Fluids and Electrolytes

The kidney regulates total body sodium balance and maintains normal extracellular and circulating volumes.⁷ The adult kidney filters 25,000 mEq of sodium per day, but it excretes less than 1% through extremely efficient resorption mechanisms along the nephron. The proximal tubule resorbs 50% to 70%, the ascending limb of the loop of Henle resorbs about 25%, and the distal nephron accounts for 10% of the filtered load of sodium. Several hormones, including renin, angiotensin II, aldosterone, and atrial natriuretic peptide, and changes in circulating volume play roles in maintaining sodium balance.⁸

Serum osmolality is tightly regulated through changes in arginine vasopressin (AVP) release and the appreciation of thirst.^9–11 AVP, also called antidiuretic hormone, is synthesized in the hypothalamus and stored in the posterior pituitary, where it is released in response to an increasing plasma osmolality. AVP is also released in response to a decreased circulating volume or hypotension, including those responses to nausea, vomiting, and possibly opioids. AVP binds to receptors in the collecting duct, increasing the permeability of the tubules to water and leading to increased water resorption and concentrated urine. Neonates are much less able to conserve or excrete water compared with older children, rendering the fluid management and volume issues important tasks of the pediatric anesthesiologist in this young age-group.¹²

The regulation of serum potassium is managed by the kidney and depends on the concentration of plasma aldosterone. Aldosterone binds to receptors on cells in the distal nephron, increasing the secretion of potassium in the urine. Neonates are much less efficient at excreting potassium loads compared with adults, and the normal range of serum potassium concentrations is therefore greater in neonates; Table 26-1 provides the normal values.¹³ Potassium regulation is affected by the acid-base status; excretion of potassium increases in the presence of alkalosis and decreases in the presence of acidosis. Causes of hyperkalemia and hypokalemia are presented in Tables 26-2 and 26-3, respectively.

TABLE 26-1 Normal Values of Serum Potassium

TABLE 26-2 Causes of Hyperkalemia

TABLE 26-3 Causes of Hypokalemia

Acid-Base Balance

The kidney is involved in the day-to-day regulation of acid-base balance and the response to the stress of illness. The kidney reclaims virtually all of the filtered bicarbonate in the proximal tubule. The kidney also regenerates the bicarbonate () lost in the neutralization of acid generated by the normal combustion of food, especially protein, and the formation of bone. New bicarbonate is generated by the cells of the distal nephron by decomposing the carbonic acid (H₂CO₃) formed from water (H₂O) and carbon dioxide (CO₂) by carbonic anhydrase. The protons (H⁺) that are generated from this process are pumped into the lumen of the collecting duct, where they combine with hydrogen phosphate () or ammonia (NH₃) generated by the catabolism of amino acids, mainly glutamine, in the tubule cells.

Infants, especially neonates, maintain a slightly acidotic pH (7.37) and decreased plasma bicarbonate concentration (22 mEq/L) compared with older children and adults (pH = 7.39; plasma bicarbonate = 24 to 28 mEq/L).¹⁴ Neonates can maintain acid-base homeostasis but are limited in their ability to respond to an acid load.¹⁵ This is especially true for preterm infants. This reduced plasma concentration in infants is the result of a reduced threshold, or the plasma concentration at which is no longer completely resorbed by the kidney.

Acute Renal Failure and Acute Kidney Injury

Acute renal failure (ARF) or acute renal insufficiency can be defined as an abrupt deterioration in the kidney’s ability to clear nitrogenous wastes, such as urea and creatinine. Concomitantly, there is a loss of ability to excrete other solutes and maintain a normal water balance. This leads to the clinical presentation of acute renal insufficiency: edema, hypertension, hyperkalemia, and uremia.

Acute kidney injury (AKI) has almost replaced the traditional term acute renal failure, which was used in reference to the subset of patients with an acute need for dialysis. With the recognition that even modest increases in serum creatinine are associated with a dramatic impact on the risk for mortality, the clinical spectrum of acute decline in GFR is broader. The minor deteriorations in GFR and kidney injury are captured in a working clinical definition of kidney damage that allows early detection and intervention and uses AKI as a replacement for the term ARF. The term ARF is preferably restricted to patients who have AKI and need renal replacement therapy.¹⁶ The prognosis of AKI is assessed in part by the use of the RIFLE criteria, which include three severity categories (i.e., Risk, Injury, and Failure) and two clinical outcome categories (Loss and End-stage renal disease) (Table 26-4).

The term ARF has often been incorrectly used interchangeably with acute tubular necrosis, which usually refers to a rapid deterioration in renal function occurring minutes to days after an ischemic or nephrotoxic event. Although acute tubular necrosis is an important cause of ARF, it is not the sole cause, and the terms are not synonymous. For the purposes of this chapter, AKI refers to the disease formerly called ARF.

Etiology and Pathophysiology

AKI is often multifactorial in origin or the result of several distinct insults. To treat AKI, it is important to understand its causes and pathophysiology. The causes of AKI are varied but in general can be classified as follows (Table 26-5):

Prerenal implies poor renal perfusion.

Renal implies intrinsic renal disease or damage.

Postrenal implies an obstruction to urine excretion.

TABLE 26-5 Causes of Acute Renal Failure

Prerenal Failure	Renal Failure	Postrenal Failure
Hypovolemia  Volume loss  Gastrointestinal, renal losses  Sequestration (burns, postoperative)	Acute glomerulonephritis  Postinfectious  Membranoproliferative glomerulonephritis  Rapidly progressive glomerulonephritis  Glomerulonephritis due to systemic disease (e.g., HUS, DIC, SLE)	Obstruction  Intrinsic (papillary necrosis due to diabetes, sickle cell disease, or analgesic nephropathy)  Intrarenal abnormalities, ureteral obstruction, obstruction of the bladder or urethra  Extrinsic (tumor compression, lymphadenopathy)
Hypotension  Shock  Vasodilators	Acute interstitial nephritis  Drug-induced hypersensitivity (penicillin)  Infections
Decreased effective blood flow  Low cardiac output  Cirrhosis  Nephrotic syndrome	Tubular disease  ATN (ischemic, nephrotoxic)  Intratubular obstruction (uric acid, oxalate)
Renal hypoperfusion  Use of ACE inhibitors  NSAIDs  Hepatorenal syndrome	Cortical necrosis  Gram-negative sepsis  Hemorrhage  Shock
Vascular occlusion  Thromboembolic phenomenon  Aortic dissection  Renal vein thrombosis (dehydration, hypercoagulable state, neoplasm)	Acute renal failure  Toxins  Organic solvents  Heavy metals  Insecticides  Hemoglobin  Myoglobin
	Chronic renal failure  Chronic interstitial nephritis  Chronic glomerulonephritis  Chronic glomerulosclerosis  Nephrocalcinosis  Obstructive uropathy  Hypertension

ACE, Angiotensin-converting enzyme; ATN, acute tubular necrosis; DIC, disseminated intravascular coagulation; HUS, hemolytic uremic syndrome; NSAIDs, nonsteroidal antiinflammatory drugs; SLE, systemic lupus erythematosus.

Prerenal insults are a common cause of AKI, accounting for up to 70% of all cases. Prerenal failure usually results from extracellular fluid loss, such as from gastroenteritis, burns, hemorrhage, or excessive diuresis. It also occurs in the setting of cardiac failure or sepsis. The common feature of this condition is diminished renal perfusion. In response to the reduction in flow, there is a compensatory increase in afferent tone, which decreases the GFR and increases the retention of salt and water. The net effect of these events is a drastic reduction in urine volume, often resulting in oliguria. If the underlying problem is recognized and treated aggressively, progressive renal insufficiency may be averted. Nonsteroidal antiinflammatory drugs, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers can aggravate prerenal azotemia by further reducing glomerular capillary pressure and the GFR.¹⁷

AKI resulting from parenchymal disease or injury accounts for 20% to 30% of cases of abrupt renal insufficiency. Common causes in infants include birth asphyxia, sepsis, and cardiac surgery. Important causes of AKI in older children include trauma, sepsis, and the hemolytic uremic syndrome. Prolonged prerenal azotemia may result in overt renal injury. Similarly, intrarenal obstruction to blood flow from thrombi or vasculitis may cause renal failure. Drugs such as aminoglycosides or amphotericin B or other nephrotoxins, including radiocontrast agents, may induce AKI through tubular injury or cause interstitial injury as a result of allergic reactions, as can be seen with penicillins. Acute glomerulonephritis is another cause of AKI in children. Rarely, pyelonephritis can lead to AKI.

The remaining causes of AKI result from the obstruction to urine flow. In total, these conditions account for less than 10% of all cases of AKI and lead to obstruction of both kidneys. Complete cessation of urine may be a clue to a postrenal cause. The obstruction can occur within the collecting system of the kidney (intrarenal), in the ureter, or in the urethra (extrarenal). Intrarenal obstruction may occur with the tumor lysis syndrome with the deposition of uric acid crystals or from medications such as acyclovir and cidofovir. Extrarenal obstruction can be caused by the presence of stones in the ureters or from external compression due to lymph nodes or tumor. As with other forms of AKI, prompt recognition and appropriate intervention to relieve an obstruction may prevent a permanent reduction in renal function.

The exact pathophysiology of AKI remains unclear, but several factors have been identified.¹⁸ There is a profound vasoconstriction in the initial phase of AKI that contributes to the reduced GFR (Fig. 26-1). Factors implicated in increased vasoconstriction include increased activity of the renin-angiotensin and the adrenergic systems and endothelial dysfunction with increased endothelin release and decreased nitric oxide synthesis. However, therapeutic interventions to increase vasodilatation, such as prostaglandin and dopamine infusions, ACE inhibitors, calcium channel blockers, and endothelin receptor antagonists, have not significantly improved established AKI.¹⁹

FIGURE 26-1 Hemodynamic factors in the pathogenesis of acute renal failure.

Another factor in the pathogenesis of AKI is renal tubule cell injury that is a direct result of a nephrotoxic agent or from an ischemic insult (Fig. 26-2). Cellular injury leads to sloughing of the brush border, swelling, mitochondrial condensation, disruption of cellular architecture, and loss of adhesion to the basement membrane with shedding of cells into the tubular lumen.²⁰ These changes, which occur within minutes of an ischemic event, contribute to the decreased GFR by obstructing the lumen of the tubule.²¹ These cellular changes allow the filtrate to leak back into the peritubular blood, reducing the excretion of solutes and the effective GFR.

FIGURE 26-2 Influences of specific injuries on the nephron in the pathogenesis of acute renal failure. ATP, Adenosine triphosphate.

Some of these cell derangements in AKI, such as a decrease in ATP concentrations,²¹ cell membrane injury by reactive oxygen molecules,²² and increased intracellular calcium levels from changes in membrane phospholipid metabolism, lead to cell death. Reactive oxygen molecules also stimulate the production of cytokines and chemokines that play a role in cell injury and vasoconstriction.

Infiltrating neutrophils, recruited during reperfusion injury after renal ischemia, mediate parenchymal damage.²³ Reperfusion injury increases intracellular adhesion molecule 1 (ICAM-1) on endothelial cells promoting the adhesion of circulating neutrophils and their eventual infiltration into the parenchyma. Neutrophils then release reactive oxygen molecules, elastases, proteases, and other enzymes that lead to further tissue injury.

Therapeutic Interventions

Therapeutic interventions in children with AKI should be aimed at the underlying cause and at improving renal function and urine flow. Children with AKI due to hypovolemia should be fluid resuscitated with at least 20 mL/kg over 30 to 60 minutes of normal saline or a balanced salt solution. For children with significant hypotension, an alternative choice is a colloid-containing solution. Children with oliguria due to hypovolemia usually respond within 4 to 6 hours with increased urine output. Although there are anecdotal reports supporting low-dose dopamine in AKI, clinical trials have not shown a benefit from dopamine in preventing or improving AKI.²⁴

Diuretics have been commonly used to treat oliguric AKI. There are several theoretical reasons why mannitol, furosemide, or other loop diuretics may ameliorate AKI. Diuretics may convert oliguric AKI to nonoliguric AKI. Loop diuretics decrease energy-driven transport in the loop of Henle, and this may protect cells in regions of hypoperfusion. However, neither mannitol nor loop diuretics can predictably convert an oliguric patient with AKI to a polyuric patient. Diuretics have not been shown in clinical studies to influence renal recovery, need for dialysis, or survival in patients with AKI.^25,26 Diuretics should be used only after the circulating volume has been adequately restored and should be stopped if there is no early response.

Dopamine has been widely used to prevent and manage AKI. In low doses (0.5 to 2.0 µg/kg/min), dopamine increases renal plasma flow, GFR, and renal sodium excretion by activating dopaminergic receptors. Infusion rates in excess of 3 µg/kg/min stimulate α-adrenergic receptors on systemic arterial resistance vasculature causing vasoconstriction; cardiac β₁-adrenergic receptors increasing cardiac contractility, heart rate, and cardiac index; and β₂-adrenergic receptors on systemic arterial resistance vasculature causing vasodilatation. In a meta-analysis of 24 studies and 854 patients, dopamine did not prevent renal failure, alter the need for dialysis, or change the mortality rate.²⁷ In a randomized clinical trial of low-dose dopamine in 328 critically ill patients, dopamine did not change the duration or severity of the renal failure, need for dialysis, or mortality.²⁸ From these data, the routine use of low-dose dopamine in patients with AKI cannot be supported.

Several other agents that were useful in experimental models of AKI have been investigated but not shown clinical success. Atrial natriuretic peptide increases GFR in animal models of AKI by increasing renal perfusion pressure and sodium excretion. Initial studies demonstrated some benefit in patients with AKI,²⁹ especially oliguric AKI,³⁰ but a subsequent study of 222 patients with oliguric AKI revealed no statistical difference between patients treated with atrial natriuretic peptide and placebo in terms of the need for dialysis or mortality.³¹ Insulin-like growth factor 1 has been beneficial in animal models of AKI, presumably by potentiating cell regeneration. However, in a multicenter, placebo-controlled trial enrolling 72 patients with AKI, insulin-like growth factor 1 did not speed recovery, decrease the need for dialysis, or alter the mortality rate.³² Thyroxine abbreviates the course of experimental acute renal failure but had no effect on the duration of renal failure in patients and increased mortality threefold (by suppression of thyroid-stimulating hormone).³³

In patients with severe AKI, renal replacement therapy through dialysis is life sustaining. The indications for initiation of dialytic therapy are persistent hyperkalemia, volume overload refractory to diuretics, severe metabolic acidosis, and overt signs and symptoms of uremia such as pericarditis and encephalopathy. Many nephrologists advocate for initiation of dialysis if the BUN value approaches 100 mg/dL or even earlier, especially in the oliguric patient, although this has not proved to alter outcome. A retrospective study that compared early (BUN <60 mg/dL) versus late (BUN >60 mg/dL) initiation of dialysis in 100 adult patients suggested that early initiation improved survival.³⁴ However, the timing of the initiation of dialysis remains an unresolved question.

The three modalities of renal replacement for the support of critically ill children and adults are hemodialysis, peritoneal dialysis, and a variation of continuous replacement therapies, such as venovenous hemofiltration (CVVH), hemodialysis (CVVHD), and hemodiafiltration (CVVHDF). No form of replacement therapy has been clearly superior to the others. However, in the individual child, one form may be more practical than the others. Hemodialysis is technically more difficult than peritoneal dialysis in the infant and hemodynamically unstable child. Continuous replacement therapies appear to cause less hemodynamic instability compared with hemodialysis but offer more predictable solute and fluid removal than peritoneal dialysis. Hemodialysis and continuous replacement therapies require large-bore vascular access to achieve the high blood flow rates necessary for these modalities.

Although the modalities are technically different, they are based on the same principles (Fig. 26-3). The aim of all renal replacement therapies is to promote the removal of nitrogenous wastes (i.e., urea), excess fluid, and excess solute, especially potassium. This is achieved by exposing blood to a salt solution (i.e., dialysate), with the two separated by a semipermeable membrane. The movement of solute occurs by diffusion (i.e., solute moves across the membrane in response to a concentration gradient) and ultrafiltration (i.e., osmotic or hydrostatic pressures). The rate of removal of water and solute waste depends on membrane characteristics (i.e., pore size and selectivity), diffusion, and ultrafiltration.³⁵

FIGURE 26-3 Principles of dialysis. Solute (pink circles) moves from the blood to the dialysate (broken arrows) in response to a concentration gradient (i.e., diffusion). The obligate passive movement of water (blue circles) attempts to maintain appropriate osmolarity. This flux of solute and water (i.e., ultrafiltration) may be enhanced by increased osmotic pressure (i.e., glucose in peritoneal dialysis fluid) or by increased hydrostatic pressure, which is created mechanically as transmembrane pressure in hemodialysis.

The permeability characteristics and surface areas are known for specific dialyzers used in hemodialysis and hemofiltration. The peritoneum serves as the dialysis membrane in peritoneal dialysis and remains physically unalterable, but changes in dialysate composition and length of time the dialysate is exposed to the peritoneal membrane changes the amount of solute and water removed. In all forms of renal replacement therapy, the therapeutic prescription is individualized for the child.

Hemodialysis

Hemodialysis is useful for AKI and is the best modality for the rapid removal of toxins, such as drug overdoses or other ingestions. Hemodialysis is very efficient, with the ability to reduce the BUN by 60% to 70%, normalize the serum potassium concentration, and remove fluid equal to 5% to 10% of the body weight in 3 to 4 hours. To accomplish this, rapid blood flows are necessary (5 to 10 mL/kg/min), which requires large-vessel venous access, but this can usually be achieved even in infants by the insertion of a double-lumen catheter into the subclavian, internal jugular, or femoral vein. In small infants, two single-lumen catheters placed in different sites may be necessary for access and return of blood. Rarely, a single-lumen catheter is used for outflow and return of blood. Modern hemodialysis machines have microprocessors that can accurately measure fluid removal, allowing precise volumes of fluid to be removed.

Hemodialysis usually requires systemic anticoagulation with heparin, the effectiveness of which can be monitored by the activated clotting time. Hemodialysis can be done without the use of an anticoagulant in the child at significant risk for bleeding by using a rapid blood flow rate and frequent rinsing of the blood circuit with saline. However, clotting of the circuit with subsequent loss of the extracorporeal blood is common.

In addition to the risk of bleeding, hemodialysis is associated with several other complications. The most common side effect is hypotension, which is usually related to aggressive volume removal but can be caused by sepsis or the release of cytokines and autokines from blood passage over the hemodialysis filter surface. Muscle cramps, headache, nausea, and vomiting are also common complaints. A more serious complication of hemodialysis is the disequilibrium syndrome that is related to rapid removal of solute from the bloodstream with slow equilibration with the tissues, particularly in the brain. This can cause cerebral edema, manifested by headache, obtundation, seizures, or coma. The disequilibrium syndrome is usually reported in children undergoing dialysis for the first time. This can be avoided by short, frequent dialysis sessions initially, especially if the BUN concentration is increased substantially. Infection of the dialysis catheter is another common problem and can be minimized with sterile central line technique.

Peritoneal Dialysis

Peritoneal dialysis has a long history as a renal replacement therapy in children.³⁶ It is relatively simple and easily performed even in small infants. Although not as efficient as hemodialysis, it is best done continuously to control solute and water balance. In contrast to hemodialysis, it is much less likely to cause hemodynamic instability. Peritoneal dialysis involves instilling dialysate fluid into the peritoneum for a set period and then draining the fluid and replacing it with fresh dialysate. This cycling removes waste products by diffusion and water by ultrafiltration as a consequence of a high glucose concentration in the dialysate. The efficacy of peritoneal dialysis depends on the volume instilled and the number of cycles per day. Most children with acute renal failure can be managed with 1- to 2-hour cycles of 5- to 30-mL/kg dwell volumes. Children with chronic renal failure are managed with greater cycle times and larger dwell volumes. The amount of fluid removed can be varied by changing the concentration of the glucose in the dialysate. Short-term peritoneal dialysis can be accomplished with a nontunneled catheter, but dialysis that should continue beyond 3 to 5 days is best achieved with a subcutaneously tunneled cuffed catheter to minimize the risk of peritonitis.

The principal complications of peritoneal dialysis are infection and mechanical problems related to the catheter. It is not uncommon to find poor drainage from the catheter, usually from fibrin occlusion of the catheter or from omentum or bowel covering the inlet holes. The catheter may leak at its point of insertion. Hernias, especially inguinal hernias in boys, may develop as a consequence of the increased abdominal pressure from the infused dialysate. Mild hyponatremia may develop in infants because of the relatively low sodium concentration (130 mEq/L) in commercial dialysate. Less common but serious complications include bowel injury and intraabdominal hemorrhage from catheter insertion and peritonitis.

Chronic Renal Failure

The loss of functioning renal mass results in a compensatory increase in filtration by the remaining renal tissue.³⁷ For example, after a unilateral nephrectomy, there is a demonstrable increase in the GFR and evidence of contralateral renal hypertrophy within the first 48 hours. By 2 to 4 weeks, the GFR has returned to 80% of normal, and there is no clinical evidence of renal dysfunction. With the loss of 50% to 75% of renal mass, there is an increase in the residual function to 50% to 80% of normal and often little evidence of clinical renal insufficiency. When the residual renal function decreases to 30% to 50% of normal, the term chronic renal insufficiency applies. At this point, acute illness and other stress states may result in acidosis, hyperkalemia, and dehydration. It is only when the residual function decreases to less than 30% of normal that the term chronic renal failure is used. At this point, electrolyte abnormalities begin to appear, and more importantly, there is limited ability of the kidney to adjust to variations in fluid and electrolyte homeostasis. The term uremia refers to the symptoms of anorexia, nausea, lethargy, and somnolence that develop as a result of chronic renal failure. Uremia ultimately results in death unless dialysis therapy or renal transplantation is performed. Initiating dialysis or transplanting a kidney is referred to as end-stage renal disease care.

Chronic renal insufficiency and chronic renal failure are both categories within the larger schema of chronic kidney disease (CKD). Although the stages are defined by categorizing continuous measures of function (i.e., GFR) and therefore are somewhat arbitrary, they do provide a context for the evaluation and management of kidney disease. There are six stages of CKD:

Despite losses of up to 90% of renal function, sodium homeostasis usually is well maintained in chronic renal failure. With large decreases in the GFR, the kidney maintains normal serum sodium by increasing the FE_Na from less than 1% up to 25% to 30%, largely through decreases in distal tubular resorption. Some of the hormonal factors involved in this adaptation include aldosterone, atrial natriuretic factor, and a poorly characterized natriuretic hormone that inhibits Na⁺/K⁺-ATPase. With chronic renal failure, the ability of the kidney to handle a wide range of sodium intake, from 1 to 250 mEq/m²/day, is lost. Instead, the kidney may be able to handle an intake of only 50 to 100 mEq/m²/day. It may be possible to decrease this obligatory excretion of sodium to 5 to 20 mEq/m²/day, although only after weeks of decreasing the sodium intake slowly. Certain children with renal disease, especially those with obstructive uropathy or tubulointerstitial disease, may be unable to adjust to a decreased sodium intake and display a salt-losing nephropathy. These children are prone to dehydration with salt restriction and may need salt supplementation for normal growth. In others, a regular diet may lead to sodium retention, volume overload, and hypertension; sodium intake must be individualized to fit the limitations of each child.

Water balance also is affected by chronic renal failure. There is an obligatory total osmolar excretion that limits the ability of the kidney to excrete free water. The concentrating ability of the kidney is affected, limiting its ability to make a maximally concentrated or dilute urine. These limitations may result in water retention and hyponatremia or dehydration if water is administered in amounts exceeding the kidney’s capabilities. These limitations must be considered in the treatment of children with chronic renal failure, particularly before surgery when free access to water is restricted.

In patients with chronic renal failure, normal serum potassium concentrations usually are maintained until the GFR is less than 10% of normal. Potassium excretion in normal and uremic states is maintained by potassium secretion in the distal nephron. In response to an increase in potassium intake or loss of renal mass, there is an increase in Na⁺/K⁺-ATPase in the remaining collecting tubules that seems to be partly responsible for augmented excretion of potassium per nephron. In uremic animals, potassium is excreted from the renal tubules at a rate sixfold greater than in nonuremic animals and 1.5 times the filtered potassium load. Partial adaptation can occur in the absence of aldosterone, but aldosterone plays an important role in the maintenance of normal potassium homeostasis. This is demonstrated by the presence of hyperkalemia in children with hyporeninemic hypoaldosteronism or in those treated with the aldosterone antagonist spironolactone.

The colon normally is responsible for the excretion of less than 13% of dietary potassium. In patients with chronic renal failure, this can increase to 50% by the activation of colonic Na⁺/K⁺-ATPase. Aldosterone augments the activity of colonic Na⁺/K⁺-ATPase. An additional mechanism that plays an essential role in the adaptation to an acute potassium load is the redistribution of potassium from the extracellular to the intracellular compartment, which depends on insulin, β-adrenergic catecholamines, aldosterone, and pH. Despite the presence of total body potassium depletion in uremia, the uptake of potassium into the cells is impaired. This contributes to the intolerance to an acute potassium load in uremia despite the ability to excrete a potassium load.

Hyperkalemia is a major problem in chronic renal failure.³⁸ In contrast, significant hypokalemia is unusual in the absence of potassium restriction, alkalosis, or diuretic therapy. Hyperkalemia can result from an extrinsic potassium load, but it also can be caused by fasting or acidosis, in which case the source of the potassium is the intracellular compartment. This can be a particular problem when a child is fasted before surgery and can be ameliorated by an infusion of glucose and insulin. Drugs that can cause hyperkalemia in renal failure include spironolactone, β-adrenergic blockers, and ACE inhibitors. When clinically significant hyperkalemia develops in a child with chronic renal failure, the first-line therapy is to stabilize the myocardium with exogenous calcium and then to redistribute the potassium into the intracellular compartment with insulin and glucose. To deliver the same dose of ionized calcium, three times as much calcium gluconate (mg/kg) must be given than calcium chloride. All doses of calcium are optimally delivered through a central venous access line because calcium infusions are irritating to peripheral veins and can cause necrosis of the skin if extravasation occurs. More definitive correction of hyperkalemia is accomplished by removing potassium from the body using dialysis or Kayexalate. At eight times the usual asthma dose, nebulized albuterol has been effective in redistributing potassium intracellularly, whereas sodium bicarbonate (NaHCO₃) administration has not been effective (Table 26-6).

TABLE 26-6 Treatment of Hyperkalemia

D, Dextrose; IV, intravenous; PO, per os (oral); PR, per rectum (suppository).

Metabolic acidosis is common in patients with chronic renal failure.³⁹ The metabolic acidosis is associated with a normal anion gap in moderate renal insufficiency, but with severe renal insufficiency, there is retention of phosphate, sulfate, and organic acids, resulting in an elevated anion gap. The primary cause of metabolic acidosis in chronic renal failure is the inability of the remaining proximal renal tubules to increase ammonium formation to keep pace with the loss of renal mass. The kidney becomes unable to generate the 1 to 3 mEq/kg/day of new bicarbonate that is necessary to compensate for that lost to buffer endogenous acid production. Previous studies have suggested a major role for decreased resorption of bicarbonate by the proximal renal tubule in chronic renal failure. Although this may occur in the presence of volume overload, severe secondary hyperparathyroidism, and disorders such as Fanconi syndrome, it is not a major mechanism causing acidosis in chronic renal failure. Except for severe phosphate depletion, decreased excretion of phosphate as a titratable acid normally does not contribute to metabolic acidosis.

One of the earliest manifestations of chronic renal failure is secondary hyperparathyroidism.⁴⁰ Secondary hyperparathyroidism, which results from inadequate formation of 1,25-(OH)₂ vitamin D (i.e., 1,25-dihydroxyvitamin D₃ or calcitriol), develops in moderate renal insufficiency in the presence of normal serum concentrations of calcium and phosphorus. With more severe renal insufficiency, overt hypocalcemia and hyperphosphatemia often develop. Hypocalcemia is caused by decreased calcium absorption from the gastrointestinal tract as a result of a true deficiency of 1,25-(OH)₂ vitamin D. Diminished release of calcium from bone occurs as a result of resistance to the action of parathyroid hormone, and calcium and phosphate are deposited in soft tissues as a consequence of hyperphosphatemia.

The kidney plays a key role in the maintenance of phosphate homeostasis by regulating its excretion. In the presence of a normal GFR, the kidney excretes 5% to 15% of the filtered load of phosphate, whereas in chronic renal failure, the kidney can increase its fractional excretion of phosphate to 60% to 80%. Through this adaptation, the kidneys are able to maintain a phosphate balance in chronic renal failure, but they do so at an increased serum phosphate concentration. At the same time, the kidneys have no reserve with which to increase phosphate excretion in response to a phosphate load. In children with chronic renal failure, a large phosphate load, such as can occur with the administration of a phosphate-containing enema, can lead to life-threatening hyperphosphatemia and hypocalcemia.

Preoperative Laboratory Evaluation

Several preoperative laboratory tests should be assessed before surgery in a child with renal insufficiency. This allows the practitioner to determine the severity of the presenting disease and provides a baseline that may be compared with intraoperative and postoperative laboratory values to ensure proper protective renal care.

Children with known renal failure, especially those with a significant reduction in renal function, require preoperative serum electrolyte and calcium concentrations and hemoglobin levels measured within 24 hours of the procedure and on the morning of the procedure if a known lability exists. Although the serum creatinine concentration is typically used as a marker for renal function, the value is not indicative of the degree of injury.

Abnormal potassium concentrations often occur in children with renal failure; acceptable limits depend on the status of the child and the trends in the potassium concentration over time. Chronic hypokalemic or hyperkalemic states are less likely to have cardiac effects than acute changes. Acute hypokalemia reduces arrhythmia threshold and increases cardiac excitability. Acute hyperkalemia may result in life-threatening arrhythmias from electrical conduction suppression. A child with chronic renal failure whose serum potassium concentrations are chronically 5.5 to 6.0 mEq/L does not need correction of the hyperkalemia, whereas a child with an acute increase to a potassium concentration greater than 5.5 mEq/L requires intervention before the surgical procedure and anesthesia. Existing acidosis must be taken into consideration in determining total body potassium concentrations, with the understanding that acute acidosis promotes extracellular hyperkalemia at a rate of 0.5 mEq/L for every decrease in pH of 0.1 unit. Treatment of hyperkalemia has several options (see Table 26-6).

Hypomagnesemia likewise predisposes a child to the risks of supraventricular and ventricular arrhythmias and should be corrected preoperatively. Hypermagnesemia or hypophosphatemia may cause muscle weakness and potentiate the action of muscle relaxants. Administration of calcium is helpful in treating hyperkalemia or hypermagnesemia.

Hemoglobin, hematocrit, and platelet counts should be part of the preoperative evaluation. Anemia is a common finding in children with renal disease, and morbidity and mortality are associated with hemoglobin concentrations less than 11 g/dL in adult patients with renal failure.^48,49 This relationship was based on the effect of anemia on the incidence of left ventricular hypertrophy and associated morbidity and may be less of a concern in children. Recombinant erythropoietin reduces the risks of cardiac compromise from left ventricular hypertrophy by increasing the hemoglobin to normal values.^50,51 Blood transfusion is generally not indicated if the hematocrit is more than 25%.

Platelet counts, although typically normal in children with renal failure, are not predictive of platelet dysfunction. The best indicator of platelet dysfunction in children with chronic renal failure is a prolonged bleeding time. Signs of coagulopathy such as petechiae should alert the practitioner of abnormal platelet function, which does not necessarily improve with platelet transfusion. Dialysis, red blood cell transfusion, and erythropoietin improve platelet dysfunction. Desmopressin (0.3 µg/kg given intravenously over 15 to 20 minutes) can improve the bleeding time in children with uremia and can minimize hypotension when given 1 hour before surgery. It releases endothelial von Willebrand factor/factor VIII complex and improves platelet function for 6 to 12 hours. Cryoprecipitate is an alternative that should be used in children who have received desmopressin and continue to have coagulopathy.

A preoperative urinalysis can be useful in identifying children with unknown renal disease, although a normal result does not always exclude the possibility that a child has significant renal disease. The use of an FE_Na estimate assists differentiating prerenal azotemia from acute tubular necrosis.

Depending on the degree of renal failure and suspected cardiac involvement, additional testing, including an electrocardiogram, a chest radiograph, and an echocardiogram, should be considered. These tests can help the practitioner determine evidence of left ventricular hypertrophy, arrhythmias, and presence or absence of pericardial effusions.

Although not proved to be reliable markers of renal injury, concentrations of serum cystatin C, which reflects the GFR better than serum creatinine, and urinary neutrophil gelatinase-associated lipocalin, which is produced in response to injury by tubular cells, may be used more in the future to provide information preoperatively.^52,53

Perioperative Dialysis

In the child with renal failure, dialysis is used to prevent hyperkalemia and remove excess water. However, excessive or overly aggressive dialysis may lead to electrolyte abnormalities and hypovolemia. Accordingly, the timing of this therapy or need for the therapy should be discussed with the child’s nephrologist. Ideally, renal failure patients on intermittent hemodialysis should be dialyzed the day before surgery to optimize their fluid and electrolyte status and minimize problems with acute fluid shifts with hypotension, hypokalemia, and anticoagulation that may occur if hemodialysis occurs the day of surgery. Children being treated with peritoneal dialysis can be dialyzed up until the day of surgery. Peritoneal dialysis should be resumed with the consideration that the child’s pulmonary function must be able to tolerate the increased abdominal distention. Consultation with the child’s nephrologist is recommended to optimize the child’s clinical status before the procedure and to arrange the appropriate timing of the peritoneal dialysis.

Medications

Children with renal failure may require that their medications be adjusted in the perioperative period. These medications typically include antihypertensives, and although proceeding with elective surgery with moderate hypertension may be acceptable, severe or labile hypertension should be controlled before surgery. Induction of anesthesia may cause hypotension in children with chronic hypertension, although preloading with balanced salt solution may offset this effect. There is a temporal relationship between adults who take ACE inhibitors for blood pressure control on the day of surgery and hypotension at induction of anesthesia and cardiac arrest.⁵⁴ Moderate hypotension was significantly more frequent in patients who discontinued their ACE inhibitor within 10 hours of their anesthetic induction compared with those who had not taken their medication for more than 10 hours before induction.⁵⁴ Additional studies and opinion leaders suggest that ACE inhibitors should be stopped the day before surgery to prevent hypotension after induction of anesthesia, although the hypotension can be easily managed, especially during total intravenous anesthesia in adults.^55–57 All other antihypertensives, immunosuppressives, and steroids should be continued. Most other medications can be safely held until they can be resumed postoperatively.

If acute hypertension is diagnosed before an urgent procedure, clonidine should be considered. Because of the risk of rebound hypertension when it is discontinued, oral therapy should be started as soon as the child can tolerate oral intake, or alternatively, a transdermal clonidine patch may be applied to avoid postoperative rebound hypertension.

Special Considerations

Children with chronic renal failure frequently present with serious medical problems that complicate anesthesia when surgery is required.^58,59 These problems stem mainly from fluid and electrolyte abnormalities, complications of chronic renal failure such as anemia and hypertension, and differences in the pharmacokinetics of anesthetic agents in children with renal failure. Although several empirical measures have been advocated for renal protection in the perioperative period, a Cochrane review concluded that no interventions, whether pharmacologic or otherwise, protected the kidney in the perioperative period.⁶⁰

In addition to routine monitoring, consideration should be given to the absolute need for arterial access because it may affect future shunt sites, careful positioning of children with renal osteodystrophy, and careful antiseptic techniques for vascular line placements due to the increased risk of infection. Strategies to maintain normothermia, including increasing the room temperature and application of a forced-air warming blanket, should be considered to avoid hypothermia. An arterial line may be useful to monitor blood pressure that may be labile during the perioperative period. An arterial or central line also facilitates checking laboratory values during prolonged procedures in children with large fluid shifts and in the severely compromised renal patient. Serum potassium concentrations must be monitored and corrected to avoid arrhythmias or conduction problems. Central venous monitoring may be valuable in this population for several reasons; peripheral venous access may be challenging due to their chronic disease, fluid management is more easily guided using central venous pressure monitoring when urine output cannot be used as an indicator of hydration status, and it ensures safe and reliable delivery of vasoactive medications and calcium.

Fluids and Blood Products

In the child with renal insufficiency, fluid management requires a balanced approach. The child must receive adequate hydration to prevent further renal deterioration in an otherwise injured kidney. Children with renal failure and a history of hypertension are at risk for hypotension and hypertension and require some degree of fluid resuscitation for stability. However, they also may have hypoalbuminemia with low oncotic pressure that puts them at risk for pulmonary edema. Ideally, if the child is euvolemic, standard fluid therapy based on typical surgical fluid management may ensue. Fluid overload must be avoided in all anuric children and in outpatients. Although common sense and years of practice suggest that normal saline is preferable to lactated Ringer solution due to the potassium load in the latter, there is evidence to the contrary. In a series of adults who underwent kidney transplantation with normal saline or lactated Ringer solution, 19% of the patients in the saline group had a potassium concentration of 6 mEq/L and 31% had a metabolic acidosis that required treatment, compared with none for both metabolic disorders in the lactated Ringer group.⁶¹ Consideration should be given to returning to lactated Ringer solution for renal failure patients.

In a child with AKI and low urine output, it is tempting to administer diuretics to increase renal blood flow and flush the renal tubules. However, the use of diuretics in a patient with renal disease may worsen renal failure by causing hypovolemia and decreased renal perfusion.

Because of the risk of bleeding in children with significant renal failure, hemoglobin concentrations should be followed closely. This is a classic and lethal complication in children with terminal uremia that results from platelet dysfunction in the presence of a normal coagulation profile and normal platelet counts. Blood and component therapy may be used in accordance with surgical losses and to keep the hemoglobin concentration greater than 11 g/dL. Other components that may be effective to alleviate surgical oozing or occult bleeding should be given based on clinical need because results of coagulation studies may not be true indicators of the coagulation status in children with platelet dysfunction.

Anesthetic Agents

The pharmacokinetics and pharmacodynamics of anesthetic agents and perioperative medications may be altered in children with renal failure. The medications most likely to be affected are those that depend on renal excretion, such as the hydrophilic, highly ionized agents. Repeated doses of medications that depend primarily on renal excretion for elimination should be administered at longer intervals or in smaller doses than they are given otherwise. Examples of commonly used perioperative medications that primarily depend on renal elimination are penicillins, cephalosporins, aminoglycosides, vancomycin, and digoxin. Anesthetic agents should be tailored according to the circumstances and child. For example, the duration of action of medications that are delivered as a single bolus depends more on redistribution than on elimination. If the volume of distribution of the medication is unchanged, the single bolus dose should be unchanged. Medications that depend only in part on renal elimination have a normal duration of action when delivered as a bolus or short-term infusion. Many anesthetics depend in part on renal elimination, including pancuronium, vecuronium, atropine, glycopyrrolate, and neostigmine. The vasoactive agents milrinone and amrinone also belong to this group. Long-acting medications and infusions must be used with caution in renal failure patients due to the risk for drug accumulation.

Because uremic children are more susceptible to excessive sedation, premedication should be kept to a minimum in these children. However, a short-acting anxiolytic such as midazolam may be used with caution in the anxious child, but if the child is encephalopathic, no premedicant should be used.

Induction of anesthesia may be carried out safely as long as the child is euvolemic and the pharmacokinetics and pharmacodynamics of the induction agent are understood and accounted for. Anesthetic agents may be affected by the presence of anemia, acidosis, and altered drug binding due to hypoproteinemia in children with renal disease. Antihypertensives such as ACE inhibitors, particularly in combination with diuretics, may lead to profound hypotension.⁶²

The dose of propofol to induce anesthesia using the bispectral index and clinical signs to indicate the state of hypnosis in adult patients with renal failure were significantly greater than in those without renal disease.⁶³ This was attributed to a larger volume of distribution in renal failure patients, consistent with previous studies of thiopental.⁶⁴ Anemia is another contributing factor. It may indirectly cause a greater plasma volume and greater cardiac output. When propofol is delivered as an infusion, no significant differences in pharmacokinetic or pharmacodynamic parameters have been observed.⁶⁵

There are insufficient data on the use of inhalational anesthetics for induction in children with renal impairment. For maintenance of anesthesia in adults, desflurane and isoflurane do not further impair renal function in those with preexisting renal disease.⁶⁶ Sevoflurane at low flows is associated with increased circuit concentrations of compound A, which is nephrotoxic in rats.^67,68 In adult patients with normal renal function, low-flow sevoflurane anesthesia has been associated with mild, transient proteinuria but no changes in BUN, creatinine level, or creatinine clearance.⁶⁹ In adults with renal insufficiency, low-flow sevoflurane has been shown to be as safe as low-flow isoflurane in terms of kidney function.⁶⁸ Overall, sevoflurane is considered safe in patients with renal disease, but low flows should be avoided. Because desflurane is minimally metabolized (rate of 0.2%) in vivo, it may be preferred even at very low flows (1 L/min).

Neuromuscular blocking drugs (NMBDs) have evolved over the years to provide a choice of relaxants for use in children with renal disease. Children with chronic renal failure may have existing autonomic neuropathy and associated delayed gastric emptying that puts them at risk for aspiration. Along with renal implications, aspiration should be anticipated when choosing a NMBD for airway management. Succinylcholine is often avoided in children with renal failure because of its well-known propensity for increasing serum potassium. However, succinylcholine does not increase the plasma potassium concentration in patients with renal failure any more than in patients with normal renal function (0.5 to 0.8 mEq/L of potassium).^70,71 Plasma potassium concentration is chronically increased in renal failure, which means that the intracellular and extracellular potassium concentrations are in equilibrium. This contrasts with patients with acute hyperkalemia in whom the intracellular and extracellular potassium concentrations are not in equilibrium, which predisposes them to ventricular arrhythmias if succinylcholine is given. In the latter case, succinylcholine is relatively contraindicated, whereas in the former case, it is not contraindicated.

The pharmacodynamics of NMBDs in children with renal insufficiency merit consideration. The onset time of rocuronium in children with renal failure (139 seconds) was significantly greater than in the control children (87.3 seconds). This difference was attributed to a greater volume of distribution and decreased serum albumin concentrations and possibly to a reduced cardiac output in children with renal failure who were taking antihypertensives. The slower onset time of rocuronium in children with renal failure must be considered when a rapid-sequence intubation is required. The duration of action of rocuronium in children with end-stage renal disease and normal renal function is similar.⁷² The time to recover a train-of-four ratio of 70% in children with renal failure was 28.9 minutes, and in those without renal failure, it was 29.4 minutes. The clearance of rocuronium is decreased in children with renal failure.⁷³ Vecuronium has an increased duration of action in adults with renal failure.⁷⁴

NMBDs such as atracurium and cisatracurium are ideal choices for children with renal insufficiency because their elimination is independent of the kidney. Despite the fact that atracurium and cisatracurium undergo spontaneous degradation by plasma esterase and Hofmann elimination, neuromuscular blockade should be monitored.⁷⁵ With appropriate monitoring and dosing, atracurium, cisatracurium, vecuronium, and rocuronium are acceptable NMBDs in children with renal disease and provide reliable durations of action after a single bolus dose. However, depending on how rocuronium and vecuronium are administered during a case, their accumulation may ultimately affect their duration of action.⁷⁵

If a prolonged neuromuscular blockade occurs, hypermagnesemia should be ruled out. In this case, calcium may be administered to help antagonize the blockade. The elimination of neostigmine may be delayed beyond elimination of atropine or glycopyrrolate, and muscarinic effects such as bradycardia, increased secretions, or bronchospasm may occur postoperatively after antagonism. Sugammadex, a selective relaxant binding agent, has reduced clearance in adults with severe renal failure.⁷⁶ The clearance of sugammadex was only 5.5 mL/min in renal failure patients but 95.2 mL/min in the control group. Despite this difference in pharmacokinetics, sugammadex can rapidly and effectively reverse the effects of rocuronium in patients with renal failure.⁷⁷

Remifentanil may be a preferred choice for a maintenance opioid in the intraoperative period in children with renal insufficiency because of its rapid metabolism by nonspecific blood and tissue esterases. The pharmacokinetics and pharmacodynamics of remifentanil are not altered in patients with renal disease, but the principal metabolite of remifentanil has reduced elimination,^78,79 which is not expected to be clinically important. Doses of other opioids should be reduced by 30% to 50% to avoid unexpected respiratory depression in children with chronic renal failure. Active metabolites of morphine and meperidine can likewise accumulate in patients with renal failure, whereas those of fentanyl and sufentanil do not. The latter opioids are preferable on that basis alone.^80–84 Prolonged antagonism of opioid effects with naloxone can be expected in renal failure patients.

Esmolol or labetalol are useful to control tachycardia and hypertension, but large doses may exacerbate hyperkalemia by blocking intracellular potassium flux. Nicardipine is an effective, short-acting antihypertensive agent that does not affect serum potassium.

Delayed emergence, vomiting and aspiration, hypertension, respiratory depression, and pulmonary edema are potential problems that should be anticipated with anesthetic emergence. Hyperkalemia as a consequence of tissue injury, catabolism, blood transfusion, and acidosis is common. Children with chronic renal failure usually have chronic metabolic acidosis with limited buffer reserve. Modest hypercapnia with emergence may lead to significant acidosis and hyperkalemia. Careful attention should be given to the fluid needs of the child postoperatively to minimize volume overload and pulmonary edema.

Regional anesthesia is a viable alternative to general anesthesia or an adjunct in many cases. The anesthesia team must pay particular attention to coagulation studies and signs of coagulopathy before embarking on any central block because abnormal platelet function puts the renal failure patient at risk for epidural hematoma.