Acute Renal Failure

1. Acute Renal Failure Chapter 45

2. Abbreviations ARF: acute renal failure ATN:�acute tubular necrosis BUN:�blood urea nitrogen CKD:�chronic kidney disease CLcr:�creatinine clearance CRRT: continuous�renal replacement therapy CT: computed tomography CVVH: continuous venovenous hemofiltration CVVHD: continuous venovenous�hemodialysis CVVHDF: continuous venovenous hemodiafiltration FENa: fractional excretion of sodium GFR:�glomerular filtration rate IHD: intermittent hemodialysis NSAID:�nonsteroidal antiinflammatory drug QALY: quality-adjusted life-year RRT: renal replacement therapy Scr: serum creatinine

3. Key Concepts Acute renal failure (ARF) is a common complication in hospitalized patients associated with high mortality ARF categorized based on anatomic area of injury or malfunction prerenal intrinsic postrenal 3

4. Key Concepts ARF risk factors advanced age acute infection preexisting chronic respiratory or cardiovascular disease dehydration chronic kidney disease ARF�lacks a specific/sensitive sign to herald onset Prevention is key Supportive management primary approach to preventing/reducing complications 4

5. Acute Renal Failure: Definition Decrease in glomerular filtration rate (GFR) associated with accumulation of waste products, including urea and creatinine relatively abrupt decline in renal function No universally accepted definition Clinicians use some combination of absolute Scr�value, change in Scr�value over time, and/or urine output as primary diagnostic criteria 5

6. Acute Renal Failure: Definition Consensus-derived definition and ARF classification system 3-tiered classification uses GFR�and urine output plus 2�clinical outcomes�that may occur subsequent to an ARF episode RIFLE risk of dysfunction (R) injury to the kidney (I) failure of the kidney (F) loss of function (L) end-stage renal disease (E) 6

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8. ARF Epidemiology Uncommon condition in healthy population annual incidence ~0.02% Incidence as high as 13% in patients with preexisting CKD Hospitalized patients high risk of ARF (incidence 7%) Incidence higher in critically ill patients (6% to 23%) 8

9. Incidence and Outcomes of Acute Renal Failure Relative to Where It Occurs 9

10. Etiology ARF categorized based on anatomic location of injury associated with precipitating factor(s) prerenal: due to decreased renal perfusion in setting of undamaged parenchymal tissue intrinsic: result of structural kidney damage, most commonly tubule�from ischemic or toxic insult postrenal: caused by obstruction of urine flow downstream from the kidney 10

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12. Etiology Community-Acquired Secondary to renal hypoperfusion from volume depletion, heart failure, or medications Hospital- and ICU-Acquired Ischemic or toxic acute tubular necrosis (ATN) 12

13. 13 Pathophysiology

14. Pseudorenal and Functional ARF Pseudorenal ARF rise in either blood urea nitrogen (BUN) or Scr suggests renal dysfunction when GFR�not diminished Functional�ARF decline in�GFR�secondary to reduced glomerular hydrostatic pressure (driving force for ultrafiltrate formation) can occur without damage to the kidney itself may be due to changes in glomerular afferent (vasoconstriction) and efferent (vasodilation) arteriolar circumference 14

15. Prerenal Acute Renal Failure Hypoperfusion of renal�parenchyma + systemic arterial hypotension Concurrent systemic hypotension caused by decline in intravascular or effective blood volume hemorrhage dehydration hypoalbuminemia diuretic therapy No systemic hypotension: possibly due to renal artery occlusion; atherosclerosis is a common cause 15

16. Intrinsic Acute Renal Failure Damage to the kidney itself Categorized by injured structure within the kidney renal vasculature (uncommon) occlusion of renal vessels glomeruli (5%) tubules (85% caused by ATN) interstitium acute interstitial nephritis (AIN) 16

17. Postrenal Acute Renal Failure May result from obstruction at any level in the urinary collection system from the renal�tubule�to urethra if obstructing process above the bladder, it must involve both kidneys or one kidney in a patient with a single functioning kidney to cause significant ARF bladder outlet obstruction neurogenic bladder or anticholinergic medications chemotherapy-induced tumor lysis syndrome 17

18. Diagnosis ARF signs and symptom highly variable, depending on etiology Determine if renal complication is acute, chronic, or result of acute changes in a CKD patient 18

19. Patient Assessment Past medical history to differentiate between acute and chronic renal failure Medication and recent procedure history may suggest causes for acute interstitial nephritis or other nephrotoxic effects Medications diuretics NSAIDs antihypertensives contrast dye other recent additions or changes 19

20. Patient Assessment Patients may have acute change in voiding habits Onset of flank pain ? urinary stone Severe headaches ? severe hypertension as result of�ARF 20

21. Patient Assessment Patients who develop renal insufficiency while hospitalized usually have acute initiating event identified from laboratory data, urine output record, medication administration records, procedure records Acute�anuria: caused by complete urinary obstruction or catastrophic event (shock, acute�cortical necrosis) Oliguria�(urine output < 500 mL/day) develops over several days, suggests prerenal�azotemia Nonoliguria (urine output > 500 mL/day) acute intrinsic renal failure, incomplete urinary obstruction 21

22. Signs and Symptoms Edema Colored or foamy urine Orthostatic hypotension in volume-depleted patients Hypertension in fluid-overloaded patients or presence of acute or chronic hypertensive kidney disease Outpatient:�change in urinary habits, sudden weight gain, flank pain Inpatient:�typically recognized by clinicians before the patient; may not experience obvious symptoms 22

23. Laboratory Tests Elevations in serum potassium, BUN, creatinine, phosphorous, or reduction in calcium and pH (acidosis) Sepsis-associated ARF: increased WBC count ATN: eosinophilia Urine microscopy: cells, casts, crystals help distinguish among possible etiologies and/or ARF severities Elevated urine specific gravity suggests prerenal ARF, as tubules are concentrating urine Urine chemistry protein ? glomerular injury blood ? damage to any kidney structure 23

24. Other Diagnostic Tests Renal ultrasonography or cystoscopy to rule out obstruction Renal biopsy rarely used; reserved for difficult diagnoses 24

25. Clinical Presentation Acute interstitial nephritis patients frequently unable to concentrate urinary solutes Evaluate blood pressure for elevations that may accompany intrinsic renal damage recent infection ? postinfective�glomerulonephritis Physical examination may detect possible postrenal obstruction urinary catheter enlarged prostate in males cervical/uterine abnormalities in females Renal artery stenosis identified via ultrasound 25

26. Laboratory Test Interpretation No consensus on degree and time frame of Scr�changes Abrupt cessation in glomerular filtration will not yield immediate measurable Scr change creatinine generation and accumulation relatively slow lag time�between test and clinical event ? lab tests may not be sensitive to small GFR changes, and fluid retention that commonly accompanies ARF dilutes retained creatinine when decreased filtration of creatinine occurs, functional�tubules�increase secretion of creatinine into urine further complicating Scr interpretation 26

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28. Laboratory Test Interpretation Cockcroft-Gault or Modification of Diet in Renal Disease equations estimate�GFR�in CKD patients not applicable for�ARF�patients with changing Scr�values renal function unstable these equations can overestimate GFR when ARF is worsening and underestimate GFR when ARF is resolving Look at sequence of Scr�values to determine if renal function is improving (values declining) or worsening (values rising) 28

29. Laboratory Test Interpretation Urine output assists in verifying observed serum laboratory values up-to-the-moment means of identifying changes dependent on hydration status, medications Anuria (urine output < 50 mL/day) suggests complete kidney failure Oliguria�(urine output < 17 mL/h) indicates kidney damage with some function is present Nonoliguric ARF (urine output > 17 mL/h) despite reasonable urine output, urine not composed of expected waste products and solutes 29

30. Laboratory Test Interpretation Damaged�tubules�may allow substantial urine production kidney electrolyte, protein, acid�base functions may be severely compromised Urine output alone unreliable marker of kidney function BUN to Scr�ratio normal renal function: < 15:1 prerenal: > 20:1 reabsorption of BUN exceeds that of creatinine 30

31. Laboratory Test Interpretation High urinary specific gravity (in absence of glucosuria or mannitol administration): intact urinary concentrating mechanism ? ARF likely prerenal Proteinuria: glomerular damage Hematuria: acute intrinsic ARF secondary to glomerular or injury to other tissue Crystals: nephrolithiasis and postrenal obstruction WBC or WBC casts: interstitial inflammation 31

32. Laboratory Test Interpretation Measurement of urine and serum electrolytes helpful in ARF� calculate fractional excretion of sodium FeNa = (UNa x Scr x 100)/(Una x SNa) Prerenal azotemia low urinary sodium concentration (< 20 mEq/L) and low fractional excretion of sodium (< 1%) in patient with oliguria� highly concentrated urine (> 500 mOsm/L) suggests stimulation of�antidiuretic hormone�and intact tubular function Tubular damage: inability to concentrate urine results in high fractional excretion of sodium (> 2%) 32

33. Differentiating ARF Causes 33

34. Urine Analysis as Guide to ARF Etiology 34

35. Differential Diagnosis of ARF on Basis of Urine Microscopic Examination Findings 35

36. Novel Biomarkers Allows for significantly earlier diagnosis of AKI 48 hrs before a rise in SCr is observed Serum cystatin C Neutrophil gelatinase-associated lipocalin (NGAL) Kidney injury molecule 1 (KIM-1) Interleukin (IL-18) Liver-type fatty acid binding protein (L-FABP) Beta trace protein (BTP) 36

37. Diagnostic Procedures If urinary catheter insertion into patient's bladder after voiding or attempt to void does not yield > 500 mL of urine ? exclude postrenal obstruction distal to the bladder as ARF cause Renal biopsies used when ARF cause not evident risk of bleeding performed only when definitive diagnosis needed to guide therapy, such as precise etiology of�glomerulonephritis 37

38. 38 Prevention of ARF

39. Desired Outcome Prevention is critical Goals prevent ARF avoid/minimize further renal insults that would worsen existing injury or delay recovery provide supportive measures until kidney function returns 39

40. Desired Outcome Preventative strategies useful in predictable cases decreased perfusion secondary to abdominal surgery coronary bypass surgery acute blood loss in trauma uric acid�nephropathy When patients with ARF�risk factors are scheduled for surgery, clinicians should know the likelihood of the patient developing ARF is high and consider preventative measures discontinue medications that may increase likelihood of renal damage (NSAIDs, ACE inhibitors) 40

41. Prevention Evaluate fluid balance: measure acute changes in weight, blood pressure Educate patient on preventative measures Treatment that can pose a risk for insult to the kidney (e.g., chemotherapy or uric acid�nephropathy) Teach patients about optimal daily fluid intake (~2 L/day) History of nephrolithiasis: dietary restrictions, depending on type of stones in the past Foley catheter: proper care and monitoring to prevent post-obstructive ARF 41

42. Prevention of AKI 42

43. Nonpharmacologic Therapies Contrast-induced nephropathy (CIN) Hydration isotonic saline: 1 mgL/kg/hr for 12 hrs before and 12 hrs after procedure sodium bicarbonate: 154 mEq/L infused at 3 mL/kg/hr for 1 hr before procedure and 1 mL/kg/hr for 6 hrs after procedure Extracorporeal blood purification prophylactic RRT current data does not demonstrate consistent significant benefit 43

44. Nonpharmacologic Therapies Administration, rate, formulation changes in cases when nephrotoxic agent use cannot be avoided Example: amphotericin B to treat fungal infections highly nephrotoxic causes�ARF�in ~30% of patients reduce nephrotoxic potential by slowing infusion rate from 4-hours to a 24-hour infusion of same dose use liposomal forms in patients with�ARF risk factors more expensive lower incidence of kidney damage 44

45. Pharmacologic Therapies Loop diuretics Dopamine Agonists Antioxidants: ascorbic acid and N-acetylcysteine Other therapies: theophylline, erythropoietin alfa (EPO), natriuretic peptides 45

46. Loop Diuretics Early experimental studies proposed theoretical advantages but clinical studies less favorable Increased urine output but lack beneficial effects on patient outcomes Some evidence of potential harm 46

47. Clinical Controversy Loop diuretics are widely used for the management of volume overload in critically ill patients (including those with concomitant AKI) Volume overload is an appropriate indication for loop diuretics, but current evidence does not support their use in prevention of AKI or treatment of oliguria

48. Dopamine Agonists Theoretical benefits: low doses of IV dopamine (=2 mcg/kg/min) should ? renal blood flow and induce natriuresis and diuresis Controlled studies have not supported theories dopamine 2 mcg/kg/min worsened renal perfusion indices compared to saline in a�crossover study�in ARF patients Current evidence does not support use of low-dose dopamine for prevention of AKI 48

49. Clinical Controversy Despite most studies not showing improved patient outcomes with its use, low-dose dopamine is still commonly used Risks associated with dopamine use (extravasation and potential dosing errors) suggest it should be avoided whenever possible Meta-analysis of low-dose dopamine studies from 1966 to 2000 concluded low-dose dopamine does not prevent ARF and its use cannot be justified

50. Antioxidants Ascorbic acid Studied in prevention of CIN Antioxidant properties thought to alleviate oxidative stress caused by CIN-associated ischemia reperfusion injury Studies have not consistently demonstrated benefit Excellent safety profile ? option for high-risk patients 50

51. Antioxidants N-Acetylcysteine Therapeutic benefit not consistently demonstrated Low cost, safety profile, tolerability, and possible benefit make it a reasonable option in high-risk patients Should only be reserved for prevention of CIN and not other types of AKI 51

52. Other Agents Theopyhlline may reduce CIN incidence with efficacy�comparable to N-acetylcysteine inconsistent findings across studies evidence currently inconclusive and more research is needed Erythropoietin alfa (EPO) small prospective randomized trial showed decreased risk of post-op AKI recent double-blind placeb0-controlled trial found no difference need larger clinical trials to demonstrate safety and efficacy 52

53. Other Agents Natriuretic peptides Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) Mediates vasodilation and natriuresis Clinical trials with anaritide and nesiritide relatively inconclusive but lower doses and longer infusion times may reduce risk of post-op AKI 53

54. Glycemic Control Insulin promising for hospital-acquired�ARF�prevention Van den Berghe et al randomized patients in a surgical intensive care unit to receive standard control (< 200 mg/dL) or intensive glucose�control measures (goal blood glucose concentrations of 80 to 110 mg/dL) tight blood glucose significantly improved mortality 41% reduction in ARF development Reduction in ARF may be consequence of total insulin dose used to treat the patient; possible direct protective effect of insulin 54

55. 55 Treatment for ARF

56. Treatment Short-term goals minimize degree of insult to the kidney reduce extrarenal complications expedite renal function recovery Ultimate goal � restore renal function to pre-ARF�baseline Prerenal � hemodynamic support and volume replacement Immune related (interstitial nephritis, glomerulonephritis) � promptly initiate immunosuppressive therapy Postrenal � remove cause of obstruction 56

57. Nonpharmacologic Initial modalities to reverse or minimize�prerenal ARF remove medications associated with diminished renal blood flow physically remove prerenal obstruction Dehydration fluid replacement oral rehydration for moderate volume-depleted patients isotonic�normal saline�IV replacement fluid of choice large volumes may be necessary typically initiated with 250 to 500 mL of normal saline over 15 to 30 minutes with assessment of volume status after each challenge 57

58. Nonpharmacologic Patients with�ARF�on top of preexisting�CKD�should not be expected to produce urine beyond preexisting baseline Anuria�or�oliguria � initiate slower rehydration (250-mL boluses or 100 mL/h infusions of�normal saline) reduces pulmonary�edema risk, especially if heart failure or pulmonary insufficiency exists Consider other replacement fluids if dehydration accompanied by severe electrolyte imbalance 58

59. Nonpharmacologic Blood loss or symptomatic anemia: transfuse RBCs to hematocrit < 30% Albumin�sometimes used as a resuscitative agent limit to individuals with severe hypoalbuminemia resistant to crystalloid therapy 59

60. Nonpharmacologic Intrinsic or post-obstructive ARF � fluid and electrolyte management may become fluid-overloaded due to aggressive fluid resuscitation concentrate drug infusion and nutrition solutions Supportive management 1st line therapy Supportive care goals: maintain adequate cardiac output and BP to allow adequate tissue perfusion 60

61. Indications for Renal Replacement Therapy (AEIOUs) 61

62. Renal Replacement Therapies Administered intermittently or continuously Optimal mode for hemodialysis�unclear varies depending on clinical presentation Choice to use continuous or intermittent RRT usually determined by physician preference, hospital resources 62

63. Intermittent Hemodialysis (IHD) Advantages available in most acute care facilities, most frequently used RRT rapid volume/solute removal and electrolyte abnormality correction usually 3 to 4 hours; blood flow rates to the dialyzer typically range from 200 to 400 mL/min Disadvantages hypotension � typically caused by rapid removal of intravascular volume over a short period of time venous access difficult in hypotensive patients limits IHD effectiveness 63

64. Continuous Renal Replacement Therapies (CRRT) CRRT variants Continuous venovenous hemofiltration (CVVH) Continuous venovenous�hemodialysis�(CVVHD) Continuous venovenous hemodiafiltration (CVVHDF) Variants differ in degree of solute and fluid clearance clinically achieved as result of diffusion,�convection, or combination of both Solute removal slower, but greater amount can be removed over a 24-hour period compared to IHD associated with improved outcomes in critically ill ARF patients 64

65. Continuous Renal Replacement Therapies (CRRT) Continuous venovenous hemofiltration (CVVH) solute and fluid clearance primarily result of�convection� convection � passive diffusion of fluids containing solutes removed while volume absent of solutes replaced to the patient 65

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67. Continuous Renal Replacement Therapies (CRRT) Continuous venovenous hemodialysis (CVVHD) solute removal primarily by diffusion ? solute molecules at higher concentration (plasma) pass through dialysis membrane to lower concentration (dialysate) and some fluid removed as function of ultrafiltration�coefficient of the dialyzer dialysate flows in countercurrent direction to plasma flow on other side of the membrane, maximized concentration gradient associated with lower incidence of clotting than CVVH because of reduced hemoconcentration; less fluid removed 67

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69. Continuous Renal Replacement Therapies (CRRT) Continous venovenous hemodiafiltration (CVVHDF) combines hemofiltration and hemodialysis utilizes convection and diffusion achieves highest solute and fluid removal rates 69

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71. Continuous Renal Replacement Therapies (CRRT) Slow extended daily dialysis (SLEDD) hybrid intermittent dialysis therapy lower blood and dialysate flow rates than IHD gentler means of achieving adequate waste product and fluid removal due to extended duration 71

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73. Clinical Controversy Some clinicians believe CRRTs are preferable to IHD because they provide more consistent fluid and waste product removal Others suggest IHD is preferable because nursing and medical staff more familiar with use and round-the-clock nursing not needed New hybrid approaches with slower removal over prolonged time period may appeal to both groups

74. Anticoagulation in CRRT Thrombosis significant concern with CRRT due to reduced blood flow rates anticoagulation necessary for most patients Typical anticoagulation unfractionated�heparin (UFH) low-molecular-weight heparin (LMWH) direct thrombin inhibitor citrate solution 74

75. Continuous Renal Replacement Therapies (CRRT) Disadvantages not all hospitals have equipment necessary requires intensive nursing care around the clock more expensive than IHD need to individualize IV replacement and�dialysate�fluids drug-dosing requirements not well known for patients receiving these therapies Commonly considered for patients with higher acuity because of intolerance of IHD-associated hypotension 75

76. Continuous Renal Replacement Therapies CRRT and hybrid extended-duration intermittent�hemodialysis�commonly used for critically ill ARF patients CRRT: more solute and water removal than with thrice-weekly hemodialysis treatments used for ESRD patients influenced dialysis prescribing in intensive care hypercatabolic ARF patients Daily IHD associated with improved survival, faster ARF resolution compared to every other day dialysis challenge to clinicians prescribing drugs and nutrition dosing guidelines based on thrice-weekly dialysis 76

77. Pharmacologic Once the kidney is damaged by acute insult, direct initial therapies to prevent further insults to the kidney and minimize extension of the injury If sepsis present, adjust antibiotic therapy for: decreased renal elimination potential increased elimination if agent removed by�hemodialysis To date, no pharmacologic approach proven to reverse decline or accelerate recovery of renal function 77

78. Pharmacologic Thyroxine, dopamine, loop diuretics of no help or worsen outcomes Loop diuretics reserved for fluid-overloaded patients who make adequate urine in response to diuretics Important to prevent pulmonary�edema; preferably with diuretics instead of more invasive RRTs Drugs that produce�diuresis�in ARF patients mannitol� loop diuretics 78

79. Pharmacologic Mannitol (osmotic diuretic) given parenterally typical starting dose mannitol (20%) 12.5 to 25 g IV over 3 to 5 minutes little�nonrenal clearance; when given to anuric or oliguric patients, mannitol remains in the patient, potentially causing hyperosmolar state may cause ARF itself; monitor carefully by measuring urine output, serum electrolytes, osmolality reserved for management of cerebral edema 79

80. Pharmacologic Loop diuretics: furosemide,�bumetanide, torsemide ethacrynic acid�typically reserved for patients allergic to sulfa compounds Furosemide advantages low cost available PO and IV reasonable safety and�efficacy� disadvantage variable oral bioavailability potential ototoxicity with high serum concentrations that may be attained with rapid, high-dose bolus infusions 80

81. Pharmacologic Torsemide and bumetanide have better oral bioavailability than furosemide Torsemide advantage longer duration of activity than other loop diuretics; allows less-frequent administration disadvantage difficult to titrate dose Loop diuretics work equally well in equipotent doses Diuretic resistance common and associated with poor patient outcome 81

82. Diuretic Resistance - Causes Excessive sodium intake overrides ability of diuretics to eliminate sodium ATN: reduced number of functioning nephrons on which the diuretic may exert its action Glomerulonephritis - heavy proteinuria intraluminal loop diuretics cannot exert effect in loop of Henle because extensively bound to urine proteins Reduced bioavailability of PO furosemide because of intestinal�edema; often associated with high preload states, further reducing PO furosemide absorption 82

83. Common Causes of Diuretic Resistance in ARF Patients 83

84. Common Causes of Diuretic Resistance in ARF Patients 84

85. Diuretic Resistance Administer loop diuretics via continuous infusion to overcome resistance less natriuresis occurs when equal doses given as bolus rather than continuous infusion adverse reactions from loop diuretics (myalgia, hearing loss) less frequent with continuous infusion Patients with low creatinine clearance may have lower rates of diuretic secretion into tubular fluid; higher doses generally used in patients with renal insufficiency 85

86. Diuretic Resistance Alternative treatment: combination therapy of loop diuretic and a diuretic from a different class Several drug combinations with loop diuretics have been investigated theophylline acetazolamide spironolactone thiazides metolazone 86

87. Diuretic Resistance Of these combinations, oral metolazone used most frequently with�furosemide Metolazone (unlike other thiazides) produces effective�diuresis�at GFR�< 20 mL/min Used successfully in management of fluid overload in patients with heart failure cirrhosis nephrotic syndrome 87

88. Diuretic Resistance Despite lack of supporting evidence, oral metolazone 5 mg commonly administered 30 minutes prior to an IV loop diuretic to allow time for absorption Combination of�mannitol�and IV loop diuretics used by some practitioners no convincing evidence of superiority of this combination to conventional dosing of either diuretic alone 88

89. Electrolyte Management Hypernatremia, fluid retention frequent ARF complications restrict sodium to < 3 g/day from all sources Excessive sodium intake common reason for diuretic therapy failure Commonly administered IV antibiotics and other medications contain significant amounts of sodium 89

90. Electrolyte Management Hyperkalemia most common electrolyte disorder in�ARF�patients > 90% of potassium renally eliminated Life-threatening cardiac arrhythmias may occur when serum potassium > 6 mmol/L Potassium restriction is essential Monitor serum potassium at least daily; twice daily for seriously ill patients Some medications promote potassium retention by kidneys and should be avoided or closely monitored 90

91. Electrolyte Management Phosphorous and magnesium also require monitoring eliminated by kidneys not removed efficiently by dialysis 91

92. Electrolyte Management Hyperphosphatemia treatment CRRT avoid calcium-containing antacids to prevent calcium phosphate precipitation in soft tissues restrict dietary phosphorous and magnesium Calcium balance usually not an issue in ARF exception: patients receiving CRRT with citrate as anticoagulant citrate binds serum calcium; without adequate calcium, blood cannot clot 92

93. Drug-Dosing Considerations Variables influencing drug response residual drug clearance accumulation of fluids can alter volume of distribution CRRT or IHD can increase drug clearance and impact fluid status Monitor serum drug concentration and pharmacodynamic responses renally eliminated drugs (> 30% excreted unchanged in urine) agents with narrow therapeutic range 93

94. Drug-Dosing Considerations If hepatic function intact, may prefer agent eliminated primarily by the liver Edema common in�ARF significantly increases volume of distribution of many drugs (especially water-soluble ones with relatively small volumes of distribution) increased fluid distribution into tissues (i.e., sepsis, anasarca in heart failure); larger�volume of distribution�for many drugs 94

95. Drug-Dosing Considerations Reductions in�cardiac output,�liver function, and volume overload alter pharmacokinetics of many drugs vancomycin aminoglycosides low-molecular-weight heparins Loading dose�may be necessary to promptly achieve desired serum concentrations expanded�volume of distribution�and prolonged elimination�half-life�extend time (3.5 times the half-life) until steady-state concentrations achieved reassess maintenance dosing regimens frequently 95

96. Clinical Controversy In volume-depleted patient requiring renally eliminated medication, dosing regimens based on initial Scr�prior to fluid therapy may underestimate renal function and drug elimination leading to subtherapeutic serum concentrations Although not standard practice, an initial 24-hour dosing regimen with a bolus might be optimal for many patients

97. Drug-Dosing Considerations ARF patients may have higher residual�nonrenal clearance�than�CKD�patients with similar CLcr reported with ceftriaxone, imipenem, vancomycin Alterations in the activity of some CYP450 enzymes have been demonstrated in patients with CKD Higher nonrenal clearance in ARF patients than anticipated based on data from CKD patients could result in subtherapeutic serum concentrations As ARF persists, nonrenal clearance approaches those observed in CKD patients 97

98. Clinical Controversy Some clinicians use a standard ESRD dosage regimen despite the fact that renal function can fluctuate Others believe that the patient�s clinical need for the drug and any other change in the volume of distribution or RRT therapy should be considered if one has any chance of achieving the target serum concentration

99. CRRT Individualization of therapy for patients receiving CRRT dependent on residual renal function drug clearance by mode of CRRT patient is receiving Factors that influence drug clearance during CRRT ultrafiltration�rate blood flow rate dialysate�flow rate Type of RRT used changes drug dosing 99

100. CRRT CRRT rapidly removes excess fluid from edematous patients changes volume of distribution�(VD) of drugs with limited distribution (low�VD�suggesting greater�proportion�in plasma or extracellular fluid) fairly rapidly Drug clearances attained by IHD, CRRTs, hybrid RRTs all differ from each other Algorithmic approach for drug dosage adjustment in patients undergoing CRRT proposed Seiving coefficients used to design initial dosage regimens for patients receiving CVVH 100

101. Intermittent Hemodialysis IHD-based dosing chart limitations variability in patients' individual pharmacokinetic�parameters differences in dialysis prescription dialyzer blood flow duration use of new IHD dialyzers Approach to�hemodialysis�may change daily, especially unstable ARF patients 101

102. Evaluation of Outcomes Vigilant monitoring essential, particularly ARF patients who are critically ill Once laboratory-based tests (e.g.,�urinalysis, fractional excretion of sodium calculations) are conducted to diagnose ARF cause, they usually do not have to be repeated Perform daily measurements of urine output, fluid intake, weight Perform therapeutic drug monitoring for drugs with narrow therapeutic window 102

103. Evaluation of Outcomes Measuring serum drug concentration prior to�hemodialysis�has advantage of allowing time for result to be reported and redosing shortly after dialysis Serum concentrations drawn after hemodialysis may reflect transiently depressed plasma concentrations until drug can reequilibrate from tissues (plasma rebound effect) After-dialysis level advantage is greater�accuracy�in determining how much drug was cleared during hemodialysis; may delay reestablishing target effects 103

104. Key Monitoring Parameters 104

105. Key Monitoring Parameters 105

106. Acknowledgements Prepared By: Amy Pai, Pharm.D., BCPS Series Editor: April Casselman, Pharm.D., CGP, BPCS Editor-in-Chief: Robert L. Talbert, Pharm.D., FCCP, BCPS, FAHA Chapter Authors: William Dager, PharmD, FCSHP Anne Spencer, Pharm.D. Section Editor: Gary R. Matzke, Pharm.D., FCP, FCCP, FASN