to 143 mL/min per 1.73 m2, with a mean of 120 mL/min per 1.73 m2.

Although more cumbersome, calculation of CrCl based on values obtained in 12- or 24-hour urine collections provide a better estimate of GFR. Once the completeness of such collections is validated based on expected creatinine excretion, CrCl is calculated using the following formula:

where U is the urinary concentration of creatinine in mg/dL, V is the total urine volume in mL, min is the time of collection in minutes, and PCr is the serum concentration of creatinine in mg/dL. To standardize the clearance of children of different sizes, the calculated result is multiplied by 1.73 m2 (surface area of a standard man in meters squared) and divided by the surface area (SA) of the child (in meters squared).

In children with impaired renal function, GFR estimates based on creatinine methods may grossly overestimate the true GFR because tubular and gastrointestinal secretion of creatinine increases disproportionately and, hence, serum creatinine concentrations are less reflective of filtration at the glomerulus. For example, Schwartz formulas overestimate GFR by 10% ± 3% when GFR is greater than 50 mL/min per 1.73 m2 but by 90% ± 15% when GFR is less than 50 mL/min per 1.73 m2. Other limitations of creatinine-based GFR determinations stem from variation of analytical assays, reference values ranging from 0.1 to 0.6 mg/dL in children under 9 years of age, diurnal variation in serum creatinine levels due to high intake of cooked meat or intense exercise, influence of body mass index, and inaccurate urine collections all of which make comparisons of GFR difficult over time, especially in growing children ( Levey et al., 1988 ). Use of cimetidine to block tubular secretion of creatinine prior to measuring CrCl in urine collections may improve such measurements ( Hellerstein et al., 1998 ).

Measurement of cystatin-C, a 13-kDa serine proteinase produced at a constant rate by all nucleated cells, is purported to be a superior endogenous marker of filtration because cystatin-C is less susceptible to variation than is plasma creatinine. A meta-analysis compared the correlation between GFR measured by inulin clearance, radiolabeled methods, nonlabeled iothalamate or iohexol and either plasma creatinine, or cystatin-C concentrations measured nephelometrically ( Dharnidharka et al., 2002 ). The correlation between GFR and cystatin-C was significantly higher compared with plasma creatinine (0.846 versus 0.742, P < 0.001). Thus, cystatin-C measurements are becoming increasingly popular in clinical practice and reference ranges have been generated in children up to 16 years of age (Bokenkamp et al., 1998 ; Finney et al., 2000 ; Harmoinen et al., 2000) ( Table 4-1 ).

TABLE 4-1   -- Nonparametric 95% reference intervals for cystatin C in different age groups






Age Group


Reference Interval

Lower Limit

Upper Limit


Preterm infants


1.34 to 2.57

1.07 to 1.42

2.47 to 2.86


Full-term infants


1.36 to 2.23

1.24 to 1.44

2.03 to 2.32


>8 days to 1 yr


0.75 to 1.87

0.71 to 0.86

1.78 to 1.91


>1 to 3 yr


0.68 to 1.60

0.65 to 0.79

1.39 to 1.67


>3 to 16 yr


0.51 to 1.31

0.48 to 0.68

1.26 to 1.35

Modified from Harmoinen A, Ylinen E, Ala-Houhala M, et al.: Reference intervals for cystatin C in pre- and full-term infants and children. Pediatr Nephrol 15:105–108, 2000, p 107, Table 1. (With kind permission of Springer Science and Business Media.)


Statistical significance versus the oldest group (including Bonferroni's correction factor 5).



Studies in renal transplant donors and in individuals with various renal disorders have shown that plasma creatinine concentration changes minimally as GFR falls to about 50 mL/min per 1.73 m2(Shemesh, 1985) ( Fig. 4-1 ). This compensation is largely due to hypertrophy and hyperfiltration of the remaining nephrons. When more than 50% of the nephrons cease to function and “renal reserve” is outstripped, serum creatinine may rise rapidly in a parabolic fashion (see Fig. 4-1 ). Thus, when a more accurate clinical assessment of GFR is desirable for research purposes, radiolabeled methods with an identity exceeding 97% give a better approximation of GFR relative to inulin clearance and may be more useful in aiding clinical decisions. In multicenter investigations conducted in the United States using a uniform method for GFR measurement, 125I-iothalamate is frequently used because this isotope has low radiation exposure and long isotope half-life and can be assayed at a central laboratory (Bajaj et al., 1996 ). Otherwise, 99mTc-diethylenetriaminepenta-acetic acid (Tc-DTPA) is frequently used to estimate GFR for routine clinical purposes. In other countries, 51Cr-ethylenediaminetetra-acetic acid (Cr-EDTA), which delivers a greater radiation dosage, is also popular as are nonlabeled iothalamate and iohexol methods.


FIGURE 4-1  Relationship of serum creatinine to GFR.  (From Shemesh O, Golbetz H, Kriss JP, et al.: Limitation of creatinine as a filtration marker in glomerulopathic patients. Kidney Int 28:830, 1985, Figure 1-3.)




Although GFR may fluctuate, the kidney retains the ability to regulate the rate of solute and water excretion according to changes in intake. This regulation is achieved by changes in tubular reabsorption rates—a phenomenon known as glomerular-tubular balance (Tucker and Blantz, 1977 ). The end result is preservation of ECF volume and chemical composition. Glomerular-tubular balance can be disturbed by several factors, including volume expansion, loop diuretics, and inappropriate secretion of antidiuretic hormone (ADH).


The proximal tubule is the site of reabsorption of large quantities of solute and filtered fluid ( Fig. 4-2 ). Many transporters subserving tubular electrolyte transport have been characterized at the genetic level, and various pathologic disorders have been elucidated ( Epstein, 1999 ). Under physiologic conditions, the proximal convoluted tubule isotonically reabsorbs 50% to 60% of the glomerular filtrate (Berry and Rector, 1991 ). The initial portion of the proximal convoluted tubule reabsorbs most of the filtered glucose, amino acids, and bicarbonate. Glucose and amino acids are absorbed actively, whereby they are transported against their electrochemical gradient, coupled to sodium (Na+). Active Na+ transport at the peritubular membrane provides the driving force that ultimately is responsible for other transport processes. The system is driven by sodium, potassium (Na+, K+) (activated) adenosine triphosphatase (Na+,K+-ATPase) or Na+ “pump,” which requires the presence of potassium (K+) in the peritubular fluid and is inhibited by ouabain. Micropuncture studies show that around 50% to 70% of the filtered Na+ is reabsorbed in this segment, mostly by a process of active cotransport.


FIGURE 4-2  Sodium and water handling by the nephron. A, Glomerulus. B, Proximal tubule, the major site for the reabsorption of Na+ (70%), Cl-, K+ (80%), HCO3- (80% to 90%), and water. The reabsorptive process is isomotic, regardless of whether the kidney is concentrating or diluting urine. C, Thin descending loop of Henle. D, Thick ascending loop of Henle. It is always impermeable to water. The medullary portion is important for the generation of free water. There is active Na+, K+, and Cl- (20% to 25%) reabsorption, which is responsible for driving the countercurrent multiplier and creating increased medullary tonicity. The cortical thick ascending limb and the early distal tubule (E) are responsible for the reabsorption of the remaining HCO3-, to as well as 5% of the filtered Na+ and Cl-. These segments are impermeable to water and are unaffected by ADH. In the late distal tubule and the cortical collecting duct (F), aldosterone action controls Na+ and K+ reabsorption and excretion. The medullary portion of the collecting duct is the major site for ADH-dependent water reabsorption. This segment is permeable to water in the presence of ADH. The vasa recta (G) is important in maintaining a concentrated medullary interstitium.



The major fraction of filtered bicarbonate (HCO3-) is absorbed early in the proximal convoluted tubule. Hydrogen (H+) gains access to luminal fluid via an Na+/H+ electroneutral exchange mechanism and forms carbonic acid. The latter is dehydrated to H2O and CO2 under the influence of carbonic anhydrase. CO2 diffuses into the cell, and HCO3- is re-formed and ultimately absorbed into the bloodstream. In general, the concentration of HCO3- is maintained at 26 mmol/L, which is slightly below the renal threshold of approximately 28 mmol/L ( Pitts and Lotspeich, 1946 ).

The renal clearance of glucose is exceedingly low even after complete maturation of glomerular filtration. The amount filtered increases linearly as plasma glucose increases. Initially, all fil-tered glucose is reabsorbed until the renal threshold has been exceeded (at around 180 mg/dL), at which point filtered glucose appears in the urine. However, maximal tubular glucose (TmG) reabsorption is attained at a filtrate glucose concentration of about 350 mg/mL ( Pitts, 1974 ). The reabsorption of glucose in the proximal tubule occurs via a carrier-mediated, Na+/glucose cotransport process across the apical membrane followed by passive facilitated diffusion and active Na+ extrusion across the basolateral membrane.

Apart from Na+, other solutes reabsorbed in the proximal tubule include K+, Ca2+, P2-, Mg2+, and amino acids. These are discussed in detail in other sections of this chapter.

The loop of Henle makes possible the formation of concentrated urine and contributes to the formation of dilute urine ( Kokko, 1979 ). This dual function is achieved through the unique membrane properties of the loop, the postglomerular capillaries, and the hypertonicity of the interstitium. The proximity of the descending and ascending portions of loop allows it to function as a countercurrent multiplier, whereas the capillaries serve as countercurrent exchangers (see Fig. 4-2 ). The descending loop of Henle abstracts water from tubular fluid, increasing the intraluminal concentrations of NaCl and other solutes. However, the intraluminal osmolality remains in equilibrium with the interstitium, where 50% of the osmolality results from urea. In the thin ascending limb of the loop of Henle, there is passive efflux of NaCl and urea into the interstitium. The thick ascending limb of the loop of Henle, by being impermeable to water, contributes to the formation of dilute urine.

The final creation of hypotonic or hypertonic urine depends on the distal tubules and collecting ducts and their interaction with ADH. In the distal convoluted tubule, Na+ reabsorption occurs against a steep gradient, largely under the influence of aldosterone. K+ is secreted by the distal tubule in association with Na+ reabsorption and H+ secretion. Moreover, this segment of the nephron acidifies the urine and is the only site of new bicarbonate formation. At the end of the collecting duct, about 1% of the filtered water and about 0.5% of the filtered Na+ appear in the final urine.


Antidiuretic hormone (ADH) plays a pivotal role in water homeostasis by acting on the most distal portion of the nephron. ADH is a cyclic octapeptide that, along with its carrier protein, neurophysin, is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus ( Zimmerman and Defendini, 1977 ). The prohormone migrates along the nerve axons to the posterior pituitary gland, where it is stored as arginine vasopressin. It is released through exocytosis ( Douglas, 1973 ).

Several variables affect ADH secretion. Physiologically, the most important factor is plasma osmolality. A very small rise in plasma osmolality is sufficient to trigger a response from the very sensitive osmoreceptors located in and around the hypothalamic nuclei leading to ADH secretion. Conversely, plasma ADH concentrations are less than 1 pg/mL at a physiologic plasma osmolality of less than 280 mOsm/kg water. The antidiuretic activity of ADH is maximal at plasma osmolality of greater than 295 mOsm/kg water, when plasma ADH exceeds 5 pg/mL ( Robertson, 2001 ). Once plasma osmolality exceeds this limit—thus surpassing the capacity of the ADH system to affect maximal fluid retention—the organism depends on thirst to defend against dehydration. Intracerebral synthesis of angiotensin II largely mediates this thirst response along with the oropharyngeal reflex. Atrial natriuretic peptide (ANP) opposes the release of ADH and of angiotensin II. In summary, plasma osmolality and Na+ are maintained within a narrow range. The upper limit of this range is determined by the sensitivity of the thirst mechanism located in the hypothalamus, whereas its lower range is affected by ADH release.

Nonosmolar factors also influence ADH secretion and may be key stimuli of ADH secretion in pathologic disorders leading to hypovolemia and hypotension. These changes are mediated by low pressure (located in the left atrium) and high-pressure (located in the carotid sinus) baroreceptors. Experimental studies suggest that this nonosmotic pathway of ADH release is less sensitive than the osmotic pathway and is triggered by a 5% to 10% fall in blood volume, whereas a 1% and 2% increase in ECF osmolality can trigger ADH release.

Nonhypovolemic conditions that stimulate ADH release often lead to diminished urine volume, hyponatremia, fractional excretion of uric acid greater than 10% and low serum uric acid level (<4 mg/dL), and urinary sodium greater than 20 mEq/L ( Albanese et al., 2001 ). These conditions result in hyponatremia. Conversely, inhibitors of ADH release or primary or acquired nephropathies may lead to an inability to respond to ADH and to conserve water and are often accompanied by polyuria with Uosm less than 150 mOsm/kg, dehydration, and hypernatremia.

ADH has a major effect on the medullary thick ascending limb and thereby influences the countercurrent multiplier mechanism and urinary concentration. More directly, ADH binds to V2 receptors in the basolateral membrane of the collecting duct leading to activation of adenylate cyclase and the formation of cyclic 3′,5′-adenosine monophosphate (cAMP) ( Dorisa and Valtin, 1976 ; Schwartz et al., 1974 ). This results in insertion of aquaporin-2 water channels in apical membranes and in activation of apical Na+ channels leading to water conservation ( Andreoli 2001 ). These effects are counterbalanced by prostaglandin E2 (PGE2) and the calcium-sensing receptor in cells of the medullary thick ascending limb that mediate saluresis and diuresis.

Polyuric syndromes can be separated on the basis of urine osmolality and generally consist of water diuresis, solute diuresis, or a mixed water-solute diuresis with typical Uosm of less than 150 mOsm/kg, 300 to 500 mOsm/kg, and 150 to 300 mOsm/kg, respectively (Oster et al., 1997). The etiology of polyuria ( Table 4-2 ) may be facilitated by obtaining a urinalysis, urine pH, and measurement of electrolytes, creatinine, osmolality, glucose, urea nitrogen, and bicarbonate, preferably in a timed urine collection together with the corresponding serum values. Such assessment may serve to prevent dehydration, acid-base disturbances, hypokalemia, or hypernatremia, which often accompany such polyuric disorders (Oster et al., 1997). Proper correction of acute hypernatremia is needed to prevent brain demyelination. Normal saline infusion may be the agent of choice in polyuric conditions associated with solute diuresis, whereas ADH and electrolyte-free fluid administration may be appropriate in cases of “pure” water diuresis. The recommended rate of correction of hypernatremia is about 10 mEq/L per 24 hours, amounting to a fall in plasma osmolality of about 20 mOsm/kg H2O per day ( Adrogue and Madias, 2000b ).

TABLE 4-2   -- Studies done to evaluate polyuria

Abbreviation (Term)




Cosm (osmolal clearance)

Urine flow (volume/unit time) necessary to excrete the urinary solution isotonically (i.e., at osmolality of the plasma)


Classic clearance formula applied to solute

Cosm(E) (electrolyte osmolal clearance)

Urine flow (volume/unit time) necessary to excrete urinary electrolytes at concentration of plasma Na


Assumes that contribution of P[K] is negligible compared with P[Na]

Cosm(NE) (nonelectrolyte osmolal clearance)

Urine flow (volume/unit time) necessary to excrete urinary nonelectrolytes isotonically (i.e., at osmolality of plasma)

Cosm - Cosm(E)

CH2O (free water clearance)

Volume of urinary solute – free water excreted per unit time

V - Cosm

CH2O(E) (electrolyte – free water clearance

Volume of urinary electrolyte – free water excreted per unit time

V - Cosm(E)

CH2O(E), rather than CH2O, influences S[Na]

UTS (urine total solute)

Measured total amount of urinary solute in 24 hr


UE (urine electrolyte solute)

Estimated total amount of urinary solute in 24 hr accounted for by electrolytes

(2) (U[Na] + U[K]) (TV)

UNE (urine nonelectrolyte solute)

Estimated total amount of urinary solute in 24 hr not accounted for by electrolytes


UAG (urinary anion gap)

Difference (in milliequivalents per liter) between sum of urinary concentrations of Na and K, and that of Cl

U[Na] + U[K] - U[Cl]

A large (positive) value usually implies a large concentration of anions other than Cl

PS (principal solute)

Principal urinary solute in millimoles per 24 hr

If PS is a monovalent ion such as Na+ or Cl-, PS is calculated as twice its total excretion

PS% (percent principal solute)

Contribution of principal solute to total solute excretion


The solute with the highest osmolal concentration in a 24-hr urine collection, expressed as a percentage of total solute excretion

Modified from Oster JR, Singer I, Thatte L, et al.: The polyuria of solute diuresis. Arch Intern Med 157:721–729, 1997, p 722, Table 1.

*Uosm indicates urine osmolality; V, urine volume/unit time; Posm, plasma osmolality; U[Na], urine sodium concentration; U[K], urine potassium concentration; P[Na], plasma sodium concentration; TV, total 24-hr urinary volume; and U[Cl], urine chloride concentration.

UEcalculations assume that the corresponding anions are monovalent.






The renin-angiotensin-aldosterone axis plays a key role in control of vascular tone, Na+ and K+ homeostasis, and, ultimately, circulatory volume and cardiovascular and renal function. Renin is an enzyme with a molecular weight of 40 kDa that is synthesized and stored in the juxtaglomerular apparatus surrounding the afferent arterioles of the glomeruli ( Davis and Freeman, 1976 ). The primary stimuli for renal renin release are reductions in renal perfusion pressure, Na+ restriction, and Na+ loss as detected by the specialized macula densa cells located in the distal tubule. Mechanical (stretch of the afferent glomerular arterioles), neural (sympathetic nervous system), and hormonal (prostaglandin E2 and prostacyclin) stimuli act in an integrated fashion to regulate the rate of renin secretion ( Fig. 4-3 ).


FIGURE 4-3  Effect of decreased intravascular volume on the renin-angiotensin-aldosterone system.



Once released into the circulation, renin cleaves the leucine-valine bond of angiotensinogen, forming angiotensin I. Angiotensin-converting enzyme present in lung, as well as in kidney, large caliber vessels, and other tissues, cleaves the carboxyl terminal (histidine-leucine dipeptide) from angiotensin I to form the biologically active angiotensin II ( Ng and Vane, 1967 ).

Angiotensin II has numerous important hemodynamic functions that are mediated largely by binding to angiotensin II T1 receptors in endothelial cells, tubular epithelial cells, and smooth muscle (Burnier and Brunner, 2000) ( Box 4-1 ). It plays a key role in regulating blood volume and long-term blood pressure regulation through stimulation of several tubular transporters of Na+ conversation largely located in the proximal tubule, as well as through its effects in enhancing aldosterone secretion and Na+ reabsorption in the distal tubule. As a potent direct smooth muscle vasoconstrictor and as an enhancer of ADH and sympathetic nervous system activity, angiotensin II also participates in short-term blood pressure regulation in disorders associated with volume depletion or circulatory depression. Research has uncovered multiple nonhemodynamic functions largely mediated by binding to T1 receptors of angiotensin II, which are particularly important in the pathophysiology of progressive renal injury ( Hall et al., 1999 ).

BOX 4-1 

Effects of Angiotensin II Mediated via AT1 and AT2 Receptor Stimulation

AT1 Receptor Stimulation



Vasoconstriction (preferentially coronary, renal, cerebral)



Sodium retention (angiotensin, aldosterone production)



Water retention (vasopressin release)



Renin suppression (negative feedback)



Myocyte and smooth muscle cell hypertrophy



Stimulation of vascular and myocardial fibrosis



Inotropic/contractile (cardiomyocytes)



Chronotropic/arrhythmogenic (cardiomyocytes)



Stimulation of plasminogen activator inhibitor-1



Stimulation of superoxide formation



Activation of sympathetic nervous system



Increased endothelin secretion

AT2 Receptor Stimulation



Antiproliferation/inhibition of cell growth



Cell differentiation



Tissue repair






Possible vasodilation



Kidney and urinary-tract development

Modified from Burnier M, Brunner HR: Angiotensin II receptor antagonists. Lancet 355:637-645, 2000, p 639, Panel 4. With permission from Elsevier.

A rise in plasma aldosterone concentration stimulates urinary K+ secretion, thus allowing maintenance of K+ balance. Aldosterone also increases the excretion of ammonium (NH+4) and magnesium (Mg2+) and increases the absorption of Na+ in the distal tubule, both by increasing the permeability of the apical membrane and by increasing the activity of Na+,K+-ATPase ( Marver and Kokko, 1983 ). The net effect is to generate more negative potential in the lumen, a driving force for increased K+ secretion. In addition, aldosterone enhances reabsorption of sodium in the cortical collecting duct through activation of the epithelial sodium specific channel, ENaC ( Greger, 2000 ). In performing these functions, aldosterone plays a key role in regulating fluid and electrolyte balance. Long-term aldosterone administration to healthy volunteers increases the extracellular fluid (ECF) volume. Clinical edema does not occur, however, because after several days the kidney “escapes” from the Na+-retaining effect while maintaining the K+-secretory effect ( August et al., 1958 ).


Atrial natriuretic peptide (ANP) is secreted by atrial monocytes in response to local stretching of the atrial wall in cases of hypervolemia (e.g., congestive heart failure or renal failure) and ultimately results in reduction of intravascular volume and systemic blood pressure ( Brenner et al., 1990 ). In the kidney, ANP acts in the medullary collecting duct to inhibit sodium reabsorption during ECF expansion. ANP induces hyperfiltration, natriuresis, and suppression of renin release and inhibits receptor-mediated aldosterone biosynthesis ( Greger, 2000 ). In the cardiovascular system, it diminishes cardiac output and stroke volume and reduces peripheral vascular resistance. Some of these effects are mediated through the influence of ANP on vagal and sympathetic nerve activity.


The internal environment of the body consists of fluids contained within compartments. Water accounts for 50% to 80% of the human body by weight. The variation in water content depends on tissue type: adipose tissue contains only 10% water, whereas muscle contains 75% water. Total body water (TBW) decreases with age, mainly as a result of loss of water in ECF. For clinical purposes, TBW is estimated at 60% of body weight in infants after 6 months of postnatal age, as well as in children and adolescents. This value is very inaccurate for low-birth-weight premature infants in whom TBW comprises as much as 80% of total body weight ( Friis-Hansen, 1971 ; Kagan, 1972 ). In term infants under 6 months of age, TBW may be approximated as 75% of total body weight ( Hill, 1990 ). Newer formulas that consider the height (cm) and weight (kg) but not the degree of adiposity or the child's surface area have improved the estimation of TBW particularly in healthy children between 3 months and 13 years of age ( Fig. 4-4 ) ( Mellits and Cheek, 1970 ; Morgenstern, 2002). TBW can be determined as follows:


FIGURE 4-4  Total body water (TBW) plotted against the parameter (Ht ×Wt) for children from 3 months to 13 years of age. The 10th, 50th, and 90th percentile curves, generated from the equations in the text, are shown. The curves for both males and females are presented.  (From Morgenstern BZ, Mahoney DW, Warady BA: Estimating total body water in children on the basis of height and weight: A reevaluation of the formulas of Mellits and Cheek. J Am Soc Nephrol 13:1884-1888, 2002, p 186, Figure 2.)




Intracellular Fluid

Intracellular fluid (ICF) represents about two thirds of the TBW, which is equivalent to 30% to 40% of total body weight. However, the proportion of ECF is much greater than that of ICF in preterm infants and reaches 60% of TBW at term. The membranes retaining this fluid allow the passive diffusion of water, whereas active transport mechanisms maintain an internal solute milieu different from that found outside the cells. K+, P2-, and Mg2+ are intracellular ions, and Na+ and Cl- are predominantly extracellular.

Extracellular Fluid

ECF accounts for about one third of TBW and is made up of two compartments: plasma and interstitial fluid. Plasma water represents 4% to 5% of body weight and 10% of TBW. It is the milieu in which blood cells, platelets, and proteins are suspended. Blood volume is usually estimated as a changing proportion, with respect to body weight. When expressed as milliliters per kilogram of body weight, it decreases with age from 80 mL/kg at birth to 60 mL/kg in adulthood.

Interstitial Fluid

This accounts for 16% of body weight and has a solute composition almost identical to that of intravascular fluid except for a lower protein concentration. In general, the bulk distribution of ions and fluids between these two compartments is determined by the Donnan effect and Starling forces.

Transcellular Fluid

The transcellular fluid compartment (1% to 3% of body weight) is a specialized subdivision of the ECF compartment. Separated from blood by endothelium and epithelium, it represents fluid collections such as cerebrospinal fluid, aqueous and vitreous humors of the eye, synovial fluid, pleural fluid, and peritoneal fluid.

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Although all nephrons of the mature kidney are formed by 36 weeks of gestation of normal intrauterine life, hyperplasia continues until the sixth postnatal month; thereafter, cell hypertrophy is responsible for increase in renal size. Growth in the size of the kidney tends to be directly proportional to increase in height ( Schultz et al., 1962 ).

While the fetal kidney receives 3% to 7% of cardiac output ( Rudolph et al., 1971 ), RBF increases gradually after birth. RBF, as measured by para-aminohippuric acid (PAH) clearance (CPAH), correlates with gestational age. For example, CPAH is 10 mL/min per m2 at 28 weeks of gestation and 35 mL/min per m2 at 35 weeks of gestation ( Fawer et al., 1979 ). CPAH corrected for body surface area doubles by 2 weeks of age and reaches adult levels at 2 years. Furthermore, changes in RBF are associated with considerable increases in the relative RBF to the outer cortex where most glomeruli are located (Olbing et al., 1973 ).

Selected renal functions measured at different ages are summarized in Table 4-3 . The GFR in the full-term newborn infant averages 40.6 ± 14.8 mL/min per 1.73 m2 and increases to 65.8 ± 24.8 mL/min per 1.73 m2 by the end of the second postnatal week ( Schwartz et al., 1987 ). GFR reaches adult levels after 2 years of age. Premature newborns have a lower GFR that increases more slowly than that in full-term infants. The low GFR at birth is attributed to the low systemic arterial blood pressure, high renal vascular resistance, and low ultrafiltration pressure together with decreased capillary surface area for filtration.

TABLE 4-3   -- Maturation of renal function with age


Premature Newborn

Full-term Newborn

1 to 2 Weeks

6 Months to 1 Year

1 to 3 Years


GFR (mL/min per 1.73 m2)

14 ± 3

40.6 ± 14.8

65.8 ± 24.8

77 ± 14

96 ± 22

Male: 125 ± 15
Female: 110 ± 15

RBF (mL/min per 1.73 m2)

40 ± 6

88 ± 4

220 ± 40

352 ± 73

540 ± 118

620 ± 92

TmPAH (mg/min per 1.73 m2)

10 ± 2

16 ± 5

38 ± 8

51 ± 20

66 ± 19

79 ± 12

Maximal concentration ability (mOsm/kg)







Serum creatinine (mg/dL)






0.8 to 1.5

TmP/GFR (mg/dL)

7.39 ± 0.37

5.58 ± 0.28

5.71 ± 0.28

3.55 ± 19

Fractional excretion of sodium (%)

2% to 6%






TmG (mg/min per 1.73 m2)

71 ± 20

339 ± 51

TmG, tubular maximum for reabsorption of glucose; GFR, glomerular filtration rate; RBF, renal blood flow; TmPAH, tubular maximum for para-aminohippuric acid; TmP, tubular maximum for phosphorus.




Despite a low GFR, full-term infants are able to conserve Na+ ( Spitzer, 1982 ). This is explained by the existence of glomerulotubular balance such that as GFR and the filtered load of Na+ increase, so does the ability of the proximal tubule to reabsorb Na+. In contrast, premies have a prolonged glomerulotubular imbalance so that GFR is high relative to tubular capacity to reabsorb Na+. The glomerulotubular imbalance is caused by structural immaturity of the proximal convoluted tubule and the incomplete development of the transport system responsible for conserving Na+. This, together with poor response of the distal tubule to mineralocorticoids in premies, results in Na+ wastage and susceptibility to hyponatremia.

The tubular mechanisms involved in the excretion of organic acids are poorly developed in neonates. The tubular transport of PAH, which is a weak acid, is around 16 ± 5 mg/min per 1.73 m2 in full-term infants and about half this value in premature babies. It increases with age and reaches adult rates ranging from 55 to 104 mg/min per 1.73 m2 by 12 to 18 months ( Spitzer, 1978 ). PAH excretion is limited by a number of factors, including low GFR, immaturity of the systems providing energy for transport, and low number of transporter molecules. This is further accentuated by a low extraction ratio for PAH and other organic acids caused by the predominance of juxtamedullary circu-lation in the immature kidney ( Calcagno and Rubin, 1963 ), a phenomenon that allows increased shunting of blood through the vasa recta and exclusion of postglomerular blood from the proximal tubular excretory surface.

Concentrating ability is low at birth, especially in premature infants. After water deprivation in the full-term newborn, urine concentrates to only 600 to 700 mOsm/kg, or 50% to 60% of maximum adult levels. Healthy children 0.5 to 3 years of age given 20 mcg of desmopressin intranasally demonstrate a gradual rise in urinary concentration starting from a mean value of 525 mOsmol/kg and reach a mean maximum plateau of 825 mOsm/kg ( Marild et al., 1992 ). The major cause for the reduced concentration of urine in the neonate is the hypotonicity of the renal medulla ( Aperia and Zetterstrom, 1982 ). Several mechanisms that contribute to interstitial hypertonicity are not well developed, including urea accumulation in the medulla ( Trimble, 1970 ), length of the loop of Henle and the collecting ducts within the medulla ( Edwards, 1981 ), and Na+ reabsorption in the ascending, water-impermeable loop ( Horster, 1978 ). In addition, the collecting duct cells in immature kidneys may be less sensitive to ADH than those of mature nephrons ( Schlondorff et al., 1978 ).

A water-loaded infant can excrete dilute urine with osmolality as low as 50 mOsm/kg. In the first 24 hours of life, however, the infant may be unable to increase water excretion to approximate water intake ( Aperia and Zetterstrom, 1982 ). The diluting capacity becomes mature by 3 to 5 weeks of postnatal life.

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The normal need for fluids varies markedly in low-birth-weight and full-term neonates, as well as during infancy and later childhood. This variability in fluid needs is caused by differences in the rate of caloric expenditure and growth, the ratio of evaporative surface area to body weight, the degree of renal functional maturation and reserve, and the amount of total body water (TBW) at different ages. For instance, compared with older children and adults, infants have greater fluid needs because of higher rates of metabolism and growth; a surface area-to-weight ratio that is about three times greater, resulting in higher insensible fluid loss; and greater urinary excretion of solutes combined with lower tubular concentrating ability, which increases obligatory fluid loss. On the other hand, as previously noted, low-birth-weight and full-term neonates have a greater percentage of TBW compared with older children and adults ( Friis-Hensen, 1971 ; Kagan et al., 1972 ). This increase in TBW results mainly from expansion of the ECF compartment, which at birth may comprise as much as 50% of the TBW. During the first 3 postnatal days, when this “extra fluid” is eliminated by the kidneys, full-term neonates require less fluid intake ( Silverman, 1961 ; Oh, 1980 ; Winters, 1982 ).

The needs of low-birth-weight infants are more variable ( Table 4-4 ) and may be markedly altered by relatively minor changes in ambient temperature or by phototherapy ( Fanaroff et al., 1972 ; Oh and Karecki, 1972 ; Wu and Hodgman, 1974 ). In contrast to more mature infants, the immature skin in very low-birth-weight infants (<1500 g) allows disproportionate evaporative heat loss relative to basal metabolic rate ( Levine et al., 1929 ; Levinson et al., 1966 ). This greater evaporative heat loss, together with a large body surface area, accounts for the much greater insensible fluid needs in infants with very low birth weight.

TABLE 4-4   -- Average fluid need of low-birth-weight infants (mL/kg per 24 hr) during first week of life[*]



Body weight (gm)

Age (days)


751 to 1000

1001 to 1250

1251 to 1500

1501 to 2000

























2 to 3
























4 to 7
























Reproduced with permission from Pediatrics in Review, volume 1, p. 313. Copyright © 1980 by the AAP.


Allowances for increased metabolic rate (cold stress, increased activity) are not included; these infants are in an incubator and naked.

Insensible water loss.

Volume required to achieve a urine osmolarity of 250 mOsm/kg of renal solute load during the first day (no sodium and protein added), 10 mOsm/kg per day on the second and third days, and 15 mOsm/kg per day on the fourth to seventh days.




Except for the first 3 postnatal days when full-term neonates require only 40 to 60 mL/kg fluid per day, in general, 100 mL of water is needed for each 100 kcal expended. Notably, an additional 15 mL of water is generated endogenously for each 100 kcal used (water of oxidation), which is also available for body functions. In premies, fluid intake may be gradually increased to 150 mL/kg per day, while 100 to 125 mL/kg per day generally suffices for infants weighing less than 10 kg. The fluid requirement decreases to 50 mL/kg per day for those weighing 11 to 20 kg and to 20 mL/kg per day for those with body weight above 20 kg. These fluid volumes are sufficient to allow excretion of dietary solute load, as well as to replace insensible fluid loss through the skin, lungs, and intestines ( Winters, 1982 ) (Table 4-5 ). It should be noted that energy expenditure and, therefore, fluid intake may be significantly increased with stress (Holliday et al., 1994) ( Table 4-6 ).

TABLE 4-5   -- Normal losses and maintenance requirements for fluid, electrolytes, and dextrose in infants and children

H2O = 100 to 125 mL/100 kcal Expended


Insensible loss (mL)



Sweat (mL)

0 to 25


Urine (mL)

50 to 75


Stool (mL)

5 to 10


Food oxidation (mL)


Na+ = 2.5 mmol/100 kcal Expended


Body growth











K+ = 2.5 mmol/100 kcal Expended


As for Na+


Cl- = 5 mmol/100 kcal Expended


As for Na+


Dextrose = 25 g/100 kcal Expended


Basal metabolic rate



Growth and tissue repair



Physical activity


Maintenance Solution (per liter of water)

 Dextrose (g)



 Na+ (mmol)



 K+ (mmol)



 Cl- (mmol)



Adapted from Winters RW: Principles of pediatric fluid therapy, ed 2. Boston, 1982, Little, Brown.




TABLE 4-6   -- Method to predict metabolic rates during critical illness



Body Weight(kg)

kcal/kg per day

0 to 10



12% per°C

10 to 20

1000 + 50/kg

Cardiac failure



1500 + 20/kg

Major surgery

15% to 25%




20% to 30%



Severe sepsis

Up to 100%




40% to 50%

Modified from Holliday MA: Fluid and nutrition support. In Holliday MA, Barratt TM, Avner ED, editors: Pediatric nephrology, ed 3. Williams and Wilkins, 1994, Baltimore, p 301, Table 14B.5.




The high fractional excretion of Na+ (FENa +) in premature infants can lead to negative Na+ balance, hyponatremia, neuro-logic disturbances, and poor growth unless an Na+ intake of 3 to 5 mmol/kg per day is given; in full-term infants and older children, 2 to 3 mmol/kg per day is sufficient ( Drukker et al., 1980 ). Premature infants have a lower renal threshold for bicarbonate. In addition, several functional and anatomic factors combine to limit tubular excretion of weak organic acids ( Avner et al., 1990 ). Consequently, premature infants may need small supplements of base. Sodium bicarbonate at 1 to 2 mmol/kg per day is generally recommended for the very small premature infant. Clinically important disturbances in acid-base status are unusual in full-term neonates unless they consume excessive amounts of protein.

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Because premature infants and mature neonates have a greater TBW-to-body weight ratio than do older infants and children, they tolerate a greater degree of dehydration before manifesting clinical symptoms. A 10% fluid deficit in such patients may produce symptoms consistent with moderate dehydration, whereas a similar deficit in adults will produce severe symptoms. However, dehydration can occur very quickly in infants because disorders such as vomiting or diarrhea very rapidly produce deficits of 50 to 100 mL/kg. Dehydration can also develop in healthy premature infants if insensible water losses are underestimated and are not adequately replaced. This situation may result from use of an open radiant warmer without appropriate plastic shields; forced convection in nonhumidified incubators; skin immaturity, resulting in greater transcutaneous evaporative fluid loss; use of phototherapy, causing insensible fluid loss; hyperthermia; or tachypnea. In older infants and children, gastrointestinal disorders are the major causes of dehydration.


Assessment of the extent and type of dehydration is important for formulating a therapeutic strategy. Table 4-7 provides guidelines for the clinical assessment of the severity of dehydration in children ( Ellis and Avner, 1985 ). Laboratory measurements should include hematocrit, blood gases, glucose, calcium, blood urea nitrogen, and albumin, as well as serum and urinary creatinine, osmolality, and electrolytes. A urinalysis should be done to detect cellular elements and to measure specific gravity. Urinary osmolality and specific gravity are of minimal value in assessing dehydration in premature infants with tubular immaturity and in infants with reduced urinary concentrating ability caused by low protein intake. In general, however, such data, together with a careful medical history, physical examination, and assessment of fluid input and loss, aid in the diagnosis of dehydration and guide adjustment of the amount and composition of fluid administration during various phases of therapy.

TABLE 4-7   -- Clinical and laboratory assessment of the severity of dehydration in children[*]

Signs and Symptoms

Mild Dehydration

Moderate Dehydration

Severe Dehydration

Weight loss (%)




Fluid deficit (mL/kg)




Vital signs



Increased; weak

Greatly increased; feeble

 Blood pressure


Normal to low

Reduced and orthostatic




Deep and rapid

General appearance


Thirsty, restless, alert

Thirsty, restless, or lethargic, but arousable

Drowsy to comatose; limp, cold, sweaty; gray color

 Older children

Thirsty, restless, alert

Thirsty, alert, postural hypotension

Usually comatose; apprehensive, cyanotic, cold

Skin turgor[†]



Greatly decreased

Anterior fontanel



Markedly depressed




Markedly sunken

Mucous membranes



Very dry


 Flow (mL/kg per hr)




 Specific gravity





When hypernatremia is present, the severity of dehydration may be clinically underestimated because of the relative preservation of extracellular fluid volume (ECFV) at the expense of intracellular fluid volume (ICFV). In such states, neurologic symptoms (lethargy alternating with hyperexcitability, progressing to focal or generalized seizures) may predominate.

With hypernatremia, the skin may have a thick, “doughy” consistency or a soft, velvety texture.



Severely dehydrated infants and children should be cared for in the intensive care unit with constant monitoring of central venous pressure and serial measurements of the initial laboratory studies. Box 4-2shows a stepwise approach to the treatment of isotonic, hypotonic, and hypertonic dehydration ( Ellis and Avner, 1985 ). Particular attention should be given to hypernatremic dehydration and brain injury. The initial measures for fluid resuscitation are to stabilize the vital signs by administering crystalloid or colloid solutions and to correct severe acid-base imbalance, hypoglycemia, and other metabolic disturbances. The objective of subsequent measures is to assess further the kind of dehydration and to plan a time course for administration of the appropriate fluid volume and chemical composition needed to correct previous deficits and to replace ongoing losses.

BOX 4-2 

Stepwise Approach to Fluid Therapy in Infants and Young Children With Moderate (100 mL/kg) to Severe (150 mL/kg) Dehydration[*]

Phase I (0 to 4 hr)



Assess vital signs and body weight, approximate fluid deficit, and begin fluid balance sheet.



Obtain blood for immediate chemical and acid-base analysis and, if possible, obtain a urine sample for chemical and microscopic determinations.



Regardless of the type of dehydration (see below), begin immediately with 0.9% NaCl at 20 to 30 mL/kg given over 1 hr or faster, depending on the severity of circulatory compromise. If the major cause of dehydration is diarrhea, a mixture of 0.45% NaCl and 0.45% NaHCO3 is preferred as the initial hydrating solution. If shock is present, administer 5% salt-poor albumin (10 mL/kg).



Stabilize vital signs by repeating step 3 if needed, and continue fluid administration at 10 mL/kg per hr until urine output is established.



On the basis of serum electrolyte values, determine the type of dehydration. Also, make a more precise assessment of the total fluid deficit and proceed to phase II.

Phase II (4 hr to 2 days)



Repeat phase I, steps 1 and 2.



Isotonic dehydration (serum [Na+]=130 to 150 mmol/L).



Replace 60% to 70% of the remaining fluid deficit over the next 24 hr using a solution containing 0.45% NaCl with 20 mmol/L KCI and 50 g/L dextrose; add 20 mmol NaHCO3/L if serum pH is <7.25. Replace maintenance fluid plus continued fluid loss using the same solution.



Replace remainder of fluid deficit over subsequent 24 hr, in addition to maintenance fluid and ongoing fluid loss, with solution containing 0.2% NaCl with 20 mmol KCI and 50 g/L dextrose.



Additional dextrose, K+, or HCO3- may be needed and is added according to serial serum measurements.



Hypotonic dehydration (serum [Na+] < 130 mmol/L).



Estimate Na+ deficit as follows: [Na+] deficit (mmol) = (135 - Serum [Na+]) ×Total body water (L). Replace 60% of fluid deficit over the next 24 hr using a similar choice of solution as in phase I, step 3, plus 5% to 10% dextrose. If serum [Na+] is <120 mmol/L or symptoms of water intoxication are present, give 12 mL/kg of 3% saline solution over 1 hr. During this period, replace maintenance fluid and ongoing fluid loss with the solution noted in phase II, step 2b.



Same as for phase II, step 2b.



Same as for phase II, step 2c.



Hypertonic dehydration (serum (Na+] > 150 mmol/L).



Add fluid deficit, 48 hr of maintenance water, and estimate of continued fluid loss to determine total volume of fluid to be administered initially at a constant rate over 48 hr.



Use a solution containing 0.2% NaCl with 40 mmol KCI/L and 25 g/L dextrose.



Add 20 mmol lactate or acetate if plasma pH is <7.25. (Do not use NaHCO3, since calcium may need to be added to the fluid.)



If serum calcium level is <8.5 mg/dL, add 1 g calcium gluconate to every 500 mL of administered fluid. Additional calcium is administered as required by serial serum values or clinical symptoms of hypocalcemia. Discontinue when serum calcium level is ≥9.0 mg/dL.



If serum [Na+] is decreasing at 0.50 mmol/L per hr, decrease rate of administration by 30% to 50%. If serum [Na+] is decreasing at <0.25 mmol/L per hr, increase rate of fluid administration by 30% to 50%.

Phase III (3 to 6 days)



Same as for phase I, steps 1 and 2.



Replace any residual fluid or solute deficits over the next 2 to 4 days using the solution described in phase II, step 2b.



For severe hypertonic dehydration (serum [Na+] >175 mmol/L), phase II therapy is continued for 3 to 4 days and subsequently may be switched to phase III therapy, step 2, when serum [Na+] is <145 mmol/L.

*  For mild dehydration (50 mL/kg), requiring parenteral fluid therapy, start therapy with phase II.

The composition of selected parenteral and oral rehydration solutions are shown in Tables 4-8 and 4-9 [8] [9]. In most infants and children receiving parenteral solutions for brief periods, the normal fluid and electrolyte needs can be easily satisfied. The caloric needs, however, are not readily met. It is customary to provide 5% dextrose in parenteral solutions. While this concentration provides only a fraction of the optimal number of calories (20% of total kilocalories needed by infants less than 1 year of age), it is sufficient to prevent ketosis. In less mature neonates, higher infusion rates of 5% dextrose generally suffice to maintain blood glucose concentrations between 50 to 90 mg/dL ( Roy and Sinclair, 1975 ; Winters, 1982 ).

TABLE 4-8   -- Composition of frequently used parenteral fluids












(g/100 mL)









Normal saline (0.9% NaCl)



½ Normal saline (0.45% NaCl)



D5 (0.2% NaCl)





3% Saline



8.4% Sodium bicarbonate (1 mEq/mL)




0 to 10

0 to 340





Ringer's lactate

0 to 10

0 to 340






Amino acid 8.5% (Travasol)













Albumin 25% (Salt poor)



150 to 160









Modified from DeYoung L, Patterson J, Johns Hopkins Hospital, Children's Medical and Surgical Center: The Harriet Lane handbook: A manual for pediatric house officers, ed 14. Mosby, 1996, p 234, Table 11.18.

Values are approximate—may vary from lot to lot.



Protein or amino acid equivalent.

Bicarbonate or equivalent (citrate, acetate, lactate).

Approximate values: actual values may vary somewhat in various localities depending on electrolyte composition of water supply used to reconstitute solution.


TABLE 4-9   -- Comparison of oral rehydration solutions and “clear fluids”






CHO, g/L

Glucose/Na+ Ratio


World Health Organization ORS































Cereal-based ORT






















Ginger ale







Apple juice







Chicken broth














Modified from Meyers A: Fluid and electrolyte therapy for children. Curr Opin Pediatr 6:303–309, 1994, p 305, Table 1.

ORS, oral rehydration solution.

Na+, K+, Cl-, and base levels are measured in mmol/L.





Provided that infants and children are less than 10% dehydrated and have minimal electrolyte abnormalities, good level of consciousness, adequate bowel sounds, and absence of signs of hypovolemia, oral rehydration may be used to replace deficits and maintain fluid volume. Commercially available preparations such as Pedialyte RS (Ross) with a Na+ content of 45 mmol/L may be used. In children with diarrhea in developing countries, the World Health Organization (WHO) has recommended the use of an inexpensive and effective oral rehydration solution consisting of 90 mmol/L Na+ and 111 mmol/L of glucose (total osmolarity, 311 mOsmol/L). However, glucose-based solutions with a lower osmolality may further optimize fluid and glucose-sodium coupled absorption in the small intestine ( Hahn et al., 2001 ).

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The optimal perioperative fluid volume and composition requirements in infants and children have not been adequately investigated. The formulas provided by Berry (1986) ( Table 4-10 ) are widely used to determine the hourly rates of intraoperative fluid volume administration, which consists of four major components:



Maintenance fluid established by Holliday and Segar (1957) based on calorie expenditure at different ages.



Estimated volume deficit incurred during preoperative fasting or gastrointestinal or by other fluid deficits; one third of such deficits may be replaced during the first hour of surgery while the remaining volume may be spread over the duration of the surgery.



Severity of surgical and nonsurgical trauma. This may comprise the largest volume of fluid loss or fluid redistribution, which derives largely from the ECF compartment.



Blood losses and fluids needed to support systemic blood pressure.

TABLE 4-10   -- Guidelines for fluids for newborn and children during the perioperative period[*]

Age (yr)

Hydrating Solution During First Hour (mL/kg)

Hydrating Solution During Following Hours



Maintenance fluid: 4 mL/kg per hr



5% to 10% dextrose in 0.75 normal saline plus 20 mEq sodium bicarbonate/L



Trauma: 6 to 10 mL/kg per hr for intra-abdominai or 4 to 7 mL/kg per hr for intrathoracic surgery replaced with Ringer's lactate



Maintenance fluid: 4 mL/kg per hr



5% Dextrose in normal saline

3 to 4


Maintenance and trauma: basic hourly fluid 4 mL/kg



5% Dextrose in normal saline



+ If mild trauma



2 mL/kg = 6 mL/kg per hr



+ If moderate trauma



4 mL/kg = 8 mL/kg per hr



+ If maximal trauma



6 mL/kg = 10 mL/kg per hr

Modified from Berry FA: Practical aspects of fluid and electrolyte therapy. In Berry FA, editor: Anesthetic Management of Difficult and Routine Pediatric Patients. New York, 1986, Churchill Livingstone, pp 107–135.


Plus blood replacement with blood or 3:1 volume replacement with crystalloid. Replace blood loss in excess of 20 mL/kg with equal volume of packed red blood cells.



A key goal of perioperative fluid management is to maintain an adequate intravascular volume without the development of hyponatremia. Perioperative patients are at risk for developing hyponatremia because of multiple factors, including prehydration with hypotonic fluid, and nausea, pain, and stress associated with surgery, that may lead to nonhypovolemic stimulation of ADH release during and after surgery (i.e., inappropriate secretion of ADH; Burrows et al., 1983 ; Arieff, 1998 ). The limited ability of such individuals to excrete a large water load may be influenced by any preexisting edema-forming disorder, obstructive uropathy, or the use of thiazide diuretics or other drugs such as narcotics and antiemetics. However, hypotonic fluid infusion is the single most important cause of acute hyponatremia developing in the intraoperative period. Acute hyponatremia results in increased water content in neurons (brain edema) without a change in solute content. This may cause subclinical symptoms such as headache, nausea, vomiting, or muscle weakness in any age group. Younger children are more susceptible to more severe hyponatremic encephalopathy due to a larger brain-to-skull ratio ( Moritz and Ayus, 2002 ). Unless there is a free water deficit, isotonic fluid infusion is recommended during the perioperative period. The need for potassium, calcium, chloride, and bicarbonate (or lactate or citrate, which may be converted to bicarbonate in individuals without hepatic failure) is more controversial. Such components are contained in lactated Ringer's solution, which is nearly isonatremic (Na+ = 130 mEq/L) and isotonic but also contains K+ (4 mEq/L), Ca2+ (0.9 mmol/L), Cl- (109 mEq/L), and lactate (27.7 mmol/L).

The amount of dextrose commonly used is 5% (equals 5000 mg/dL or 278 mmol/L). Although this is more than 50 times more concentrated than normal plasma glucose concentration (90 to 100 mg/dL or ≈5 mmol/L), the energy delivery based on the volume of fluid given to an infant weighing 10 kg amounts to 50 kcal for the first hour of surgery. Such energy supply is particularly important in preventing hypoglycemia in premature and full-term neonates who have greater energy requirements than older children, but may lead to hyperglycemia in 0.5% to 2% of pediatric patients. This disorder may be less common in children receiving regional anesthesia, which reduces the hyperglycemic effects of surgery per se. Although such transient hyperglycemia is purported to have various potential deleterious consequences, these have not been well substantiated. A review suggests that a solution of lactated Ringer's with 1% dextrose is sufficient to prevent both hypoglycemia and hyperglycemia ( Berleur et al., 2003 ) in most children excluding premature and term neonates. This practice, however, is not yet widely used.


Guidelines for the intraoperative fluid and electrolyte management of premature and term neonates are largely based on available knowledge of renal physiology rather than on data obtained from clinical investigation. The physiology of the healthy neonate is influenced by the short tubular length and is characterized by immature reabsorption mechanisms, an activated renin-angiotensin-aldosterone system, and low circulating ADH concentrations ( Avner et al., 1990 ; El-Dahr and Chevalier, 1990 ). Thus, healthy preterm neonates weighing less than 1300 g, or of less than 32 weeks' gestation, have fractional excretion rates of Na+ (FENa +) that range from 8.2% to 2.1% from 28 to 32 weeks' gestation, with further gradual decrease to less than 1% at term ( Arant, 1978 ; Delgado et al., 2003 ); such rates may increase to 15% with stress. The high FENa + in preterm infants is ascribed to decreased Na+ reabsorption in the proximal tubule together with hyporesponsiveness of the distal tubule to aldosterone (Sulyok et al., 1979 ). When combined with a negative Na+ balance due to inadequate Na+ supplementation as well as decreased sensitivity of the collecting duct to ADH, up to one third of such infants develop significant hyponatremia (Na+ < 130 mEq/L), often manifesting with neurologic disturbances during the first 6 weeks of life ( Roy and Sinclair, 1975 ).

Both premature and term neonates have a limited capacity to excrete K+, possibly because of distal tubular insensitivity to aldosterone. Hence, baseline reference plasma K+ concentrations range from 3.9 to 5.9 mEq/L. Moreover, both preterm and term neonates are capable of producing maximally dilute urine while concentrating capacity is limited. Yet, hyponatremia may develop after administration of large volumes of hypotonic fluids because fluid excretion may be limited mainly because of low GFR. Stress may cause profound reduction in GFR in premature and term neonates through release of various extrarenal vasoactive and hormonal substances that modify the response of “immature kidneys,” thereby further disturbing fluid and electrolyte homeostasis. The higher body content of water and the higher metabolic rate, as well as a propensity to metabolic acidosis and hypocalcemia in premature newborns, are other important factors in deciding the volume and composition of intraoperative fluids.

Such considerations support the avoidance of boluses of hypotonic fluids while keeping in mind the lower age- and size-appropriate circulatory pressures that may serve as the goal of fluid management. In the absence of the expected physiologic fluid loss, which may range from 5% to 15% of body weight during the first 3 days of postnatal life, fluid volume during this time period may be limited to 60 mL/kg per day while blood pressure support may be sustained with small infusions (5 mL/kg) of 5% albumin or other blood products as needed. Beyond 3 days of life, maintenance fluid volume is gradually increased to 150 mL/kg per day. Deficits beyond the expected physiologic losses and ongoing losses and allowance for surgical trauma may be replaced by a similar fluid composition, but the volume replacement may be more gradual or less rapid than outlined for older infants and children (see Table 4-10 ). Na+ bicarbonate and calcium may be supplemented, while K+ should be limited. Also, a higher glucose concentration is generally desirable in premature infants. My preferred fluid composition is 0.75 normal saline with 20 mEq sodium bicarbonate/L (total Na+ = 135 mmol/L) in 5% to 10% dextrose, as well as 20 mEq/L KCl if plasma K+ falls below 3.5 mEq/L. Close attention to change in body weight and urine output and serial measurements of plasma electrolytes are essential in guiding the perioperative fluid management of the sick premature and full-term neonate.


The key goal of intraoperative management is to expand the circulatory volume and to maintain systemic blood pressure between the 90th and 95th percentile for age gender and height percentile ( Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents, 1996 ), so as to allow for adequate perfusion of the renal allograft. An adult kidney may sequester up to 250 mL of blood, and in infants, nearly 50% of the cardiac output may be directed toward perfusion of the allograft. To ensure adequate perfusion of the allograft the anesthesiologist actually needs to maximize the circulatory volume of the recipient, mainly with crystalloid or packed cytomegalovirus-safe, leukocyte-poor red blood cells if hemoglobin is below 9 g/dL, while closely monitoring the central venous pressure (CVP) and systemic MABP during vessel anastomosis. Near the completion of the vascular anastomoses, 20% mannitol (0.5 to 1.0 g/kg) and intravenous furosemide, 1 mg/kg, may be given before the cross-clamps are released. Before cross-clamp release, CVP should be maintained at 8 to 12 cm H2O, and the systolic blood pressure and MABP above 120 mm and 70 mm Hg, respectively. If the MABP is inadequate to achieve good renal perfusion of the adult kidney, a constant dopamine infusion of up to 5 mcg/kg per min may be started. Intraoperative blood gases may be monitored frequently, because clamping of the aorta and accumulation of lactic acid can result in metabolic acidosis and vasoconstriction. The critical goal is to obtain immediate allograft function; hypotension after cross-clamp release in an infant with inadequate circulatory volume and an underperfused allograft is a potential catastrophe.

Intravenous furosemide (1 to 2 mg/kg per dose), 25% salt-poor albumin (0.5 g/kg per dose), 20% mannitol (0.3 to 0.5 g/kg per dose), or 0.9 normal saline solution (10 mL/kg bolus) may be given to help promote urine output in the immediate postoperative period.

The volume and composition of intravenous fluid administered during the first 48 postoperative hours are essential to ensure continued renal function. The urine output frequently exceeds 5 mL/kg per hr. Thus, insensible losses are quantitatively less important. In children with such high urine output, we routinely reduce the concentration of dextrose to 1% to prevent hyperglycemia, which may compound osmotic diuresis due to high preoperative blood urea nitrogen concentrations. Urine output is replaced on a milliliter-for-milliliter basis. In infants and children with body weight below 30 kg, the CVP should be maintained in the range of 5 to 10 cm H2O and MABP greater than 70 mm Hg. Our preferred fluid solution during the first 24-48 hours consists of 1% dextrose, 0.45 mEq/L NaCl solution, and 10 to 20 mEq sodium bicarbonate per liter. During the first 24 to 36 hours, additional fluid boluses of 10 mL/kg of normal saline or a 5% albumin solution may be given if CVP falls below 5 cm H2O with the goal of maintaining a urine output above certain arbitrary limits (5, 4, and 3 mL/kg per hr for body weight <10 kg, <20 kg, and <30 kg, respectively). In conjunction with such fluid boluses, we also administer intravenous furosemide (1 mg/kg) because renal allografts tend to be diuretic dependent in the early perioperative setting.

Serum electrolytes (Na+, K+, Cl-, HCO3-, Ca2+, P2-, Mg2+) may be monitored at 8- to 12-hour intervals during the first 2 postoperative days. Potassium chloride is given separately as needed when the plasma K+ falls below 3.5 mEq/L. In infants and young children, close monitoring of fluid balance and cardiovascular examination are essential to prevent electrolyte imbalance and fluid overload, which may result in severe hypertension or pulmonary edema, or, in reduction of intravascular volume and acute tubular necrosis (ATN). A bladder catheter inserted intraoperatively is necessary for accurate measurement of urine volume. Unless there are specific urologic indications, the catheter is removed after 4 to 5 days.

Immediate measures must be undertaken to improve postoperative oliguria. Besides the most easily correctable causes of oliguria such as hypovolemia or a malfunctioning catheter, other potential causes include vascular bleeding or occlusion, ATN due to prolonged cold ischemia storage, hyperacute rejection, or urinary extravasation or obstruction. In patients with oxalosis, precipitation of calcium oxalate crystals in the graft may cause acute allograft failure. Children with delayed graft function, congestive heart failure, or marked electrolyte abnormalities may require removal of fluid by hemodialysis or peritoneal dialysis. Fluid removal should be performed cautiously to avoid allograft hypoperfusion.

Copyright © 2008 Elsevier Inc. All rights reserved. -

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier


Among the many kidney functions, sodium homeostasis via multiple or redundant systems is paramount ( Greger, 2000 ). About 75% of the filtered Na+ is reabsorbed in the proximal tubule by the luminal Na+/H+ exchanger and by the basolateral Na+,K+-ATPase. Such reabsorption is increased by the action of angiotensin II, which preferentially constricts the efferent arteriole, thereby increasing filtration fraction and limiting fluid reentry into the peritubular capillaries. Dopamine has an opposing effect in this tubule segment causing natriuresis. About 20% of NaCl reabsorption occurs in the ascending loop of Henle via the electroneutral Na+/K+/2Cl- transporter (NKCC2), leading to formation of dilute urine. Vasopressin and loop diuretics inhibit such reabsorption. In the distal tubule, Na+ is reabsorbed by a thiazide-sensitive Na+/Cl- cotransporter. In the connecting tubule and in the cortical collecting duct, Na+ is reabsorbed by the sodium-specific amiloride-sensitive epithelial sodium channel (ENaC). ENaC is activated by aldosterone. In the medullary collecting duct, Na+ reabsorption is under the influence of ANP.

Much experimental evidence suggests that regulation of ECF volume and maintenance of systemic blood pressure prevail over Na+ homeostasis; plasma Na+ concentration and plasma osmolality are secondary regulators ( Bricker, 1982 ; Rees et al., 1984 ; Gennari, 1998 ; Kumar and Berl, 1998 ; Scheinman et al., 1999 ). Thus, in the strict sense, virtually all of the conditions associated with hyponatremia are primarily disorders of ADH excess with an impaired ability to excrete free water. Disturbances in serum Na+ concentration may be associated with hypervolemia, normovolemia, or hypovolemia.

▪ HYPONATREMIA (Plasma Na+ <135 mmol/L)

In infants and children, hyponatremia occurs much more frequently than hypernatremia. Although premature and full-term infants are capable of producing hypotonic urine, large hypotonic fluid loads cannot be excreted, especially during the first 6 weeks of postnatal life. This is most evident during the first week of life, when only 10% to 50%, rather than 80%, of an intravenous challenge of 5% dextrose in water is excreted within 4 hours. The major factor limiting the response to a fluid challenge, especially in preterm infants during the first 5 weeks of postnatal life, is the physiologically low GFR and low urinary flow rate ( Svenningsen and Aronson, 1974 ; Leake et al., 1976 ). Moreover, high urinary Na+ excretion and negative Na+ balance may contribute to the hyponatremia found in about one third of low-birth-weight premature infants ( Engelke et al., 1978 ). This Na+ wasting has been attributed to deficient proximal and distal tubular reabsorption of Na+ in such infants ( Sulyok et al., 1979 ).

A positive water balance, rather than Na+ wasting, has also been implicated in the hyponatremia of healthy premature infants ( Rees et al., 1984 ; Sulyok et al., 1985 ). Low serum albumin concentrations and reduced plasma oncotic pressure may also lead to fluid retention and “late hyponatremia” in preterm infants ( Menon et al., 1986 ). Thus, independent of the specific pathologic process, preterm infants are at high risk of developing hyponatremia. Therefore, electrolytes should be monitored frequently during the first 4 to 6 weeks of life, especially in infants of less than 34 weeks gestation. Other causes of hyponatremia in neonates are shown in Table 4-11 . In older infants and children, hyponatremia may occur with dehydration, edema-forming states, and syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Such conditions may be differentiated clinically at the bedside. In addition, the simple laboratory studies described in the section on dehydration may reveal urinary hypotonicity, suggesting water intoxication, or dilutional hyponatremia associated with renal failure.

TABLE 4-11   -- Causes of hyponatremia


Infants and Children


Prolonged use of diuretics in mother or infant

Diuretics (thiazides, osmotic diuretics)

Oxytocin for labor

Arginine vasopressin

Dopamine >5 mcg/kg per min


Prostaglandin infusion


Excessive administration of electrolyte-free solutions











Nonsteroidal anti-inflammatory agents




Hypotonic 1.5% glycine irrigant




Selective serotonin reuptake inhibitors


All conditions listed for neonates

Endocrine Disorders



Adrenogenital syndrome


Adrenal insufficiency problems

Glucocorticoid deficiency


Decreased atrial natriuretic peptide

SIADH due to asphyxia



All conditions listed for neonates

Renal Disorders


Nephrotic syndrome

Multicystic kidneys

Acute or chronic renal failure

Obstructive uropathy

Medullary cystic kidneys

Polycystic kidney disease


Renal tubular acidosis

Chronic pyelonephritis

Acute or chronic renal failure

Drug-induced tubulointerstitial nephritis


Hypokalemic nephropathy


Metabolic alkalosis




Postobstructive diuresis


All conditions listed for neonates

Gastrointestinal Disorders

Dilute formulas











Bowel edema


Protein-losing enteropathy



Central Nervous System Disorders




Cerebral salt wasting


Reset osmostat


Negative Na+ balance caused by high FENa + in infants ≤34 weeks gestation

Congestive heart failure

“Third-space” from burns, peritonitis, or severe muscle injury

Hypoalbuminemia and decreased oncotic pressure

Water intoxication (psychogenic polydipsia, dilute formulas)

Osmotic diuresis caused by hyperalimentation and low TmG

Physical and emotional stress


Cystic fibrosis

Congestive heart failure


Hydrops fetalis


Congenital nephrotic syndrome



Rickettsial disease


Fresh-water drowning

Pulmonary disorders

Pseudohyponatremia in patients with hypoproteinemia, hyperglycemia, or hyperlipidemia


Prolonged exercise

CNS, central nervous system; FENa+, excreted fraction of filtered sodium; SIADH, syndrome of inappropriate antidiuretic hormone; TmG, tubular maximum for glucose reabsorption.




Surgery and anesthesia stimulate ADH release. This may persist for 2 or more days and may result in acute hypotonic hyponatremia, particularly when hypotonic fluids are also administered. Even isotonic fluid administration may not prevent hyponatremia due to ADH release, because such individuals often excrete urine with sodium and potassium concentrations higher than plasma. This is partly because of high ANP concentrations that may coexist in this setting. The syndrome of SIADH is discussed separately.

Several causes of hyponatremia require special emphasis. Pseudohyponatremia is associated with normal plasma osmolality and occurs in the setting of severe hyperlipidemia, hyperproteinemia, or disorders in which solutes other than sodium such as glucose, mannitol, or sorbitol result in high plasma osmolality. Administration of thiazide diuretics to individuals with cardiac failure may impair distal tubular dilution of urine and the ability to excrete a water load. Finally, large amounts of hypotonic fluid intake during prolonged exercise can cause acute symptomatic hyponatremia and noncardiogenic pulmonary edema, particularly under high ambient temperatures when sweat sodium and chloride are high or when nonsteroidal anti-inflammatory agents are administered.

In hyponatremic patients who require parenteral fluids, the decision to correct the plasma Na+ level may be based both on clinical symptoms and signs and on the rapidity with which the disorder developed. Children are especially prone to neurologic symptoms ( Laureno and Karp, 1997 ; Lauriat and Berk, 1997 ; Albanese et al., 2001 ). In clinical practice, the most important prophylactic measure for preventing hyponatremia is to avoid the infusion of hypotonic fluids. Common symptoms and signs of hyponatremia include headache, fatigue, nausea, and vomiting; seizures and respiratory arrest are more severe and sometimes delayed manifestations. Guidelines for replacing such sodium deficits may be based on the following formula:

For example, the amount of 3% saline solution needed to raise the plasma Na+ to 125 mmol/L in a 10-kg infant with a plasma Na+ concentration of 115 mmol/L (assuming that TBW is 65% of body weight) may be calculated as follows:

In asymptomatic children, the Na+ deficit of 65 mmol may be replaced by 422 mL of normal saline (154 mmol/L) given over 24 hours; symptomatic children may receive 127 mL of 3% saline solution (513 mmol/L) given at a rate of about 5 mL/kg per hr, that is, 2.5 mmol/kg per hr.

With chronic hyponatremia (over 48 hours in duration), adaptive increases in neuronal osmolytes (glutamine, taurine, phosphocreatinine, myoinositol) diminish cellular uptake of water, hence preventing brain edema ( Gullans and Verbalis, 1993 ). Thus, in contrast to acute hyponatremia, in which brain edema combined with noncardiogenic pulmonary edema and hypoxia can disrupt neuronal function, such events are uncommon with chronic hyponatremia. Edema-forming disorders such as nephrosis, liver failure, or congestive heart failure are frequently associated with chronic hyponatremia in children. Although physiologic mechanisms stimulate both sodium and fluid retention aimed at preventing hypovolemia, hypovolemic stimuli for ADH release result in free fluid retention and hyponatremia. Treatment includes the possible correction of the primary disorder, the elimination of diuretics and other offending agents, and limitation of electrolyte-free water intake. Because most individuals with chronic hyponatremia are asymptomatic, and because slow recovery of brain osmolytes coupled with iatrogenic correction of chronic hyponatremia can result in fatal or serious pontine and extrapontine myelinolysis, the rate of correction of serum sodium should be slow (about 0.3 mEq/L per hr) ( Ayus, 1987 ; Adrogue and Madias, 2000a ).

Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a diagnosis by exclusion. It is a hypo-osmolar, saline-resistant form of hyponatremia that occurs in the absence of dehydration, hypoadrenalism, renal failure, hypothyroidism, or myxedema. The nonhypovolemic and nonhypotonic release of ADH impairs the ability of the kidneys to excrete free water.

The main causes of SIADH in infants and children are shown in Box 4-3 . Hyponatremia due to SIADH is uncommon in premature and full-term infants before 4 to 6 weeks of postnatal life because of factors that limit the urinary concentrating ability to values below 600 mOsm/kg. These factors include a low dietary solute intake, low circulating levels of ADH, and tubular hyporesponsiveness to endogenous ADH ( Svenningsen and Aronson, 1974 ; Godard et al., 1979 ). Because of these circumstances, it is indeed difficult to establish the diagnosis of SIADH in such infants. In children with bacterial meningitis, ADH may be directly released through leaky, inflamed vessels, with secondary alterations in the blood-brain barrier. Despite the hyponatremia, mean plasma ADH levels are relatively high rather than suppressed (3.3 U/mL versus 1 U/mL) in such children, and SIADH develops in about 50% ( Kaplan and Feigin, 1978 ).

BOX 4-3 

Disorders Associated With Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Central Nervous System Disorders



Asphyxia in newborns (intraventricular hemorrhage in neonates, mask ventilation)






Meningitis (viral, bacterial, tuberculous)



Cerebrovascular accident (stroke)



Postpituitary surgery



Brain tumors



Brain abscesses






Head trauma



Guillain-Barré syndrome



Lupus cerebritis

Pulmonary Disorders



Atelectasis or pneumothorax in newborns



Positive pressure ventilation






Hyaline membrane disease



Pneumonia (viral, bacterial)












Positive-airway pressure breathing



Ligation of patent ductus arteriosus













Selected serotonin reuptake inhibitors

The diagnosis of SIADH should be suspected in any child with asphyxia, meningitis, brain tumor, trauma, surgery, or pulmonary disease who does not appear dehydrated but has hyponatremia, hypochloremia, persistent natriuresis, decreased plasma osmolality (<270 mOsm/kg), and urine that is not maximally dilute (>100 mOsm/kg). The blood urea nitrogen (BUN) and plasma uric acid levels are frequently reduced.

Na+ excretion in SIADH may vary depending on the extent of ECF expansion, which may raise the GFR and suppress aldosterone release. In addition, intravascular volume expansion stimulates the secretion of ANP, which enhances the renal excretion of Na+. Moreover, Na+ excretion will match or exceed Na+ intake.

The initial treatment of children with SIADH with a few or no symptoms may consist of restricting fluid intake to between one half and two thirds of the maintenance rate, or 800 to 1000 mL/m2 per day. For severely symptomatic children, 3% saline may be given at a rate of 2.5 mmol/kg per hr, or 5 mL/kg per hr to maintain serum Na+ concentrations at or above 125 mmol/L. In patients with urinary osmolality greater than 500 mOsm/kg, an alternative method for faster correction of severe hyponatremia is to use loop diuretics to inhibit reabsorption of free water while replacing measured urinary Na+losses. In young children, such treatment must be monitored especially closely to prevent volume contraction, hypokalemia, or acid-base imbalance. Furosemide at a dose of 1 mg/kg may be given intravenously one or two times daily. Other therapies used to manage adults with SIADH, such as osmotically active agents, dimethyl chlortetracycline, and lithium carbonate, are generally not used in children with this condition. V1a and V2 receptor blockers are newer agents that may soon become available and may be more effective in managing this disorder ( Palm et al., 2001 ).

▪ HYPERNATREMIA (Plasma Na+ >145 mmol/L)

The causes of hypernatremia in infants and children are listed in Table 4-12 . Hypernatremia commonly results from excessive water loss and inadequate water intake and occurs most frequently in individuals who are unable to communicate or satisfy their own thirst by accessing water. Thus, infants and debilitated individuals of any age are particularly susceptible to this disorder. A primary lack of thirst sensation is a very rare cause of this disorder in children. The condition has been caused by improper mixing of formulas and is also increasingly reported with inadequate breastfeeding ( Manganaro et al., 2001 ; Oddie et al., 2001 ). It is also increasingly recognized as a complication in hospitalized very ill individuals with edema in association with renal failure, heart failure, hypotension, or liver failure resulting in impaired sodium excretion and sodium overload ( Kahn, 1999 ; Adrogue and Madias, 2000 ). Administration of isotonic saline given to maintain systemic blood pressure together with associated hyperglycemia may promote hypernatremia in these settings. Also, the deliberate use of hypertonic saline for the treatment of brain edema has occasionally resulted in severe hypernatremia (Peterson et al., 2000 ).

TABLE 4-12   -- Causes of hypernatremia



Hypernatremia Caused by Pure Water Loss



Inadequate water replacement of mucocutaneous fluid losses, especially in low-birth-weight infants or young children with fever and lack of access to water; phototherapy; or use of radiant warmers.



Central diabetes insipidus (low plasma ADH concentration)



Congenital thalamic/pituitary disorders



Acquired: trauma or tumor involving the thalamic/pituitary areas



Nephrogenic diabetes insipidus with failure of thirst response (high plasma ADH concentration)



Congenital distal tubular and collecting duct unresponsiveness to ADH



Biochemical: hypercalcemia, hypokalemia



Dietary: severe protein malnutrition or marked restriction in NaCl intake



Drug-induced: lithium carbonate, demeclocycline, amphotericin B



Anesthetic-induced: methoxyflurane






Hypernatremia Caused by Water Loss in Excess of Sodium Loss



Lactation failure (breast feeding)



Overdressing of neonates and infants



Neonates receiving phototherapy or kept in incubators without normothermal control



Diarrhea or colitis






Profuse sweating



Hyperosmolar nonketoric coma



Hypertonie dialysis



Renal disorders with partial diabetes insipidus or limited concentrating ability, including chronic renal failure, polycysric kidney disease, medullary cystic disease, pyelonephritis, obstructive uropathy, amyloidosis, and sickle cell nephropathy



High protein intake with high urea appearance rate



Diuretics: mannkol, furosemide



Hypernatremia Caused by Sodium Excess



Excess NaCl intake secondary to improper preparation of oral formulas or electrolyte solutions



Excessive administration of NaHCO3



Ingestion of NaCl tablets, sea water, or near-drowning in sea water



Inadequate free fluid relative to NaCl intake because of defective thirst mechanism or unconsciousness



Cushing's syndrome or excessive administration of glucocorricoids



Hyperaldosteronism or excessive administration of mineralocorticoids.



Premature infants and full-term neonates are also prone to hypernatremia because, in addition to an inability to excrete a water load, they are unable to excrete a large solute load (Aperia et al., 1975a, 1975b, 1977 [13] [12] [11]). The renal response to an Na+ load improves gradually, so that by the end of the first year of life, Na+ excretion reaches maximal levels of 16 mmol/hr per 1.73 m2 ( Aperia et al., 1975b ). The limited ability to excrete an Na+ load appears to result from a reduced GFR and tubular inability to significantly increase the fractional excretion of Na+ (FENa +) because of the effect of aldosterone in increasing distal tubular Na+ reabsorption.

Signs and symptoms associated with hypernatremia in infants include muscle weakness, hyperpnea, apnea, bradycardia, restlessness, a high-pitched cry, lethargy, insomnia or coma, and muscular hypertonicity ( Finberg and Harrison, 1955 ). Older children may exhibit thirst, lethargy, confusion, muscle irritability, rhabdomyolysis, respiratory arrest, seizures, or coma. Tachycardia and hypotension are symptoms of hypovolemia, which is an ominous sign suggestive of extreme dehydration. Because of hypertonicity, fluid shift from the intracellular compartment may result in brain shrinkage, subarachnoid hemorrhage, and permanent brain injury when chronic adaptive solute gain fails to maintain cell volume. Even with such correction, the ensuing neuronal hyperosmolality may predispose to cerebral edema and serious neurologic consequences when rehydration with hypotonic fluid is used aggressively.

The initial laboratory investigation of hypernatremia is similar to that noted in the section on dehydration. In the absence of dehydration, the treatment of hypernatremia depends largely on the underlying disorder. The judicious administration of insulin and avoidance of colloids may be needed in patients with hyperosmolar nonketotic hyperglycemic coma. On the other hand, the administration of free water, together with appropriate replacement of arginine vasopressin, is useful for treatment of central diabetes insipidus. Surgery may be used to treat several endocrinopathies, whereas thiazides and a diet low in osmotic activity may be of benefit in nephrogenic diabetes insipidus.

In children with acute hypernatremia due to pure water loss such as those with nephrogenic diabetes insipidus, a hypotonic fluid may be given at a rate that will decrease plasma osmolality by no more than 2 mOsmol/kg per hour calculated using the following formula:

For example, to calculate the water deficit in a 10-kg infant with diabetes insipidus, a current serum Na+ concentration of 160 mmol/L, and a desired plasma Na+ concentration of 140 mmol/L, the following applies:

In children with hypotonic sodium loss, this fluid deficit, together with ongoing fluid losses occurring during the time of replacing such deficits, may be infused as ⅛ or ¼ saline with 1% to 2% dextrose.

With chronic hypernatremia, correction of plasma osmolality may occur at a rate of less than 1 mOsmol/kg per hr, or a reduction in serum sodium of less than 0.5 mEq/L. Hypotonic fluids given at a low rate are the most suitable for this purpose. In individuals with accidental sodium loading, furosemide, combined with adequate replacement of urine volume with 5% dextrose in water, is usually effective unless renal failure is present, in which case dialysis may be of benefit.

Hypernatremic Dehydration

This disorder is relatively common in premature infants of less than 27 weeks gestation ( Baumgart, 1982 ; Baumgart et al., 1982 ). Its typical presentation, however, is in infants less than 12 months of age, with diarrhea being the usual predisposing cause. Such infants have inadequate access to free water, increased insensible water loss, proportionally greater water loss than Na+ loss from the gastrointestinal tract, and, at times, a positive solute balance from the improper use of electrolyte solutions used to manage the diarrhea ( Paneth, 1980 ). Patients with hypertonic dehydration often do not have dehydration of the interstitial fluid compartment and thus may not manifest the poor skin turgor, dryness of mucous membranes, and postural changes in pulse and blood pressure often associated with isotonic or hypotonic dehydration. Muscular hypertonicity may result in nuchal rigidity. Other potential complications include brain hemorrhage and edema following rehydration because of fluid shifting into the brain. Because of impaired insulin secretion initial serum glucose concentrations often exceed 130 mg/dL in 50% and 200 mg/dL in 25% of children with hypernatremia. Hence, the amount of dextrose administered to such individuals may be limited or insulin may be given to prevent further hyperglycemia, osmotic diuresis, and hypernatremia. Hypocalcemia also occurs in 10% to 20% of patients with hypertonic dehydration. The management of this disorder is outlined in Box 4-2 .

Copyright © 2008 Elsevier Inc. All rights reserved. -

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier


Potassium (K+) is the principal cation in the intracellular fluid (ICF), ranging in concentration from 140 to 160 mmol/L; the normal K+ concentration in ECF varies between 3.5 and 5.5 mmol/L (same as 3.5 and 5.5 mEq/L). The low proportion of ECF K+ to ICF K+ is necessary to maintain transmembrane electrical potential, which is essential for proper function of muscle and neural tissue ( Suki, 1976 ).


Total body K+ content correlates with body weight and height and depends on muscle mass ( Pierson et al., 1974 ; Patrick, 1977 ). In a healthy 20-year-old adult, total body K+ approximates 58 mmol/kg, a value that decreases progressively with age as muscle mass decreases and body fat increases. In children, total body K+ is 38 mmol/kg or less ( Pierson et al., 1974 ). More than 90% of body K+ is intracellular, and most of that is in muscle tissue. Of the extracellular K+, only 1.4% is contained within the ECF, whereas the remaining 8.6% is contained in the bone matrix.

The daily need for K+ is about 2 mmol/100 kcal of expended energy. The daily intake from a standard Western diet is estimated to be 0.75 to 1.5 mmol/kg body weight. Typically, approximately 90% of the K+ ingested each day is eliminated in the urine. Less than 15% is eliminated in the stool while a negligible amount is lost through the skin. The amount of K+ eliminated in stool increases, however, with a significant degree of renal failure ( Hayes et al., 1967 ), reaching 34% of dietary intake at a GFR of less than 5 mL/min per 1.73 m2.

The renal tubular mechanisms involved in K+ homeostasis have been extensively reviewed ( Halperin and Kamel, 1998 ). Nearly 85% of the filtered K+ is reabsorbed in the proximal tubule and the ascending thick limb of the loop of Henle. The amount of K+ in the final urine depends on the amount of intake and on the tubular secretion of K+.

Two key hormones lower ECF K+ acutely through redistribution in various tissues. Insulin causes Na+ to enter and H+ to exit cells through the electroneutral Na+/H+ exchanger, and epinephrine (and β2-adrenergic agonists) activates the Na+,K+-ATPase, which exports three Na+ ions for each two K+ ions that enter the cell. Although epinephrine possesses both α- and β-adrenergic properties, it first causes a hyperkalemic response (during the first 1 to 3 minutes) and then a sustained decrease in plasma K+ concentration through trapping of K+ in cells by maintenance of an intracellular net negative charge that is essential in determining the electronegative resting membrane potential. By contrast, α-adrenergic agonists raise plasma K+ concentration by modifying muscle K+ uptake ( Rosa et al., 1980 ).

Chronic K+ homeostasis is largely regulated by secretion of K+ by principal cells that predominate in the renal cortical collecting duct and are located in smaller numbers in the connecting tubule. The main mechanisms of K+ secretion are depicted in Figure 4-5 . Secretion is aided by (1) the plasma aldosterone level that is stimulated by angiotensin II and by high plasma K+ concentrations. Aldosterone activates the epithelial Na+ channel (ENaC). This results in Na+ reabsorption and development of an electronegative lumen voltage that favors K+ secretion. An ATP-sensitive ROMK channel aids the efflux of K+ into the tubular lumen. Many primary adrenal disorders or renal disorders associated with high circulating levels of renin and angiotensin II may lead to secondary stimulation of aldosterone and result in hypokalemia. (2) The peritubular fluid K+ concentration directly stimulates Na+/K+-ATPase and may be the most important mediator of K+ secretion. (3) High urinary flow rates are associated. (4) Hypomagnesemia, possibly through inactivation of the Na+/K+-ATPase pump; (5) higher pH in the lumen of the cortical collecting duct; and (6) reabsorption of bicarbonate and Na+influence the electronegativity in the lumen of the cortical collecting duct.


FIGURE 4-5  Major factors that regulate K+ secretion in principal cells. Sodium is reabsorbed across the luminal membrane through ENaC Na+ channels, with the resultant cellular depolarization increasing the electrical driving force for K+ secretion through ROMK K+ channels. (1) Elevation of peritubular [K+] (circular arrowheads) increases the density of luminal ENaC and ROMK channels, which promote both K+ secretion by increasing the electrical driving force and K+ permeability, respectively. Increases in peritubular [K+] also activate the Na+,K+-ATPase pump in the basolateral membrane and stimulate aldosterone release. (2) Aldosterone (diamond arrowheads) increases the density of ENaC (but not ROMK) channels and activates the Na+,K+-ATPase pump, both of which increase the driving force for K+ secretion. The surface area of the BLM containing the Na+, K+-ATPase pump undergoes amplification during prolonged exposure to either increased peritubular [K+] or aldosterone. (3) Kaliuretic factors, including K+ itself, have been proposed to somehow directly increase K+ secretion. For example, high luminal [K+] may directly increase the activity of ROMK channels.  (From Gennari FJ, Segal AS: Hyperkalemia: An adaptive response in chronic renal insufficiency. Kidney Int 62:1-9, 2002, p 4, Figure 3.)




Understanding of such mechanisms provides physiologic explanations for plasma K+ alterations and for therapeutic rationale. An example is the individual with hypovolemia and hyperkalemia. The kidney guards against extracellular volume contraction by raising angiotensin II levels. The latter increases bicarbonate reabsorption in the proximal and distal tubules such that the cortical collecting duct lumen becomes less electronegative and favors NaCl retention but reduced K+ secretion despite elevated aldosterone levels. In this clinical setting low urinary flow rate also contributes to hyperkalemia. This is in contrast to euvolemic or hypervolemic individuals, in whom a high plasma K+ concentration inhibits proximal tubular bicarbonate reabsorption while it directly stimulates aldosterone release, thereby promoting K+ secretion (along with Cl- and HCO3-) in the cortical collecting duct. In this setting Na+ is reabsorbed through the important effect of aldosterone in activating the specific epithelial Na+channel (ENaC) at the apical membrane of principal cells ( Halperin and Kamel, 1998 ). When ENaC is blocked by trimethoprim, amiloride, or triamterene, kaliuresis is inhibited.

▪ HYPOKALEMIA (Plasma K+ <3.5 mmol/L or <3.5 mEq/L)

Although hypokalemia usually implies total body K+ depletion, it can also be caused by transcellular shifts of K+ without extrarenal losses. Several classifications of hypokalemia have been devised depending on whether the condition is acute or chronic, with or without K+ shift, renal or extrarenal. One classification is shown in Box 4-4 . Because the etiology of renal K+ wasting is extensive, it may be facilitated by further subclassification on the basis of systemic blood pressure ( Box 4-5 ).

BOX 4-4 

Causes of Hypokalemia

Hypokalemia Without Potassium Depletion




High white blood cell count

Transcellular Shifts



Metabolic alkalosis



Insulin excess



β-Adrenergic agonists



Barium intoxication



Toluene intoxication



Hypokalemic periodic paralysis



Delirium tremens

Hypokalemia With Potassium Depletion




Inadequate nutritional intake



Chloride-deficient infant formula

Extrarenal Causes



Copious perspiration (cystic fibrosis)



Gastrointestinal losses/malabsorption



Chronic diarrhea






Gastrointestinal fistulas



Ostomy/short gut syndrome






Rectal villous adenoma






Laxative abuse



Full-thickness burns

Renal Causes



Renal tubular acidosis (RTA, types I and II)



Fanconi syndrome



Carbonic anhydrase inhibitors



Correction phase of metabolic alkalosis

Chloride Depletion



Vomiting/gastric drainage with metabolic alkalosis



Congenital chloride diarrhea



Cystic fibrosis



Diuretics (thiazide, loop, osmotic)




Potassium Wasting



Bartter's syndrome



Gitelman's syndrome



Liddle's syndrome



Renal artery stenosis (high renin and aldosterone release)



Mineralocorticoid excess (Cushing's syndrome, hyperaldosteronism, prolonged use of glucocorticoids, licorice ingestion, 17α- or 11β-hydroxylase deficiency)



Pyelonephritis and other interstitial nephritides



Magnesium depletion



Postobstructive diuresis



Diuretic phase of acute tubular necrosis



Antibiotics (carbenicillin, penicillins, amphotericin B, aminoglycosides, cidofovir)

BOX 4-5 

Renal Wasting of Potassium in Relation to Systemic Blood Pressure

Renal Wasting of K+ Associated With Normal Blood Pressure

High Renin, High Aldosterone



Renal tubular acidosis



Bartter's syndrome



Gitelman's syndrome



Magnesium-losing tubulopathy



Calcium-losing tubulopathy



Osmotic diuresis (hyperglycemia)



Covert diuretic abuse



Prolonged emesis or nasogastric suction



Drugs (penicillins, amphotericin B, aminoglycosides, cisplatin, ifosfamide)

Renal Wasting of K+ Associated With Hypertension

Low Renin, High Aldosterone



Aldosterone-producing adenoma



Idiopathic hyperaldosteronism



Dexamethasone-suppressible hyperaldosteronism



Adrenocortical carcinoma

Low Renin, Low Aldosterone



17α-Hydroxylase deficiency



11β-Hydroxylase deficiency



11β-Hydroxysteroid dehydrogenase deficiency, licorice ingestion



Liddle's syndrome

High Renin, High Aldosterone



Malignant hypertension



Renal artery stenosis



Renin-secreting tumor (Wilms, nephroblastomatosis)



Chronic renal disease

Gill JR, Santos F, Chan JCM: Disorders of potassium metabolism. In Chan JCM, Gill JR, editors: Kidney electrolyte disorders. New York, 1990, Churchill Livingstone, Table 4-6 , p 157.


Hypokalemia Without Potassium Depletion

Pseudohypokalemia can result by increased uptake of K+ when large numbers of leukemic cells (white blood cell count of 100,000 to 250,000 mm3) are allowed to stand at room temperature ( Adams et al., 1981 ). This confounding effect is eliminated by rapid separation of plasma or by cold storage of blood samples at 4°C.

Hypokalemia caused by intracellular shift of K+ is particularly common in metabolic or in respiratory alkalosis, and approximates a 0.6-mmol/L fall for every 0.1-unit increase in blood pH ( Kim and Brown, 1968 ; Adrogue and Madias, 1981 ). Endogenous or exogenous β-adrenergic agonists such as albuterol, dopamine, dobutamine, and theophylline mediate transcellular shifts of K+ (see earlier discussion). Barium poisoning ( Roza and Berman, 1971 ) or toluene intoxication resulting from the inhalation of paint or glue vapors ( Streicher et al., 1981 ) can produce hypokalemia by trapping K+within the cells. Insulin administration activates the Na+,K+-ATPase, resulting in active K+ uptake and hypokalemia. This is frequently encountered during the treatment of diabetic ketoacidosis.

Hypokalemic periodic paralysis is a rare autosomal dominant disorder characterized by recurrent episodes of flaccid paralysis of the trunk and limbs lasting 6 to 24 hours. Paralysis may be accompanied by cardiac arrhythmias, which may be provoked by high carbohydrate intake, exertion, and a high Na+ diet ( Griggs et al., 1970 ). This condition is more common in the Asian population and is characterized by low urinary K+ excretion, low transtubular potassium gradient (TTKG), and no acid-base disturbances ( Lin et al., 2001 ). Dietary restriction of salt and carbohydrates together with spironolactone may help prevent such attacks. Intravenous K+ infusion should be avoided as rebound hyperkalemia can occur. Potassium-sparing diuretics and the ingestion of foods rich in K+ are of limited benefit in treating or in preventing the disorder. Notably, affected individuals are susceptible to malignant hyperthermia with administration of general anesthesia.

Potassium Depletion

K+ depletion accounts for most cases of hypokalemia. Three basic disturbances can affect total body K+ balance and result in cellular depletion: poor nutritional intake, extrarenal loss of K+, and renal loss of K+.

Nutritional Causes

A deficient diet alone seldom causes symptomatic hypokalemia because K+ is ubiquitous in foodstuffs. In adults, a reduction in K+ intake to less than 10 mmol/day for 7 to 10 days will cause a relative total body K+ deficit of 250 to 300 mmol, or a decrement of 7% to 8% ( Wormersley and Darragh, 1955 ). Occasionally K+ depletion occurs in hospitalized patients maintained on K+-free intravenous fluids. In these instances, the kidney responds by appropriately decreasing K+ excretion, although it cannot produce K+-free urine.

Extrarenal Causes

Diarrhea, vomiting, and abuse of laxatives result in hypokalemia via a complex process. In addition to K+ loss in vomiting and stool, these conditions cause intravascular volume contraction, secondary hyperaldosteronism, and enhanced urinary excretion of K+. In children, diarrhea is often accompanied by hyperchloremic metabolic acidosis ( Welfare et al., 2002 ), whereas laxative abuse is associated with normal acid-base status or mild metabolic alkalosis.

Copious perspiration from intense physical exertion in a hot environment causes K+ depletion ( Knochel et al., 1972 ). This condition is characterized by normal plasma K+ concentration with total body K+ depletion and a high rate of urinary K+ excretion. Loss of K+ via sweat and secondary hyperaldosteronism explains the depletion state and the urinary loss; the sustained normal plasma K+ level, however, is not adequately explained. The human colon responds to aldosterone in a similar fashion resulting in an increase in the renal collecting duct transepithelial potential difference followed by an increase in Na+,K+-ATPase activity ( Thompson and Edmonds, 1971 ). Glucocorticoids are kaliuretic, and evidence suggests that their effect is independent of any action on the mineralocorticoid receptor (Bia et al., 1982 ). Furthermore, glucocorticoids appear to cause an increase in K+ and a decrease in Na+ stool concentration associated with increased Na+,K+-ATPase activity ( Charney et al., 1975 ).

Renal Causes

Renal wastage of K+ occurs by several different yet interrelated mechanisms. First, an increased Na+/K+ exchange may occur in the distal tubule in conditions associated with increased circulating mineralocorticoid or glucocorticoid concentrations resulting in circulatory volume expansion and suppression of plasma renin and aldosterone levels. Hypokalemia often occurs in Conn's syndrome (Ganguly and Donohue, 1983 ). It also occurs in 30% of patients with adrenal hyperplasia (Cushing's syndrome) ( Prunty et al., 1963 ). The ingestion of certain foods and use of glucocorticoids or other drugs possessing mineralocorticoid activity can also result in hypokalemia. Licorice, for example, contains large amounts of glycyrrhizic acid, which impairs adrenal 11β-hydroxysteroid dehydrogenase action. This impairs the degradation of endogenous glucocorticoids, resulting in a mineralocorticoid-like response ( Brem, 2001 ).

Second, increased delivery of Na+ to the distal tubule, which occurs in various proximal tubulopathies, including proximal renal tubular acidosis and Fanconi's syndrome, may enhance K+ secretion. Similarly, thiazides and loop diuretics increase the delivery of Na+ to the distal nephron, thus promoting K+ excretion ( Kassirer and Harrington, 1977 ). This effect by diuretics is augmented by concomitant Cl- depletion ( Kassirer and Harrington, 1977 ) and by contraction alkalosis ( Seldin and Rector, 1972 ).

Third, large concentrations of nonabsorbable anions in the distal tubules, such as penicillins, increase the electronegativity of tubular fluid and induce kaliuresis and hydrogen ion secretion ( Lipner et al., 1975 ). Carbenicillin is particularly notorious for causing hypokalemia because it is secreted actively in the proximal tubule, and high concentrations of the anion are delivered to the distal nephron (Stapleton et al., 1976 ).

Fourth, kaliuresis may occur secondary to direct damage to the renal epithelium. Conditions such as pyelonephritis and other interstitial nephritides may be associated with hypokalemia. Similarly, antibiotics such as amphotericin B, polymyxin, and outdated tetracycline can lead to K+ depletion through their direct toxic effects on the renal tubules ( Chesney, 1976 ). Aminoglycosides result in magnesium as well as K+ wasting, probably because of a change in the permeability of the renal epithelium to these cations ( Humes et al., 1982 ). Experimentally, hypokalemia tends to occur within the first 7 days of aminoglycoside administration and often occurs in the absence of overt acute tubular necrosis and renal failure. This tubular defect and the risk of hypokalemia usually resolve within 1 to 2 weeks after discontinuation of the drug.

Fifth, several genetic disorders are known to cause K+ depletion. Box 4-5 characterizes such disorders of hypokalemia based on the presence or absence of hypertension. Hypertensive disorders may be associated with high peripheral renin activity (renovascular disorders comprise the majority of such causes in children) or low renin states that are associated with either increased plasma mineralocorticoid or glucocorticoid levels or with more direct activation of the principal cell amiloride-sensitive Na+ channel (ENaC) in the cortical collecting duct resulting in salt retention, chronic volume expansion, renin and aldosterone suppression (hence “pseudoaldosteronism”), and hypertension as exemplified in Liddle's syndrome. In the latter disorder, treatment consisting of blockade of the mineralocorticoid receptor with spironolactone, or of the aldosterone receptor by amiloride, is less effective than the combination of triamterene and a low-salt diet.

Manifestations of Potassium Depletion

Hypokalemia results in multiple biochemical and neurophysiologic disturbances ( Weiner and Wingo, 1997 ) ( Box 4-6 ). Chronic hypokalemia and moderate degrees of acute K+ depletion (5% to 10% of total body K+) are generally well tolerated. More profound deficits result in clinical manifestations independent of the underlying cause of hypokalemia.

BOX 4-6 

Pathophysiologic Consequences of Hypokalemia




Peripheral nerves (paresthesias)



Skeletal muscle (fatigue, weakness, cramps, flaccid paralysis, rhabdomyolysis, myoglobinuria)



Smooth muscle (paralytic ileus, increased vascular pressor resistance)




Concentration defect (polyuria, nocturia)



Sodium retention



Increased ammonia production, enhanced bicarbonate reabsorption



Reduced renal blood flow, decreased GFR



Predisposition to urinary tract infection



Interstitial fibrosis



Cyst formation




Metabolic alkalosis



Impaired hepatic glycogen storage



Impaired protein metabolism



Insulin resistance



Increased plasma ammonia



Growth retardation




Impaired growth hormone release



Impaired insulin secretion



Decreased aldosterone secretion



Increased renin release



Increased synthesis of prostaglandins

Gill JR, Santos F, Chan JCM: Disorders of potassium metabolism. In Chan JCM, Gill JR, editors: Kidney electrolyte disorders. New York, 1990, Churchill Livingstone, Table 4-7 , p 158.


Biochemical consequences of hypokalemia include impairment in insulin release ( Rowe et al., 1980 ) and insulin end-organ sensitivity, thereby increasing the risk of hyperglycemia or precipitation of frank diabetes mellitus. Metabolic alkalosis results from direct stimulation of proximal tubular bicarbonate reabsorption and ammonia genesis by increased proton secretion via H+,K+-ATPase located in the collecting duct and by decreasing citrate excretion. Inadequate ADH response and increased synthesis of angiotensin II in the central nervous system may cause polyuria. Hypokalemia may raise plasma ammonia levels in patients with reduced hepatic function. Also, chronic renal K+ wasting may predispose to formation of renal cysts and interstitial fibrosis ( Torres, 1990 ).

Many of the symptoms of acute hypokalemia relate to disturbed neuromuscular functions. Skeletal muscle weakness due to cell hyperpolarization is the earliest manifestation of K+ depletion. Plasma K+concentrations below 3.0 mEq/L lower the resting cell membrane potential and thereby increase the voltage needed to reach the threshold and initiate an action potential ( Fig. 4-6 ). The symptoms include restless leg syndrome, fatigue, muscle cramps, paralysis, and rhabdomyolysis. Frank muscle necrosis may occur with serum K+ concentrations below 2.0 mEq/L ( Knochel, 1982 ). Cardiac manifestations of hypokalemia include abnormalities in rhythm as a result of slowed repolarization ( Helfant, 1986 ). The presence of electrocardiographic changes helps to exclude spurious hypokalemia and may aid the decision to manage the hypokalemia urgently ( Fig. 4-6 ). Abnormalities include depression of the ST segment, lower T-wave voltage, and appearance of U waves. Patients receiving cardiac glycosides are especially at risk of developing such abnormalities. Hypokalemia also impairs the cardiovascular responses to norepinephrine and angiotensin II.


FIGURE 4-6  Typical action potential profile. Normal threshold is influenced by Ca2+ concentrations, whereas K+ concentrations affect the resting potential.  (From Leaf A, Cotran RS: Renal pathophysiology, ed 2. New York, 1980, Oxford University Press, p 119, Figure 1.2.)




K+ depletion may lead to several functional and structural abnormalities in the kidney, including reduced RBF and GFR, renal hypertrophy, tubuloepithelial dilation, vacuolization, and sclerosis ( Relman and Schwartz, 1956 ). Functionally, patients develop urinary acidification and concentration defects and polyuria.

Diagnosis of Hypokalemia

When hypokalemia is diagnosed, the underlying pathophysiologic cause may not be apparent. Measurement of urinary K+ levels may be helpful. A urinary concentration less than 10 mEq/L suggests nearly maximal conservation and usually implies extrarenal loss of K+. Urinary K+ concentrations exceeding 30 mEq/L suggest the kidney is a likely route for the depletion. In patients maintained on diuretics, the caveat is that within hours of discontinuation of these agents, the kidney responds by conserving K+.

Treatment of Hypokalemia

The treatment of hypokalemia requires extreme caution, as the magnitude of loss is difficult to measure clinically. In the absence of cellular shifts, the percent of total body K+ deficit may be grossly estimated from the plasma concentration and intracellular K+ content (0.40 ×body weight ×145 mEq/L) as follows:

The concurrence of hypokalemia and metabolic acidosis suggests an even greater K+ depletion. In such children the correction of the acidosis should follow, rather than precede, the correction of hypokalemia. Guidelines for potassium supplementation in dietary or medication forms are available for adults but not for children ( Cohn, 2000 ). Such supplements should be given with close monitoring of blood levels, particularly when combined with potassium-sparing diuretics such as amiloride and spironolactone. Providing details of managing children with specific disorders associated with chronic hypokalemia is beyond the scope of this chapter. Supplemental K+ at a dosage of 3 to 5 mEq/kg per day (plus maintenance amounts) may be given orally as the chloride salt, because most disorders are associated with chloride depletion. Several liquid and salt preparations are available. Microencapsulated salt preparations are associated with a lower rate of gastrointestinal bleeding and hemorrhage. In patients with combined K+ and phosphate depletion, the phosphate salt is recommended. Magnesium correction may help improve the hypokalemia, especially in refractory states such as Gitellman syndrome ( Whang et al., 1992 ). High K+-containing foods are useful in individuals managed with laxatives and diuretics.

Intravenous K+ repletion is often desirable for the management of acute hyperkalemia, particularly when neuromuscular or electrocardiographic alterations are clinically evident. Concentrations as high as 40 mEq/L may be given peripherally. Higher concentrations should be administered in large veins to prevent phlebitis. Concentrations exceeding 60 mEq/L generally are not recommended. In special clinical situations, higher K+ concentrations may be delivered in limited fluid volumes by diluting 20 mEq of KCl in 100 mL in a Soluset with a microdip and infusing it at a rate not to exceed 0.5 mEq/kg per hr (maximum, 30 to 40 mEq/hr). Such higher infusion rates, although reserved for life-threatening situations, can be given perioperatively in hypokalemic children with close cardiac monitoring and frequent measurement of plasma K+ concentrations.

▪ HYPERKALEMIA (Plasma K+ >5.5 mEq/L in Infants and Children, or >6 mmol/L in Neonates)

Conditions causing hyperkalemia are listed in Box 4-7 . Hyperkalemia may result from a surprisingly small increase in total body K+ or may result rapidly from transcellular shift. Normally, the kidney provides the crucial defense against slight elevations in serum K+ level. Thus, with a few exceptions, hyperkalemia occurs with high frequency in conditions characterized by decreased urine flow rates or marked reduction in GFR. In the absence of renal insufficiency, drugs are responsible for most cases of hyperkalemia. Several agents may cause hyperkalemia by increasing the K+ load, by facilitating transcellular K+ efflux, or by impairing renal excretion of K+ (Perazella, 2000) ( Table 4-13 ).

BOX 4-7 

Causes of Hyperkalemia




Ischemic blood drawing






Thrombocytosis (>1,000,000/mm3)



Leukocytosis (>500,000/mm3)



Familial “leaky red blood cell”



Infectious mononucleosis

Transcellular Shifts



Metabolic acidosis



Hyperglycemia with insulin insufficiency



Extracellular hypertonicity



Tissue damage: trauma, exercise, burns, rhabdomyolysis, asphyxia, catabolic states, sepsis, rejection of transplanted organs (such as liver, kidney)



Drugs (see Table 4-13 )



Familial hyperkalemic periodic paralysis

Increased Potassium Load



Dietary excess, oral or intravenous K+ supplementation



Use of aged bank blood/hemolysis






High doses of K+-containing medications (such as potassium penicillin)

Decreased Renal Excretion of Potassium



Acute renal failure



Chronic renal failure



Low-birth-weight infants



Spitzer-Weinstein syndrome



Drugs (see Table 4-13 )



Hyporeninemic hypoaldosteronism



Type I and type II pseudohypoaldosteronism



Addison's disease (hypoaldosteronism)



Obstructive uropathy



Impaired steroidogenesis (congenital adrenal hyperplasia, mitochondrial disorders, Smith-Lemli-Opitz syndrome)

TABLE 4-13   -- Medications that can cause hyperkalemia and their mechanism of action



Increased Potassium Input

Potassium supplements and salt substitutes

Potassium ingestion

Nutritional and herbal supplements

Potassium ingestion

Stored packed red blood cells

Potassium infusion

Penicillin G potassium

Potassium ingestion

Transcellular Potassium Shifts


Decrease β2-driven potassium uptake

Intravenous amino acids (lysine, arginine, and ε-aminocaproic acid)

Release of potassium from cells


Depolarize cell membranes

Digoxin intoxication

Decrease Na+, K+-ATPase activity

Impaired Renal Excretion

Potassium-sparing diuretics



Aldosterone antagonism


Block Na+ channels in principal cells


Block Na+ channels in principal cells

Nonsteroidal anti-inflammatory drugs

Decrease aldosterone synthesis


Decrease renal blood flow and glomerular filtration rate

ACE Inhibitors and Angiotensin II Receptor Blockers


Decrease aldosterone synthesis


Decrease renal blood flow and glomerular filtration rate

Trimethoprim and pentamidine

Block Na+ channels in principal cells

Cyclosporine and tacrolimus

Decrease aldosterone synthesis


Decrease Na+, K+-ATPase activity


Decrease K+ channel activity


Decrease aldosterone synthesis

Modified from Perazella MA: Drug-induced hyperkalemia: Old culprits and new offenders. Am J Med 109:307–314, 2000, p 308, Table 2.

ACE, angiotensin-converting enzyme.




Transcellular Shift

Among conditions associated with altered K+ distribution across cell membranes is poorly controlled insulin-dependent diabetes mellitus. The mechanism is twofold: hyperglycemia causes hypertonicity with resultant extrusion of K+ from cells, whereas insulin deficiency does not promote K+ entry into the cells ( Ammon et al., 1978 ). These effects are independent of aldosterone response and level of renal function.

Cellular damage from rhabdomyolysis, burns, tissue necrosis, or fulminant rejection of a grafted organ may release large quantities of K+ into the extracellular space. In patients with normal renal function, most of the excess K+ is easily excreted. In those with large tumor lysis after induction of chemotherapy ( Araseneau et al., 1973 ) or those with renal impairment, however, hyperkalemia may occur.

During metabolic acidosis, part of the hydrogen ion load is buffered within cells in exchange for K+. It has been noted that for every 0.1-U decrease in blood pH, serum K+ changes by 0.6 mEq/L. Changes in plasma HCO3- concentration per se may influence K+ concentration independent of changes in pH. Clinically, serum K+ can be decreased with bicarbonate administration in the absence of metabolic acidosis ( Fraley and Adler, 1977 ).


Ischemic blood drawing is a very common cause of pseudohyperkalemia, especially in infants and young children undergoing blood sampling by lancing and squeezing the finger or heel or because of hemolysis from prolonged application of tourniquets. Several conditions cause false elevations in plasma K+ concentrations, including thrombocytosis ( Ingram and Seki, 1962 ), leukocytosis ( Chumbley, 1970 ), hemolysis, and sampling of ischemic blood. In general, immediate determination of K+ in plasma instead of in serum minimizes the release of K+ from the cellular components and avoids the development of pseudohyperkalemia.

High Potassium Intake

An oral intake of as little as 50 mmol of K+ (<2% of normal body K+ content) by an adult can cause a transient increase in plasma K+ of 0.5 to 1.0 mmol/L. From 70% to 90% of this load is sequestered intracellularly within 15 to 30 minutes and ultimately excreted in the urine. Thus, when renal function is normal, large amounts of K+ may be ingested without adverse sequelae. However, the intravenous administration of K+ at a rate higher than 0.5 mmol/kg per hr may result in life-threatening hyperkalemia. In patients with renal insufficiency, hyperkalemia may occur due to increased excretory burden associated with large doses of potassium penicillin (106 U contain 1.7 mEq K+), juices with high K+ content, overuse of salt substitutes (1 g contains 10 to 13 mEq of K+), and the administration of banked stored blood (1 L contains 15 to 20 mEq of K+) ( Bostic and Duvernoy, 1972 ).

Decreased Potassium Excretory Capacity

Regardless of the underlying cause, impaired renal function predisposes to K+ retention and hyperkalemia. However, hyperkalemia is uncommon even in advanced renal failure unless endogenous or exogenous loads are excessive. Nonoliguric individuals with impaired GFR can excrete ordinary dietary intakes of K+ until GFR decreases to as low as 5 mL/min per 1.73 m2 ( Gonick et al., 1971 ). An increase in K+ secretion per nephron, as well as increased colonic secretion ( van Ypersele de Strihou, 1977 ), helps to prevent hyperkalemia in severe renal failure. If hyperkalemia occurs with a GFR above 10% of normal, other causes should be sought, such as worsening metabolic acidosis, increased catabolism, cell injury, hemorrhage, or use of potassium-sparing diuretics.

The most common clinical setting in which hyperkalemia occurs is acute oliguric renal failure of any etiology. In addition to the decreased excretory capacity, an increased K+ burden is imposed by an increased catabolic rate. The daily increase in K+ concentration averages 0.3 to 0.5 mmol/L in oliguric acute renal failure under optimal conditions of nutrition, whereas the increase exceeds 0.7 mmol/L in patients with trauma, a high rate of catabolism, or both ( Schrier, 1979 ).

Hyporeninemic hypoaldosteronism accounts for more than 50% of adults or older children with unexplained hyperkalemia accompanying adequate, albeit decreased, GFR ( Schambelan et al., 1980 ). Most patients have a component of chronic interstitial renal disease, and more than half have diabetes mellitus.

Obstructive uropathy may be associated with a defect in K+ excretion associated with a mild hyperchloremic acidosis, decreased fractional excretion of K+, and mild hyperkalemia ( Battle et al., 1981 ) because of end-organ resistance to the action of aldosterone or because of hypoaldosteronism per se.

Many drugs or drug combinations can cause hyperkalemia, particularly when KCl supplements are coadministered (Perazella, 2000) (see Table 4-13 ). For example, a potassium-sparing diuretic and an angiotensin-converting enzyme inhibitor can result in life-threatening hyperkalemia-induced arrhythmia, especially in diabetics with renal insufficiency or other high-risk groups. The mechanisms may involve (1) direct suppression of renin release by β-blockers or by prostaglandin synthetase inhibitors leading to secondary hypoaldosteronism, (2) lowering aldosterone synthesis by angiotensin-converting enzyme inhibitors, or (3) inhibition of Na+,K+-ATPase and other transporters in principal cells by digitalis, trimethoprim, cyclosporine, or tacrolimus. Succinylcholine increases plasma K+ concentration by increasing the permeability of muscle membranes during depolarization ( Gronert and Theye, 1975 ).

Adrenal destruction due to hemorrhage, tumor, infection, autoimmune polyglandular syndrome, or adrenoleukodystrophy can cause an Addison-like presentation with fatigue, muscle weakness, hypotension, and hyponatremia. Congenital disorders associated with reduced steroidogenesis may have a similar clinical presentation ( Ten et al., 2001 ; Bonny and Rosier, 2002 ). Hereditary disorders with similar sodium wasting and hyperkalemia, but with increased, rather than low, plasma renin and aldosterone levels, include the autosomal dominant (self-limited) and autosomal recessive (permanent) forms of pseudohypoaldosteronism I. In these disorders, a defective mineralocorticoid receptor is responsible for hyponatremia, hyperkalemia, and metabolic acidosis ( Ten et al., 2001 ; Bonny and Rosier, 2002 ). In contrast, pseudohypoaldosteronism Type II (Gordon syndrome) is a sporadic or autosomal dominant condition associated with hypertension, suppressed plasma renin activity, normal plasma aldosterone concentration, and mild hyperchloremic acidosis that respond well to thiazide diuretic ( Milford, 1999 ).

Manifestations of Hyperkalemia

The clinical manifestations of hyperkalemia relate to interference with the electrophysiologic activities of muscle. Under the influence of hyperkalemia, the ratio of intracellular to extracellular K+ is decreased, resulting in delayed depolarization, hastened repolarization, and slow conduction velocity ( Knochel, 1982 ). The most important effect involves the heart. Diagnostic electrocardiographic alterations include tenting or symmetric peaking of the T wave in the precordial leads and depression of the ST wave ( Fig. 4-7 ). In severe hyperkalemia, there is widening of the QRS complex, lengthening of the PR interval, first-degree or second-degree heart block, disappearance of the P wave, and, finally, atrial standstill. Ventricular fibrillation or asystole follows the development of a sinusoid wave. Although the magnitudes of hyperkalemia and of cardiotoxicity correlate well, arrhythmias may develop with even mild hyperkalemia when other metabolic abnormalities such as hyponatremia, acidosis, or calcium disorders coexist.


FIGURE 4-7  The relationship between plasma potassium concentration and electrocardiographic changes.  (From Winters RW: The body fluids in pediatrics. Boston, 1973, Little, Brown, p 134, Figure 10.1.)




Hyperkalemia affects electrical activities in noncardiac muscle as well. Such manifestations as paresthesias, weakness, and flaccid paralysis that spare the head and trunk are not rare.

Clinical Evaluation of Dyskalemia

The initial step involves a clinical assessment of circulatory volume ( Halperin and Kamel, 1998 ; Rodriguez-Soriano, 1990 ). Assuming that Na+ and fluid conservation mechanisms are intact, the next step is to assess if the excretion of K+ is appropriate compared with expected values in healthy children ( Rodriguez-Soriano, 1990 ). If K+ excretion is abnormal, urinary flow rate and K+ excretion rate are measured separately. The flow rate in the terminal portion of the cortical collecting duct (CCD) is proportional to the osmolar particles in urine, which consist primarily of urea derived from protein metabolism, with Na+ and Cl- contributing to a lesser extent. This is derived as follows:

where U refers to urine and P refers to plasma. Under the influence of ADH, a minimum flow rate in the CCD is 1 L for each 300 mOsmol excreted, which is approximately the osmolality of plasma. Thus, a lesser osmolality in the CCD would result in a lower flow rate and reduced net K+ secretion.

If the flow rate in the CCD is adequate, then the ability of principal cells to secrete K+ depends largely on the appropriate activity and secretion of K+ by ENaC and ROMK channels (see Fig. 4-5 ). This is assessed by measurement of urinary chloride excretion and by estimation of the transtubular [K+] gradient, or, TTKG:

This equation provides an estimate of the K+ concentration in the CCD relative to plasma K+ concentration after correcting for further water reabsorption past the CCD, in the medullary collecting duct, under the influence of ADH. TTKG values under 4.9 in infants or under 4.1 in children indicate a reduced ability to secrete K+ due to hypoaldosteronism or pseudohypoaldosteronism and prompt further investigation of renal and adrenal disorders ( Rodriguez-Soriano, 1990 ). Such evaluation may consist of venous blood gas, electrolyte measurement of gastric fluids, urinary nitrogen, plasma renin, aldosterone, cortisol and corticosterone concentrations, and, possibly, identification of mutated genes.

Treatment of Hyperkalemia

The strategy of managing hyperkalemia ( Box 4-8 ) depends on the plasma K+ concentration, renal function, and cardiac manifestations. Mild to moderate hyperkalemia without major electrocardiographic changes responds to a simultaneous decrease in K+ intake and increase in Na+ intake. In certain instances, loop diuretics may be used to increase K+ excretion.

BOX 4-8 

Treatment of Hyperkalemia

Treatment of Mild Hyperkalemia



Decrease dietary K+ burden



Discontinue K+-containing medications or K+-sparing diuretics



Eliminate conditions that favor hyperkalemia (acidosis, sodium restriction)

Treatment of Moderate to Severe Hyperkalemia

To Reverse Membrane Effects



Calcium gluconate, 100 to 200 mg/kg per dose

To Produce Transcellular Shifts



Sodium bicarbonate, 1 to 2 mmol/kg per dose



Glucose, 0.3 to 0.5 g/kg as 10% glucose solution with insulin, 1 U per 4 to 5 g glucose IV



Albuterol by nebulizer




To Remove Potassium



Kayexalate, 1 g/kg per dose PO or enema



Furosemide (Lasix), 1 mg/kg per dose IV



Dialysis (hemodialysis or peritoneal dialysis)



Hemofiltration (continuous arteriovenous hemofiltration or continuous venovenous hemofiltration with or without dialysis)

The fastest means of reversing cardiotoxicity is to antagonize the membrane effects of high plasma K+ concentration. Calcium decreases the threshold potential of excitable tissue, thus restoring the normal difference between threshold and transmembrane potentials (see Fig. 4-6 ).

Calcium gluconate, infused intravenously at 100 to 200 mg/kg per dose, is an effective initial measure even in the absence of hypocalcemia.

If the clinical setting permits administration of a high fluid volume rate, a solution consisting of glucose and insulin added to 0.9 N NaCl is the most effective means for lowering plasma K+ concentration (10% glucose solution, with insulin added at a ratio of 1 unit per 4 or 5 g of glucose). In children with metabolic acidosis, K+ can be driven intracellularly by intravenous NaHCO3 given at 1 to 2 mEq/kg per dose. Both treatment measures decrease plasma K+ levels within minutes and are effective regardless of acid-base or insulin status. Hyperventilation (with resultant hypocapnia and respiratory alkalosis) abruptly increases the urinary excretion of K+. Its effect, however, is not sustained beyond 24 hours ( Gennari, 2002 ).

Sodium polystyrene sulfonate (Kayexalate), a cation exchange resin, can be administered at a dose of 1 g/kg, in sorbitol for oral use, or in mineral oil for rectal instillation. This dosage may be repeated every 2 to 4 hours. Typically, plasma K+ concentration decreases by 1 mEq/L per dose. The onset of action for the oral route is 1 to 4 hours, whereas an enema removes K+ within 30 to 60 minutes. In patients with renal failure, repeated administration of Kayexalate may impose a high Na+ load with resultant hypertension and edema.

Dialysis may be useful in the treatment of hyperkalemia, especially in patients with renal failure. Hemodialysis can remove 1 mEq K+/kg per hour. The duration of this effect depends on the rate of ongoing endogenous release of K+. Peritoneal dialysis is less efficient than hemodialysis, but it can be performed more safely in small infants and children.

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Copyright © 2005 Mosby, An Imprint of Elsevier


Pharmacologic agents that promote diuresis represent a major advance in the treatment of edema and hypertension. The principal therapeutic purpose of these agents is to induce a negative Na+ and fluid balance. The increase in urine output merely reflects the linkage of salt and water transport in the kidney: solute reabsorption limits the osmotic reabsorption of water, and “diuresis” ensues.


In this section diuretics are classified according to the site of action in the nephron. This system is oversimplified, because several agents have pharmacologic effects that are not localized to a single tubular site ( Table 4-14 ).

TABLE 4-14   -- Site, mechanism, duration of action, and dose of diuretics







Site of Action


Mechanism of Action[*]




Dose (mg/kg per day)


Proximal tubule

Acetazolamide (Diamox)

Carbonic anhydrase inhibitor

1 to 2


4 to 6

5 to 7




Osmotic diuretic

1 to 2



0.5 to 1.0 g/kg per dose


Ascending loop of Henle

Fursemide (Lasix)

Inhibition of chloride reabsorption

0.5 to 1

2 to 4

6 to 8

2 to 6 (oral)

Very potent







1 to 6 (IV)



Bumetanide (Bumex)


0.25 to 0.5


5 to 8

0.08 to 0.6 (oral)

Very potent







0.04 to 0.4 (IV)



Ethacrynic acid (Edecrin)


0.5 to 1

2 to 4

6 to 8

1 to 2

Very potent

Distal convoluted tubule (early)

Hydrochlorothiazide (Hydrodiuril)

Inhibition of sodium reabsorption

1 to 2

4 to 6

12 to 24

2 to 3.5



Chlorothiazide (Diuril)


1 to 2

4 to 6

12 to 24

20 to 40



Metolazone[†] (Zaroxolyn)




24 to 36

0.5 to 5.0 mg/day

Moderate to potent

Distal convoluted tubule (late) and collecting duct

Spironolactone (Aldactone)

Competitive inhibitor of aldosterone

8 to 24

24 to 48

48 to 72

1 to 2



Triamterene (Dyrenium)

Direct effect by reducing electrical potential between cell and lumen

2 to 4

6 to 8

19 to 24




See text for details of mechanisms of action.

Metolazone acts at the proximal tubule (as a carbonic anhydrase inhibitor) and hence can be used in patients with renal failure, unlike the other thiazides. It is only available in oral form.


Proximal Tubule Diuretics


This is a nonmetabolizable sugar that is osmotically active. Mannitol is freely filtered at the glomerulus, but it is poorly reabsorbed and, hence, it obligates the renal excretion of water ( Warren and Blantz, 1981 ). It limits water reabsorption in segments of the nephron that are freely permeable to water, namely, the proximal tubule, the descending limb of Henle's loop, and the collecting tubule. This results in a decreased gradient for NaCl reabsorption in the late proximal and distal tubule, which, together with a mannitol-induced washout of the hypertonic medullary interstitium brought about by increased blood flow, potentiates natriuresis. The magnitude of the natriuresis depends on the pretreatment intravascular volume status and on RBF.

Mannitol has limited use when GFR is severely compromised and may aggravate congestive heart failure or other conditions in which intravascular volume is often increased.

In nonedematous oliguric conditions, mannitol may be used to increase water excretion in preference to natriuresis. It is also useful in the prophylaxis of acute renal failure due to its ability to expand the extracellular volume, increase tubular fluid flow, redistribute blood to hypoxic inner cortical and outer medullary regions, and scavenge free radicals ( Warren and Blantz, 1981 ). The rationale for using mannitol in oliguric acute renal failure is to convert the condition into a nonoliguric one, thereby permitting easier management of fluids, nutritional support, and electrolytes. In addition, mannitol has been reported to decrease the incidence of acute renal failure in cardiopulmonary bypass surgery ( Rigden et al., 1984 ), myoglobinuria ( Eneas et al., 1979 ), transfusion of mismatched blood (Byrne, 1966), and contrast nephropathy (in patients with chronic renal failure) ( Anto et al., 1981 ). The usual dose is 0.5 g/kg given intravenously as a 12.5% solution. A good response is usually observed within 2 hours and consists of a urine output of at least three times the volume injected (10 to 12 mL/kg). In oliguric conditions, however, loop diuretics may be used initially because these may be effective without risking further intravascular volume expansion.

Because osmotic diuretics such as mannitol reduce TBW and intracellular volume, they help to decrease intracranial pressure in neurosurgical conditions associated with brain edema and to decrease intraocular pressure in ophthalmologic procedures. They also ameliorate symptoms associated with dialysis-related disequilibrium syndrome ( Arieff, 1982 ).

Acetazolamide (Diamox)

This carbonic anhydrase inhibitor causes sodium bicarbonate diuresis and a reduction in total body bicarbonate stores. Its effectiveness is limited by the development of hyperchloremic metabolic acidosis. The bicarbonaturia induces phosphaturia ( Beck and Goldberg, 1973 ), whereas the metabolic acidosis increases calcium excretion ( Lemman et al., 1967 ). Both factors are responsible for renal stone formation and nephrocalcinosis during prolonged use of acetazolamide. It can cause severe K+ wasting, especially during the acute bicarbonaturic phase.

Therapeutically, acetazolamide may be effective in the chronic treatment of glaucoma ( Maren, 1987 ), in alkalinization of the urine ( Conger and Falk, 1977 ), in the treatment of acute mountain sickness (Greene et al., 1981 ), to stimulate ventilation in central sleep apnea ( White et al., 1982 ), to reduce endolymph formation in Meniere's disease ( Brookes et al., 1982 ), and in the treatment of refractory hydrocephalus ( Vogh, 1980 ).

Loop Diuretics

These agents are rapidly absorbed from the gastrointestinal tract and are excreted by glomerular filtration and by tubular secretion ( Rane et al., 1978 ). Diuretic response is usually very rapid after intravenous administration and greatly exceeds that produced by most other diuretic agents.

Loop diuretics inhibit the Na+/K+/2Cl-(NKCC2) electroneutral cotransport system in the luminal membrane of both the medullary and the cortical segments of the ascending limb of Henle's loop, where 20% of the filtered Na+ and Cl- are reabsorbed ( Burg et al., 1973 ). They also inhibit NaCl transport at the level of the proximal and distal tubules ( Imbs et al., 1987 ) and are known to possess weak carbonic anhydrase inhibitory properties ( Radtke et al., 1972 ). Loop diuretics tend to increase RBF without increasing GFR, especially after intravenous administration. Increased RBF is associated with a redistribution of blood flow from the medulla to the cortex and within the cortex ( Higashio et al., 1978 ). The hemodynamic effects appear to involve the renin-angiotensin system and vasodilatory prostaglandins ( Gerger, 1983 ). These hemodynamic effects have not been linked to the diuretic response, however, and tend to be short-lived.

By markedly increasing the movement of solute in the distal segments of the nephron, loop diuretics induce potent diuresis and natriuresis. The large Na+ load presented to the distal tubule is associated with increased K+ and H+ ion secretion. Thus, hypokalemia and metabolic alkalosis may ensue. The hypercalciuric action of loop diuretics makes them suitable agents for treatment of hypercalcemia (Dirks, 1979 ), but their use in newborns with chronic respiratory disorders has been implicated in the development of nephrocalcinosis ( Schell-Feith et al., 2000 ).

In addition to inducing rapid diuresis, loop diuretics appear to improve cardiac function before the onset of diuresis by increasing venous capacitance ( Dikshit et al., 1973 ). These drugs are also effective in the treatment of refractory edema as long as interstitial fluid can be mobilized without compromising intravascular volume. Because furosemide, ethacrynic acid, and bumetanide are effective with GFR as low as 10 mL/min per 1.73 m2, they are useful for management of edema in patients with chronic renal failure. Despite the obvious benefits of high-dose furosemide in certain experimental models of acute renal failure ( deTorrente et al., 1978 ), its use in humans for conversion of oliguric acute renal failure to a nonoliguric state is controversial ( Brown et al., 1981 ). All loop diuretics are ototoxic when given in large dosages to patients with severe renal failure ( Gallagher and Jones, 1979 ). Unique to the loop diuretics, ototoxicity has been ascribed to drug-induced changes in the electrolyte composition of endolymph.

Finally, furosemide must be used cautiously in infants with hyperbilirubinemia because it is highly protein bound ( Prandota and Pruitt, 1975 ) and thus capable of displacing bilirubin from albumin (Wenneberg et al., 1977 ). This phenomenon usually occurs with repeated dosages exceeding 1 mg/kg ( Aranda et al., 1978 ).

Distal Convoluted Tubule Diuretics

The diuretic action of thiazides depends on the direct inhibition of the Na+/Cl- cotransporter in the distal convoluted tubule ( Kunau et al., 1975 ), which is accompanied by enhanced excretion of K+ and hypokalemia. By increasing Na+ delivery to the cortical collecting duct, thiazides induce a kaliuresis that rivals that of loop diuretics, whereas the natriuresis of furosemide is 5 to 10 times greater than that produced by thiazides.

Apart from their use in managing edema and hypertension, thiazides have also been used successfully for treatment of hypercalciuria because they augment the reabsorption of calcium in the distal tubule (Sutton, 1986 ). Thiazides can also reduce polyuria and polydipsia in nephrogenic diabetes insipidus ( Shirley et al., 1982 ). Such beneficial effect probably results from plasma volume depletion with an attendant decrease in GFR, which promotes NaCl and obligatory fluid reabsorption in the proximal tubule. This effect of thiazides is augmented by dietary salt restriction. Finally, thiazides are useful in the treatment of proximal renal tubular acidosis, characterized by marked bicarbonaturia. Depletion of intravascular volume is necessary to increase proximal bicarbonate reabsorption, an effect that is also promoted by restricting dietary Na+ ( Donckerwolke et al., 1970 ).

Combined therapy with thiazides and loop diuretics can be used to manage refractory edema due to cirrhosis, nephrotic syndrome, or severe cardiac dysfunction. Synergy occurs when these classes of diuretics are administered together. NaCl delivery out of the proximal tubule is increased, whereas Na+ reabsorption is inhibited in the loop of Henle and distal tubule. Thus, the resulting diuretic action is greater than that achieved with either agent alone ( Ghose and Gupta, 1981 ). Similarly, metolazone, a thiazide-like diuretic, is particularly useful in the management of edema accompanying congestive heart failure and renal disorders including nephrotic syndrome and states of decreased renal function. While other thiazides lose their diuretic effectiveness at a CrCl of about 30 to 40 mL/min, metolazone retains its effectiveness, especially when used in conjunction with loop diuretics. This is attributed to its action on the proximal tubule in addition to its action on the distal diluting tubular segments. A limiting factor to the use of metolazone is its availability in tablet form, which may preclude its use in patients whose gastrointestinal tract cannot be used. In such instances, chlorothiazide may be used intravenously in conjunction with loop diuretics.

Adverse effects of thiazides include hypokalemia, metabolic alkalosis, carbohydrate intolerance ( Hoskins and Jackson, 1978 ), hyperuricemia ( Manuel and Steele, 1974 ), hyponatremia in the presence of severe restriction of dietary Na+, and hypercalcemia ( Popovtzer et al., 1975 ). In general, the hypercalcemia resolves within a few days.

Late Distal Tubule Diuretic

These diuretics are primarily K+-sparing diuretics. Because of their distal site of action, they are not potent when used alone. Their major use is as adjuncts to thiazide or loop diuretics. Spironolactone competitively antagonizes aldosterone ( Corvol et al., 1981 ), whereas triamterene and amiloride inhibit the epithelial Na+ channel (ENaC) in the cortical collecting duct and thereby limit kaliuresis ( Stoner et al., 1974 ). In addition, triamterene may depress the GFR through its effect on urinary prostaglandin E2 excretion ( Favre et al., 1982 ). In general, these agents should be used cautiously in children with renal failure because of the danger of hyperkalemia. Furthermore, concurrent use of K+-sparing diuretics and K+ supplements is hazardous.

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

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Inhalational and intravenous anesthetics and many intravenous and oral analgesics and sedatives may influence renal function through their hemodynamic, cardiovascular, autonomic, and neuroendocrine effects. The trauma of surgery and possible accompanying dehydration per se are more likely, however, to result in renal dysfunction through elevations in plasma renin, aldosterone, and ADH that accompany surgery. These perturbations are reduced by morphine or halothane anesthesia ( Philbin et al., 1978 ). Prolonged release of ADH associated with surgical stress and use of anesthetics, combined with high infusions of hypotonic fluids, may result in hyponatremia. Moreover, well-hydrated patients may not experience reductions in glomerular filtration ( Philbin et al., 1981 ) and may actually experience increases in RBF with subsequent increases in urine output and sodium excretion ( Bastron et al., 1981 ).

More direct nephrotoxic acute renal failure was common before discontinued use of the fluorinated anesthetic methoxyflurane ( Pezzi et al., 1966 ; Halpren et al., 1973 ). Inhaled anesthetics in current use, such as sevoflurane and halothane, result in lesser amounts of metabolic byproducts composed of inorganic fluoride, as well as oxalic acid, and hence, renal dysfunction is rare with these agents. Fluoride, in particular, may decrease ATP availability and thereby impair the action of the Na+,K+-ATPase in the loop of Henle and in the collecting duct. This may result in a salt-losing, vasopressin-resistant high urine output renal dysfunction ( Whitford and Taves, 1973 ). Conversely, a preexisting reduction in GFR may prolong the pharmacologic half-life of many agents that have significant renal elimination, such as morphine, and thereby exacerbate their hemodynamic and other systemic adverse effects. Moreover, because of short tubular length and enzymatically immature secretory mechanisms, proximal tubular secretion of propofol metabolites and of other substances may be limited in infants under 6 months of age. Awareness of the previously discussed developmental differences in GFR and tubular function in preterm and term neonates and early infancy is essential to determine the choice and dosage modification of many such agents.

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Calcium plays many vital physiologic roles, not the least of which is to maintain the health of bones. It is essential for the stability of cellular membranes and regular neuromuscular excitation-contraction coupling, blood coagulation, and transport and secretory functions of the cell. Furthermore, Ca2+ acts as a “second messenger” in the signal transduction of extracellular hormones and other substances that affect numerous cellular functions.

Calcium Homeostasis

A typical adult diet contains about 800 mg of elemental Ca2+, of which only 20%, or about 4 mmol (160 mg), is absorbed principally in the duodenum and jejunum. This net Ca2+ absorption is closely matched by renal excretion such that all but 4 mmol of the 270 mmol of Ca2+ filtered by the kidneys is excreted in the urine. This contrasts with a net Ca2+ absorption of 40% to 45% in infants and as high as 80% in low-birth-weight infants and breastfed babies ( Liu et al., 1989 ; Matkovic et al., 1992 ). Normal daily bone turnover in adults accounts for 14 mmol of Ca2+ and comprises only a small proportion of the bone reservoir consisting of about 20 moles, or 800 g.

Plasma Ca2+ is maintained at a concentration of 9 to 10.5 mg/dL (2.2 to 2.4 mmol/L) as total calcium, with approximately 40% of this value comprising the protein-bound nonfiltratable fraction, and 10% is chelated. Ionized calcium accounts for 47% of the total circulating Ca2+ and ranges from 4 to 5 mg/dL (1.0 to 1.25 mmol/L) ( Moore, 1970 ).

The extent of protein binding per deciliter of plasma is approximately 0.8 mg of Ca2+ for every 1 g of albumin and 0.16 mg for each 1 g of globulin. Furthermore, a threefold increase in serum phosphate or sulfate concentration results in a 10% decrease in serum Ca2+ concentration. In addition, the binding of Ca2+ to albumin is pH-dependent between pH 7 and 9. An acute increase or decrease in the pH by 0.1 U results in an increase or a decrease, respectively, of protein-bound Ca2+ of 0.2 mg/dL (0.05 mmol/L). Thus, infusion of blood products, rapid correction of metabolic acidosis by infusion of sodium bicarbonate, or acute alkalosis caused by hyperventilation in the presence of hypocalcemia may precipitate tetany and/or seizures because of increased binding of Ca2+ to albumin. Calcium homeostasis is complex and occurs at three main levels, often involving similar calcitropic hormones, receptors, and transporters.

In the small intestine, Ca2+ is absorbed via two mechanisms: (1) a nonsaturable passive paracellular pathway such that a high Ca2+ intake results in higher Ca2+ absorption, and (2) an active energy-dependent intracellular pathway that predominates when calcium intake is low. This latter mechanism is highly influenced by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3 or calcitriol], which stimulates the synthesis and/or activity of enterocyte apical Ca2+ transporters known as CaT1 and ECaC. Calcium crosses the cytoplasm bound to calbindin-D9K and then is extruded against an electrochemical gradient at the basolateral side by plasma membrane Ca2+-ATPase (PMCA). Disorders leading to hypersensitivity or increased synthesis of 1,25(OH)2D3 can result in increased intestinal absorption and hypercalciuria. Lactose stimulates calcium absorption even in the absence of vitamin D via an effect that may involve 25-hydroxylase ( Lester et al., 1982 ). This may explain the higher plasma Ca2+ levels seen in infants. The efficiency of intestinal Ca2+ absorption depends on needs, age, sex, dietary intake, pregnancy, and vitamin D status.

The kidneys play a major role in Ca2+ homeostasis. The mechanisms of renal transport have been reviewed extensively by Suki and Rouse (1991) , Bushinsky (2001) , and Frick and Bushinsky (2003) and are reviewed here briefly. Only the fraction of Ca2+ not bound to protein is filtered, accounting for 60% of the plasma concentration. About 70% of the filtered Ca2+ is reabsorbed in the proximal convoluted tubule through a paracellular pathway involving solvent drag of salt and water (convection). It is then returned to the circulation from the interstitium. About 20% of the filtered Ca2+ is reabsorbed in the thick ascending limb of Henle's loop via both paracellular and transcellular processes. Paracellin is the major protein component of the paracellular tight junction. Similar to the pathway of magnesium reabsorption ( Fig. 4-8A and B ), the Ca2+-sensing receptor (CaSR) detects small changes in interstitial Ca2+ concentrations and regulates the apical ROMK channel, thereby producing a lumen-positive voltage that drives Ca2+ through the tight junctions. In this tubular segment mutations in paracellin, NKCC2 transporter, ROMK, or CaSR, or inhibition of the NKCC2 transporter by loop diuretics, can result in significant hypercalciuria, nephrocalcinosis, and osteopenia. The distal convoluted tubule reabsorbs 8% of the filtered calcium mainly via an active transcellular transport. This mechanism is similar to that found in enterocytes except for intracellular calcium transport occurring through binding to calbindin-D28K and extrusion mainly by a Na+/Ca2+ exchanger and less by PMCA. This mechanism is influenced by parathyroid hormone (PTH) and perhaps by other calcitropic hormones.


FIGURE 4-8  (A) Magnesium reabsorption in the thick ascending limb of the loop of Henle. Driving force for the paracellular reabsorption of magnesium and calcium is the lumen-positive electrochemical gradient generated by the transcellular reabsorption of NaCl. (B)Magnesium reabsorption in the distal convoluted tubule. In this segment, magnesium is reabsorbed by an active transcellular pathway involving an apical entry step probably via a magnesium permeable ion channel and a basolateral exchange mechanism, presumably an Na+/Mg2+ exchanger. The molecular identity of this exchanger is still unknown. See text for details. ADH, autosomal dominant hypocalcemia.  (From Konrad M, Weber S: Recent advances in molecular genetics of hereditary magnesium-losing disorders. J Am Soc Nephrol 14:249-260, 2003, p 251, Figure 4-3 [A] and [B].)




Bone reabsorption and formation also contribute to calcium homeostasis. The mechanisms by which osteoclasts and osteoblasts affect these processes are less well understood, but several hormonal regulators and transport processes are thought to resemble those found in intestine and kidney.

PTH is a major regulator of serum Ca2+ homeostasis. PTH acts via cAMP to increase proximal tubular Ca2+ excretion while it increases reabsorption in the distal and collecting ducts, so that the net effect is conservation of Ca2+ ( Suki and Rouse, 1991 ). PTH also resorbs Ca2+ from the vast skeletal reservoir of Ca2+ and increases intestinal Ca2+ absorption by stimulating 1α-hydroxylase and calcitriol synthesis by proximal tubular epithelium, thereby guarding against hypocalcemia. High plasma phosphorus concentrations directly stimulate PTH release. This causes phosphaturia and raises serum Ca2+concentration by the body's tendency to maintain a constant Ca2+ ×P2- product. Conversely, preterm infants fed diets low in phosphorus develop hypophosphatemia and are susceptible to hypercalcemia through direct stimulation of calcitriol synthesis.

Calcitriol is another major independent homeostatic factor. It increases intestinal absorption of Ca2+, and, in concert with PTH, it stimulates osteoclast-mediated resorption of bone. High serum calcium concentrations, on the other hand, interact with the parathyroid cell Ca2+-sensing receptors to inhibit PTH secretion. High calcitriol levels also exert a negative feedback role on PTH secretion.

Other endogenous or exogenous substances play a lesser role in Ca2+ homeostasis. A hypercalcemic substance produced in several malignant or paraneoplastic syndromes is known as PTH-related peptide (PTHrP). The N-terminal of PTHrP functions like PTH and often contributes to humoral or tumoral hypercalcemia. Increased synthesis of other hypercalcemic cytokines such as interleukins-1,-6, and -11, as well as tumor necrosis factor-α and prostaglandins, may also be released in various malignancies ( Mundy and Guise, 1997 ). Macrophages may be an important source of such factors that act synergistically to produce significant osteolysis. Glucocorticoids lower calcium levels by reducing its intestinal absorption. Excessive thyroid hormone accelerates bone turnover, and calcitonin lowers serum calcium by increasing its excretion at the medullary portion of the thick ascending limb of the loop of Henle while inhibiting bone turnover. Immobilization may raise serum calcium levels by lowering the inflow of calcium into bone hydroxyapatite. Hypervitaminosis D, or a combination of vitamin A administration and decreased vitamin A catabolism in individuals with reduced renal function, may cause hypercalcemia by stimulating intestinal absorption.

Hypocalcemia (Plasma Ionized Calcium <1.0 mmol/L, or Total Calcium <7.0, 8.0, and 8.8 mg/dL, or <1.7, 2.0, and 2.2 mmol/L in Preterm, Term Newborns, and Children, Respectively)

The causes of hypocalcemia in neonates and children are listed in Box 4-9 , and the biochemical features of these disorders are shown (Umpaichitra et al., 2001) ( Table 4-15 ). “Early neonatal hypocalcemia” develops within the first 48 hours after birth in about 33% of infants less than 37 weeks gestation, in 50% of infants of insulin-dependent diabetic mothers, and in 30% of infants with neonatal asphyxia. In this disorder, there appears to be a significant correlation between gestational age and serum calcium levels. Plasma PTH concentrations are usually normal. Hence, the mechanism for the hypocalcemia may involve decreased calcium intake associated with increased P2- loading ( Tsang et al., 1973 ) and possibly resistance to the action of PTH ( Linarelli et al., 1972 ). Elevated calcitonin levels have been recently suggested as a cause of early hypocalcemia, particularly in neonatal asphyxia ( Venkataraman et al., 1987 ).

BOX 4-9 

Causes of Hypocalcemia[*]

Early Neonatal Hypocalcemia



Preterm (related to decreased PTH secretion)



Neonates with asphyxia (limitation of calcium intake)



Infants of diabetic mothers (related to maternal urinary magnesium loss because of glycosuria leading to hypomagnesemia)

Late Neonatal Hypocalcemia (End of the First Week of Life)



Dietary phosphate loading







Childhood Hypocalcemia



Vitamin D-related: Vitamin D-deficient rickets, vitamin D-dependent rickets type I (1β-hydroxylase deficiency), and type II (end-organ resistance to calcitriol)



Parathyroid hormone-related: Hypoparathyroidism, pseudohypoparathyroidism type I and type II



Calcium/phosphorus-related: Malabsorption, hyperphosphatemia



Organ-related: Hepatic rickets, acute pancreatitis, renal osteodystrophy



Miscellaneous: Drugs, such as calcitonin, phosphate, and bisphosphonates; magnesium deficiency; calcium-sensing receptor defect

Modified from Umpaichitra V, Bastian W, Castells S: Clin Pediatr (Phila) 40:306, 2001, Table 1.


*  Causes at different ages at onset can overlap.

TABLE 4-15   -- Causes of hypocalcemia and their biochemical profile clues




Causes of Hypocalcemia




Alk Phos


1,25(OH) 2D3



Vitamin D–deficient rickets

↓, ↔

↔, ↓


Vitamin D–dependent rickets type I

↓, ↔

Vitamin D–dependent rickets type II

↓, ↔


↔, ↓


↔, ↓

Rickets of prematurity

↔, ↓

↔, ↓

↔, ↓


Renal osteodystrophy

↔, ↑

Calcium-sensing receptor defect



↔, ↓

Mg deficiency


Modified from Umpaichitra V, Bastian W, Castells S: Hypocalcemia in children: Pathogenesis and management. Clin Pediatr 40:305–312, 2001, p 307, Table 2.

Ca, calcium; P, phosphorus; PTH, parathyroid hormone; Alk Phos, alkaline phosphatase; Mg, magnesium; ↔, normal; ↓, decrease; ↑, increase; ?, difficult to interpret owing to different degree of renal immaturity in preterm infants; *, decrease or normal or increase; **, decrease or normal or slight increase (relatively low for degree of hypocalcemia).





In term infants, hypocalcemia may occur 5 to 7 days after birth, often associated with the ingestion of cow's milk ( Root and Harrison, 1976 ). Maternal vitamin D status may also play an important role in late neonatal hypocalcemia ( Cockburn et al., 1980 ). Nutritional deficiency of vitamin D, inadequate photoconversion of vitamin D, and decreased calcium intake are currently uncommon causes of hypocalcemia and rickets in infants. In the neonate with micrognathia, hypertelorism, fishmouth, low-set posteriorly rotated ears, and cardiac disease, one must consider branchial dysembryogenesis, or DiGeorge anomaly. In this disorder, there is aplasia or hypoplasia of the parathyroid glands in association with diverse genetic deletions that can be detected by fluorescent in situ hybridization (FISH) DNA probes ( Hong, 1998 ).

In children, autoimmune disorders that are either isolated or associated with other polyglandular syndromes comprise the majority of causes of acquired hypoparathyroidism and are often diagnosed by detection of specific autoantibodies directed against various endocrine tissues. Pseudohypoparathyroidism is associated with mutations in the PTH receptor, which is a G protein-coupled receptor. Circulating PTH levels are high, but there is PTH resistance in bone and kidney or in the kidney alone ( Farfel et al., 1999 ). In the first subtype (Ia), the phenotype consists of hereditary osteodystrophy (Albright's), short fingers, short stature, mental retardation, and subcutaneous calcifications, whereas in subtype Ib, the phenotype is normal. Pseudohypoparathyroidism type II is caused by disturbances in the pathway past the PTH receptor. Plasma PTH levels are also increased in this disorder.

Hypocalcemia is a frequent complication of hypomagnesemia. Three mechanisms have been suggested: resistance to the action of PTH ( Estep et al., 1969 ); subnormal secretion of PTH ( Suh et al., 1973 ); and defective Ca2+/Mg2+ exchange in bone ( Chase and Slatopolsky, 1974 ). Correction of hypomagnesemia has been shown to restore calcium homeostasis.

Hepatic disorders that interfere with vitamin D and other fat-soluble vitamin absorption and conversion to 25-vitamin D3, or calcidiol, can cause hypocalcemia particularly in debilitated or immobilized individuals. In children with renal failure due to a variety of chronic renal disorders, impaired conversion of calcitriol by proximal tubular α-hydroxylase to the active calcitriol form, along with phosphate retention, impaired intestinal absorption of Ca2+, and high circulating PTH concentrations that impair osteoclastic activity, all combine to cause hypocalcemia ( Slatopolski and Delmez, 1992 ). Mutations in 1α-hydroxylase lead to vitamin D-resistant rickets, an autosomal dominant disorder presenting at 4 to 12 months of age with low serum Ca2+ but normal 25-vitamin D3 levels. If calcitriol levels are normal, hypocalcemia can be the result of mutations in the vitamin (calcitriol) D receptor (VDR), which is also an autosomal dominant, vitamin D-resistant condition presenting at 3 to 12 months with rickets and alopecia ( Levine and Carpenter, 1999 ).

Manifestations of Hypocalcemia

Many of the symptoms associated with hypocalcemia are attributed to increased neuromuscular excitability. These symptoms include numbness and tingling of the hands, toes, and lips; irritability, anxiety, and depression; prolonged QT interval; cardiac arrhythmias; and congestive heart failure. In the neonatal period, jitteriness, twitching, and seizures are more common. The seizures may be generalized or focal and usually are short-lived but repetitive, with very little postictal depression. Chvostek's and Trousseau's signs and a high-pitched cry are useful indications, especially in the older infant and child. Infants may have cyanosis, vomiting, or feeding intolerance, whereas older children may present with laryngospasm. With prolonged hypocalcemia, cataracts can develop because of the increased intake of Na+ and water by the lens ( Ireland et al., 1968 ).

Treatment of Hypocalcemia

If hypocalcemia is not life threatening, it is preferable to administer a calcium-containing solution amounting to 15 mg of elemental calcium/kg body weight infused over a period of 4 to 6 hours. For clinical emergencies (seizures, tetany), 10% calcium gluconate is infused, preferably in a large vein or central venous catheter, to provide an elemental Ca2+ dosage of 2 to 4 mg/kg body weight in newborns and 2 to 3 mg/kg body weight in children, given over 5 to 10 minutes under constant electrocardiographic monitoring. Subsequently 25 to 50 mg of intravenous elemental Ca2+/kg body weight per day may be used until hypocalcemia resolves. If hypomagnesemia is also present, 50% magnesium sulfate (48 mg elemental Mg2+/mL) at a dosage of 6 mg of elemental Mg2+/kg body weight may be infused over 1 hour.

Hypoparathyroidism requires the use of calcitriol at an initial dosage of 0.01 mcg/kg body weight daily to maintain plasma Ca2+ concentrations between 8.5 and 9.0 mg/dL. Monitoring of plasma levels and urinary Ca2+ excretion may limit the risk of hypercalcemia, hypercalciuria, and nephrocalcinosis (evident on renal ultrasound). In vitamin D-dependent rickets type I, the dose of calcitriol is 10 to 15 ng/kg per day combined with elemental calcium of 500 to 1000 mg/day. Children with vitamin D-deficient rickets may receive vitamin D (ergocalciferol or Drisdol, 8000 units/mL = 0.2 mg/mL) at 2000 to 10,000 IU/day orally for 4 to 8 weeks, or a single oral megadose of 200,000 to 600,000 IU (Strosstherapy), which is safe and more effective, particularly when compliance is in question. Oral or intravenous calcitriol may be used in pseudohypoparathyroidism or in children with chronic renal failure to increase intestinal absorption Ca2+ and suppress PTH secretion.

Hypercalcemia (Plasma Ionized Calcium >1.35 mmol/L or >5.4 mg/dL, or Total Calcium >10.5 mg/dL, or 2.6 mmol/L)

It is important to exclude pseudohypercalcemia as a cause of hypercalcemia in individuals with essential thrombocytosis after clotting of phlebotomized blood. The causes of hypercalcemia vary by age (Box 4-10 ) ( Rodd and Goodyer, 1999 ; Ziegler, 2001 ). Although hypercalcemia is uncommon in newborns, the most common cause is iatrogenic resulting from excessive administration of calcium salts. Other causes in this age group include idiopathic infantile hypercalcemia, which is usually mild; more severe hypercalcemia occurs in Williams syndrome. Primary neonatal hyperparathyroidism is a very rare disorder caused by homozygous inheritance of mutations in the Ca2+-sensing receptor that result in familial hypocalciuric hypercalcemia (FHH). Although these patients—heterozygous parents are often asymptomatic, the condition may be life-threatening in the offspring due to plasma calcium of 15 to 30 mg/dL, unexplained anemia, hepatosplenomegaly, and nephrocalcinosis. Primary hyperparathyroidism is extremely rare in childhood but may occur in the multiple endocrine adenoma syndrome, in which hypercalcemia, hypercalciuria, and nephrolithiasis relate to elevated levels of 1,25(OH)2D3 ( Broadus et al., 1980 ).

BOX 4-10 

Causes of Hypercalcemia




Iatrogenic (calcium salts)



Idiopathic infantile hypercalcemia



Williams syndrome



Vitamin D



Vitamin D intoxication



Subcutaneous fat necrosis



Parathyroid related






Neonatal severe hyperparathyroidism



Secondary hyperparathyroidism



Familial hypocalciuric hypercalcemia



PTHrP (humoral hypercalcemia) tumor related



PTH receptor mutation—Jansen's metaphyseal chondrodysplasia












Vitamin A intoxication



Blue-diaper syndrome



Thiazide diuretics




Primary hyperparathyroidism



“Tertiary hyperparathyroidism”



Ectopic secretion of PTH by tumors



Neoplasms (bony metastases)



Neoplastic production of 1,25(OH)2D3



Phosphate depletion with hypophosphatemia



Sarcoidosis, tuberculosis, and other granulomatous disorders






Milk-alkali syndrome



Medications (thiazide diuretics, theophylline, lithium, salicylate intoxication, vitamin D or vitamin A intoxication)












Multiple fractures



Acute renal failure

PTH, parathyroid hormone; PTHrP, parathyroid hormone-related protein

Diagnostic Studies

Diagnostic studies to consider in newborns and in children with hypocalcemia or hypercalcemia are shown ( Box 4-11 ) ( Rodd and Goodyer, 1999 ). In general, PTHrP and calcitrophic cytokines need not be measured unless plasma PTH levels are normal or suppressed and the cause of hypercalcemia is cryptic. If PTHrP is measured, the blood tube should contain a proteinase inhibitor.

BOX 4-11 

Evaluation of Infants With Persistent Hypercalcemia



Blood—Total and ionized calcium, pH, phosphorus, alkaline phosphatase, creatinine, intact PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D



Urine—Calcium/creatinine ratio, tubular reabsorption of phosphate



Renal ultrasonography



Other tests that can be performed, if the above do not yield a diagnosis






Vitamin A



Parents—serum calcium and urine calcium



Long bone X-rays

From Rodd C, Goodyer P: Hypercalcemia of the newborn: etiology, evaluation, and management. Pediatr Nephrol 13:542-547, 1999, p 545, Table 2.


Manifestations of Hypercalcemia

Newborns and infants with hypercalcemia present with nonspecific symptoms such as failure to thrive because of anorexia and vomiting. Irritability, lethargy, hypotonia, and seizures are common with more severe hypercalcemia. Bradycardia, a short OT interval, and hypertension are other findings. In older children, nausea, vomiting, constipation, and vague central nervous system symptoms of headaches and fatigue may be apparent. Renal function may be markedly decreased because of diminished RBF due to vasoconstriction induced by hypercalcemia and by circulatory volume depletion due to acquired nephrogenic diabetes insipidus. Nephrocalcinosis, nephrolithiasis, hematuria, and sterile pyuria may occur secondary to hypercalciuria. An inability to concentrate the urine because of resistance to the action of ADH may result in polyuria, polydipsia, and dehydration. Hypokalemia may occur secondary to diuresis. The development of rapid and severe hypercalcemia (>17 mg/dL) can result in dehydration, azotemia, coma, and death.

Management of Hypercalcemia

The first step in the management of acute hypercalcemia is to discontinue all of the sources of calcium and vitamin D. In neonates, a formula with low calcium and vitamin D content may be used (Calci-loXD; Ross Laboratories) along with immediate provision of hydration consisting of normal saline at 20 mL/kg body weight per hr for 4 hours. Excretion of calcium may be further promoted by intravenous furosemide at a dosage of 0.5 to 1.0 mg/kg body weight given every 6 hours with frequent monitoring of plasma ionized Ca2+, Na+, K+, Cl-, and Mg2+ concentrations. Supplementation with such ions is essential. Thiazides are anticalciuric and are contraindicated. Calcitonin given at 4 to 8 IU/kg body weight subcutaneously every 6 hours is particularly useful if there is concurrent renal insufficiency. Methylprednisolone at 1 mg/kg body weight per 24 hr may be useful in this setting. Biphosphonates inhibit macrophage and osteoclast activity and are increasingly used to treat hypercalcemia but also to prevent osteoporosis, osteopathy, or calcinosis. Pamidronate at a single dose of 0.5 mg/kg intravenously (may be repeated daily as needed for 3 days) is the agent of choice in tumoral hypercalcemia, vitamin D intoxication, resistant hypercalcemia, or in newborns with subcutaneous fat necrosis and elevated plasma 1,25(OH)2D3 concentrations. Etidronate at an oral dosage of 5 mg/kg per dose given twice daily along with sodium supplementation at 3 mmol/kg per day is also effective for managing chronic disorders. In severe hypercalcemia or when oliguria or renal insufficiency is present, dialysis with a low calcium dialysate concentration (1.25 mmol/L) is recommended. In cases of severe neonatal hyperparathyroidism due to homozygous FHH or other forms of primary hyperparathyroidism, expeditious parathyroidectomy may be lifesaving.


Magnesium is the fourth most abundant cation in the body, and it is largely located intracellularly. Its principal role is to stabilize electrically excitable membranes. Magnesium is also an important co-factor of numerous important enzymes, including adenosine triphosphatase (Na+,K+-ATPase) ( Gums, 1987 ), alkaline phosphatase, and adenylate cyclase and is essential in oxidative phosphorylation, protein synthesis, and DNA metabolism.

Magnesium Homeostasis

Normal plasma magnesium levels range from 1.7 to 2.5 mg/dL or 0.7 to 1.0 mmol/L. In general, plasma levels of Mg2+ correlate well with tissue levels; such correlation is poor, however, in circumstances such as renal failure or hepatic cirrhosis ( Cohen and Kitzes, 1982 ).

Despite being very abundant in the body, defense against hypomagnesemia is limited by (1) an inappropriately low parathyroid secretion when plasma levels are below 1.0 mg/dL, (2) PTH resistance at the skeletal level, and (3) decreased calcitriol levels predisposing to combined hypocalcemia ( Agus, 1999 ). Hypomagnesemia is very common in hospitalized individuals, particularly when nutritional intake is low for 3 or more days.

An average Western diet provides 400 mg of Mg2+ (16 mmol) per day, of which 30% to 50% is absorbed in the jejunum and ileum ( Brannan et al., 1976 ). Intestinal absorption can increase to 80% in the presence of mild hypomagnesemia (plasma Mg2+ <1.2 mg/dL, <1.0 mEq/L, or <0.5 mmol/L). In the blood, 30% of Mg2+ is bound to proteins and is not filtered at the glomerulus. Of the filtered Mg2+, about 3% is excreted in the urine.

Once filtered, Mg2+ is reabsorbed in the proximal tubule (15% to 20%), in the thick ascending limb of the loop of Henle (65% to 76%), and in the distal convoluted tubule (5% to 10%). As with Ca2+, the bulk of Mg2+ reabsorption occurs in the thick ascending limb of Henle's loop via a passive paracellular mechanism that is facilitated by the positive transepithelial voltage generated by apical Na+ entry and diffusion of K+ into the lumen generated by the interplay of the apical NKCC2 cotransporter, the basolateral Na+,K+-ATPase, and the return of K+ into the tubular lumen via the action of ROMK (Konrad and Weber, 2003) (see Fig. 4-8 A). The resultant change in luminal charge affects the configuration of structural proteins, especially that of paracellin-1 (also known as “claudin 16”) present in tight junctions. Mutations in paracellin-1 become manifest in early childhood with often familial hypomagnesemia, hypercalciuria, hematuria and nephrocalcinosis leading to polyuria, and progressive decline in GFR such that one third of these children develop renal failure by age 15 years ( Weber et al., 2001 ).

Interference with NKCC2 cotransport by loop diuretics diminishes the luminal voltage and leads to Mg2+ wasting, hypomagnesemia, and hypocalcemia. Metabolic acidosis, K+ depletion, and hypophosphatemia may cause magnesuria by affecting the transepithelial voltage. In contrast, Mg2+ transport in the distal convoluted tubule is active and transcellular (see Fig. 4-8 B). Specific, but not well-characterized, Mg2+ channels transport Mg2+ in and out of the cells in this region and are influenced by multiple agents, including the Mg2+-sparing diuretics amiloride and chlorothiazide (Cole and Quamme, 2000; Konrad and Weber, 2003). Mutations in these channels or in the Ca2+/Mg2+-sensing receptor (CaSR), which inhibits Na+, Ca2+, and Mg2+ absorption at the basolateral membrane (DiStefano et al., 1997 ), are responsible for several inherited disorders ( Box 4-12 ), which often present in infancy and childhood with symptoms related to hypomagnesemia.

BOX 4-12 

Inherited Disorders of Renal Magnesium Handling

Primary Inherited Disorders of Renal Magnesium Handling



Hypomagnesemia with secondary hypocalcemia (HSH)



Infantile isolated hypomagnesemia with autosomal dominant inheritance (IDH)



Infantile primary hypomagnesemia with autosomal recessive inheritance

Other Inherited Disorders



Idiopathic hypermagnesuria



Congenital hypomagnesemia not yet classified

Hypomagnesemia Associated With Hypercalciuria and Nephrocalcinosis



Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC)

Inherited Disorders Associated With Abnormal Extracellular Mg2+/Ca2+ Sensing



Autosomal dominant hypoparathyroidism



Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism (FHH)

Hypomagnesemia Associated With Abnormal Renal NaCl Transport



Gitelman's syndrome (GH)



Bartter's syndrome



Classic form (cBS)



Antenatal form with hyperprostaglandin E (aBS/HPS)



With sensorineural hearing loss (BSND)

Cole D, Quamme GA: Inherited disorders of renal magnesium handling. J Am Soc Nephrol 11:1937-1947, 2000, p 1940, Table 2. (With kind permission of Springer Science and Business Media.)


Etiology and Manifestations of Dysmagnesemia

Hypomagnesemia (Plasma Concentration <1.7 mg/dL, or <0.7 mmol/L)

Hypomagnesemia is far more common and more clinically relevant than hypermagnesemia (>2.5 mg/dL, or >1.0 mmol/L). Genetic disorders resulting in renal Mg2+ wasting are highlighted in Box 4-12 , and nonheritable or acquired causes of hypomagnesemia and its clinical manifestations are shown in Box 4-13 (Elin, 1988). Pediatric transplant recipients maintained on cyclosporine or tacrolimus are particularly susceptible to hypomagnesemia. This disorder is associated with an increase in the fractional excretion of Mg2+ ( Barton et al., 1987 ). Experimental studies demonstrate that cyclosporine leads to a decrease in the serum magnesium concentration, associated with renal Mg2+ wasting and Mg2+ shift into tissue compartments with no effect on intestinal absorption of Mg2+ ( Barton, 1989 ).

BOX 4-13 

Causes of Hypomagnesemia




Chronic diarrhea



Bowel bypass or resection



Congenital inflammatory bowel disease



Malabsorption syndromes



Tropical sprue



Gluten enteropathy



Laxative abuse






Specific magnesium malabsorption



Prolonged nasogastric suctioning



Caloric malnutrition

Renal Excretion



Gitelman's syndrome



Acute renal failure



Renal tubular acidosis



Chronic pyelonephritis



Postobstructive diuresis



Primary renal tubular magnesium wasting



Drug induced












Amphotericin B
























Ethacrynic acid












Osmotic agents



















Nutritional Deficiencies



Malnutrition or eating disorders



Magnesium-free parenteral feedings



Long-term alcohol abuse

Endocrine Disorders















Diabetes mellitus















Syndrome of inappropriate secretion of antidiuretic hormone



Excessive lactation




Insulin treatment for diabetic ketoacidosis



High-catecholamine states



Major trauma or stress



Hungry-bone syndrome

Multiple Mechanisms



Chronic alcoholism



Alcohol withdrawal



Major burns



Liquid-protein diet



Acute porphyria




Gestational diabetes



Gestational hyperparathyroidism



Gestational hypoparathyroidism



Exchange transfusion (citrate)

Modified from Elin RJ: Magnesium metabolism in health and disease. Dis Mon 34:161-218, 1988, Table 1.


Because of the type of clinical conditions leading to hypomagnesemia and because hypomagnesemia per se may contribute to refractory hypokalemia and hypocalcemia, it is common to find concurrent hypokalemia, hypocalcemia, and metabolic alkalosis. Symptoms may be exclusively attributed to hypomagnesemia only after excluding these other electrolyte disturbances. Patients with renal wasting of magnesium present with nephrocalcinosis, nephrolithiasis, and decreased GFR. Neurologic symptoms resemble those of hypocalcemia and may include personality changes, tremors, seizures, and carpopedal spasm.


Hypermagnesemia occurs frequently in individuals with acute renal failure who also consume a high level of dietary Mg2+ or because of cellular efflux in association with acute ketoacidosis or pheochromocytoma crisis. Although individuals with plasma Mg2+ concentrations below 10 mg/dL are usually asymptomatic, hypermagnesemia may cause central nervous system depression, decreased deep-tendon reflexes, muscle weakness, respiratory muscle paralysis, hypotension, bradycardia, heart block, and other arrhythmias.

Etiology and Management of Dysmagnesemia

Diagnosis of Dysmagnesemia

In individuals with normal renal function and absence of renal Mg2+ wasting, a fractional excretion of Mg2+ (FEMg 2 +) below 0.5% indicates low dietary intake or gastrointestinal losses of Mg2+, whereas an FEMg 2 + over 2% suggests renal Mg2+ wasting.

where UMg 2 + and PMg 2 + and Ucr and Pcr are the urinary and plasma concentrations of Mg2+ and creatinine, respectively. In this equation, plasma Mg2+ concentration is multiplied by 0.7 because only 70% of plasma Mg2+ is free. This implies that administration of albumin or blood products may further lower the ionized form of Mg2+ and precipitate symptoms. In individuals with low normal plasma Mg2+ concentrations, total body Mg2+ depletion may be confirmed by an Mg2+ excretion in a 24-hour urine collection amounting to less than 80% after an intravenous or intramuscular load of 2.4 mg/kg of lean body mass (this may be administered over 4 hours as the chloride or the sulfate solution in 5% dextrose in water or normal saline) ( Gullestad et al., 1994 ).

Management of Dysmagnesemia

The first step is to discontinue offending medications and to attempt to correct the primary etiology of hypomagnesemia ( Box 4-15 ). In individuals with tetany or cardiac arrhythmias, intravenous Mg2+may be infused slowly to avoid hypotension. The usual dosage is 0.2 mEq/kg (0.1 mmol/kg, or, 2.4 mg/kg) every 4 to 6 hours until blood levels exceed 1.0 mg/dL (0.4 mmol/L, or 0.8 mEq/L). The intravenous or intramuscular administration of 25 to 50 mg/kg body weight of magnesium sulfate solution, or 0.2 to 0.4 mEq/kg body weight of elemental Mg2+, is also preferred in symptomatic individuals with normomagnesemia who exhibit refractory hypokalemia or hypocalcemia. Amiloride may be used to reduce renal Mg2+ wasting by stimulating reabsorption in the cortical collecting duct. Because Mg2+ has a low renal tubular threshold (1.3 to 1.7 mEq/L), intravenous infusions or large single oral loads of Mg2+ are quickly excreted in the urine. Thus, smaller, more frequent doses or use of oral sustained-release preparations, such as Slow-Mag or Mag-Tab SR, are more effective. Symptomatic hypermagnesemia may be acutely managed by dialysis using a dialysate Mg2+ concentration of 0.2 mmol/L, as well as calcium infusion or anticholinesterase administration.

BOX 4-15 

Treatment of Magnesium Depletion

The following guidelines are suggested for treatment of magnesium deficiency regardless of etiology:



It is important to know that the kidneys are producing urine and that the BUN (blood urea nitrogen) and/or creatinine is normal. Magnesium may be needed and may be administered even in an instance of renal insufficiency, but the treatment must be monitored by frequent serum or plasma level assays.



On the first day of therapy, at least 1 mEq mg/kg per day should be given parenterally. Subsequently, at least 0.5 mEq mg/kg per day should be given for 3 to 5 days. If parenteral fluid therapy continues, at least 0.2 mEq/kg per day should be given.



Give the above in intravenous infusions if such infusions are being given anyway; otherwise, intramuscular administration is satisfactory.



The following schedule for an average adult is safe and effective. (1) Intramuscular route: [ampules of 1 g MgSO4(H2O)7, 50% solution = 8.13 mEq Mg2+] Day 1: 2.0 g (16.3 mEq) every 4 hours for six doses. Days 2 to 5: 1.0 g (9.1 mEq) every 6 hours. (2) Intravenous route (same ampules) Day 1: 6 g (41 mEq) in each liter of fluid and at least 2 L of 83 mEq. Days 2 to 5: A total of 6 g (49 mEq) distributed equally in total fluids of the day.
If the patient's condition requires continued intravenous infusions, 2 g of MgSO4 should be given daily in the infusion as long as infusions are necessary. When a patient who has a reason to have magnesium deficiency is convulsing, 2.0 g of MgSO4 solution may be administered intravenously in a 10-minute period. For symptomatic infants and children, such doses may be 0.025 g MgSO4/kg, or 0.2 to 0.3 mEq/kg per dose of elemental mg2+, in 10 minutes.



Oral preparations

Magnesium oxide

(Uro-Mg) 50 mEq magnesium per g of salt


(Mag-Ox) 50 mEq magnesium per g of salt

Magnesium chloride

(Slo-Mag) 9.75 mEq magnesium per g of salt

Magnesium lactate

(MagTab) 7.6 mEq magnesium per g of salt





Note: 50% solution of MgSO4 = 500 mg/mL (1 g/2 mL), or 49.3 mg elemental Mg2+/mL, or 98.6 mg elemental Mg2+/2 mL. Given an atomic gram weight of 24.3 and a valence of 2 for Mg2+, 98.6 mg = 4.058 mmol or 8.13 mEq elemental Mg2+/g salt.



Example. A 10-kg infant with seizures, hypomagnesemia, and an adequate serum calcium level may receive 2.0 mEq elemental Mg2+ (0.2 mEq/kg • 10 kg). This may be accomplished by diluting 0.5 mL of the 50% MgSO4 in 9.5 mL of dextrose and infusing over 2 to 10 minutes.

Adapted from Flink EB, et al.: Magnesium deficiency and magnesium toxicity in man. In Prasad AS, Oberleas D, editors: Trace elements in human health and disease. New York, 1976, Academic Press, p 13.



Most total body P2- exists in the form of the inorganic phosphate, but it also exists in an organic intracellular form, where it is the major anion. Phosphorus is an integral component of intracellular nucleic acids and cell membrane phospholipids and is involved in phosphorylation of proteins and lipids. Severe hypophosphatemia (<1 mg/mL) may have profound effects on all body functions through its effect in limiting 2,3-diphosphoglycerate and oxygen dissociation from hemoglobin and by reducing phosphate available for synthesis of high energy bonds in the form of adenosine triphosphate (ATP), which is involved in virtually all energy-requiring processes ( Knochel, 1977 ). Phosphorus, along with Ca2+, is a major constituent of bone.

Phosphorus Homeostasis

Approximately 85% of the total body P2- is in bone (hydroxyapatite, octacalcium phosphate, and amorphous calcium phosphate) ( Raisz, 1977 ) and teeth, while 15% is a constituent of carbohydrate, lipid, and protein in soft tissues and 0.1% is in the ECF.

Serum P2- concentration is maintained between 3.0 and 8.5 mg/dL, depending on age ( Parfit and Kleerekoper, 1980 ). It is highest in infants (4.5 to 8.5 mg/dL) and is relatively high in children (3.7 to 5.9 mg/dL), presumably because of increased concentrations of growth hormone and reduced levels of gonadal hormones until the completion of adolescence.

BOX 4-14 

Clinical and Laboratory Manifestations of Hypomagnesemia




Muscle fasciculation

Positive Chvostek's sign

Positive Trousseau's sign



Arrhythmias (torsades de pointes)

ECG changes

Central Nervous System

Personality change









Modified from Elin RJ: Magnesium metabolism in health and disease. Dis Mon 34:161-218, 1988, Table 4.


About 50% to 60% of dietary P2- is absorbed in the small intestine, especially in the duodenum and jejunum, via an active vitamin D-dependent process which is Na+-dependent ( Harrison and Harrison, 1961 ), and by passive diffusional flux through paracellular pathways. The absorption of P2- depends on the availability of adequate glucose, Na+, P2-, and Ca2+. Absorption is decreased by the ingestion of antacids such as aluminum hydroxide, which binds phosphorus in the gut and thereby inhibits gastrointestinal absorption.

At least 90% of plasma P2- appears in the glomerular ultrafiltrate. Most of the filtered P2- is reabsorbed in the proximal tubule. The process is active and Na+-dependent, and it occurs against an electrochemical gradient ( Suki and Rouse, 1991 ). The amount of P2- in the urine closely parallels the amount absorbed by the intestine. Normally the kidney excretes 10% to 20% of the filtered P2-, suggesting that the maximal capacity of the tubules to reabsorb P2-, or Tmp, is met or exceeded. Saline expansion causes phosphaturia, which can be blocked by total parathyroidectomy. In the absence of PTH, the reabsorption of P2- by the pars recta and the distal nephron is complete and accounts for the hyperphosphatemia in hypoparathyroidism ( Knox et al., 1977 ).

The urinary excretion of P2- depends on the oral intake of P2- (high intake causing increased excretion), the oral intake of Ca2+ (high intake causing hypophosphaturia), the presence of catabolism (high catabolic rates causing hyperphosphatemia and hyperphosphaturia), acid-base status (chronic metabolic acidosis decreasing the tubular reabsorption of P2- by decreasing the Vmax of Na+/P2- cotransport in the brush border membrane of the proximal tubule) ( Kempson, 1982 ), and the levels of PTH and calcitriol. Severe respiratory alkalosis stimulates glycolysis and carbohydrate phosphorylation resulting in secondary intracellular shift of phosphate. Untreated diabetes causes hypophosphatemia through volume expansion, osmotic diuresis, or ketonuria and also through extracellular shift after insulin administration.

Phosphate transport at the proximal tubule is the main means for regulating total body phosphate balance. The latter process is largely mediated by a type IIa Na+/P2- electrogenic cotransporter (NPT2a) in the proximal tubule ( Murer et al., 2000 ; Kronenberg, 2002; Tenenhouse and Murer, 2003 ). An increase or a decrease in the number of NPT2a in the brush border cell membrane is associated with either an increase or a decrease in P2- reabsorption. Modulators of NPT2a endocytosis, internalization, recycling, and lysosomal degradation include PTH, fibroblast growth factor (FGF-23), and several proteins that interact with this phosphate transporter. High levels of PTH or FGF-23 increase NPT2a endocytosis and breakdown and cause phosphaturia. Reduction in dietary phosphate lowers PTH levels while concurrently promoting insertion of NPT2a at the apical membrane thereby promoting phosphate reabsorption ( Fig. 4-9 ).


FIGURE 4-9  Regulation of the NPT2a sodium-phosphate cotransporter and synthesis of 1,25-dihydroxyvitamin D3 in the renal proximal tubule. Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) both lead to rapid internalization and subsequent lysosomal destruction of NPT2a. A low-phosphate diet causes the insertion of NPT2a into the plasma membrane. PTH and a low-phosphate diet both stimulate production of 25-hydroxyvitamin D 1α-hydroxylase messenger RNA (mRNA), whereas FGF-23 lowers mRNA levels.  (From Kronenberg HM: NPT2a—The key to phosphate homeostasis. N Engl J Med 347:1022-1024, 2002, p 1022, Figure 1. Copyright © 1974 Massachusetts Medical Society. All rights reserved)




Human disorders of phosphate transport may relate to aberrations in these phosphate-regulating genes. Certain tumors can cause oncogenic hypophosphatemic osteomalacia (OHO) by stimulating mRNA encoding for FGF-23, while activating mutations of FGF-23 can cause autosomal dominant hypophosphatemic rickets (ADHR). Another phosphate-regulating gene is named PHEX (Phosphate-regulating gene with Homology to Endopeptidases on the X chromosome). Many mutations in this gene, which is largely expressed in osteoblasts, osteoclasts, and odontoblasts, lead to decreased degradation of FGF-23, which may be the key defect in X-linked hypophosphatemic rickets (XLH). However, the mechanism by which PHEX dysfunction leads to renal phosphate wasting is unclear (Kronenberg, 2002).

Regulation of phosphate shifts in and out of bone is principally mediated by PTH and calcitriol synthesized mainly by proximal tubular epithelial cells. Several plasma proteins prevent precipitation of calcium phosphate in vessels and soft tissues, whereas alkaline phosphatase aids deposition of such minerals in bone. Other hormones that may affect the renal handling of P2- include vasopressin, thyroxin, glucagon, insulin, and glucocorticoids ( Ritz et al., 1980 ). The antiphosphaturic action of growth hormone is believed to occur via mechanisms involving increased reabsorption of Na+, release of insulin, or increased synthesis of 1,25(OH)2D3.

Hypophosphatemia stimulates calcitriol synthesis. The adaptive increases in plasma calcitriol concentrations on bone and intestine raise serum phosphate levels and cause hypercalciuria. This is evident in hereditary hypophosphatemic rickets (HHPR) but not in the disorders involving excessive amounts or activating mutations of FGF-23 (XLH, ADHR, or OHO) in which calcitriol expression is suppressed. The transporter abnormality in HHPR remains elusive.

Hypophosphatemia (Plasma Concentration <2.5 mg/dL)

The etiologies of hypophosphatemia are summarized in Box 4-16 . Because it is found in most foods, particularly in dairy products, and because intestinal absorption is efficient and minimally regulated, phosphorus depletion is rare except in patients with hyperparathyroidism. Hypophosphatemia usually coexists with total body P2- depletion, which is defined precisely as P2- content in lean muscle below 0.28 mol/g dry weight. One may occur without the other, however, particularly when the decrease in serum P2- results from intracellular shifts ( Popovtzer and Knochel, 1986 ).

BOX 4-16 

Causes of Hypophosphatemia

Excessive Renal Losses as Primary Cause



Drugs: Cyclosporine, tacrolimus, diuretics, salicylates, carbonic anhydrase inhibitors



Primary hypophosphatemic rickets



Hereditary hypophosphatemic rickets with hypercalciuria



Postobstructive diuresis



Renal tubular acidosis



Postrenal transplantation



Fanconi syndrome



Recovery from acute tubular necrosis



Potassium deficiency



Oncogenic osteomalacia or rickets



Vitamin D deficiency and dependency (also related to decreased intestinal absorption)



Volume expansion or osmotic diuresis (hyperglycemia)

Negative Intestinal Balance as Primary Cause



Breastfed premature infants



Term infants fed with low phosphate source



Use of phosphate-binding antacids



Decreased dietary intake (rare) especially with dialysis and phosphate binders



Vomiting or gastric suction




Acute Flux of Plasma Phosphate to Intracellular and Skeletal Pools[*]



Nutritional recovery, usually TPN associated



Therapy of diabetic ketoacidosis



Salicylate intoxication



Alkalosis (especially respiratory)



Androgen therapy



Burn therapy



Hungry-bone phenomenon



Increased tumor burden (uptake by tumor cells)

*  The serum phosphate is maintained but total body pools are depressed. In many of these conditions, recovery results in restoration of intracellular phosphate, precipitating acute hypophosphatemia.

Clinical manifestations of hypophosphatemia are quite diverse and may be due to the underlying disorder (e.g., pseudofractures and osteopenia in chronic hypoparathyroidism) or because of hypoxic effects on any and all body processes resulting in hemolysis, rhabdomyolysis, respiratory muscle paralysis, myocardial failure, encephalopathy, or neuropsychiatric symptoms and in secondary disturbances in renal tubular bicarbonate, magnesium, calcium, and glucose reabsorption. Plasma Ca2+ concentration may increase due to stimulation of calcitriol and from mobilization of bone Ca2+ due to reduction in the blood Ca2+ ×P2-product. Glucose intolerance may occur with severe P2- depletion ( Marshall et al., 1978 ). Osteomalacia, rickets, hypercalcemia, hypercalciuria, and distal tubular acidification defects (Kurtz and Hsu, 1978 ) are known to occur in chronic hypophosphatemia of any cause. Chronic administration of antacids (e.g., calcium carbonate or aluminum hydroxide) combined with inadequate P2-intake may result in severe hypophosphatemia. In addition to acting as P2- binders, antacids can induce net P2- secretion in the gut and create a negative P2- balance.

Many genetic disorders causing hypophosphatemia are characterized by an abnormal response to PTH, alteration in the structure and function of renal tubular transporters, or defective regulatory proteins within the proximal tubular epithelium. Several of these disorders are inherited and are associated with other metabolic disturbances such as aminoaciduria, glucosuria, hypocalcemia, rickets, and growth failure.

Hypophosphatemia is commonly seen after successful renal transplantation. Contributory factors include the persistence of preexisting parathyroid hyperplasia, volume expansion and osmotic diuresis in the immediate postoperative period, glucocorticoid administration (which increases the renal excretion of P2- and inhibits the gastrointestinal absorption of this ion), ingestion of antacids (which also function as phosphate binders), and an inherent renal tubular defect for P2- reabsorption that is independent of all other hormonal and metabolic factors ( Parfit et al., 1986 ).

Moderate hypophosphatemia (plasma concentrations of 1.0 to 2.5 mg/dL) generally results in few symptoms and can be managed with oral rather than intravenous phosphate salts. Whenever possible, this may be accomplished through dietary supplements. One quart of milk provides about 1 g of elemental phosphorus (≈32 mmol). The dosage of oral salt supplements ranges from 1.0 to 3.0 mmol/kg per day, with the larger dosages given to infants. Children with hypophosphatemia after renal transplantation may temporarily require phosphate replacement with Neutra-Phos and calcitriol supplements. This drug combination is also effective in the management of children with hypophosphatemic rickets.

Symptomatic children, those with profound hypophosphatemia (plasma concentration <1.0 mg/dL), or children requiring parenteral nutrition may be managed with intravenous phosphate at about 50% of the oral dosage. The choice of the preparation, including sodium phosphate or potassium phosphate, of either oral or intravenous phosphate preparations (see Table 4-13 ), depends on plasma K+concentrations and level of renal function.


The pathogenesis of hyperphosphatemia is related to redistribution of P2- from the intracellular compartment, P2- overdose, or decreased renal clearance of P2- ( Box 4-17 ). Symptoms result from the reciprocal decrease in serum calcium. Convulsions, cardiac arrhythmias, laryngospasm, and tetany may reflect hypocalcemia. Also, hyperphosphatemia can produce, contribute to, or be associated with acute renal failure. Conditions such as crush injury, tumor lysis syndrome, rhabdomyolysis, and hemolysis are often associated with oliguria and acute renal failure. The most serious side effect of hyperphosphatemia relates to calcium-phosphorus precipitation in the form of hydroxyapatite crystals in nonosseous tissue including the cornea, lungs, kidneys, pancreas, blood vessels, and brain.

BOX 4-17 

Causes of Hyperphosphatemia

Decreased Glomerular Filtration Rate



Acute and chronic renal failure

Increased Tubular Reabsorption of Phosphate

Parathyroid Dysfunction



Hypoparathyroidism (transient hypoparathyroidism of infancy, pseudohypoparathyroidism; transient parathyroid resistance of infancy)

Other Endocrine Causes



Hyperthyroidism, tumoral calcinosis, growth hormone excess; juvenile hypogonadism



High ambient temperature

Increased Phosphate Loads

Exogenous Loads



Enemas and laxatives; vitamin D intoxication; parenteral phosphate; blood transfusions; white phosphorus burns; phosphorus-rich cow's milk

Endogenous Loads



Cellular shift in diabetic ketoacidosis; lactic acidosis; tissue hypoxia; rhabdomyolysis; cytotoxic therapy of neoplasms; hemolysis; malignant hyperthermia




Familial intermittent hyperphosphatemia

Copyright © 2008 Elsevier Inc. All rights reserved. -

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier


Elucidation of nephron transporters and their interacting substrates has greatly enhanced our understanding of fluid and electrolyte regulation in children and in adults. However, unlike in adults, anatomic, metabolic, and physiologic differences stemming from the evolving aspects of development ranging from prematurity to adolescence result in a spectrum of responses of the nephron to perturbations in fluid and electrolyte balance. This treatise provides guidelines for fluid and electrolyte management based on an understanding of renal function and tubular transporter physiology in health and disease and during various periods of childhood.

Copyright © 2008 Elsevier Inc. All rights reserved. -

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier


Acker et al., 1998. Acker CG, Johnson JP, Palevsky PM, et al: Hyperkalemia in hospitalized patients.  Arch Intern Med  1998; 158:917-924.

Adams et al., 1981. Adams PC, Woodhouse KW, Adela M: Exaggerated hypokalemia in acute myeloid leukemia.  Br Med J  1981; 282:1034.

Adrogue and Madias, 1981. Adrogue HJ, Madias NE: Changes in plasma potassium concentration during acute acid-base disturbances.  Am J Med  1981; 71:456.

Adrogue and Madias, 2000b. Adrogue HJ, Madias NE: Hypernatremia.  N Engl J Med  2000; 342:1493-1499.

Adrogue and Madias, 2000a. Adrogue HJ, Madias NE: Hyponatremia.  N Engl J Med  2000; 342:1581-1589.

Agus, 1999. Agus ZS: Hypomagnesemia.  J Am Soc Nephrol  1999; 10:1616-1622.

Albanese et al., 2001. Albanese A, Hindmarsh P, Stanhope R: Management of hyponatraemia in patients with acute cerebral insults.  Arch Dis Child  2001; 85:246-251.

Ammon et al., 1978. Ammon RA, May WS, Nightingale SD: Glucose-induced hyperkalemia with normal aldosterone levels.  Ann Intern Med  1978; 89:349.

Andreoli, 2001. Andreoli TE: The polyuric hypertonic syndrome.  Nephrol Dial Transplant  2001; 16(suppl 6):10-12.

Anto et al., 1981. Anto HR, Chou SY, Poroush JG, et al: Infusion intravenous pyelography and renal function: Effects of hypertonic mannitol in patients with chronic renal insufficiency.  Arch Intern Med  1981; 131:1652.

Aperia et al., 1977. Aperia A, Broberger O, Herin P, et al: A comparative study of the response to an oral NaCl and NaHCO3 load in newborn preterm and full term infants.  Pediatr Res  1977; 11:1109.

Aperia et al., 1975b. Aperia A, Broberger O, Thodenius J, et al: Development of renal control of salt and fluid homeostasis during the first year of life.  Acta Paediatr Scand  1975; 64:393.

Aperia et al., 1975a. Aperia A, Broberger O, Thodenius J, et al: Renal control of sodium and fluid balance in newborn infants during intravenous maintenance therapy.  Acta Paediatr Scand  1975; 64:725.

Aperia and Zetterstrom, 1982. Aperia A, Zetterstrom R: Renal control of fluid homeostasis in the newborn infant.  Clin Perinatal  1982; 9:523.

Aranda et al., 1978. Aranda JV, Perez J, Sitar DS: Pharmacokinetic disposition and protein binding of furosemide in newborn infants.  Pediatr Pharmacol Ther  1978; 93:507.

Arant, 1978. Arant Jr BS: Developmental patterns of renal functional maturation compared in the human neonate.  J Pediatr  1978; 92:705-712.

Araseneau et al., 1973. Araseneau JC, Bagley CL, Anderson T, et al: Hyperkalemia, a sequel of the chemotherapy of Burkitt's lymphoma.  Lancet  1973; 1:10.

Arieff et al., 1976. Arieff A, Llach F, Massry SG: Neurological manifestations and morbidity of hyponatremia: Correlation with brain water and electrolytes.  Medicine  1976; 55:121.

Arieff, 1982. Arieff AI: Dialysis disequilibrium syndrome: Current concepts on pathogenesis.   In: Schriener GE, Winchester JF, ed. Controversies in nephrology, 4. Washington, DC: Georgetown University Press; 1982:367.

Arieff, 1998. Arieff AI: Postoperative hyponatremic encephalopathy following elective surgery in children.  Pediatr Anaesth  1998; 8:1-4.

August et al., 1958. August JT, Nelson D, Thorn G: Response of normal subjects to large amounts of aldosterone.  J Clin Invest  1958; 37:1549.

Avner et al., 1990. Avner ED, Ellis D, Ichikawa L, et al: Normal neonates and the maturational development of homeostatic mechanisms.   In: Ichikawa I, ed. Pediatric textbook of fluids and electrolytes,  Baltimore: Williams & Wilkins; 1990:107-118.

Ayus et al., 1987. Ayus JC, Krothapalli RK, Arieff AI: Treatment of symptomatic hyponatremia and its relation to brain damage.  N Engl J Med  1987; 317:1190-1195.

Bajaj et al., 1996. Bajaj G, Alexander SR, Browne R, et al: 125Iodine-iothalamate clearance in children. A simple method to measure glomerular filtration.  Pediatr Nephrol  1996; 10:25-28.

Barton et al., 1987. Barton CH, Vaziri ND, Martin DC, et al: Hypomagnesemia and renal magnesium wasting in renal transplant recipients receiving cyclosporine.  Am J Med  1987; 83:693.

Barton et al., 1989. Barton CH, Vaziri ND, Mina-Araghi S, et al: Effects of cyclosporine on magnesium metabolism in rats.  J Lab Clin Med  1989; 114:232.

Bastron et al., 1981. Bastron RD, Pyne JL, Inagaki M: Halothane-induced renal vasodilatation.  Anesthesiology  1981; 50:126.

Battle et al., 1981. Battle DC, Arruda JAL, Kurtzman NA: Hyperkalemic distal tubular acidosis associated with obstructive uropathy.  N Engl J Med  1981; 304:373.

Baumgart et al., 1982. Baumgart S, Langman CB, Sosulski R, et al: Fluid, electrolyte, and glucose maintenance in the very low birth-weight infant.  Clin Pediatr  1982; 21:199.

Baumgart, 1982. Baumgart S: Radiant energy and insensible water loss in the premature newborn infant under a radiant warmer.  Clin Perinatal  1982; 8:483.

Bayliss, 1902. Bayliss WM: On the local reactions of the arterial wall to changes in internal pressure.  J Physiol (Lond)  1902; 28:220.

Beck and Goldberg, 1973. Beck LM, Goldberg M: Effects of acetazolamide and parathyroidectomy on renal transport of sodium, calcium and phosphate.  Am J Physiol  1973; 224:1136.

Berleur et al., 2003. Berleur MP, Dahan A, Murat I, et al: Perioperative infusions in paediatric patients: Rationale for using Ringer-lactate solution with low dextrose concentration.  J Clin Pharm Ther  2003; 28:31-40.

Berry and Rector, 1991. Berry CA, Rector Jr FC: Renal transport of glucose, amino acids, sodium, chloride and water.   In: Brenner BM, Rector Jr FC, ed. The kidney,  Philadelphia: WB Saunders; 1991:245.

Bia et al., 1982. Bia MJ, Tyler K, DeFronzo RA: The effect of dexamethasone on renal electrolyte excretion in the adrenalectomized rat.  Endocrinology  1982; 111:882.

Blantz, 1977. Blantz RC: Dynamics of glomerular ultrafiltration in the rat.  Fed Proc  1977; 36:2602.

Bockenhauer, 2001. Bockenhauer D: Ion channels in disease.  Curr Opin Pediatr  2001; 13:142-149.

Bokenkamp et al., 1998. Bokenkamp A, Domanetzki M, Zinck R, et al: Cystatin C—a new marker of glomerular filtration rate in children independent of age and height.  Pediatrics  1998; 101:875-881.

Bonioli and Bellini, 1991. Bonioli E, Bellini C: Therapy for hereditary nephrogenic diabetes insipidus.  J Pediatr  1991; 119:331-332.

Bonny and Rossier, 2002. Bonny O, Rossier BC: Disturbances of Na/K balance: Pseudohypoaldosteronism revisited.  J Am Soc Nephrol  2002; 13:2399-2414.

Bostic and Duvernoy, 1972. Bostic O, Duvernoy WFC: Hyperkalemic cardiac arrest during transfusion of stored blood.  J Endocrinol  1972; 5:407.

Brannan et al., 1976. Brannan PG, Vergne-Marini P, Pak CYC, et al: Magnesium absorption in the human small intestine.  J Clin Invest  1976; 57:1418-1421.

Brem, 2001. Brem AS: Insights into glucocorticoid-associated hypertension.  Am J Kidney Dis  2001; 37:1-10.

Brenner et al., 1990. Brenner BM, Ballermann BJ, Gunning ME, et al: The diverse biological actions of atrial peptides.  Physiol Rev  1990; 70:665.

Brenner and Beeuwkes, 1978. Brenner BM, Beeuwkes III R: The renal circulations.  Hosp Pract  1978; 13:35.

Bricker, 1982. Bricker NS: Sodium homeostasis in chronic renal disease.  Kidney Int  1982; 21:886.

Broadus et al., 1980. Broadus AE, Horst RL, Lang R: The importance of circulating 1,25-dihydroxy vitamin D in the pathogenesis of hypercalciuria and renal stone formation in primary hyperparathyroidism.  N Engl J Med  1980; 302:421.

Brookes et al., 1982. Brookes GB, Hodge RA, Booth JB, et al: The immediate effects of acetazolamide in Meniere's disease.  J Laryngol Otol  1982; 96:57.

Brown et al., 1981. Brown CB, Ogg CS, Cameron JS: High dose furosemide in acute renal failure: A controlled trial.  Clin Nephrol  1981; 13:90.

Burg et al., 1973. Burg M, Stoner L, Cardinal J, et al: Furosemide effect on isolated perfused tubules.  Am J Physiol  1973; 225:119.

Burrows et al., 1983. Burrows FA, Shutack JG, Crone RK: Inappropriate secretion of antidiuretic hormone in a post-surgical pediatric population.  Crit Care Med  1983; 11:527-531.

Bushinsky and Monk, 1998. Bushinsky DA, Monk RD: Calcium.  Lancet  1998; 352:306-311.

Bushinsky, 2001. Bushinsky DA: Disorders of calcium and phosphorous homeostasis.   In: Greenberg A, ed. Primer on kidney diseases,  ed 3. San Diego: Academic Press; 2001:107-115.

Byme, 1966. Byme JJ: Shock.  N Engl J Med  1966; 275:659.

Calcagno and Rubin, 1963. Calcagno PL, Rubin MI: Renal extraction of para-aminohippurate in infants and children.  J Clin Invest  1963; 42:1632.

Charney et al., 1975. Charney AN, Kinsey MD, Myers L, et al: NaK-activated adenosine triphosphatase and intestinal electrolyte transport.  J Clin Invest  1975; 56:653.

Chase and Slatopolsky, 1974. Chase LR, Slatopolsky E: Secretion and metabolic efficacy of parathyroid hormone in patients with severe hypomagnesemia.  J Clin Endocrinol Metab  1974; 38:363.

Chesney, 1976. Chesney RW: Drug-induced hypokalemia.  Am J Dis Child  1976; 130:1055.

Chevalier and Kaiser, 1985. Chevalier RL, Kaiser DL: Effects of acute uninephrectomy and age on renal blood flow autoregulation in the rat.  Am J Physiol  1985; 249(5 Pt 2):F672-F679.

Chumbley, 1970. Chumbley LC: Pseudohyperkalemia in acute myelocytic leukemia.  JAMA  1970; 211:1007.

Cockburn et al., 1980. Cockburn F, Belton NR, Purvis RJ, et al: Maternal vitamin D intake and mineral metabolism in mothers and their newborn infants.  Br Med J  1980; 28:11.

Cohen and Kitzes, 1982. Cohen L, Kitzes R: Relationship of bone and plasma magnesium in magnesium-deficient cirrhosis patients.  Isr J Med Sci  1982; 18:679.

Cohn et al., 2000. Cohn JN, Kowey PR, Whelton PK, et al: New guidelines for potassium replacement in clinical practice: A contemporary review by the National Council on Potassium in Clinical Practice.  Arch Intern Med  2000; 160:2429-2436.

Conger and Falk, 1977. Conger JF, Falk SA: Intrarenal dynamics in the pathogenesis and prevention of acute urate nephropathy.  J Clin Invest  1977; 59:786.

Corvol et al., 1981. Corvol P, Claire M, Oblin ME, et al: Mechanism of the antimineralocorticoid effect of spironolactones.  Kidney Int  1981; 20:1.

Davies and Shock, 1950. Davies DF, Shock NW: Age changes in glomerular filtration rate, effective renal plasma flow, and tubular excretory capacity in adult males.  J Clin Invest  1950; 29:496.

Davis and Freeman, 1976. Davis JO, Freeman RH: Mechanisms regulating renin release.  Physiol Rev  1976; 56:1.

Delgado et al., 2003. Delgado MM, Rohatgi R, Khan S, et al: Sodium and potassium clearances by the maturing kidney: Clinical-molecular correlates.  Pediatr Nephrol  2003; 18:759-767.

deTorrente et al., 1978. deTorrente A, Miller PD, Cronin RE, et al: Effects of furosemide and acetylcholine in norepinephrine-induced acute renal failure.  Am J Physiol  1978; 235:131.

Dharnidharka et al., 2002. Dharnidharka VR, Kwon C, Stevens G: Serum cystatin C is superior to serum creatinine as a marker of kidney function: A meta-analysis.  Am J Kidney Dis  2002; 40:221-226.

Di Stefano et al., 1997. Di Stefano A, Desfleurs E, Simeone S, et al: Ca2+ and Mg2+ sensor in the thick ascending limb of the loop of Henle.  Kidney Blood Press Res  1997; 20:190-193.

Dikshit et al., 1973. Dikshit K, Vyden JK, Forrester JS, et al: Renal and extrarenal hemodynamic effects of furosemide in congestive heart failure after acute myocardial infarction.  N Engl J Med  1973; 288:1087.

Dirks, 1979. Dirks JH: Mechanism of action and clinical use of diuretics.  Hosp Pract  1979; 14:99.

Donckerwolcke et al., 1970. Donckerwolcke RA, Vanstekelenburg J, Tilddburg J, et al: Therapy of bicarbonate losing tubular renal acidosis.  Arch Dis Child  1970; 45:774.

Dorisa and Valtin, 1976. Dorisa TP, Valtin H: Cellular actions of vasopressin in the mammalian kidney.  Kidney Int  1976; 10:46.

Dorkin and Brenner, 1991. Dorkin LD, Brenner BM: The renal circulations.   In: Brenner BM, Rector Jr FC, ed. The kidney,  Philadelphia: WB Saunders; 1991:164.

Douglas, 1973. Douglas WW: How do neurons secrete peptides? Exocytosis and its consequences, including “synaptic vesicle” formation in the hypothalamo-neurohypophyseal system.  Prog Brain Res  1973; 39:21.

Drukker et al., 1980. Drukker A, Goldsmith DI, Spitzer A, et al: The renin-angiotensin system in newborn dogs. Developmental patterns and response to acute saline loading.  Pediatr Res  1980; 14:304.

Edwards, 1981. Edwards BR: Postnatal development of urinary concentrating ability in rats: Changes in renal anatomy and neurohypophyseal hormones.   In: Spitzer A, ed. The kidney during development,  Paris: Masson; 1981:233.

El-Dahr and Chevalier, 1990. El-Dahr SS, Chevalier RL: Special needs of the newborn infant in fluid therapy.  Pediatr Clin North Am  1990; 37:323-336.

Ellis and Avner, 1985. Ellis D, Avner ED: Fluid and electrolyte disorders in pediatric patients.   In: Puschett JB, ed. Disorders of fluid and electrolyte balance,  New York: Churchill Livingstone; 1985:217.

Eneas et al., 1979. Eneas JF, Schoenfeld PY, Humphreys MH: The effect of infusion of mannitol-sodium bicarbonate on the clinical course of myoglobinuria.  Arch Intern Med  1979; 139:801.

Engelke et al., 1978. Engelke SC, Shah BL, Vasan U, et al: Sodium balance in very low birth weight infants.  J Pediatr  1978; 93:837.

Epstein, 1999. Epstein FH: Genetic disorders of renal electrolyte transport.  N Engl J Med  1999; 340:1177-1187.

Epstein, 1957. Epstein FH: Renal excretion of sodium and the concept of a volume receptor.  Yale J Biol Med  1957; 29:282.

Estep et al., 1969. Estep H, Shaw WA, Watlington C, et al: Hypocalcemia due to hypomagnesemia and reversible parathyroid hormone unresponsiveness.  J Clin Endocrinol Metab  1969; 29:842.

Fanaroff et al., 1972. Fanaroff AA, Wald M, Gruber HS, et al: Insensible water loss in low birth weight infants.  Pediatrics  1972; 50:236.

Farauhar et al., 1961. Farauhar MG, Wissig SL, Palade GE: Glomerular permeability. I. Ferritin transfer across the normal glomerular capillary wall.  J Exp Med  1961; 113:47.

Farfel et al., 1999. Farfel Z, Bourne HR, Iiri T: The expanding spectrum of G protein disease.  N Engl J Med  1999; 340:1012-1120.

Favre et al., 1982. Favre L, Glasson P, Valloton MB: Reversible acute renal failure from combined triamterene and indomethacin.  Ann Intern Med  1982; 96:317.

Fawer et al., 1979. Fawer CL, Torrado A, Guignard JP: Maturation of renal function in full-term and premature neonates.  Helv Pediatr Acta  1979; 34:11.

Felsenfeld et al., 1986. Felsenfeld AJ, Gutman RA, Drezner M, et al: Hypophosphatemia in long-term renal transplant recipients; effects on bone histology and 1,25-dihydroxycholecalciferol.  Miner Electrolyte Metab  1986; 12:233.

Finberg and Harrison, 1955. Finberg L, Harrison HE: Hypernatremia in infants: An evaluation of the clinical and biochemical findings accompanying this state.  Pediatrics  1955; 16:1-14.

Finney et al., 2000. Finney H, Newman DJ, Thakkar H, et al: Reference ranges for plasma cystatin C and creatinine measurements in premature infants, neonates and older children.  Arch Dis Child  2000; 82:71-75.

Fraley and Adler, 1977. Fraley DS, Adler S: Correction of hyperkalemia by bicarbonate despite constant blood pH.  Kidney Int  1977; 12:354.

Frick and Bushinsky, 2003. Frick KK, Bushinsky DA: Molecular mechanisms of primary hypercalciuria.  J Am Soc Nephrol  2003; 14:1082-1095.

Friis-Hensen, 1971. Friis-Hensen B: Body composition during growth. In vivo measurements and biochemical data correlated to differential anatomical growth.  Pediatrics  1971; 47:264.

Gallagher and Jones, 1979. Gallagher KL, Jones JK: Furosemide-induced ototoxicity.  Ann Intern Med  1979; 91:744.

Ganguly and Donohue, 1983. Ganguly A, Donohue JP: Primary aldosteronism: Pathophysiology, diagnosis and treatment.  J Urol  1983; 129:241.

Gennari, 1998. Gennari FJ: Hypo-hypernatraemia: disorders of water balance.   In: Davidson AM, Camerom JS, Grunfeld JP, et al ed. Oxford textbook of clinical nephrology, 1. ed 2. Oxford, England: Oxford University Press; 1998:175-200.

Gennari, 1998. Gennari FJ: Hypokalemia.  N Engl J Med  1998; 339:451-458.

Gennari and Segal, 2002. Gennari FJ, Segal AS: Hyperkalemia: An adaptive response in chronic renal insufficiency.  Kidney Intl  2002; 62:1-9.

Gerger, 1983. Gerger JG: Role of prostaglandins in the hemodynamic and tubular effects of furosemide.  Fed Proc  1983; 42:1707.

Gertz et al., 1966. Gertz KH, Mangos JA, Braum G, et al: Pressures in the glomerular capillaries of the rat kidney in relation to arterial blood pressure.  Pflugers Arch  1966; 288:369.

Ghose and Gupta, 1981. Ghose RR, Gupta SK: Synergistic action of metal ozone with “loop” diuretics.  Br Med J  1981; 282:1432.

Godard et al., 1979. Godard C, Geering JM, Geering K: Plasma renin activity related to sodium balance, renal function, and urinary vasopressin in the newborn infant.  Pediatr Res  1979; 13:742.

Gonick et al., 1971. Gonick HC, Kleeman CR, Rubini ME, et al: Functional impairment in chronic renal disease. III. Studies of potassium excretion.  Am J Med Sci  1971; 261:281.

Graham and Kellermeyer, 1968. Graham RC, Kellermeyer RW: Bovine lactoperoxidase as a cytochemical protein tracer for electron microscopy.  J Histochem Cytochem  1968; 16:275.

Greene et al., 1981. Greene MK, Kerr AM, McIntosh IB, et al: Acetazolamide in prevention of acute mountain sickness: A double-blind controlled crossover study.  Br Med J  1981; 283:811.

Greger, 1985. Greger R: Ion transport mechanisms in thick ascending limb of Henle's loop of mammalian nephron.  Physiol Rev  1985; 65:760.

Greger, 2000. Greger R: Physiology of renal sodium transport.  Am J Med Sci  2000; 319:51-62.

Griggs et al., 1970. Griggs RC, Engel WK, Resnick JS: Acetazolamide treatment of hypokalemic periodic paralysis. Prevention of attacks and improvement of persistent weakness.  Ann Intern Med  1970; 73:39.

Gronert and Theye, 1975. Gronert GA, Theye RA: Pathophysiology of succinylcholine induced hyperkalemia.  Anesthesiology  1975; 43:89.

Guay-Woodford, 1998. Guay-Woodford LM: Bartter syndrome: Unraveling the pathophysiologic enigma.  Am J Med  1998; 105:151-161.

Gullans and Verbalis, 1993. Gullans SR, Verbalis JG: Control of brain volume during hyperosmolar and hypo-osmolar conditions.  Annu Rev Med  1993; 44:289.

Gullestad et al., 1994. Gullestad L, Midtvedt K, Dolva , et al: The magnesium loading test: Reference values in healthy subjects.  Scand J Clin Lab Invest  1994; 54:23-31.

Gums, 1987. Gums JG: Clinical significance of magnesium: A review.  Drug Int Clin Pharmacol  1987; 21:240-246.

Hahn et al., 2001. Hahn S, Kim Y, Garner P: Reduced osmolarity oral rehydration solution for treating dehydration due to diarrhea in children: Systematic review.  Br Med J  2001; 323:81-85.

Hall et al., 1999. Hall JE, Brands MW, Henegar JR: Angiotensin II and long-term arterial pressure regulation: the overriding dominance of the kidney.  J Am Soc Nephrol  1999; 10(suppl 12):S258-S265.

Halperin et al., 2001. Halperin ML, Bichet DG, Oh MS: Integrative physiology of basal water permeability in the distal nephron: Implications for the syndrome of inappropriate secretion of antidiuretic hormone.  Clin Nephrol  2001; 56:339-345.

Halperin and Kamel, 1998. Halperin ML, Kamel KS: Potassium.  Lancet  1998; 352:135-140.

Halpren et al., 1973. Halpren BA, Kempson RC, Coplon NS: Interstitial fibrosis and chronic renal failure following methoxyflurane anesthesia.  JAMA  1973; 223:1239.

Harrison and Harrison, 1961. Harrison HE, Harrison HC: Intestinal transport of phosphate: Action of vitamin D, calcium and potassium.  Am J Physiol  1961; 201:2001.

Hayes et al., 1967. Hayes Jr CP, McLeod ME, Robinson RR: An extrarenal mechanism for the maintenance of potassium balance in severe chronic renal failure.  Trans Assoc Am Physicians  1967; 50:207.

Helfant, 1986. Helfant RH: Hypokalemia and arrhythmias.  Am J Med  1986; 80(suppl 4A):13.

Hellerstein et al., 1998. Hellerstein S, Berenbom M, Alon US, et al: Creatinine clearance following cimetidine for estimation of glomerular filtration rate.  Pediatr Nephrol  1998; 12:49-54.

Hellerstein et al., 2001. Hellerstein S, Simon SD, Berenbom M, et al: Creatinine excretion rates for renal clearance studies.  Pediatr Nephrol  2001; 16:637-643.

Hendricks et al., 1981. Hendricks SA, Lippe B, Kaplan SA, et al: Differential diagnosis of diabetes insipidus: Use of DDAVP to terminate the seven-hour water deprivation test.  J Pediatr  1981; 98:244-246.

Herbacznska-Cedro and Vane, 1973. Herbacznska-Cedro K, Vane JR: Contribution of intrarenal generation of prostaglandins in autoregulation of renal blood flow in the dog.  Circ Res  1973; 33:428.

Higashio et al., 1978. Higashio T, Abe Y, Yamamoto K: Renal effects of bumetanide.  J Pharmacol Exp Ther  1978; 207:212.

Hill, 1990. Hill LL: Body composition, normal electrolyte concentrations, and maintenance of normal volume, tonicity, and acid-base metabolism.  Pediatr Clin North Am  1990; 37:241.

Holliday and Segar, 1957. Holliday MA, Segar WE: The maintenance need for water in parenteral fluid therapy.  Pediatrics  1957; 19:823-832.

Hong, 1998. Hong R: The Di-George anomaly (catch 22, DiGeorge/velocardiofacial syndrome).  Semin Hematol  1998; 35:282-290.

Horster, 1978. Horster M: Principles of nephron differentiation.  Am J Physiol  1978; 235:F387.

Hoskins and Jackson, 1978. Hoskins B, Jackson CM: The mechanism of chlorothiazide-induced carbohydrate intolerance.  J Pharmacol Exp Ther  1978; 206:423.

Humes et al., 1982. Humes HD, Weinberg JM, Knauss TC: Clinical and pathophysiologic aspects of aminoglycoside nephrotoxicity.  Am J Kidney Dis  1982; 2:5.

Imbs et al., 1987. Imbs JL, Schmidt M, Giesen-Crouse E: Pharmacology of loop diuretics: State of the art.  Adv Nephrol  1987; 16:137.

Ingram and Seki, 1962. Ingram Jr RH, Seki M: Pseudohyperkalemia with thrombocytosis.  N Engl J Med  1962; 267:895.

Ireland et al., 1968. Ireland AW, Hornbrook JW, Neale FC, et al: The crystalline lens in chronic surgical hypoparathyroidism.  Arch Intern Med  1968; 122:406.

Jones et al., 1998. Jones G, Strugnell SA, DeLuca HF: Current understanding of the molecular actions of vitamin.  D. Physiol Rev  1998; 78:1193-1231.

Jose et al., 1975. Jose PA, Slotkoff LM, Montgomery S, et al: Autoregulation of renal blood flow in the puppy.  Am J Physiol  1975; 229:983.

Kagan et al., 1972. Kagan BM, Stanincova V, Felix NS, et al: Body composition of premature infants: Relation to nutrition.  Am J Clin Nutr  1972; 25:1153.

Kahn, 1999. Kahn T: Hypernatremia with edema.  Arch Intern Med  1999; 159:93-98.

Kaloyanides and DiBona, 1976. Kaloyanides GJ, DiBona GF: Effect of an angiotensin II antagonist on autoregulation in the isolated dog kidney.  Am J Physiol  1976; 230:1073.

Kaplan and Feigin, 1978. Kaplan SL, Feigin RD: The syndrome of inappropriate secretion of antidiuretic hormone in children with bacterial meningitis.  J Pediatr  1978; 92:758.

Kassirer and Harrington, 1977. Kassirer JP, Harrington JT: Diuretics and potassium metabolism: Reassessment of the need, effectiveness and safety of potassium therapy.  Kidney Int  1977; 11:505.

Keller et al., 2003. Keller G, Zimmer G, Mall G, et al: Nephron number in patients with primary hypertension.  N Engl J Med  2003; 348:101-108.

Kelly, 1998. Kelly J: Disorders of sodium balance.  Lancet  1998; 352:1146-1147.

Kempson, 1982. Kempson SA: Effect of metabolic acidosis on renal brush border membrane adaptation to low phosphorus diet.  Kidney Int  1982; 22:225-233.

Kim and Brown, 1968. Kim WG, Brown Jr EB: Potassium transfer with constant extracellular pH.  J Lab Clin Med  1968; 71:678-685.

Kleinman and Lubbe, 1972. Kleinman LI, Lubbe RJ: Factors affecting the maturation of glomerular filtration rate and renal plasma flow in the newborn dog.  J Physiol  1972; 223:395-409.

Knochel et al., 1972. Knochel JP, Dotin LN, Hamburger RJ: Pathophysiology of intense physical conditioning in a hot climate.  J Clin Invest  1972; 51:242.

Knochel, 1982. Knochel JP: Neuromuscular manifestations of electrolyte disorders.  Am J Med  1982; 72:521.

Knochel, 1977. Knochel JP: The pathophysiology and clinical characteristics of severe hypophosphatemia.  Arch Intern Med  1977; 137:203.

Knoers and Monnen, 1990. Knoers N, Monnen LAH: Amiloride-hydrochlorothiazide versus indomethacin-hydrochlorothiazide in the treatment of nephrogenic diabetes insipidus.  J Pediatr  1990; 117:499-502.

Knoers and Monnens, 1992. Knoers N, Monnens LAH: Nephrogenic diabetes insipidus: Clinical symptoms, pathogenesis, genetics and treatment.  Pediatr Nephrol  1992; 6:476-482.

Knox et al., 1977. Knox FG, Osswald H, Marchand GR, et al: Phosphate transport along the tubule.  Am J Physiol  1977; 233:F261.

Kokko, 1979. Kokko JP: Renal concentrating and diluting mechanisms.  Hosp Pract  1979; 14:110.

Kumar and Berl, 1998. Kumar S, Berl T: Sodium.  Lancet  1998; 352:220-228.

Kunau et al., 1975. Kunau Jr RT, Walter DR, Webb HL: Clarification of action of chlorothiazide in the rat nephron.  J Clin Invest  1975; 56:401.

Kurnik and Hruska, 1984. Kurnik BRC, Hruska KA: Effects of 1,25-dihydroxycholecalciferol on phosphate transport in vitamin D-deprived rats.  Am J Physiol  1984; 247:F177-F182.

Kurnik and Hruska, 1985. Kurnik BRC, Hruska KA: Mechanism of stimulation of renal phosphate transport by 1,25-dihydroxycholecalciferol.  Biochem Biophys Acta  1985; 817:42-50.

Kurtz and Hsu, 1978. Kurtz E, Hsu CH: Impaired distal nephron acidification in chronically phosphate deprived rats.  Pflugers Arch  1978; 377:229.

Laureno and Karp, 1997. Laureno R, Karp BI: Myelinolysis after correction of hyponatremia.  Ann Intern Med  1997; 126:57-62.

Lauriat and Berl, 1997. Lauriat S, Berl T: The hyponatremic patient: Practical focus on therapy.  J Am Soc Nephrol  1997; 8:1599-1607.

Leake et al., 1976. Leake RD, Zabauddin S, Trygstad CW, et al: The effects of large volume intravenous infusion on neonatal renal function.  J Pediatr  1976; 89:968.

Lemman et al., 1967. Lemman Jr J, Litzow JR, Lennon JR: Studies of the mechanism by which metabolic acidosis augments urinary calcium excretion in man.  J Clin Invest  1967; 46:1318.

Lester et al., 1982. Lester GE, Vander Wiel CJ, Gray TK, et al: Vitamin D deficiency in rats with normal serum calcium concentrations.  Proc Natl Acad Sci USA  1982; 79:4791.

Levey et al., 1993. Levey AS, Greene T, Schluchter MD, et al: Glomerular filtration rate measurements in clinical trials.  J Am Soc Nephrol  1993; 4:1159-1171.

Levey et al., 1988. Levey AS, Perrone RD, Madias NE: Serum creatinine and renal function.  Annu Rev Med  1988; 39:465-490.

Levine and Carpenter, 1999. Levine BS, Carpenter TO: Evaluation and treatment of heritable forms of rickets.  Endocrinologist  1999; 9:358-365.

Levine et al., 1929. Levine SZ, Wilson JR, Kelly M: The insensible perspiration on infancy and childhood. I. Its constancy in infants under various physiologic factors.  Am J Dis Child  1929; 37:791.

Levinson et al., 1966. Levinson H, Linsao L, Swyer PR, et al: A comparison of infra-red and convective heating for newborn infants.  Lancet  1966; 2:1346.

Lin et al., 2001. Lin SH, Lin YF, Halperin ML: Hypokalemia and paralysis.  QJM  2001; 94:133-139.

Lineralli et al., 1972. Lineralli LG, Bobik J, Bobik C: Newborn urinary cyclic AMP and developmental renal responsiveness to parathyroid hormone.  Pediatrics  1972; 50:14.

Lipner et al., 1975. Lipner HI, Rusany R, Dasgupta M, et al: The behavior of carbenicillin as a nonabsorbable anion.  J Lab Clin Med  1975; 86:183.

Liu et al., 1989. Liu Y-M, Neal P, Ernst J, et al: Absorption of calcium and magnesium from fortified human milk by very low birth weight infants.  Pediatr Res  1989; 25:496.

Luscher et al., 1992. Luscher TF, Boulanger CM, Dohi Y, et al: Endothelium-derived contracting factors.  Hypertension  1992; 19:117.

Maier et al., 1981. Maier M, Starlinger M, Wagner M, et al: The effect of hemorrhagic hypoperfusion on urinary kallikrein excretion, renin activity and renal cortical blood flow in the pig.  Circ Res  1981; 48:386.

Manganaro et al., 2001. Manganaro R, Mami C, Marrone T, et al: Incidence of dehydration and hypernatremia in exclusively breast-fed infants.  J Pediatr  2001; 139:673-675.

Manuel and Steele, 1974. Manuel MA, Steele TH: Changes in renal urate handling after prolonged thiazide administration.  Am J Med  1974; 57:741.

Maren, 1987. Maren TH: Carbonic anhydrase: General perspective and advances in glaucoma research.  Drug Dev Res  1987; 10:255.

Marild et al., 1992. Marild S, Jodal U, Jonasson G, et al: Reference values for maximal renal concentrating capacity in children by the desmopressin test.  Pediatr Nephrol  1992; 6:254-257.

Marsden and Brenner, 1991. Marsden PA, Brenner BM: Nitric oxide and endothelins: Novel autocrine/paracrine regulators of the circulation.  Semin Nephrol  1991; 11:169.

Marshall et al., 1978. Marshall WP, Banasiak MF, Kalkhoff RK: Effects of phosphate deprivation on carbohydrate metabolism.  Harm Metab Res  1978; 10:369.

Marver and Kokko, 1983. Marver D, Kokko JP: Renal target sites and the mechanism of action of aldosterone.  Miner Electrolyte Metab  1983; 9:1.

Matkovic and Heaney, 1992. Matkovic V, Heaney RP: Calcium balance during human growth: Evidence for threshold behavior.  Am J Clin Nutr  1992; 55:992.

McCrory, 1972. McCrory WW: Developmental nephrology,  Cambridge, MA, Harvard University Press, 1972.

Mellits and Cheek, 1970. Mellits ED, Cheek DB: The assessment of body water and fatness from infancy to adulthood.  Monogr Soc Res Child Dev  1970; 35:12-26.

Menon et al., 1986. Menon RK, Fouseca V, Dandoya P: Late hyponatremia in preterm infants.  J Pediatr  1986; 108:487.

Milford, 1999. Milford DV: Investigation of hypertension and the recognition of monogenic hypertension.  Arch Dis Child  1999; 81:452-455.

Moore, 1970. Moore EW: Ionized calcium in normal serum, ultrafiltrates, and whole blood determined by ion-exchange electrodes.  J Clin Invest  1970; 49:318.

Moritz and Ayus, 2002. Moritz M, Ayus JC: Disorders of water metabolism in children: Hyponatremia and hypernatremia.  Pediatr Rev  2002; 23:371-380.

Mundel and Shankland, 2002. Mundel P, Shankland SJ: Podocyte biology and response to injury.  J Am Soc Nephrol  2002; 13:3005-3015.

Mundy and Guise, 1997. Mundy GR, Guise TA: Hypercalcemia of malignancy.  Am J Med  1997; 103:134-135.

Murer et al., 2000. Murer H, Hernando N, Forster I, Biber J: Proximal tubular phosphate reabsorption: Molecular mechanisms.  Physiol Rev  2000; 80:1373-1409.

Narins, 2001. Narins RG: Hyponatraemia—review of a controversial case.  Nephrol Dial Transplant  2001; 16(suppl 6):36-37.

Ng and Vane, 1967. Ng KKF, Vane JR: Conversion of angiotensin I to angiotensin II.  Nature  1967; 216:762.

Nussberger et al., 1990. Nussberger J, Waeber B, Brunner HR: Clinical pharmacology of ACE inhibition.  Cardiology  1990; 76(suppl 2):11-22.

Oddie et al., 2001. Oddie S, Richmond S, Coulthard M: Hypernatraemic dehydration and breast feeding: A population study.  Arch Dis Child  2001; 85:318-320.

Oh and Karecki, 1972. Oh W, Karecki H: The effects of radiant warmer on insensible water loss in newborn infants.  Am J Dis Child  1972; 124:230.

Oh, 1980. Oh W: Fluid and electrolyte therapy in low birth weight infants.  Pediatr Rev  1980; 1:313.

Olbing et al., 1973. Olbing J, Blaufox MD, Aschinberg LC, et al: Postnatal changes in glomerular blood flow distribution in puppies.  J Clin Invest  1973; 52:2885.

Osswald et al., 1978. Osswald H, Spielman WS, Knox FG: Mechanism of adenosine-mediated decreases in glomerular filtration rate in dogs.  Circ Res  1978; 43:465.

Palm et al., 2001. Palm C, Reimann D, Gross P: The role of V2 vasopressin antagonists in hyponatremia.  Cardiovasc Res  2001; 51:403-408.

Paneth, 1980. Paneth N: Hypernatremic dehydration of infancy.  Am J Dis Child  1980; 134:785.

Parfit et al., 1986. Parfit AM, Kleerekoper M, Cruz C: Reduced phosphate reabsorption unrelated to parathyroid hormone after renal transplantation: Implications for the pathogenesis of hyperparathyroidism in chronic renal failure.  Miner Electrol Metab  1986; 12:356.

Parfitt and Kleerekoper, 1980. Parfitt AM, Kleerekoper M: Clinical disorders of calcium, phosphorus and magnesium metabolism.   In: Maxwell MH, Kleeman CR, ed. Clinical disorders of fluid and electrolyte metabolism,  New York: McGraw-Hill Book; 1980:947.

Patrick, 1977. Patrick J: Assessment of body potassium stores.  Kidney Int  1977; 11:476.

Peterson et al., 2000. Peterson B, Khanna S, Fisher B, et al: Prolonged hypernatremia controls elevated intracranial pressure in head-injured pediatric patients.  Crit Care Med  2000; 28:1136-1143.

Pezzi et al., 1966. Pezzi PJ, Frobese AS, Greenberg SR: Methoxyflurane and renal toxicity.  Lancet  1966; I:73.

Philbin and Coggins, 1978. Philbin DM, Coggins CH: Plasma antidiuretic hormone levels in cardiac surgical patients during morphine and halothane anesthesia.  Anesthesiology  1978; 49:95.

Philbin et al., 1981. Philbin DM, Levine FH, Kono K, et al: Attenuation of the stress response to cardiopulmonary bypass by the addition of pulsatile flow.  Circulation  1981; 64:808.

Pierson et al., 1974. Pierson Jr RN, Lin DHY, Phillips RA: Total body potassium in health: Effects of age, sex, height, and fat.  Am J Physiol  1974; 226:206.

Pitts and Lotspeich, 1946. Pitts RF, Lotspeich WD: Bicarbonate and the renal regulation of acid-base balance.  Am J Physiol  1946; 147:136.

Pitts, 1974. Pitts RF: Tubular disorders.   In: Pitts RF, ed. Physiology of the kidney and body fluids,  Chicago: Year Book Medical Publishers; 1974:71.

Popovtzer and Knochel, 1986. Popovtzer MM, Knochel JP: Disorders of calcium, phosphorus, vitamin D and parathyroid hormone activity.   In: Schrier RW, ed. Renal and electrolyte disorders,  Boston: Little, Brown & Co; 1986:251.

Popovtzer et al., 1975. Popovtzer MM, Subryan VL, Alfrey AC, et al: The acute effect of chlorothiazide on serum-ionized calcium. Evidence for a parathyroid hormone-dependent mechanism.  J Clin Invest  1975; 55:1295.

Prandota and Pruitt, 1975. Prandota J, Pruitt AW: Furosemide binding to human albumin and plasma of nephrotic syndrome.  Clin Pharmacol Ther  1975; 17:159.

Prie et al., 2002. Prie D, Huart V, Bakouh N, et al: Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter.  N Engl J Med  2002; 347:983-991.

Prunty et al., 1963. Prunty FTG, Brooks RV, Dupre J, et al: Adrenocortical hyperfunction and potassium metabolism with “non-endocrine” tumors and Cushing's syndrome.  J Clin Endocrinol Metab  1963; 23:737.

Radtke et al., 1972. Radtke HW, Rumrich G, Kinne-Saffran E, et al: Dual actions of acetazolamide and furosemide on proximal volume absorption in the rat kidney.  Kidney Int  1972; 1:100.

Raisz, 1977. Raisz LG: Bone metabolism and calcium regulation.   In: Avioli LV, Karne SM, ed. Metabolic bone disease, vol 1,  New York: Academic Press; 1977:1.

Rane et al., 1978. Rane A, Villeneuve JP, Stone WJ, et al: Plasma binding and disposition of furosemide in the nephrotic syndrome and in uremia.  Clin Pharmacol Ther  1978; 24:199.

Rao and Shanmugam, 1979. Rao TLK, Shanmugam M: Succinylcholine administration—another contraindication?.  Anesth Analg  1979; 58:61.

Rees et al., 1984. Rees L, Shaw JCL, Brook CGD, et al: Hyponatremia in the first week of life in preterm infants.  Arch Dis Child  1984; 59:423.

Reimann and Gross, 1999. Reimann D, Gross P: Chronic, diagnosis-resistant hypokalaemia.  Nephrol Dial Transplant  1999; 14:2957-2961.

Relman and Schwartz, 1956. Relman AS, Schwartz WB: The nephropathy of potassium depletion.  N Engl J Med  1956; 255:195.

Rigden et al., 1984. Rigden SP, Dillon MJ, Kind PR, et al: The beneficial effect of mannitol on postoperative renal function in children undergoing cardiopulmonary bypass surgery.  Clin Nephrol  1984; 21:148.

Ritz et al., 1980. Ritz E, Kreusser W, Bommer J: Effects of hormones other than parathyroid hormones on renal handling of phosphate.   In: Massry SG, Fleisch H, ed. The renal handling of phosphate,  New York: Plenum Press; 1980:137.

Robertson et al., 1972. Robertson CR, Deen WM, Troy JL, et al: Dynamics of glomerular ultrafiltration in the rat. III. Hemodynamics and autoregulation.  Am J Physiol  1972; 223:1191.

Robertson, 2001. Robertson G: Antidiuretic hormone: Normal and disordered functions.  Endocrinol Metab Clin North Am  2001; 30:671-694.

Robertson, 1983. Robertson GL: Thirst and vasopressin function in normal and disordered states of water balance.  J Lab Clin Med  1983; 101:351.

Rodd and Goodyer, 1999. Rodd C, Goodyer P: Hypercalcemia of the newborn: etiology, evaluation, and management.  Pediatr Nephrol  1999; 13:542-547.

Rodriguez-Soriano et al., 1990. Rodriguez-Soriano J, Ubetagoyena M, Vallo A: Transtubular potassium concentration gradient: A useful test to estimate renal aldosterone bio-activity in infants and children.  Pediatr Nephrol  1990; 4:105-110.

Rodriguez-Soriano and Vallo, 1988. Rodriguez-Soriano J, Vallo A: Renal tubular hyperkalaemia in childhood.  Pediatr Nephrol  1988; 2:498-509.

Root and Harrison, 1976. Root AW, Harrison HE: Recent advances in calcium metabolism.  J Pediatr  1976; 88:1.

Rosa et al., 1980. Rosa RM, Silva P, Young JB, et al: Adrenergic modulation of extra-renal potassium disposal.  N Engl J Med  1980; 302:431.

Rowe et al., 1980. Rowe JW, Tobin JD, Rosa RM, et al: Effect of experimental potassium deficiency on glucose and insulin metabolism.  Metabolism  1980; 29:498.

Roy and Sinclair, 1975. Roy RN, Sinclair JC: Hydration of the low birth weight infants.  Clin Perinatal  1975; 2:393.

Roza and Berman, 1971. Roza O, Berman LB: The pathophysiology of barium: Hypokalemic and cardiovascular effects.  J Pharmacol Exp Ther  1971; 177:433.

Rudolph et al., 1971. Rudolph AM, Heymann MA, Teramo AW, et al: Studies on the circulation of the previable human fetus.  Pediatr Res  1971; 5:452.

Ryan and Karnovsky, 1976. Ryan GB, Karnovsky MJ: Distribution of endogenous albumin in rat glomerulus. Role of hemodynamic factors in glomerular barrier function.  Kidney Int  1976; 9:36.

Schambelan et al., 1980. Schambelan M, Sebastian A, Biglieri EG: Prevalence, pathogenesis, and functional significance of aldosterone deficiency in hyperkalemia patients with chronic renal insufficiency.  Kidney Int  1980; 17:89.

Scheinman et al., 1999. Scheinman SJ, Guay-Woodford LM, Thakker RV, et al: Genetic disorders of renal electrolyte transport.  N Engl J Med  1999; 340:1177-1187.

Schell-Feith et al., 2000. Schell-Feith EA, Kist-van Holthe JE, Conneman N, et al: Etiology of nephrocalcinosis in preterm neonates: Association of nutritional intake and urinary parameters.  Kidney Int  2000; 58:2102-2110.

Schiffrin, 2002. Schiffrin EL: Vascular and cardiac benefits of angiotensin receptor blockers.  Am J Med  2002; 113:409-418.

Schlondorff et al., 1978. Schlondorff D, Wever H, Trizna W: Vasopressin responsiveness of renal adenylate cyclase in newborn rats and rabbits.  Am J Physiol  1978; 234:F16-F21.

Schnermann et al., 1984. Schnermann J, Briggs JP, Weber PC: Tubulo-glomerular feedback, prostaglandins, and angiotensin in the autoregulation of glomerular filtration rate.  Kidney Int  1984; 25:53.

Schrier, 1979. Schrier RW: Acute renal failure.  Kidney Int  1979; 15:205.

Schultz et al., 1962. Schultz DM, Giordano DA, Schultz DH: Weights of organs of fetuses and infants.  Arch Pathol  1962; 74:244.

Schwartz et al., 1987. Schwartz GL, Brion LP, Spitzer A: The use of plasma creatinine concentration for estimating glomerular filtration in infants, children and adolescents.  Pediatr Clin North Am  1987; 34:571.

Schwartz et al., 1974. Schwartz IL, Shlatz LI, Kinne-Saffran E: Target cell polarity and membrane phosphorylation in relation to the mechanism of action of antidiuretic hormone.  Proc Natl Acad Sci USA  1974; 71:2695.

Seldin and Rector, 1972. Seldin DW, Rector Jr FC: The generation and maintenance of metabolic alkalosis.  Kidney Int  1972; 1:306.

Selkurt et al., 1949. Selkurt EE, Hall PW, Spencer MP: Influence of graded arterial pressure decrement on renal clearance of creatinine, p-amino-hippurate and sodium.  Am J Physiol  1949; 159:369.

Shaer, 2001. Shaer AJ: Inherited primary renal tubular hypokalemic alkalosis: A review of Gitelman and Bartter syndromes.  Am J Med Sci  2001; 322:316-332.

Shipley and Study, 1951. Shipley RE, Study RS: Changes in renal blood flow, extraction of insulin, glomerular filtration rate, tissue pressure and urine flow with acute alterations of renal artery blood pressure.  Am J Physiol  1951; 167:676.

Shirley et al., 1982. Shirley DG, Walter SJ, Laycock JF: The anti-diuretic effects of chronic hydrochlorothiazide treatment in rats with diabetes insipidus: Renal mechanism.  Clin Sci  1982; 63:533.

Shoemaker, 1999. Shoemaker LR: Expanding role of biphosphonate therapy in children.  J Pediatr  1999; 134:264-267.

Silverman, 1961. Silverman WA: Dunham's premature infants, ed,  New York: Paul B Hoeber; 1961:531.

Slatopolsky and Delmez, 1992. Slatopolsky E, Delmez J: Bone disease in chronic renal failure and after renal transplantation.   In: Coe FL, Favus MJ, ed. Disorders of bone and mineral metabolism,  New York: Raven Press; 1992:905.

Smith, 1943. Smith HW: Lectures on the kidney,  Lawrence, KS: University Extension Division of University of Kansas; 1943:97.

Spitzer, 1978. Spitzer A: Renal physiology and functional development.   In: Edelman Jr CM, ed. Pediatric kidney disease,  Boston: Little, Brown & Co; 1978:25.

Spitzer, 1982. Spitzer A: The role of the kidney in sodium homeostasis during maturation.  Kidney Int  1982; 21:539.

Stapleton et al., 1976. Stapleton FB, Nelson B, Vats TS, et al: Hypokalemia associated with antibiotic treatment.  Am J Dis Child  1976; 130:1104.

Stein, 1985. Stein JH: The pathogenetic spectrum of Banter's syndrome.  Kidney Int  1985; 28:85.

Stoner et al., 1974. Stoner LC, Brug MB, Orloff J: Ion transport in cortical collecting tubule: Effect of amiloride.  Am J Physiol  1974; 227:453.

Streicher et al., 1981. Streicher HZ, Gabow PA, Moss AH, et al: Syndromes of toluene sniffing in adults.  Ann Intern Med  1981; 94:758.

Suh et al., 1973. Suh SM, Tashjian Jr AH, Matsuo N: Pathogenesis of hypocalcemia in primary hypomagnesemia: Normal end-organ responsiveness to parathyroid hormone, impaired parathyroid gland function.  J Clin Invest  1973; 51:531.

Suki and Rouse, 1991. Suki WN, Rouse D: Renal transport of calcium, magnesium, and phosphorus.   In: Brenner BM, Rector Jr FC, ed. The kidney,  Philadelphia: WB Saunders; 1991:340-423.

Suki, 1976. Suki WN: Disposition and regulation of body potassium: An overview.  Am J Med Sci  1976; 272:31.

Sulyok et al., 1985. Sulyok E, Kovacs L, Lichardus B, et al: Late hyponatremia in premature infants: Role of aldosterone and arginine vasopressin.  J Pediatr  1985; 106:990.

Sulyok et al., 1979. Sulyok E, Varga F, Gyory E, et al: Postnatal development of renal sodium handling in premature infants.  J Pediatr  1979; 95:787-792.

Sutton, 1986. Sutton RA: Calcium disorders.   In: Dirks JH, Sutton RA, ed. Diuretics: Physiology, pharmacology and clinical use,  Philadelphia: WB Saunders; 1986:259.

Svenningsen and Aronson, 1974. Svenningsen NW, Aronson AS: Postnatal development of renal concentrating capacity as estimated by DDAVP-test in normal and asphyxiated neonates.  Biol Neonate  1974; 25:230.

Ten et al., 2001. Ten S, New M, Maclaren N: Addison's disease.  J Clin Endocrinol Metabl  2001; 86:2909-2922.

Tenenhouse and Murer, 2003. Tenenhouse HS, Murer H: Disorders of renal tubular phosphate transport.  J Am Soc Nephrol  2003; 14:240-247.

The ADHR Consortium, 2000. The ADHR Consortium : Autosomal dominant hypophosphatemic rickets is associated with mutations in FGF23.  Nat Genet  2000; 26:345-348.

Thompson and Edmonds, 1971. Thompson BD, Edmonds CJ: Comparison of effects of profound aldosterone administration on rat colon and renal electrolyte excretion.  J Endocrinol  1971; 50:163.

Thurau, 1964. Thurau K: Renal hemodynamics.  Am J Med  1964; 36:698.

Torres et al., 1990. Torres VE, Young WF, Offord KP, Hattery RR: Association of hypokalemia, aldosteronism and renal cysts.  N Engl J Med  1990; 322:345-351.

Trimble, 1970. Trimble ME: Renal response to solute loading in infant rats: Relation to anatomical development.  Am J Physiol  1970; 219:1089.

Tsang et al., 1973. Tsang RC, Light IJ, Sutherland JM, et al: Possible pathogenic factors in neonatal hypocalcemia of prematurity.  J Pediatr  1973; 82:423.

Tucker and Blantz, 1977. Tucker BJ, Blantz RC: An analysis of the determinants of nephron filtration rate.  Am J Physiol  1977; 232:447.

Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents, 1996. Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents : A work group report from the National High Blood Pressure Education Program.  Pediatrics  1996; 98:649-658.

van Ypersele de Strihou, 1977. van Ypersele de Strihou C: Potassium homeostasis in renal failure.  Kidney Int  1977; 11:49.

Venkataraman et al., 1987. Venkataraman PS, Tsang RC, Chen IW, et al: Pathogenesis of early neonatal hypocalcemia: Studies of serum calcium, gastrin, and plasma glucagon.  J Pediatr  1987; 110:599.

Vogh, 1980. Vogh DP: The relation of choroid plexus carbonic anhydrase activity to cerebrospinal fluid formation: Study of three inhibitors in cat with extrapolation to man.  J Pharmacol Exp Ther  1980; 213:321.

Warren and Blantz, 1981. Warren SE, Blantz RC: Mannitol.  Arch Intern Med  1981; 141:493.

Weber et al., 2001. Weber S, Schneider L, Peters M, et al: Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.  J Am Soc Nephrol  2001; 12:1872-1881.

Weiner and Wingo, 1997. Weiner DI, Wingo CS: Hypokalemia—consequences, causes and correction.  J Am Soc Nephrol  1997; 7:1179-1188.

Welfare et al., 2002. Welfare W, Sasi P, English M: Challenges in managing profound hypokalemia.  Br Med J  2002; 324:269-270.

Wenneberg et al., 1977. Wenneberg RP, Rasmussen LF, Ahlfors CE: Displacement of bilirubin from human albumin by three diuretics.  J Pediatr  1977; 90:647.

Whang et al., 1992. Whang R, Whang DD, Ryan MP: Refractory potassium depletion: A consequence of magnesium deficiency.  Arch Intern Med  1992; 152:40-45.

White et al., 1982. White DP, Zwillich CW, Pickett CK, et al: Central sleep apnea: Improvement with acetazolamide therapy.  Arch Intern Med  1982; 142:1816.

Whitford and Taves, 1973. Whitford GM, Taves DR: Fluoride-induced diuresis: Renal-tissue solute concentrations, functional, hemodynamic and histologic correlates in the rat.  Anesthesiology  1973; 39:416.

Winters, 1982. Winters RW: Principles of pediatric fluid therapy,  ed 2. Boston, Little, Brown & Co., 1982.

Wormersley and Darragh, 1955. Wormersley RA, Darragh JH: Potassium and sodium restriction in the normal human.  J Clin Invest  1955; 34:456.

Wu and Hodgman, 1974. Wu PYK, Hodgman JE: Insensible water loss in preterm infants: Changes with postnatal development and nonionizing radiant energy.  Pediatrics  1974; 54:704.

Yared and Yoskioka, 1989. Yared A, Yoskioka A: Autoregulation of glomerular filtration in the young.  Semin Nephrol  1989; 9:94.

Zelikovic, 2001. Zelikovic I: Molecular pathophysiology of tubular transport disorders.  Pediatr Nephrol  2001; 16:919-935.

Ziegler, 2001. Ziegler R: Hypercalcemic crisis.  J Am Soc Nephrol  2001; 12:S3-S9.

Zimmerman and Defendini, 1977. Zimmerman EA, Defendini R: Hypothalamic pathways containing oxytocin, vasopressin, and associated neurophysins.   In: Moses AM, Share L, ed. Neurohypophysis: International Congress on the Neurohypophysis,  Basel: S Karger; 1977.