Section 4: Renal/Fluids and Electrolytes

PURPOSE OF INTRAVENOUS (IV) FLUID THERAPY: WHY “MAINTENANCE”?

Parenteral fluids are typically administered to patients whose spontaneous and/or enteral intake is insufficient to meet physiologic needs. Delivering a particular quantity of water, dextrose, and electrolytes every hour at a weight-based “maintenance rate” is intended to meet the cellular requirements for basic functionality. The widely used formula for calculating this rate (the “4-2-1 rule”) was developed in 1957 and was popularized as much for simplicity as for accuracy. Its original proponents utilized a rough estimate of patient energy requirements to extrapolate fluid needs, escalating stepwise with increases in weight, to arrive at the “4-2-1” progression. This approximation results in a “maintenance” hourly value providing the necessary intake to meet a minimum of one's basal metabolic needs, but likely not those accompanying routine physical activities. It is worth noting that this formula was developed based on data from hospitalized, bedridden patients.¹

CALCULATION OF THE MAINTENANCE FLUID RATE

Based on the estimations of the rising energy requirement with each kilogram of body weight, a patient's maintenance IV rate is calculated as shown in Table 48-1.

As stated earlier, calculations are done according to the “4-2-1” rule. This rate can be used solely for parental fluid administration or as a goal for the total hourly fluid intake (also taking into account continuous infusions and/or high-volume medications). Patients with normal end-organ function (e.g., those children simply nil per os [NPO] prior to surgery) may tolerate delivery of a full “maintenance” IV fluid volume in addition to other medications, infusions, and flushes without complication. Contrast this with a fluid-overloaded child with multiorgan dysfunction, who may not tolerate much “surplus” IV volume without cardiopulmonary consequences. In this instance, it may be beneficial to limit total hourly intake to the calculated maintenance rate, delivering only a portion of the total via continuous IV fluids. Fluid restriction, even to intake rates below maintenance, can be appropriate in patients with impaired renal function, pulmonary pathology, or fluid overload.

CHOOSING IV FLUID COMPOSITION

Choice of intravenous fluids should be made with an understanding of both the clinical situation and the respective risk–benefit profile.

The three major components of IV fluids are as follows:

• Base sodium content: One of the primary determinants of serum osmolality. All intravenous fluids use sodium and chloride as the primary contributors to solution tonicity in order to allow for safe intravenous administration. IV fluids can be isotonic (similar tonicity to plasma), hypotonic, or hypertonic, depending primarily on their respective sodium and dextrose content.

  

Hypotonic fluid administration, using relatively low sodium concentrations, has been implicated in the development of iatrogenic hyponatremia and a similarly hypotonic serum.²

• Dextrose: Provides some nutritional value, typically expressed as a percentage (% = grams of solute /100 mL of fluid volume)

  • Glucose Infusion Rate (GIR): Key to avoiding a catabolic state and maintaining euglycemia when IV fluids are the only source of calories. GIR calculation requires the following formula:

    

  • Recommendations for a minimum GIR are based on age:

    5 mg/kg/min for <6 years of age; 2.5 mg/kg/min for ≥6 years old

  • “D5” (5 g/100mL volume) given at maintenance rate does not deliver an adequate GIR in children under 6 years of age

• Additives: Provide essential electrolytes for cellular function and compensate for ongoing losses

  • Potassium: Most effectively delivered as potassium chloride. Daily potassium requirement related to 24-hour fluid needs; amounts to approximately 1 to 2 mEq/100 mL water. This is typically provided using IV fluids with a potassium concentration of 20 to 40 mEq/L. Potassium acetate and potassium phosphate are also used, most often in diabetic ketoacidosis.

  • Sodium bicarbonate: Indicated in normal anion gap metabolic acidosis caused by renal or gastrointestinal losses of bicarbonate and in certain drug exposures or toxidromes.

The content of the most commonly used IV fluid preparations is illustrated in Table 48-2.

Note the osmolality of 0.9% (normal) saline and lactated Ringer's (LR), two formulations considered isotonic to serum despite having higher and lower osmolality than blood. In general, isotonic crystalloids (without dextrose) are appropriate for rapid administration to provide urgent intravascular volume expansion during states of hypovolemia and/or shock. Bolus infusion of fluids containing dextrose is avoided as it may cause a transient hyperglycemia, encouraging an osmotic diuresis and contributing to further volume depletion.

Examples of clinical scenarios with specific fluid recommendations:

• Metabolic acidosis: 0.9% normal saline will provide an excess chloride load while running at a maintenance rate, potentially resulting in hyperchloremia and a worsening non-anion gap acidosis

• Renal insufficiency, oliguria: Avoid potassium additives

• Traumatic brain injury, central nervous system (CNS) pathology: Avoid sodium chloride concentrations less than 0.9%, hypotonic fluids and hyponatremia; avoid 5% albumin

ROUTE OF DELIVERY: IS A PERIPHERAL IV SUFFICIENT?

Most preparations are safe to administer through peripheral access, especially at rates approximating maintenance. However, special consideration should be paid to hypertonic formulations, such as 3% saline, which may not be safe to deliver through a peripheral vein. Smaller-diameter vessels can be the setting for local hemolytic reactions when the hypertonic solution contacts the epithelium. Central venous access allows for access of larger-bore vasculature, containing relatively more blood around the entry site of the catheter and its solution. This “excess” local blood serves to “dilute” the infusing fluid before it can contact the vessel wall and promote a reaction. As such, central venous access should be obtained when anticipating a prolonged infusion of hypertonic fluid. A similar access plan is prudent when giving fluids that are significantly hypotonic, such as “half-” or “quarter-normal” saline without dextrose.

An understanding of tonicity again becomes important with higher dextrose concentrations. Preparations containing more than 12.5% dextrose are usually not safe or appropriate to deliver via peripheral access, and a central venous catheter may be required to meet nutritional goals via the parenteral route if higher calories are desired.

• Central venous access: All fluids are safe, including hypotonic or hypertonic fluids, dextrose content >12.5%

• Peripheral access only: Isotonic fluids (0.9% NaCl or LR without dextrose or dextrose with ½ normal saline [NS] or dextrose with ¼ NS) or any fluid with less than 12.5% dextrose is safe

THE ADVERSE EFFECTS OF INTRAVENOUS FLUIDS

Intravenous fluids are a therapy with an appropriate dose and duration like any other drug. Some side effects of maintenance IV fluids can carry significant morbidity and even mortality.

Side effects of intravenous fluids include:

• Metabolic acidosis

• Tissue edema

• Organ damage to the brain, kidney, and lungs

• Sodium derangements

• Coagulation abnormalities

• Dilutional anemia leading to unnecessary blood transfusions

• Fluid overload: Increasing evidence has shown that excessive fluid administration and subsequent overload can have detrimental effects on the outcomes of all manner of pediatric patients, such as those with septic shock, acute kidney injury, and acute respiratory distress syndrome (ARDS). In such patients, as alluded to earlier, sometimes a set goal of “maintenance fluid delivery” must be adjusted to incorporate all sources of intravenous intake. Additionally, patient fluid status is best viewed as another “vital sign,” with cumulative balance reported alongside heart rate and blood pressure. When appropriate, it may be useful to calculate the percentage of overload in a given patient, using the following formula:

  $Fluidoverload=[ [Intake(mL)−Output(mL)]÷Wt (kg) ]×100%$

Percentage of fluid overload can be useful to determine management strategy, such as initiation of diuresis or renal replacement therapy for fluid removal.

FOUR PHASES OF INTRAVENOUS FLUID THERAPY

During critical illness, dynamic physiologic changes make fluid needs time-dependent as well. Data suggest up to 20% of critically ill patients receive “inappropriate” intravenous fluids. A recent framework describes the changing role of IV fluids during the course of critical illness by stratifying fluid needs by stage: rescue, optimization, stabilization and de-escalation.

• Rescue: Active (decompensated) shock state, requires rapid isotonic fluid boluses for volume expansion and resuscitation.

• Optimization: Compensated shock states, arrest less likely; fluid given more judiciously, continue to optimize cardiac function, improve perfusion, and avoid (further) organ dysfunction.

  • Use gradual fluid challenges instead of rapid boluses.

• Stabilization: Steady state, absence of shock; fluid to replace ongoing losses, support basic metabolism.

• De-escalation: Early recovery, consider cessation of extraneous fluids, work toward fluid removal and a negative fluid balance.

Stabilization and de-escalation seek to avoid the known adverse effects of aggressive fluid management, accumulation, and overload. Not all patients will enter critical illness in the rescue phase, and those without signs of shock may not require any rapid fluid administration at all. Of course, patients may regress at any point, which should prompt a reassessment of fluid needs.³

SODIUM ABNOMALITIES

HYPONATREMIA

• Serum sodium (S_Na) < 135 mEq/L (mmol/L)

• Prevalence: Up to 40% of pediatric inpatients, often iatrogenic from hypotonic IV fluid

  • Severe symptoms, morbidity, mortality with rapid S_Na decline (>1 mEq/hr)

• Pathophysiology: Osmolality of serum largely dependent on sodium, regulated by antidiuretic hormone (ADH), thirst mechanisms

  • In hyponatremia, normal regulatory mechanisms fail to maintain homeostasis

    • Resultant water/sodium imbalance results in hypotonic serum, regardless of total body water, sodium content

• Etiology: Causes of abnormal sodium levels can be differentiated by the total body sodium level (high or low), the response of ADH, and the volume status of the patient (see Table 49-1)

  • Factitious, pseudohyponatremia

    • Hyperglycemia creates an osmotic gradient in plasma favoring extracellular water shift out of the cells

    • S_Na “diluted” by ≈2 mEq/L for each 100 mg/dL rise in glucose

  • Normal body sodium

    • Syndrome of inappropriate antidiuretic hormone (SIADH): ADH inappropriately high , patient is typically euvolemic

      • Caused by many medications, pulmonary infections, increased intrathoracic pressure from mechanical ventilation, oncologic processes

    • Water intoxication (psychogenic polydipsia): ADH appropriately low , patient is typically euvolemic

  • Decreased body sodium

    • ADH appropriately elevated as the patient is hypovolemic from:

      • Gastrointestinal (GI) tract losses (vomiting, diarrhea)

      • Sepsis

      • Diuretics

      • Salt wasting: Kidney (renal tubule, concentrating defects), central nervous system (injury may alter sympathetic input to kidney), adrenal insufficiency (e.g., 21-hydroxylase deficiency)

      • Drain output (e.g., external ventricular drain [EVD])

  • Increased body sodium

    • ADH appropriately decreased as the patient is hypervolemic

      • Congestive heart failure, renal failure

      • Nephrotic syndrome

• Clinical signs and symptoms:

  • Acute hyponatremia

    • Rate of decline dictates symptoms more than specific S_Na

      • No time for compensation mechanisms to deploy

      • Cannot offset intracellular water shifts

    • Seizures, lethargy, headache, cerebral edema

  • Chronic hyponatremia

    • Hyponatremia for >24 hours and/or developing over days

    • Compensatory mechanisms change intracellular osmolality, can mitigate risk of cerebral edema

    • Vague neurological, GI symptoms (irritability, fatigue, vomiting)

• Treatment:

  • Key elements: Tailor therapy to severity of symptoms, underlying cause(s)

  • Severe central nervous system (CNS) symptoms (seizures)

    • 3% NaCl to quickly raise S_Na to ≈ 125 mEq/L (or lower if symptoms abate)

    • Rapid creation of osmolar gradient favors extracellular water reducing intracellular edema

  • Shock/hemodynamic instability

    • 0.9% NaCl to quickly expand intravascular volume, re-establish blood and oxygen delivery to vital organs

  • Factitious hyponatremia

    • Treat primary disease process (e.g. insulin infusion for diabetic ketoacidosis [DKA])

  • Normal total body sodium, euvolemia (SIADH)

    • Fluid restriction to ≈1/3 to 2/3 of hourly maintenance rate

    • Avoid hypotonic fluids

  • Decreased total body sodium, hypovolemia

    • Calculate sodium deficit

      $(DesiredserumNa−ActualserumNa)×0.6×Weight(kg)$

    • Must consider maintenance needs and any ongoing losses in calculations

      • Maintenance sodium needs ≈ 2 to 3 mEq/100 mL fluid

    • Replace with 0.9 normal saline (NS) (154 mEq/L) or 3% saline (513 mEq/L) depending on venous access and symptoms

    • Raise S_Na by NO MORE THAN 0.5 to 1 mEq/hr

      • Correcting too rapidly can cause central pontine myelinolysis

HYPERNATREMIA

• Serum sodium (S_Na) > 145 mEq/L

• Prevalence: Less common than hyponatremia, can cause irreversible pathology

• Pathophysiology: Most often from excessive free water losses, usually via GI tract

  • GI fluids are “hyponatremic” compared to blood

    • Relatively more water (vs. sodium) is lost per unit volume of GI fluid

  • Leads to CNS symptoms as the developing osmolar gradient favors extracellular water movement, “drying out” cerebral tissue (cells shrink, tear the surrounding/bridging vasculature)

• Etiology:

  • Increased body sodium

    • Salt intoxication, poisoning

      • Infant formula improperly prepared, intentional sodium “overdose”

      • Hyperosmolarity prompts thirst and ADH release, leading to free water intake/retention will prompt water intake leading to retention and weight gain (opposite of hypernatremic dehydration)

    • Salt water drowning

  • Normal body sodium

    • Increased insensible fluid losses with free water losses exceeding sodium losses

      • Especially smaller children, infants (more surface area per body volume)

    • Diabetes insipidus

      • Excessive free water lost in dilute, poorly concentrated urine

      • Central (CNS dysfunction, ADH deficient) vs. nephrogenic (ADH resistant)

  • Decreased body sodium

    • GI losses (vomiting, diarrhea)

    • Poor intake

      • Limited access to drinking water

      • Cannot effectively communicate thirst (infants)

    • Osmotic diuresis

      • Renal excretion of nonelectrolyte solutes, increasing urine osmolality

      • Free water “trapped” in urine, more water than sodium excreted

• Clinical signs and symptoms:

  • Vomiting, lethargy, irritability, muscle weakness

  • Seizures, coma, intracranial hemorrhage

• Treatment:

  • Shock/hemodynamic instability

    • 0.9% NaCl to quickly expand intravascular volume, re-establish renal blood flow

  • Calculate free water deficit

    $Freewaterdeficit(mL)=(MeasuredSNa−DesiredSNa)×4mLkg×Weight(kg)$

    • Replace over ≈ 48 hours along with maintenance needs, ongoing losses

      • Can replace with enteral water or hypotonic fluids

      • For S_Na > 170 mEq/L, use “3 mL/kg” in calculations

      • Avoid correcting by >10 to 15 mEq/L in 24 hours

POTASSIUM ABNORMALITIES

HYPOKALEMIA

• Serum potassium (S_K) less < 3.5 mEq/L

• Overview:

  • Common in hospitalized children, especially ICUs

  • Nearly all (98%) potassium contained inside cells

    • Mediated by Na-K ATPase on cell membrane, pulling in K⁺ against its gradient

    • Essential for muscle contraction, nerve conduction, cellular metabolism

    • Excesses excreted in urine, augmented by aldosterone

• Etiology:

  • Normal body potassium

    • Alkalosis

      • K⁺/H⁺ pump on cell membranes moves H⁺ into serum to offset alkalosis, K⁺ moves into cells (keeps transition electrically neutral)

    • Medications/hormones (β-agonists, insulin)

      • Stimulate Na-K ATPase

  • Decreased body potassium

    • Poor intake

    • Renal, GI losses

      • Emesis: Upper GI fluids have a low K⁺ content, but Cl⁻ loss/metabolic alkalosis enhances renal K⁺ excretion

      • Diarrhea: Lower GI fluids have a high K⁺ content (up to 50 mEq/L)

      • Renal losses enhanced with diuretics, tubular disorders/injury, renal tubular acidosis (RTA)

• Clinical signs and symptoms:

  • Neurologic

    • Weakness, paralysis, ileus, dysrhythmias

  • Cardiac (electrocardiogram [ECG] changes)

    • T waves flat or absent, conduction delays, U waves develop

• Treatment:

  • Symptomatic

    • Intravenous KCl, especially if enteral route is not feasible

      • 0.5 to 1 mEq/kg, maximum dose 40 mEq, given slowly (<1 mEq/kg/hour)

  • Asymptomatic, S_K <3 mEq/L

    • Enteral route encouraged, lower risk of transient hyperkalemia/dysrhythmia

      • 1 mEq/kg, can be given every 6 hours

      • Monitor for nausea and emesis

  • Asymptomatic, S_K > 3 mEq/L

    • Increase dietary/IV fluid content of potassium

  • Other considerations

    • Correct concurrent hypomagnesemia (enhances renal K⁺ losses)

    • Add potassium-sparing diuretic (e.g., spironolactone) to offset aldosterone

HYPERKALEMIA

• S_K > 5.5 mEq/L, severe with S_K > 7 mEq/L

• Etiology:

  • Factitious

    • Hemolysis of red blood cells sample due to delay in testing/difficulty obtaining sample

    • Leukocytosis or thrombocytosis

      • K⁺ released from the excess cells during sample collection

  • Increased potassium load

    • Iatrogenic

      • Large-volume red cell transfusion, total parenteral nutrition

  • Shift/release from intracellular stores

    • Acidosis

      • K⁺/H⁺ pump moves H⁺ into cells to offset acidosis, K⁺ out to maintain neutrality

    • Hemolysis

    • Crush injury, rhabdomyolysis, burns

    • Tumor lysis syndrome

  • Diminished excretion

    • Renal failure

    • Acute kidney injury, renal dysfunction, or chronic kidney disease

      • Drop in glomerular filtration rate (GFR) brings less Na⁺ to collecting ducts for exchange with K⁺, less potassium excreted

      • Tubular dysfunction, pyelonephritis, sickle cell disease

      • Type 4 RTA, congenital adrenal hyperplasia (hypoaldosteronism)

    • Medications

      • ACE inhibitors, spironolactone

• Clinical signs and symptoms:

  • Generally absent, mild until S_K >7 mEq/L

  • Cardiac conduction changes, dysrhythmias

    • S_K 6 to 7 mEq/L: Peaked T waves, shortened QT interval

    • S_K 7 to 8 mEq/L: Prolonged PR interval, widening of QRS complex

    • S_K >8 mEq/L: P waves disappear, QRS complex merges with T wave to yield “sine wave,” ventricular fibrillation, asystole

  • Neurologic: Ascending weakness or paralysis (Guillain-Barré–like syndrome), disorientation, paresthesia

• Treatment depends on level and symptoms:

  • S_K<6.5 mEq/L, no ECG changes:

    • Discontinue exogenous potassium and any medications decreasing excretion

    • Sodium polystyrene sulfonate (aka Kayexalate) 1 to 2 g/kg/dose PO/PR

  • S_K >6.5 mEq/L and/or ECG changes:

    • Stabilize cardiac membranes

      • IV calcium chloride (10–25 mg/kg) or calcium gluconate (50–100 mg/kg)

    • Shift serum potassium out of bloodstream, into cells

      • Inhaled beta-agonist (albuterol)

      • IV insulin (0.2 U/g of glucose) and glucose (1 gm/kg)

      • IV sodium bicarbonate (1–2 mEq/kg)

    • Decrease total body potassium

      • Loop diuretics

      • Sodium polystyrene sulfonate

      • Dialysis (hemodialysis preferred)

CALCIUM ABNORMALITIES

HYPOCALCEMIA

• Serum ionized calcium (S_ica) ≤ 4.5 mg/dL (1.3 mmol/L), total calcium < 8.8 mg/dL (2.2 mmol/L)

• Overview:

  • Calcium, phosphate balance maintained by interplay of parathyroid hormone (PTH), vitamin D, and calcitriol on the GI tract, bone, and kidneys

    • PTH prompts kidneys to reabsorb calcium, bones to release calcium, and convert calcidiol to calcitriol

    • Calcitriol and vitamin D enhance calcium absorption in GI tract

  • Ionized calcium is active form, usually correlates well with total calcium

    • Correlation altered by plasma albumin

      • Roughly half of total body calcium as S_ica, remainder binds albumin or plasma anions

      • Albumin decrease of 1 g/dL will drop total by 0.8 mg/dL, may not affect S_ica

      • No change in S_ica = no symptoms

    • Correlation altered by plasma pH

      • Decreases in pH (acidosis) displaces calcium from albumin leading to more circulating active calcium = S_ica increases

• Etiology:

  • Hypoparathyroidism

    • Compromised PTH production or release

    • DiGeorge syndrome

    • Mitochondrial disorders

    • Autoimmune polyglandular syndromes

    • Post-thyroid surgery

    • Heavy metal deposits in parathyroid glands (Wilson's disease)

  • Pseudohypoparathyroidism

    • Organs show resistance to PTH effects

    • Multiple genetic mutations yield phenotypes/subtypes

    • Elevated serum PTH, hyperphosphatemia

  • Inappropriate intake, absorption, metabolism of calcium (or vitamin D)

    • Malnutrition

    • GI disease, fat malabsorption

    • Limited exposure to sunlight

    • Liver, kidney dysfunction

    • Prolonged antibiotics, which impair calcium absorption

    • Hypovitaminosis D

  • Ongoing electrolyte disturbances

    • Hyperphosphatemia: suppresses PTH

    • Hypomagnesemia

  • Drug or therapy side effects

    • Citrate-containing blood products or continuous renal replacement therapy (CRRT)

    • Bisphosphonates

    • Loop diuretics

• Clinical signs and symptoms:

  • Generally when S_ica <4.3 mg/dL (<1.1 mmol/L), total <7 mg/dL (<1.75 mmol/L)

  • Neuromuscular

    • Cramping, paresthesia, spasms (carpopedal, laryngeal, bronchial)

    • Effects augmented by alkalosis

  • Central nervous system

    • Seizures, altered mental status, psychiatric symptoms (depression, anxiety)

  • Cardiovascular

    • Prolongation of QT interval, myocardial dysfunction, hypotension, dysrhythmias

• Treatment:

  • IV replacement:

    • For severe hypocalcemia, ECG changes, overt symptoms (tetany, hypotension)

    • Calcium chloride (10–20 mg/kg), requires central venous access

    • Calcium gluconate (50–200 mg/kg), caution with hepatic dysfunction

  • Correct simultaneous hypomagnesemia (impedes PTH secretion, fosters resistance)

HYPERCALCEMIA

• Total calcium > 10.5 mg/dL (2.6 mmol/L), ionized calcium > 5.5 mg/dL (1.4 mmol/L)

• Etiology:

  • Hyperparathyroidism

    • Parathyroid adenomas, renal disease

  • Malignancy

    • Solid tumor, leukemia, bone metastases

    • Relatively uncommon in children (compared to adults)

  • Increased calcium intake

  • Hypervitaminosis A, D

  • Immobilization

  • Medications

    • Thiazide diuretics, lithium, theophylline

• Clinical signs and symptoms:

  • Mild (<12 mg/dL, 3 mmol/L)

    • Fatigue, constipation, psychiatric disturbances

  • Moderate (12–14 mg/dL, 3–3.5 mmol/L)

    • Polyuria, polydipsia, nausea, weakness, kidney injury

  • Severe (>14 mg/dL, >3.5 mmol/L)

    • Lethargy, coma, bradycardia, arrhythmias

• Treatment:

  • Avoid excess intake, adjust/discontinue medications raising serum calcium

  • IV hydration, loop diuretics

  • Bisphosphonates, calcitonin for severe hypercalcemia

  • Many need emergency renal replacement therapy

PHOSPHATE ABNORMALITIES

HYPOPHOSPHATEMIA

• Normal ranges vary with age, likely due to changes in bone growth. Lower limit of normal approximately 5 mg/dL for neonates, 4 mg/dL for toddlers, 3 mg/dL for older children

• Overview:

  • Serum level determined by the balance between dietary intake, absorption, and excretion by the kidney

• Renal excretion is normally efficient as very elevated phosphate intake may not alter serum content

• Most filtered phosphate is reabsorbed in proximal tubules

  • PTH augments phosphate excretion by inhibiting tubular reabsorption

  • Vitamin D increases phosphate (and calcium) absorption

• Etiology:

  • Poor/inadequate intake

• Parenteral nutrition with absent/inadequate supplementation

• Phosphate binders

• GI tract losses

  • Cellular shifts

• Correction of metabolic acidosis

• Diabetic ketoacidosis, with correction

• Hyperventilation

• Refeeding syndrome

  • Increased losses

• Renal wasting (Fanconi's syndrome)

• Clinical signs and symptoms: Many are manifestations of ATP depletion

  • Neurologic

• Encephalopathy, seizures, coma

• Muscle atrophy and weakness

  • Cardiovascular

• Myocardial dysfunction, arrhythmias (ventricular)

  • Respiratory

• Decreased contractility of diaphragm, dependence on mechanical ventilation

• Cellular hypoxia as red cell 2,3-DPG levels fall = increased affinity of hemoglobin for oxygen, less released to the tissues

  • Musculoskeletal

• Proximal myopathy, rhabdomyolysis

• Increased bone resorption

  • Gastrointestinal

• Dysphagia, ileus

  • Renal: Acute kidney injury (AKI)

  • Hematologic

• Rigidity of red blood cells, hemolysis

• Impaired white blood cell phagocytosis, chemotaxis

• Thrombocytopenia, platelet dysfunction

• Treatment:

  • Serum level >1 mg/dL

• Enteral route preferred, KPhos or NaPhos 1 mmol/kg divided q6 to q8h

  • Serum level < 1 mg/dL

• IV route preferred, 0.1 to 0.5 mmol/kg given over ≈ 6 hours

  • With resolving metabolic acidosis

• Treat underlying cause, hypophosphatemia typically resolves

  • Dipyridamole: To increase absorption of phosphate by the kidneys

HYPERPHOSPHATEMIA

• Normal ranges vary with age, likely due to changes in bone growth. Upper limit of normal approximately 8 mg/dL for neonates, 6.5 mg/dL for toddlers, 5.5 mg/dL for older children

• Etiology:

  • Cell/tissue breakdown

    • Tumor lysis

    • Muscle injury, necrosis, rhabdomyolysis

    • Hemolysis (rarely)

  • Extracellular shift

    • Metabolic acidosis

      • Lactic acidosis, diabetic ketoacidosis (DKA)

      • Aerobic metabolism/glycolysis compromised, yields intracellular surplus or unused phosphate which is excreted into the serum

  • Renal insufficiency, failure

  • Hypoparathyroidism

  • Vitamin D toxicity

  • Medications

    • Bisphosphonates

    • Amphotericin B (liposomal)

• Clinical signs and symptoms: Many due to concurrent refractory hypocalcemia

  • Cardiovascular

    • Prolongation of QT interval, hypotension, myocardial dysfunction and failure

  • Neurological

    • Altered mental status, seizures, coma

  • Neuromuscular

    • Tetany, paresthesias

• Treatment:

  • Limit exogenous intake

  • Phosphate binders

  • IV hydration, loop diuretics

  • Acetazolamide to augment renal excretion

MAGNESIUM ABNORMALITIES

HYPOMAGNESEMIA

• Serum magnesium S_Mg < 1.5 mg/dL

• Overview:

  • Homeostasis: Not hormonally driven, relies on passive reabsorption in loop of Henle

    • Little redistribution between tissue stores and serum

    • Symptoms with small deficits, as extracellular magnesium lost

  • Monitor for concurrent hypokalemia, hypocalcemia

• Etiology:

  • GI tract losses

    • Diarrhea, vomiting, malabsorption

  • Renal losses

    • Augmented by diuretics (loop, thiazide), antibiotics (aminoglycosides)

  • Pancreatitis

  • Chronic use of proton pump inhibitors

  • Hypercalcemia

• Uncontrolled diabetes mellitus

• Post-transplant patients on calcineurin inhibitors

• “Hungry bone syndrome” after thyroidectomy, parathyroidectomy, or correction of metabolic acidosis

• Clinical signs and symptoms:

  • Neuromuscular

    • Muscle tremors, tetany, seizures, involuntary (choreoform) movements, nystagmus

    • Apathy, delirium, coma

  • Cardiovascular

    • Widening of QRS complex, peaking of T waves, widening of PR interval, dysrhythmias

  • Electrolyte disturbances

    • Hypocalcemia, hypokalemia

• Treatment:

  • Magnesium sulfate 25 to 50 mg/kg IV (maximum of 2 g/dose)

HYPERMAGNESEMIA

• S_Mg > 2.3 mg/dL

• Etiology:

  • Renal dysfunction

  • Significant magnesium load

  • Tumor lysis syndrome

  • Primary hyperparathyroidism

  • Lithium toxicity

• Clinical signs and symptoms:

  • Neurologic

• Nausea, headache, lethargy, flushing

• Abnormal/absent deep tendon reflexes

  • Cardiac

• Hypotension, bradycardia, heart block, cardiac arrest

  • Respiratory

• Apnea, respiratory failure

• Treatment:

  • Discontinue exogenous magnesium

  • IV hydration, loop diuretics

  • Urgent/emergent dialysis for severe neurologic, cardiac abnormalities

  • IV calcium for magnesium antagonism

COMMON ELECTROLYTE DEFICITS, CLINICAL SYMPTOMS, AND DOSING OF IV THERAPIES - SEE TABLE 49-2

SUGGESTED READINGS

DEFINITIONS

URINARY TRACT INFECTION (UTI)

• An infection of the kidney, ureter, bladder, or urethra.

PYELONEPHRITIS

• Inflammatory process of the kidney or upper urinary tract = UTI + systemic symptoms

UROSEPSIS

• UTI/pyelonephritis + systemic inflammatory response syndrome (SIRS) criteria

ETIOLOGY

COMMON ORGANISMS

• Ascending genitourinary (GU) infections: E. coli, gram-negative bacteria (Klebsiella, Proteus, Enterobacter, Pseudomonas), gram-positive bacteria (enterococci, staphylococci, group B Streptococcus)

• Catheter-associated UTI (CAUTI): fungi

PREDISPOSING RISK FACTORS

• Congenital anomalies: hydronephrosis, posterior urethral valves, vesicoureteral reflux

• Neurologic abnormalities: neurogenic bladder, quadriplegia

• Dysfunctional elimination: constipation, voiding dysfunction

• Indwelling catheters

• Sexual activity

CLINICAL MANIFESTATIONS

NEONATES/INFANTS

• Fever of unknown origin

• Jaundice

• Irritability

• Poor feeding or failure to thrive (FTT)

OLDER CHILDREN

• Fever

• UTI symptoms: urinary frequency, urgency, dysuria, enuresis

• Pain: flank, back, abdominal, costovertebral angle (CVA), suprapubic

SYSTEMIC SYMPTOMS IN ANY AGE

• Fever, chills, rigors

• Nausea/vomiting, diarrhea

• Shock

DIAGNOSIS

LABORATORY EVALUATION

• Urinalysis (UA): pyuria + bacteriuria +/− hematuria

  • Routine “test of cure” not necessary

  • Repeat within 48 to 72 hours if clinical response is poor

• Positive urine Gram stain and culture

  • Any bacteria from suprapubic tap

  • >50k CFU/mL from catheterization specimen

  • >100k CFU/mL from “clean catch” (exclude polymicrobial growth)

• Blood culture: to identify concomitant bacteremia

IMAGING

• Recommended for the following patients:

  • Children <5 years with febrile UTI

  • Females <3 years with first UTI

  • Males of any age with first UTI

  • Children with recurrent UTI

  • Children who do not respond promptly to antimicrobial therapy

• Renal-bladder ultrasound:

  • Identifies gross anatomy abnormalities

  • Obtain in patients with poor clinical response within 48 hours of antimicrobial therapy

• Voiding cystourethrogram (VCUG):

  • Identifies vesicourethral reflux (VUR)

  • Perform immediately after therapy

• Technetium 99m-dimercaptosuccinic acid (^99mTc-DMSA) scan:

  • Identifies acute pyelonephritis (of limited value) and renal scars (if performed >5 months after infection)

TREATMENT

See Surviving Sepsis Guidelines to reverse shock

ANTIMICROBIAL THERAPY

• Empiric IV antibiotics:

  • Second- (cefuroxime) or third-generation (cefotaxime, ceftriaxone) cephalosporin

  • Ampicillin-sulbactam

  • Gentamicin

• Switch to enteral antimicrobial: afebrile and able to tolerate enteral medications

• Narrow antimicrobial therapy: based on culture results

• Duration: 10 to 14 days

COMPLICATIONS

RENAL OR PERINEPHRIC ABSCESS

• Suspect when fever is persistent despite appropriate antimicrobial therapy

• Treatments: drainage + antimicrobial therapy

SUGGESTED READINGS

NORMAL RENAL FUNCTION AND THE DEFINITON OF AKI

The kidneys are responsible for many physiologic functions imperative to homeostasis, including:

• Excretion of organic anions, water-soluble metabolites and drugs

• Regulation of acid–base balance

• Regulation of sodium, chloride, and potassium serum levels

• Regulation of serum osmolality and free water balance

• Production of erythropoietin

• Vitamin D metabolism

• Regulation of systemic vascular resistance through production of renin and angiotensin

The kidneys also receive up to 20% of the cardiac output, making them very sensitive to changes in blood pressure, oxygen delivery, and/or cardiac output.

Acute kidney injury (AKI) is a broad clinical term that includes the subtle signs of renal impairment such as edema or acidosis and extends to complete renal failure and anuria. Staged definitions have been developed to accommodate for the wide clinical variability of patients with a diagnosis of AKI.

CAUSES OF PEDIATRIC AKI

Classically the causes of AKI have been categorized as pre-renal, intrinsic, and post-renal. However, the causes of AKI in critically ill children are more complex and multifactorial than these categories suggest.

Common causes of AKI in the PICU include:

• Hypoxic-ischemic injury

• Sepsis, cytokine, or toxin mediated

• Multiorgan dysfunction syndrome

• Nephrotoxic medications

  • Causes 25% of pediatric AKI: aminoglycosides, NSAIDs, radiopaque contrast, immunosuppressive therapy

• Oxidative stress and hypoxia

• Intravascular volume depletion

• Glomerulonephritis

• Interstitial nephritis: idiopathic or drug induced

• Tumor lysis syndrome

• Rhabdomyolysis

• Acute tubular necrosis

• Renal vascular thrombus

• Hemolytic uremic syndrome

• Obstruction of urinary flow from posterior urethral valves, nephrolithiasis, trauma

Children with critical illness are especially vulnerable to AKI as intrinsic renal function does not approach adult levels until over 1 year of age. Neonates and premature infants in normal health have an estimated glomerular filtration rate (GFR) of 50 to 60 mL/min/1.73 m² whereas a healthy adult GFR is approximately120 mL/min/1.73 m².¹

DIAGNOSING PEDIATRIC AKI

Approximately 10% of critically ill children will have AKI, most often around the third hospital day.² The presence of any signs of renal dysfunction, including fluid overload, systemic hypertension (blood pressure >95th percentile for age and sex), and/or electrolyte derangement should prompt investigation for AKI. The clinical correlate to describe renal function is the GFR, expressed in mL/min/1.73 m².

SERUM CREATININE AS A MEASURE OF GFR

The most available serum biomarker of renal function is serum creatinine (SCr). There is a simple bedside calculation to convert SCr levels to an estimated GFR³:

This equation often overestimates renal function, especially in extremes of age and renal function.

As a by-product of muscle mass with dynamic changes in excretion and renal tubule absorption, SCr has multiple disadvantages as an indicator of renal function in children with critical illness.

• The following factors affect SCr levels regardless of actual renal function:

  • Protein malnutrition

  • Age: SCr is very insensitive to small changes in renal function in young children

  • Sex

  • Critical illness

  • Muscle mass

  • Fluid balance: SCr levels should be adjusted for the net fluid balance of a patient to correct for dilution from fluid overload⁴:

    $AdjustedSCr=SCr×(1+[ Netfluidbalance(L)Wt(kg)×0.6 ])$

ADULT DEFINITIONS OF AKI

The Kidney Disease: Improving Global Outcomes (KDIGO) international consensus defined AKI in 2012 as an:

• Increase in SCr by ≥0.3 mg/dL within 48 hours; OR

• Increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the 7 days prior; OR

• Urine output < 0.5 mL/kg/hr for 6 hours⁵

PEDIATRIC DEFINITIONS AND STAGING CRITERIA FOR AKI

Consensus definitions or staging criteria have been developed for children; similar to the adult definitions, pediatric definitions for AKI rely primarily on SCr and urine output. The pediatric “Risk” “Injury” “Failure” “Loss” and “End-Stage” (pRIFLE) and Acute Kidney Injury Network (AKIN) are the current definitions and criteria most commonly used by pediatric critical care physicians (Table 51-1)⁶.

In a paradigm shift, the Renal Angina Index includes clinical context to describe patients at high risk for AKI in the 2 days after the threshold for “angina” is surpassed (Table 51-2).⁷

DIAGNOSTIC OPTIONS (OTHER THAN SCR) IN PEDIATRIC AKI

It can take up to 2 days and loss of 50% or more of glomerular function for elevations in SCr to occur. Other diagnostic and screening tests used to clinically monitor for and detect AKI include:

• Urinalysis: Casts can indicate tubular damage; microscopic hematuria or proteinuria can indicate glomerular damage

• Renal ultrasound: Rule out vascular thrombi, obstruction

• Renal near infrared regional spectroscopy (NIRS): Monitors for dynamic changes in renal oxygen uptake in patients at high risk of AKI

• Novel biomarkers: Many new serum and urinary tests have been established to replace SCr; none has risen to widespread use. A functional panel of several biomarkers likely holds the most promise for early detection of AKI but is not yet available. The two novel biomarkers most in clinical use in PICUs are:

  • Cystatin C: serum or urine, detects earlier and more subtle changes in renal function than SCr

    • AKI threshold >1.0 mg/L

    • Modified Schwartz equation uses serum cystatin C, height (ht), SCr, and blood urea nitrogen (BUN) to estimate GFR with more accuracy that the original Schwartz equation³:

    $eGFR=39.1[ ht(m)SCr(mg/dL) ]0.516×[ 1.8cysC(mg/L) ]0.294×[ 30BUN(mg/dL) ]0.169×[ ht(m)1.4 ]0.188×(1.099​ifmale)$

  • Neutrophil gelatinase-associated lipocalin (NGAL): serum or urine, proven to detect changes in renal function in several pediatric populations but is not yet clinically available for use

    • AKI threshold >150 ng/mL in serum and > 50 μg/mL in urine

PEDIATRIC AKI MANAGEMENT

No therapies or curative medications exist for pediatric AKI. The key to managing AKI is avoiding further damage through the following tactics:

• Optimize hemodynamics and oxygen delivery

  • Aim for normotension: Renal dose dopamine and supraphysiologic blood pressures have shown no benefit in pediatric AKI and may be detrimental.

  • No role for fenoldopam: selective dopamine agonist, increases renal blood flow, has shown no improvement in pediatric AKI.

  • Avoid transfusions if possible: Transfusing packed red blood cells (pRBCs) likely carries more risk than benefit in augmenting oxygen delivery, depending on the level of anemia. The high potassium load from stored blood products, the extra volume loading, and the potential for transfusion reactions are dangerous side effects of pRBCs that must be considered before administering blood products, especially if the hemoglobin is above 7 mg/dL.

• Optimize nutrition: Use of indirect calorimetry can be helpful to ensure dynamic nutritional needs are met. Renal replacement therapy may be necessary to allow delivery of full nutrition.

• Avoid nephrotoxic medications: Including aminoglycosides, NSAIDs, antifungal agents, calcinuerin inhibitors, and contrast media for computerized tomography (CT) scans.

• Renal replacement therapy (RRT): No standard timing, dosage, or duration has been agreed upon (see Chapter 52 for more details).

• Avoid fluid overload (FO): Increased fluid administration and FO >10% to 20% has been independently associated with mortality in children with AKI and/or requiring renal replacement therapy.²

  • Limit fluid intake to the insensible fluid loss rate = 300 to 400/m²/day or about one-third of the maintenance IV fluid rate if the body surface area is unknown.

    1. If eating, avoid free water, potassium- or phosphorous-containing food, or a high protein load. Renal formulas such as Suplena are ideal for calorie density and electrolyte composition.

    2. If on total parenteral nutrition, minimize potassium and limit protein to < 2 grams per day unless on renal replacement therapy.

  • Diuretic therapy: Diuretics are often used to mitigate further fluid accumulation and improve FO; no prospective pediatric data supports this practice. Electrolyte derangements, hypochloremic alkalosis, and azotemia are expected and manageable side effects from diuretic use (Table 51-3).

OUTCOMES OF PEDIATRIC AKI

AKI increases mortality in children with multiorgan failure, after organ and stem cell transplantation, on extracorporeal membrane oxygenation (ECMO), with acute respiratory distress syndrome (ARDS), and in septic shock independent of PRISM II scores. In survivors, AKI increases length of mechanical ventilation, inotrope need, and length of stay in the PICU and in the hospital.²

LONG-TERM OUTCOMES OF PEDIATRIC AKI

Evidence is growing that a significant amount of previously healthy children after a single episode of AKI during critical illness will have long-term renal impairment. In one study, up to 70% of children with AKI from aminoglycoside therapy had renal impairment 1 year after discharge,⁸ and this persists in 40% to 50% of children at 3- and 5-year follow-up.²

No consensus guidelines regarding referral to nephrology exist for pediatric AKI after PICU discharge, and current practice is highly variable.⁶

THE PHYSIOLOGY OF RENAL REPLACEMENT THERAPY

Renal replacement therapy (RRT), or “dialysis,” uses the basic concept of molecular movement across a semipermeable membrane to provide particle and water removal from the blood.¹

This requires two types of movements:

• Diffusion: Solute exchange across a membrane between two solutions based on concentration gradient (from high to low concentration), permeability of the membrane, and surface area of the membrane

  • Used in HEMODIALYSIS or whenever a dialysate is used

  • Favors small particle movement

  • Faster movement with a large concentration gradient

• Convection: Solute movement or “drag” with filtration across a membrane driven either by hydrostatic or osmotic pressures independent of concentration gradient

  • ULTRAFILTRATION: Water removal across a membrane using a pressure gradient

  • Particles AND water move together; if removing large amounts, will have to provide replacement fluid with electrolytes to compensate for filtration losses

  • Removes small and medium-sized particles; amount depends on amount of filtered water and the sieving coefficient of the membrane

  • Large particles will not be removed if they are larger than the pores of the membrane

RENAL REPLACEMENT THERAPY MODALITIES

PERITONEAL DIALYSIS (PD)

• Description: Uses the peritoneum as the membrane for both convection- and diffusion-based solute clearance. Need a healthy, intact peritoneum (no diaphragmatic hernias, adhesions, or active peritonitis).

• Advantages: Can be run emergently and continuously without vascular access; PD catheters can be placed at the bedside percutaneously by the intensivist or interventional radiologist if pediatric surgeons are unavailable.

• Indications: Efficacious in fluid overload and is less invasive and has little hemodynamic impact, making it safe in neonates and infants.

  • Does not work in hyperammonemia or for drug clearance in toxic exposures

• Complications: Hernias, peritonitis, hyperglycemia, respiratory compromise if giving dwells of more than 60 mL/kg, dialysate leakage, pleural effusions.

INTERMITTENT HEMODIALYSIS (IHD)

• Description: Removes venous blood from the patient into an extracorporeal circuit past a membrane to provide mainly diffusion in a rapid manner via a 3- or 4-hour session

• Advantages: Effective for small molecule clearance

• Indications: Good for hyperkalemia, toxic exposures, tumor lysis syndrome

  • Contraindicated in hemodynamic instability, severe uremia (see “Disequilibrium Syndrome” later)

• Considerations: Solute clearance depends on molecular weight, dialysate flow, membrane properties, and blood flow

• Complications: Discussed in detail later

CONTINUOUS RENAL REPLACEMENT THERAPY (CRRT)

• Description: Removes venous blood from the patient into an extracorporeal circuit past a membrane to provide diffusion and/or convention, intended to run 24 hours a day

• Advantages: Provides slow, gentle adjustable removal of fluid and waste over time, more precise in reaching solute clearance and ultrafiltration goals than PD

• Indications: Hemodynamically unstable patients, effective in all indications for RRT

• Complications: Discussed in detail later

• Types of CRRT

  • SCUF (slow continuous ultra-filtration): Free water and some small molecule clearance, no replacement fluid or dialysate is typically used

  • CVVH (continuous veno-venous hemofiltration): Convective-based solute clearance that requires replacement fluids

  • CVVHD (continuous veno-venous hemodialysis): Diffusion-based solute clearance, removes small particles down a concentration gradient; minimal convection

  • CVVHDF (continuous veno-venous hemodiafiltration): Both high-grade convection (replacement fluids) and diffusion (dialysate)

INDICATIONS FOR RENAL REPLACEMENT THERAPY

RRT is indicated emergently for any life-threatening changes in fluid, electrolyte, or acid–base balance.

RECOMMENDED INDICATIONS FOR RRT IN CRITICALLY ILL CHILDREN

• Acute kidney injury with or without oliguria

• Toxic ingestion

  • RRT modality: IHD is the preferred modality, may need to augment with CRRT to avoid rebound peak plasma levels in specific situations.

  • Considerations: The clearance of a drug depends on a sieving coefficient that is determined by molecular weight, charge, volume of distribution, and stoichiometry. Drugs that have a large volume of distribution, such as vancomycin, will take a long time to clear from the body.

    $Seivingcoefficient=Drugconcentrationinthefiltrate(Cf)Drugconcentrationintheplasma(Cp)$

  The more protein-bound the drug, the harder it is to remove from the blood because of the molecular size of albumin, a large molecule. Using albumin 2 to 4 mg/dL in the dialysate can improve the efficiency of clearing protein-bound drugs.

• Inborn errors of metabolism with hyperammonemia

  • RRT modality: CRRT is preferred because of high efficiency and prevents rebound levels as seen after one session of IHD; NOT CLEARED WITH PD

• Severe electrolyte imbalance refractory to medical therapy (hyperkalemia, hypercalcemia, hyperphosphatemia)

• Symptomatic uremia: No longer using a strict numeric threshold to determine need for RRT for uremia

• Fluid overload >10% to 15%: Equates to a positive fluid balance of >100 to 150 mL/kg; or fluid overload resistant to medical management and leading to systemic hypertension, edema, multiorgan failure, and/or cardiovascular instability

CONTROVERSIAL USES OF RRT

RRT has been used for immunomodulation in multiorgan failure due to septic shock. Studies have shown CRRT can remove some inflammatory mediators nonselectively; however, under closer investigation only a small percentage of cytokines is actually removed from plasma due to molecular size and structure. Despite adjusting modalities and filters, there have not been any reports of sustained or significant decreases in plasma cytokine levels using CRRT alone.² There are neither supporting data nor current recommendations to use CRRT in children with septic shock without signs of AKI.

WRITING A PRESCRIPTION FOR CONTINUOUS RENAL REPLACEMENT THERAPY

The subspecialty in charge of ordering CRRT fluids, flow rates, and electrolyte composition is institution dependent. Pediatric intensivists are more commonly taking ownership in place of pediatric nephrologists, especially in hospitals where pediatric nephrologists are not available.

BLOOD FLOW RATES

Small-solute prescription is written in terms of volume of either dialysis fluid (diffusion) and/or replacement fluid (convection) as mL/kg/hr in adults or mL/1.73m²/hr in children. Typical CRRT flow rate is 2 to 2. 5 L/1.73 m²/hr divided between dialysate and replacement. This requires a blood flow rate of approximately 3 to 5 mL/kg/min.³ If using CRRT for hyperammonemia, the recommended flow rate is much higher at 8 L/1.73 m²/hr. Flow rates used in CRRT are slower than IHD but can achieve the same daily clearance over 24 hours with less metabolic variation from a single IHD session.

FLUID REMOVAL RATES

If ordering CRRT, it is important to determine the daily fluid balance goal for your patient. When ordering this, divide the daily goal by 24 to obtain the hourly fluid removal goal. The bedside nurse will use this goal to adjust the amount of fluid removed every hour to adjust for large volume medications or blood products. Current recommendations in hemodynamically unstable children are to set the first 24-hour fluid goal at euvolemia and then begin gentle fluid removal over 48 to 72 hours.

DIALYSATE OR REPLACEMENT FLUID COMPOSITION

The primary electrolytes in standard solutions used for RRT are sodium, potassium, calcium, magnesium, chloride, glucose, and bicarbonate or lactate. There are commercially available solutions that differ in terms of electrolyte composition and the inclusion or exclusion of calcium. Electrolytes can be added to these base solutions to tailor the effects of CRRT to custom patient goals (Table 52-1).

• Specific fluid composition considerations:

  • Bicarbonate versus lactate: Bicarbonate-based solutions are used for both diffusion and convection and are recommended over lactate-based solutions for patients with AKI and shock.⁴ If a patient is acidotic, the highest bicarbonate concentration is ideal as it will provide a higher serum bicarbonate level to buffer the patient's acidosis.

  • Calcium: Calcium-free solutions should be chosen if using citrate regional circuit anticoagulation. This will allow titratable control over the serum calcium level using the separate calcium infusion.

  • Potassium and phosphorous: If providing RRT to a patient without AKI, repletion of phosphorous will be necessary, as dialysate and filtration fluids do not typically contain any phosphorous. Use of any dialysate without potassium will quickly remove all potassium from the blood and is not recommended.

ANTICOAGULATION

• Heparin versus citrate: Heparin- and citrate-based protocols exist for anticoagulation to avoid circuit and filter clotting. Heparin requires systemic anticoagulation and can infer bleeding and drug-related risks. The current recommendation is to use citrate regional circuit anticoagulation in CRRT unless a contraindication exists, such as severe liver failure or previous citrate toxicity.

• Citrate anticoagulation: When using citrate, calcium levels in the circuit and patient must be carefully monitored. The calcium bound by citrate in the circuit has to be returned to the patient via a continuous infusion of calcium chloride via an additional access point in the circuit after filtration or, if need be, via an additional central line.

  • Goal levels of calcium

    • Circuit: 0.2 to 0.4 mmol/L (0.8–1.6 mg/dL)

    • Patient: 1.1 to 1.3 mmol/L (4.4–5.2 mg/dL)³

  • Ordering citrate and calcium infusions

• Typical citrate rates are 1.5 times the blood flow rate.

• Calcium infusion should run at approximately 0.4 times the citrate rate.

• Flow rates of citrate should start at approximately 50% lower in neonates because hepatic metabolism of citrate is immature in this age group.

TECHNICAL CONSIDERATIONS

• Obtaining venous access: Both intermittent hemodialysis and CRRT require temporary or permanent venous access (Table 52-2). The right internal jugular vein is the preferred site for placement, followed by the femoral veins. The subclavian should be used in emergency settings only. The catheter should be at least 10 to 14 French to allow adequate blood flow rates³; children under 30 kg will require smaller catheters based on weight.

• Priming the circuit: The circuit must be filled with a fluid prior to initiation of CRRT. A typical CRRT circuit can hold approximately 120 to 200 mL of fluid. Normal saline is the fluid of choice if the volume in the circuit is a small percentage of the patient's blood volume. If circuit volume represents more than 10% of the patient's blood volume (which is 60–80 mL/kg), packed red blood cells (RBCs) are a more appropriate priming fluid to prevent hypotension and anemia. Depending on the modality of RRT and the type of circuit used, this could affect any patient less than 15 kg.

  • If blood priming, it is important NOT to reinfuse the blood prime into the patient after RRT is complete, or else it can potentiate volume overload and hypertension.

• Temperature of fluids: Ensure all dialysate and replacement fluids are warmed up to 34.5°C to 37.5°C to avoid hemodynamic instability and hypothermia; higher temperature fluids also provide more efficient solute clearance.

CHOOSING THE TIMING, DOSAGE, AND TYPE OF RENAL REPLACEMENT THERAPY

“EARLY” VERSUS “LATE”

Theoretically, initiating RRT prior to the onset of the damaging effects of metabolic derangements like uremia or fluid overload should provide a survival benefit for children requiring RRT. Retrospective adult data supported the use of early RRT and higher filtration rates in septic shock patients and were validated in two prospective randomized controlled trials (RCTs). However, starting RRT before AKI occurs is not recommended, as prophylactic RRT in adults at risk for AKI without evidence of azotemia provided no survival benefit.²

Pediatric data have not been as conclusive about when to start RRT, except in cases of fluid overload (FO). The only consistent independent risk factor for mortality in children requiring RRT remains percent fluid overload at the time of RRT initiation.⁵ Estimated glomerular filtration rate (GFR), age, weight, urine output, diuretic use, and severity of illness are all not consistently significantly associated with mortality in pediatric patients with AKI on RRT. Data do agree that having FO greater than 10% to 20% from ICU admission to RRT initiation is an independent risk factor for mortality in several disease states, with an adjusted odds ratio of mortality as high as 8.5.⁶ Using CRRT to remove fluid after this threshold is passed does not lessen the mortality risk; only starting RRT before it is met does.¹ Being 20% fluid overloaded equates to having a net fluid balance of 200 mL/kg.

“HIGH DOSE” VERSUS “LOW DOSE”

Two large randomized, multicenter adult studies—the Randomized Evaluation of Normal versus Augmented Level Renal Replacement Therapy (RENAL) Study and the Veterans Administration/ National Institutes of Health Acute Renal Failure Trial Network (ATN) Study—showed no survival or renal recovery benefit from increasing RRT above 20 to 25 mL/kg/hr of effluent flow.⁷ Although no prospective pediatric data exist, retrospective data show no outcome improvement associated with CRRT dose.⁸ The most recent Kidney Disease: Improving Global Outcomes (KDIGO) international consensus guidelines recommend delivering an effluent volume of 25 mL/kg/hr, which equates to the standard pediatric CRRT flow rate of 2 to 2.5 L/1.73m²/hr.⁴

IHD VERSUS CRRT

In theory, CRRT should provide more gradual solute and fluid removal leading to fewer episodes of renal and gastrointestinal (GI) ischemia to allow for faster recovery and improved survival than IHD. There are consistent data and strong recommendations for CRRT over IHD in cases of hemodynamic instability and cerebral edema because of avoidance of blood pressure variability and osmotic cellular shifts.⁹ Other indications are less clear.

Prospective randomized adult studies suggest that use of IHD is associated with higher mortality than CRRT in critically ill patients. The RENAL and ATN studies also found that renal recovery and mortality were worse in patients receiving IHD versus CRRT even after adjusting for severity and organ-failure scoring.⁷ The conclusion of the adult data is that CRRT is the only appropriate strategy in critically ill patients at risk for hemodynamic instability if renal recovery is to be optimized.

Recent advances in technology have changed the choice of RRT modality by pediatric nephrologists from predominantly PD to now most often CRRT. The Prospective Pediatric CRRT Registry provided data that shows that CRRT is safe and feasible in infants less than 10 kg irrespective of disease severity, contrary to initial beliefs. No prospective randomized pediatric studies exist that compare IHD to CRRT; however, in the critical care unit, CRRT is a safe and feasible option with less hemodynamic and metabolic impact and should be considered first in most circumstances.¹ Choice of modality should also include consideration of the comfort of each institution's staff to administer the therapy. CRRT requires extensive resource utilization, knowledge, and comfort, which could overcome its potential benefit in certain clinical situations.

PICU COMPLICATIONS FROM BLOOD-BASED RENAL REPLACEMENT THERAPY

PEDIATRIC RRT OUTCOMES

• Renal Recovery: Use of RRT does not affect potential for recovery of renal function.

• Mortality: Survival rates for critically ill children with AKI receiving RRT have not changed over the last few decades, persisting around 52%. Survival is lower in those receiving PD (49%–64%) and CRRT (34%–58%) than those receiving IHD (73%–89%).¹

TIMING OF COMPLICATIONS

The risk of complications is greatest at the initiation of CRRT. It is essential for intensive care physicians to be at the bedside when starting CRRT to provide close monitoring of all vital signs, especially blood pressure, heart rate, oxygen saturation, and neurologic status. Rescue doses of calcium and vasopressors may be necessary depending on the stability of the patient.

LIST OF COMPLICATIONS FROM CRRT OR IHD

• Related to catheter placement or maintenance: Infection, bleeding, thrombosis, pneumothorax, and the other complications associated with placement and maintenance of a large-bore central venous catheter

• Hemodynamic instability: Especially upon initiation of CRRT from fluid shifts and inflammatory response

• Disequilibrium syndrome: Only seen in IHD

  • Mechanism: If urea is cleared from blood too quickly, it can cause acute cerebral edema and death

• Hypothermia

• Air embolism

• Anaphylaxis

• Hemorrhage

• Leukopenia

• Electrolyte derangements: Most often sodium, phosphorous, and magnesium

• Metabolic alkalosis: Caused by the normal hepatic metabolism of each citrate molecule into three bicarbonate molecules

• Bradykinin release syndrome: Life-threatening allergic-type reaction causing rapid hypotension, rash, wheezing, and bradycardia

  • Mechanism: When acidic whole blood (used to prime a circuit or from the patient) comes in contact with a specific type of dialysis circuit, the AN-69, it can cause a massive bradykinin release. This leads to profound hypotension and an anaphylactic reaction.

  • Timing: Immediate, <5 minutes

  • Management: Treat like anaphylaxis. May be avoided by rinsing the membrane with bicarbonate, increasing the pH of the blood in circuit or patient, or avoiding use of the AN-69 membrane. The AN-69 membrane is specifically used in small patients and in septic shock as it supposedly provides optimal cytokine removal.

• Citrate toxicity (previously “citrate lock”)

  • Mechanism: Occurs in patients on CRRT when the citrate infusion is not cleared by normal hepatic metabolism. Citrate then binds to free calcium and forms circulating complexes within the blood, raising the total calcium to very high levels. Ionized calcium should stay the same until more citrate accumulates; then is able to bind and it will start to fall. Tetany can result.

  • Management: Once total calcium exceeds 11.5 mg/dL, stop or decrease the citrate infusion and increase circuit clearance by higher dialysate or replacement flow rates.

• Rapid clearance of medications

  • PICU considerations: Most notably catecholamine infusions used for blood pressure support can be cleared during CRRT.

  • Management: May need higher doses of affected medications while on CRRT.

• To assess if medication doses should be adjusted when on CRRT, go to the Dialysis of Drugs Handbook: http://www.seanmeskill.com/DialysisDrugs2010.pdf

END-STAGE KIDNEY DISEASE (ESKD) IN CHILDREN

Definition: Sustained estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m² (chronic kidney disease or CKD stage 5), requiring either dialysis or kidney transplantation (renal replacement therapy).

Causes: Causes of CKD/ESKD in children differ vastly from those in adults. Hypertension and diabetes mellitus, although common causes of ESKD in adults, are exceedingly rare as causes in children. The most common causes of CKD/ESKD in children are:

• Congenital renal anomalies (57%): Obstructive uropathy (21%), renal aplasia/hypoplasia/dysplasia (18%), reflux nephropathy (8%), polycystic kidney disease (4%)

• Glomerular disease (17%—but 45% of patients >12 yr): Focal segmental glomerulosclerosis (FSGS) most common

• Other (25%): Unknown; hemolytic uremic syndrome (HUS); genetic disorders (cystinosis, oxalosis, Alport's syndrome); interstitial nephritis¹

Kidney transplantation is preferred over dialysis as treatment for ESKD in children, as the risk for death is more than four times higher on dialysis than after kidney transplantation.²

TYPES OF KIDNEY TRANSPLANTATION

Preemptive kidney transplantation: “Preemptive” denotes a kidney transplant performed before a patient requires initiation of dialysis therapy. These transplants result in superior long-term outcomes compared to transplants done after starting dialysis.³ Preemptive transplants can be done with either living or deceased donor kidney grafts. This approach is not possible or recommended for some conditions (e.g., conditions requiring pretransplant nephrectomies, such as persistent nephrotic syndrome, chronic severe pyelonephritis, and malignant renovascular hypertension).

Note: Patients receiving preemptive kidney transplants, by definition, still have adequate urine output via their native kidneys. This makes using urine output by itself as a marker of transplant graft function postoperatively problematic.

Deceased donor kidney transplantation: The organ is obtained by accruing waiting time on the deceased donor/cadaver kidney list. Highly sensitized patients or those listed for multiple organs are given preference on the list. There is also a pediatric advantage for those listed before turning 18 years old.

Living donor kidney transplantation: Related or unrelated living donors donate one kidney after a thorough medical and psychological evaluation process. Living donor transplants in general demonstrate superior long-term outcomes compared to deceased donor kidney transplantation.

CONTRAINDICATIONS TO KIDNEY TRANSPLANTATION

Contraindications to kidney transplant include sepsis, uncontrolled malignancies, irreversible multisystem organ failure not correctable by transplant, and severe cardiac or pulmonary disease that can't be cured by multiorgan transplant. Active underlying disease (e.g., systemic lupus erythematosus [SLE] or anti-GBM antibody disease) is also a contraindication for transplantation.

IMMUNOSUPPRESSION IN PEDIATRIC KIDNEY TRANSPLANT

INDUCTION THERAPY

• Purpose: To prevent T-cell activation in the perioperative period, when risk of acute rejection is highest.

• *IL-2 receptor antibodies/antagonists (basiliximab): Used for most standard-risk first transplant recipients in our center.

• Alemtuzumab (anti-CD52 monoclonal antibody): Depletes T and B lymphocytes, monocytes, natural killer cells. Used for second transplants, higher immunological risk recipients in our center, but used in standard-risk protocols for induction therapy in many adult centers.

• Antilymphocyte globulin (rATG-thymoglobulin): In our center, used more for cellular rejection treatment than for induction therapy, but widely used in many pediatric centers for induction therapy.

• *IV corticosteroids (methylprednisolone): In our center, standard-risk recipients receive only three daily doses of IV steroids, followed by no maintenance steroid treatment. Steroid use varies widely between pediatric transplant centers.

MAINTENANCE THERAPY

• Oral steroids are not typically used for maintenance immunosuppression for most standard-risk kidney transplant recipients in our center (proven benefits in growth and no increase in risk of rejection).⁴ Many pediatric centers do still use corticosteroids as part of their standard maintenance immunosuppression protocols.

• *Tacrolimus (FK-506), calcineurin inhibitor (CNI): Binds to calcineurin (cytosolic receptor) to inhibit transcription of several cytokines by activated T cells. Less rejection and less toxicity than with older CNI (cyclosporine). Side effects include nephrotoxicity, neurotoxicity, hypertension, and diabetes mellitus. Trough levels are followed for medication adjustment given variable metabolism and narrow therapeutic index.

• *Mycophenolate mofetil (MMF), antimetabolite: Inhibitor of inosine 5-phosphate dehydrogenase and guanosine monophosphate synthetase to reduce de novo purine synthesis in T and B lymphocytes (inhibits lymphocyte proliferation and antibody production). MMF has largely replaced azathioprine (less bone marrow toxicity). Side effects are dose related and include diarrhea, leukopenia, and anemia.

• Sirolimus (rapamycin) and other mTOR inhibitors: Block proliferation of lymphocytes in response to IL-2. These medications are not frequently used as part of the protocol at our center due to the potential effect of increasing nephrotoxicity of CNIs, as well as possible side effects of hyperlipidemia, poor wound healing, and proteinuria.

*Denotes standard immunosuppression at our center.

PERIOPERATIVE MANAGEMENT OF KIDNEY TRANSPLANT RECIPIENTS**

**This section is center specific. Protocols may differ significantly between transplant centers.

Each kidney transplant candidate who is either scheduled for living donor kidney transplant or who is active on the deceased donor list has an individualized protocol that will be provided to all managing residents and fellows on admission for kidney transplant.

GENERAL PRINCIPLES

Foley catheter drainage is usually maintained for 3 to 7 days postoperatively (depending on urological history) to keep the bladder decompressed and prevent stress on the bladder-to-transplant ureter anastomosis/potential urine leak. At our center, a ureteral stent is left in place due to concern for postoperative edema/obstruction at this anastomosis. The stent is electively removed 4 to 6 weeks after the transplant.

Initial fluid management is with cc:cc urine output (UOP) replacement to keep overall fluid balance even. If hourly urine output is high, lower dextrose fluid is prescribed. Additional fluid boluses may be given for hypotension/low central venous pressure (CVP) or low UOP. Conversely, overall fluid may be limited if delayed graft function (DGF) is suspected and there are concerns for fluid overload, but these decisions should be made in conjunction with the transplant team.

POST-TRANSPLANT COMPLICATIONS

EARLY/IMMEDIATE

• Delayed Graft Function (DGF): Requirement for dialysis or lack of improvement in baseline degree of native kidney failure in the first week post-transplantation. Grafts with delayed function may have lower long-term graft survival rates. Potential causes of DGF include:

  • Ischemia-reperfusion injury (acute tubular necrosis or ATN): Most common cause of DGF

  • Transplant renal artery or vein thrombosis: Ultrasound (US) with Doppler and/or nuclear renal scan to diagnose; usually an indication for emergent return to operating room. Higher risk in nephrotic patients, significant hypotensive episodes, multiple arteries/complicated or small vasculature.

  • Urologic abnormalities: Urinary leak, hematoma, obstruction. Suspicion usually investigated with US.

  • Hyperacute or accelerated rejection

  • Immediate recurrence of focal segmental glomerulosclerosis (FSGS)

EARLY/ACUTE (1–12 WEEKS POST-TRANSPLANT)

• Acute rejection: Acute cellular (ACR) or antibody-mediated (AMR) rejection

• Calcineurin inhibitor toxicity

• Urinary obstruction

• Hypovolemia/ATN

• Recurrent disease: FSGS (most frequently recurring glomerular disease), membranoproliferative glomerulonephritis, IgA nephropathy, atypical hemolytic uremic syndrome (aHUS), primary hyperoxaluria, SLE (recurrence rare)

LATE/ACUTE (>3 MONTHS)

• Rejection: ACR and/or AMR

• Calcineurin inhibitor toxicity

• Urinary obstruction

• Hypovolemia/ATN

• Infection/pyelonephritis, BK virus nephropathy

• Recurrent or de novo kidney disease

PROGRESSIVE/CHRONIC (>1 YEAR)

• Chronic allograft nephropathy (CAN): Most likely due to chronic rejection/AMR

• Calcineurin inhibitor toxicity

• Viral infections (e.g., BK virus nephropathy)

• Hypertensive nephrosclerosis

• Recurrent or de novo kidney disease

REJECTION

Kidney graft dysfunction without otherwise apparent cause needs to be investigated by kidney graft biopsy. Type of rejection and grading (usually according to Banff criteria) are necessary to determine appropriate treatment.

ACUTE CELLULAR REJECTION (ACR)

• Borderline or less severe grades of ACR may be treated with IV and/or oral steroid bursts.

• More severe ACR is usually treated with steroids + a course of IV thymoglobulin. Such treatment often requires placement of a central line.

ANTIBODY-MEDIATED REJECTION (AMR)

• When AMR is suspected or seen on biopsy (often with presence of peritubular capillaritis and/or positive C4d staining), the recipient's donor-specific antibody (DSA) levels are measured.

• In addition to IV and/or oral steroids, significant AMR is often treated with multiple plasma exchange/plasmapheresis procedures, with the goal of lowering the recipient's level of circulating DSAs. A hemodialysis catheter is required for this therapy, unless the patient still has a functioning arteriovenous (AV) fistula that may be accessed.

• Intravenous immunoglobulin (IVIG) infusions (promote opsonization and clearance of DSAs) and rituximab (depletes B cells that may contribute to DSA production) are also often used in AMR treatment protocols.

• Resistant cases of AMR may be treated with a trial of bortezomib (a proteasome inhibitor that targets plasma cells) therapy.

INFECTION

Infections are the most common cause of hospitalization during the first 2 years post-transplant (exceed hospitalizations for rejection).⁵ Whereas urinary tract infections (UTIs) and pulmonary infections are frequent during the early post-transplant period, viral infections become more important later post-transplant.

• Cytomegalovirus (CMV): CMV may cause disease either from primary infection or from reactivation of primary infection. Infection may be asymptomatic or may manifest as fever, cytopenias, hepatitis, pneumonia, or allograft dysfunction. At our center, all seropositive recipients (and seronegative recipients of seropositive allografts) receive 6 to 12 months of valganciclovir prophylaxis.

• Epstein-Barr virus (EBV): EBV primary infection is usually a severe monolike illness. Reactivation of EBV in a seropositive recipient is usually without symptoms. EBV can induce B-cell proliferation in patients on immunosuppression, leading to post-transplant lymphoproliferative disease (PTLD). PTLD can have a spectrum of severity, ranging from mild/polymorphic proliferation limited to tonsillar/lymphoid tissue (may be self-limited or treated with reduction in immunosuppression) to true monomorphic lymphoma requiring chemotherapy and cessation of immunosuppressive therapy.

• BK virus: This polyoma virus takes up latent residency in uroepithelial cells, where it may become reactivated during states of immunosuppression. It can first be detected in the urine by polymerase chain reaction (PCR) and then in the blood when it gets to high enough levels. Higher levels of this viremia are associated with BK nephropathy and graft dysfunction. Treatment is generally with decrease in immunosuppression +/- antiviral therapy (leflunomide, cidofovir). Cidofovir is often reserved for more severe disease, as the medication itself is nephrotoxic. Kidney transplant recipients are screened regularly for the presence of BK viruria and/or viremia.

• Varicella: Varicella infection in an immunocompromised host can cause severe disease, including encephalitis, hepatitis, pneumonitis, and death. Nonimmune transplant recipients who have a close contact exposure should receive prophylaxis within 72 hours of exposure. Clinical disease should be treated with IV acyclovir. Varicella vaccine is a live virus vaccine and is usually avoided in patients on chronic immunosuppression.

• Herpes simplex virus (HSV): HSV can also cause either primary or reactivation disease. Acyclovir or valacyclovir can be used to treat infection. Severity of infection dictates whether IV or oral therapy may be appropriate.

• Human papillomavirus (HPV): Warts caused by HPV are common in transplant recipients, and immunosuppressed hosts are also at higher risk for malignancy (e.g., cervical cancer) associated with this virus. Vaccination according to the recommended schedule should be strongly encouraged, as this is a nonlive vaccine.

MALIGNANCY

There is an estimated 2.6% to 6% incidence of malignancy following pediatric kidney transplant. The majority (about 80% of these) are PTLD. The reported incidence of non-PTLD malignancies is approximately sevenfold higher than in the general pediatric population.⁶ Skin cancers and native renal cell carcinoma are the most common non-PTLD malignancies in transplant survivors. Routine cancer surveillance should be stressed in long-term primary care follow-up of these individuals.

HYPERTENSION

Hypertension is common after kidney transplantation in children, occurring in up to 80%.⁷ Potential causes of hypertension after kidney transplant include fluid overload, steroid treatment, calcineurin inhibitor use or toxicity, rejection, transplant renal artery stenosis, or urinary tract obstruction.

ANEMIA

Anemia is also very common, with an incidence of up to 80% as well.⁸ Causes are usually multifactorial: iron deficiency, side effects of immunosuppressive therapy, bone disease, declining graft function/relative erythropoietin deficiency.

POST-TRANSPLANT DIABETES MELLITUS (PTDM)

Treatment with calcinueurin inhibitors (especially tacrolimus) and steroids increase risk for developing DM after kidney transplantation. The incidence in pediatric patients is increasing and may be up to 7%.⁹