940 SECTION VII Pediatric Critical Care Renal molecular weight, protein binding (80% less likely to be cleared), charge (cationic drugs less likely to be cleared), Vd (Vd 0 7 L/kg less likely to be c[.]
940 S E C T I O N V I I Pediatric Critical Care: Renal molecular weight, protein binding (80% less likely to be cleared), charge (cationic drugs less likely to be cleared), Vd (Vd 0.7 L/kg less likely to be cleared), and water solubility (lowwater-solubility drugs are less likely to be cleared).17 When dosing antibiotics, one must also understand the pattern of bactericidal activity and presence/duration of postantibiotic effect.13 For example, an antibiotic with a low Vd, a molecular weight of 547 Da, low protein binding, and high water solubility is going to be readily cleared by convective modes of CRRT but not by diffusive modes If the bactericidal activity of this antibiotic is based on time above MIC, with no postantibiotic effect, a continuous infusion or frequent intermittent administration may be required to adequately treat an infection on CVVH or CVVHDF Another dosing strategy used in CRRT uses the sieving coefficient (Sc) Many studies have looked at the Sc of the drug to help understand how freely it crosses the dialysis membrane.17 Sc (Concentration of drug in the ultrafiltrate)/(Concentration of drug in the plasma) An Sc of indicates free removal across the dialysis membrane, while an Sc of means no removal.17 The Sc of a medication can be found only through study data and is therefore not available for all medications However, the Sc can be estimated by assuming that the Sc is equal to the free fraction of drug in the plasma.13 Using the Sc, the clearance of drug can be estimated by the specific CRRT modality Example: CVVH clearance estimation (flow rate of ultrafiltrate) (Sc).17 Many of the same properties that influence medication dosing in CRRT hold true for IHD Medication clearance in IHD is more impacted by Vd because medications with a high Vd are more difficult to remove in IHD In CRRT, there is a constant re-equilibration of drug between the tissues and plasma allowing increased medication clearance.13 In contrast, with IHD, the rate of extracorporeal drug removal from the plasma exceeds the reequilibration from the tissues.13 This leads to a posttreatment rebound of plasma concentrations that has to be taken into account when evaluating post-IHD drug levels.13 There have been multiple advances in IHD equipment over the past 20 years; thus, older studies regarding medication removal in IHD may not be applicable to current practice.11 High-flux dialysis filters are now routinely used, which allows for clearance of molecules of 20,000 Da or less IHD medication clearance is highly reliant on IHD time, volume removed, IHD frequency (e.g., daily vs every other day), and the previously mentioned physiochemical properties of the drug Similar to CRRT dosing, tertiary drug dosing resources assume that the patient is anuric and that the entirety of clearance depends on dialysis, which is not always applicable to the patient situation Consideration of administering medications cleared by IHD after the dialysis session should be routinely done or supplemental doses should be used after each dialysis session In general, most patients need less frequent dosing of renally cleared medications while on IHD due to the significantly reduced or lack of clearance between IHD sessions Some centers are starting to use a variation of IHD referred to as slow low-efficiency dialysis (SLED) or slow extended daily dialysis, which uses the same IHD equipment but runs the session over to 10 hours There is very little information available for medication dosing in this modality Caution should be taken to not overdose or underdose medications in this situation, and drug monitoring should be used when possible.11 PD is the most inefficient form of dialysis for medication removal A typical PD prescription targets a clearance of urea close to 10 mL/min.11 Since almost all drug molecules are larger than urea, medication clearance would be expected to be low Due to this level of clearance, patients on PD are at higher risk of drug accumulation and should have level monitoring when possible.11 Overall, medication dosing in RRT is a very complex and dynamic situation Initial or loading doses in patients requiring RRT rarely need to be adjusted However, subsequent dosing needs to be evaluated based on expected total patient clearance (intrinsic clearance dialysis clearance).13,17 Weighing the risks of underdosing with the risks of overdosing may help guide decision-making while monitoring for medication side effects or disease progression.13,18 When available, obtaining drug levels should be the gold standard of monitoring while on any form of RRT, especially for narrow therapeutic window medications Kidney as a Therapeutic Target: Diuretics and Agents Regulating Renal Excretion Diuretics and agents regulating renal excretion are a diverse group of drugs that act on the kidney to increase salt or water excretion In the intensive care setting, these drugs are commonly prescribed for mobilization of excess body fluid by promoting diuresis, which, in turn, decreases extracellular fluid volume They are used in the treatment of arterial hypertension, electrolyte imbalances, and edematous states, such as cerebral, pulmonary, or general edema; ascites; hepatic cirrhosis; and congestive heart failure (CHF) Less common indications include disorders of calcium metabolism, glaucoma, nephrogenic diabetes insipidus, and drug overdoses Renal tubular cells transport solute and water from the apical cell membrane to the basolateral cell membrane Reabsorption of sodium is central to the kidney’s ability to reabsorb water and other solutes (e.g., glucose, amino acids, bicarbonate) Apical cell sodium entry is mediated by channels that permit sodium to enter by diffusion or transport by specific proteins located on the apical cell membrane In all renal tubular cells, the sodium-potassium adenosine triphosphatase located on the basolateral membrane maintains the low intracellular sodium concentration that favors sodium movement from the tubular fluid into the renal tubular cell Diuretics inhibit sodium reabsorption by blocking sodium channels or sodium transport proteins located on the apical cell membrane at discrete sites along the nephron Diuresis is associated with a decrease in vascular volume that stimulates movement of sodium and water from the interstitial space into the vascular space as well as stimulation of counterregulatory pathways that serve to maintain an adequate extracellular fluid volume The response to diuretics is determined by the amount and time course of drug reaching the site of action and sensitivity of the active site to the diuretic There exists a therapeutic threshold (minimal concentration) that must be reached at the site of action before any response is noted and a maximal response (ceiling) above which no further response will occur even if more drug reaches the site of action The amount and time course of drug reaching the site of action, and tubular response to the diuretic, are influenced by the route and frequency of administration as well as drug and disease states that modify the amount of diuretic reaching the tubular fluid An example is the twofold to threefold increase in loop diuretic dosage required for response in patients with decreased kidney function In kidney failure, the entry of loop diuretics into the tubular fluid is limited by decreased renal blood flow and competitive inhibition of diuretic transport by “uremic toxins.” Adequate tubular fluid diuretic concentration and response can be achieved with the administration of high doses of loop diuretic.20 CHAPTER 77 Renal Pharmacology Carbonic Anhydrase Inhibitors Mechanism and Sites of Action Carbonic anhydrase (CA) enzymes are located at the brush border membrane of the proximal tubule cells and inside of all proximal tubule cells CA catalyzes the dehydration of carbonic acid to water and carbon dioxide and inhibition of CA in these sites, leading to a decrease in hydrogen ion formation and a subsequent decrease in sodium transport from the lumen into proximal tubule cells This results in an increase of sodium in the tubular fluid and a decrease in HCO3 reabsorption Efficacy on Urinary Excretion and Therapeutic Uses CA inhibitors are generally considered to be weak diuretics Their diuretic efficacy is impeded by sodium reabsorption downstream at several nephron sites Acetazolamide, the most commonly used CA inhibitor, is more clinically useful for its extrarenal effects than its diuretic effects Clinically, acetazolamide is used to treat metabolic alkalosis caused by loop diuretics, glaucoma, acute mountain sickness, and occasionally epilepsy However, its long-term use is limited by the metabolic acidosis that develops because of the bicarbonate loss in the urine Adverse Effects In addition to metabolic acidosis, adverse effects of acetazolamide include paresthesia, drowsiness, and renal calculi Osmotic Diuretics Mechanism and Sites of Action Osmotic diuretics are freely filtered at the glomerulus They act on both the proximal tubule and on the loop of Henle (primary site of action) and function as solutes in water, increasing tubular osmolality This, in turn, promotes water retention in tubular fluid, expanding extracellular fluid and increasing renal blood flow Ultimately, these processes increase urine volume Efficacy on Urinary Excretion and Therapeutic Uses Osmotic diuretics increase urinary excretion of most electrolytes (Na1, K1, Ca21, Mg21, Cl–, HCO3, and phosphate) Mannitol, a sugar alcohol, is the prototypical osmotic diuretic Extraction of water from the intracellular compartments to the extracellular fluid volume that is associated with mannitol administration is clinically useful in cerebral edema, glaucoma, management of drug toxicities, and the prevention of dialysis disequilibrium syndrome Adverse Effects Mannitol-induced expansion of extracellular fluid volume may be sufficient to perpetuate CHF, pulmonary edema, and significant hyponatremia in patients with renal failure in whom the half-life of mannitol is prolonged and the ability to excrete free water is limited.21 Loop Diuretics Mechanism and Site of Action Loop diuretics decrease sodium reabsorption by inhibiting the electroneutral Na1/K1/2Cl2 cotransporter located on the apical cell membrane in the ascending limb of Henle This inhibition increases distal tubular concentration of sodium and reduces 941 TABLE Pharmacokinetics of Loop Diuretics 77.2 Drug Relative Potency Oral Bioavailability (%) Half-Life (h) Furosemide ,60 ,1.5 Bumetanide 40 ,80 ,0.8 Ethacrynic acid 0.7 ,100 ,1 Torsemide ,80 ,3.5 Data from Brunton L, Chabner B, Knollman B Goodman and Gilman’s The Pharmacological Basis of Therapeutics 12th ed New York: McGraw Hill Professional; 2010 water reabsorption by increasing the tubular fluid osmotic force and reduction of hypertonicity of medullary interstitium Pharmacokinetics Loop diuretics display similar efficacy but differ slightly in pharmacokinetic characteristics Bumetanide and torsemide are almost completely absorbed after oral administration, whereas the absorption of furosemide is extremely variable, with an average bioavailability of 50% in adults and up to 84% in neonates.22,23 The onset of diuretic effect is within minutes of intravenous (IV) administration of a loop diuretic and 30 to 60 minutes after oral administration The duration of diuretic effect is short (2–6 hours); this short duration often results in the need for multiple doses or a continuous infusion to achieve the desired effect (Table 77.2).22,23 Ethacrynic acid is a less potent loop diuretic that does not contain a sulfonamide moiety and is the preferred agent for patients with documented reactions to sulfonamide-based diuretics Evidence that supports allergic cross-reactivity between sulfonamide antimicrobials and nonantimicrobials is scarce and inconclusive Therefore, patients with known allergies to sulfa-containing antimicrobials would be expected to tolerate these agents.24,25 Effects on Urinary Excretion and Adverse Effects Loop diuretics are the most potent diuretics due to the large percentage of the filtered sodium that is reabsorbed (25%) in the ascending limb of Henle They also markedly increase calcium and magnesium excretion The potential for profound fluid and electrolyte loss with loop diuretics mandates close monitoring of body fluid volume and serum electrolytes during therapy Increased delivery of sodium to the distal nephron segments has three significant physiologic consequences First, because sodium reabsorption in the thick ascending limb results in a lumenpositive transepithelial voltage that drives passive magnesium and calcium reabsorption, inhibition of sodium reabsorption by loop diuretics diminishes the transepithelial voltage and causes an increase in the urinary excretion of calcium and magnesium Accordingly, long-term use of loop diuretics is associated with hypomagnesemia, hypercalciuria, and calcium-based kidney stones.26–29 Specifically, with furosemide therapy, studies have shown an association with an increased risk of bone fractures.29,30 The second physiologic consequence of increased sodium delivery to the distal nephron segments is enhanced potassium secretion Sodium reabsorption by the principal cell in the collecting duct favors potassium secretion into the tubular fluid and promotes hypokalemia.31 942 S E C T I O N V I I Pediatric Critical Care: Renal Finally, the increased sodium delivery to the distal nephron is associated with acute and chronic adaptive processes that enhance distal sodium reabsorption and diminish diuretic efficacy.32 Loop diuretic–induced ototoxicity is mainly associated with higher-dose IV therapy or with low doses when given with other ototoxic agents and is often reversible upon discontinuation of the agent.33,34 Other adverse effects of these agents include nephrotoxicity, hyperuricemia, hypochloremia, drug fever (likely due to dehydration), and paresthesias Therapeutic Uses Loop diuretics are mainly used in management of edematous states, such as cirrhosis with ascites, nephrotic syndrome, CHF, and iatrogenic volume overload Loop diuretics have also been used in bronchopulmonary dysplasia (BPD) in preterm infants with the potential benefits of decreasing oxygen need or ventilator support, though there is insufficient evidence in improving longterm outcomes.35 Thiazide and Thiazide-like Diuretics Mechanism and Site of Action Thiazides such as chlorothiazide, hydrochlorothiazide, and thiazidelike diuretics (metolazone and chlorthalidone) decrease sodium reabsorption by inhibiting the Na1/Cl2 cotransporter located on the apical membrane in the distal tubule Pharmacokinetics Thiazide diuretics have similar efficacy; the main difference resides in potency and duration of action (Table 77.3) Metolazone and chlorthalidone display a longer duration of effect than chlorothiazide and hydrochlorothiazide However, the biological effect of thiazide agents is prolonged compared with their elimination rates; thus, dosing is usually once or twice a day Effects on Urinary Excretion and Therapeutic Uses Thiazide diuretics are less effective than loop diuretics because less sodium reabsorption occurs in the distal tubule (5%–10%) compared with the ascending limb of Henle Thiazide diuretics have a synergistic effect on fluid and electrolyte excretion when combined with loop diuretics.36,37 Thiazide drugs are relatively ineffective in the setting of renal failure because of the decreased delivery of drug into the tubular fluid and the limited distal tubule sodium reabsorption In contrast to the calcinuric effect of loop diuretics, thiazide diuretics enhance calcium reabsorption and may have a beneficial effect in children with nephrocalcinosis/nephrolithiasis and hypercalciuria Thiazide diuretics similar to loop diuretics are used for treatment of various edematous states (CHF, hepatic cirrhosis, nephrotic syndrome, chronic renal failure) They also remain acceptable first-line options for hypertension management and have been used in children with BPD Adverse Effects Thiazides can cause hyperuricemia, hypokalemia, hyponatremia, and hypercalcemia These agents can also cause hyperlipidemia and can decrease glucose tolerance Potassium-Sparing Diuretics Mechanism and Site of Action The potassium-sparing diuretics are made up of two types that differ in their mechanism of action (1) Renal epithelial sodium channel inhibitors (triamterene and amiloride) decreases sodium reabsorption by blocking the apical membrane sodium channel in the principal cells of the cortical-collecting duct Sodium reabsorption in the cortical-collecting duct results in a transepithelial voltage that favors the secretion of potassium and hydrogen ions (2) Mineralcorticoid receptor antagonists (spironolactone and eplerenone) prevent the binding of aldosterone to a cytosolic receptor, resulting in decreased activity of Na1/K1 adenosine triphosphatase and a decrease in the number of apical sodium channels Effects on Urinary Excretion and Therapeutic Uses Although potassium-sparing diuretics can enhance diuresis, particularly in patients receiving loop or thiazide diuretics, the main clinical benefit of these agents is a reduction in the potassium excretion induced by loop and thiazide diuretics Spironolactone is effective in primary and secondary hyperaldosteronism (e.g., liver disease) and, when given with other diuretics, has potential pulmonary improvement in infants with developing lung disease.38 Adverse Effects Potassium-sparing diuretics are not recommended in patients with renal failure or patients who have an increased risk of developing hyperkalemia Vasopressin Antagonists TABLE Pharmacokinetics of Thiazide and Thiazide-like 77.3 Diuretics Drug Relative Potency Oral Bioavailability (%) Half-Life (h) Chlorothiazide 0.1 9-56 (dose dependent) ,1.5 Hydrochlorothiazide ,70 ,2.5 Chlorthalidone ,65 ,47 10 ,65 8–14 Metolazone Data from Brunton L, Chabner B, Knollman B Goodman and Gilman’s The Pharmacological Basis of Therapeutics 12th ed New York: McGraw Hill Professional; 2010 Mechanism of Action and Therapeutic Uses Vaptans are nonpeptide arginine vasopressin antagonists that inhibit the arginine vasopressin–stimulated absorption of free water in the medullary collecting duct In contrast to other diuretics, the vasopressin antagonists increase urine flow without increasing the renal elimination of sodium Conivaptan and tolvaptan have been used in patients with euvolemic or hypervolemic hyponatremia associated with the inappropriate secretion of antidiuretic hormone or CHF.39 Because the immature kidneys of neonates and infants are resistant to arginine vasopressin, the efficacy of these agents may be less effective compared with older children.40 Adverse Effects Vaptans are mostly tolerated, with common adverse effects such as thirst, dry mouth, hypotension, and injection site phlebitis.41 CHAPTER 77 Renal Pharmacology Diuretic Resistance An inadequate diuretic response results from disease or drugrelated alterations in diuretic pharmacokinetics or pharmacodynamics, high dietary salt intake, or adaptive processes.32 During diuretic-induced extracellular volume depletion, short-term and long-term adaptive processes protect the intravascular volume However, when these adaptive processes interfere with the diuretic responsiveness before the desired reduction in extracellular fluid volume is achieved, they contribute to diuretic resistance Short-term adaptation results from enhanced postdiuretic sodium retention The brisk diuresis associated with diuretics activates counterregulatory pathways that enhance sodium reabsorption and maintain extracellular fluid volume Counterregulatory mechanisms involved in the short-term adaptation to diuretics include a decrease in atrial natriuretic peptide, increased renal sympathetic activity, increased antidiuretic hormone, stimulated renin-angiotensinaldosterone system, and a reduced GFR The balance favors sodium and water excretion when the diuretic concentration in the renal tubular fluid is sufficient to inhibit sodium reabsorption When the concentration of diuretic in the tubular fluid is below the threshold needed to elicit sodium excretion, the balance favors sodium and water reabsorption In patients ingesting a generous amount of salt, which may be either dietary or associated with obligate fluids or medications, postdiuretic sodium reabsorption may compensate entirely for the diuretic-induced sodium losses, resulting in no change in extracellular fluid volume Long-term adaptation occurs after several days of diuretic use and is characterized by a diminished response to each successive dose of diuretic.32 Adaptation occurs because of the persistence of short-term counterregulatory mechanisms as well as functional and structural changes that enhance the sodium reabsorptive capability of the distal tubule.32,42,43 If patient response to moderate doses of a diuretic fails to be adequate, several dosing strategies may help overcome the apparent diuretic resistance, including high-dose diuretic therapy, combination diuretic therapy, or a continuous diuretic infusion In patients with edema, the dose-response curve may be shifted to the right, indicating that a greater amount of drug is needed in the renal tubule to produce the desired diuretic response In patients who have renal failure or patients who receive drugs that inhibit the secretion of diuretic from the blood into the renal tubule, the dose-response curve is normal The problem lies in the inability to get a sufficient concentration of diuretic into the renal tubule In both situations, an intermittent high-dose diuretic regimen may overcome the impaired rate of tubular secretion and increase the urinary diuretic concentration sufficiently to elicit a response High-dose therapy is associated with an increased risk of fluid and electrolyte abnormalities and a risk of toxicity related to high blood concentrations Because sodium reabsorption in the kidney is sequential and many of the adaptive processes increase sodium reabsorption distal to the site of diuretic action, combination therapy—including loop diuretics and diuretics that work on the distal tubule—may be effective Part of the effectiveness of combination diuretic therapy resides in the longer duration of effect for thiazides that prevents the postdiuretic sodium reabsorption noted with the shorter-acting loop diuretics Fluid and electrolyte abnormalities are more common with combination drug therapy The final strategy to overcome diuretic resistance is the use of a continuous infusion loop diuretic Use of continuous infusion avoids the high and low serum concentrations associated with toxicity and resistance Continuous infusions result in a steady 943 diuretic effect and may avoid the rapid hemodynamic changes and stimulation of counterregulatory processes associated with rapid changes in extracellular fluid volume.44,45 Though not routinely done in practice, there is evidence that supports more diuresis when continuous infusion of loop diuretics is preceded by a loading dose.46 Diuretic response may also be further augmented by the addition of a distally acting diuretic Medications for the Prevention/Reversal of Acute Kidney Injury AKI in the ICU can be caused by physiologic changes leading to diminished renal perfusion, such as hypovolemia, hypotension, and decreased cardiac output, or by nephrotoxic medications Common nephrotoxic agents used in the ICU are radiocontrast agents, antibiotics (e.g., vancomycin), antivirals (e.g., IV acyclovir), vasopressors (e.g., epinephrine), and nonsteroidal antiinflammatory drugs (e.g., ketorolac) Patients in the ICU generally have multiple physiologic and medication-derived risk factors for the development of AKI Drug-specific strategies to prevent kidney injury for highly nephrotoxic medications such as IV acyclovir and cidofovir have been studied and found to be effective Acyclovir is an acyclic guanosine derivative used predominantly to treat herpes simplex virus in the ICU It is highly renally cleared and relatively insoluble in the urine, leading to tubular drug crystal formation.47 These crystals cause obstructive nephropathy and are responsible for AKI rates of 10% to 48% in high-dose acyclovir IV regimens.48 It has become common practice to dilute IV acyclovir, slow infusion rates, and use IV fluids and furosemide to maintain adequate urine flow through the kidney as ways to prevent crystal formation and AKI.47,49 Cidofovir is a nucleoside analog of cytosine used in the ICU predominantly for adenovirus and cytomegalovirus infections.50 Cidofovir’s nephrotoxicity is predominantly from direct cytotoxicity of tubular cells after influx by the organic anion transporter (OAT) intracellularly.51 Hyperhydration and probenecid have been shown to ameliorate the risk of nephrotoxicity when administered around cidofovir dosing.51,52 Probenecid is an OAT inhibitor and thus inhibits the influx of cidofovir intracellularly and minimizes direct cytotoxicity.51,52 Many other medications have been studied for the general prevention and treatment of AKI IV fluid therapy has been shown to be consistently effective for the prevention of AKI but not for treatment Little evidence suggests that the general use of mannitol, furosemide, or dopamine prevents the development of AKI in high-risk patients or changes the outcome in patients with established acute renal failure.53,54 Nevertheless, the use of loop diuretics may increase urine output and ease patient care by improving fluid management and permitting increased nutrition.53 For an in depth review of acute renal failure and nephrotoxic medications, see Chapter 77 Key References Alqahtani F, Koulouridis I, Susantitaphong P, Dahal K, Jaber BL A metaanalysis of continuous vs intermittent infusion of loop diuretics in hospitalized patients J Crit Care 2014;29(1):10-17 Ellison DH Clinical pharmacology in diuretic use Clin J Am Soc Nephrol 2019;14(8):1248-1257 Fissell WH Antimicrobial dosing in acute renal replacement Adv Chronic Kidney Dis 2013;20(1):85-93 944 S E C T I O N V I I Pediatric Critical Care: Renal Hoorn EJ, Ellison DH Diuretic resistance Am J Kidney Dis 2017; 69(1):136-142 Matzke GR, Aronoff GR, Atkinson AJ, et al Drug dosing consideration in patients with acute and chronic kidney disease-a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO) Kidney Int 2011;80(11):1122-1137 Pasala S, Carmody JB How to use… serum creatinine, cystatin C and GFR Arch Dis Child Educ Pract Ed 2017;102(1):37-43 Rodieux F, Wilbaux M, Van den Anker JN, Pfister M Effect of kidney function on drug kinetics and dosing in neonates, infants, and children Clin Pharmacokinet 2015;54(12):1183-1204 Veltri MA, Neu AM, Fivush BA, Parekh RS, Furth SL Drug dosing during intermittent hemodialysis and continuous renal replacement therapy: special considerations in pediatric patients Paediatr Drugs 2004;6(1):45-65 Zachwieja K, Korohoda P, Kwinta-rybicka J, et al Modification of the Schwartz equations for children increases their accuracy at eGFR 60 mL/min/1.73 m2 Ren Fail 2016;38(5):787-798 The full reference list for this chapter is available at ExpertConsult.com ... in improving longterm outcomes.35 Thiazide and Thiazide-like Diuretics Mechanism and Site of Action Thiazides such as chlorothiazide, hydrochlorothiazide, and thiazidelike diuretics (metolazone... Pharmacokinetics of Thiazide and Thiazide-like 77.3 Diuretics Drug Relative Potency Oral Bioavailability (%) Half-Life (h) Chlorothiazide 0.1 9-56 (dose dependent) ,1.5 Hydrochlorothiazide ,70 ,2.5... effect of loop diuretics, thiazide diuretics enhance calcium reabsorption and may have a beneficial effect in children with nephrocalcinosis/nephrolithiasis and hypercalciuria Thiazide diuretics similar