Nephrology PRN Focus Session AKI in the ICU: The Roles of Medication and CRRT Activity No L01-P (Knowledge-Based Activity)

Transcription

1 Nephrology PRN Focus Session AKI in the ICU: The Roles of Medication and CRRT Activity No L01-P (Knowledge-Based Activity) Tuesday, October 18 1:30 p.m. 4:30 p.m. Convention Center: Rooms 319 & 320 Moderator: Thomas D. Nolin, Pharm.D., Ph.D. Assistant Professor, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania Agenda 1:30 p.m. AKI: What Is It? John A. Kellum, M.D., FACP, FCCM Professor, Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 2:15 p.m. Options and Evidence for RRT in AKI Paul M. Palevsky, M.D. Chief, Renal Section, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania; Professor of Medicine, Renal- Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 3:00 p.m. Drug-Induced AKI in the ICU Joseph F. Dasta, R.Ph., M.S., FCCP Professor Emeritus, The Ohio State University College of Pharmacy; Adjunct Professor, The University of Texas College of Pharmacy, Austin, Texas 3:45 p.m. Pharmacokinetic and Drug Dosing Considerations During RRT Mariann D. Churchwell, Pharm.D., BCPS Assistant Professor, University of Toledo College of Pharmacy, Toledo, Ohio Faculty Conflict of Interest Disclosures Mariann D. Churchwell: no conflicts to disclose. Joseph F. Dasta: consultant/member of advisory board for Cadence Pharmaceuticals, Hospira, Pacira Pharmaceuticals, Otsuka America Pharmaceuticals, Edge Therapeutics; speaker s bureau for Cadence Pharmaceuticals. John A. Kellum: no conflicts to disclose. Paul M. Palevsky: consultant/member of advisory board for sanofi-aventis, CytoPheryx; received grant funding/research support from Spectral Diagnostics, Inc. Annual Meeting

2 Learning Objectives 1. Define acute kidney injury (AKI). 2. Discuss contemporary AKI diagnostic criteria. 3. Describe mechanism of an risk factors for AKI in the ICU. 4. Describe the most commonly used RRT modalities. 5. Discuss the evidence supporting use of various RRT modalities. 6. Identify drugs commonly implicated in the development of AKI. 7. Describe the major mechanisms of drug-induced AKI. 8. Dsicuss strategies used to minimize drug-induced AKI. 9. Discuss the pharmacokinetic alterations observed in patients with AKI. 10. Identify important drug-related determinants of removal by RRT. 11. Describe CRRT-specific properites that influence drug removal. Self-Assessment Questions Self-assessment questions are available online at Annual Meeting

3 Options and Evidence for Renal Replacement Therapy in Acute Kidney Injury Paul M. Palevsky, M.D. Chief Renal Section VA Pittsburgh Healthcare System Professor of Medicine University of Pittsburgh School of Medicine

4 Conflicts of Interest Medical Advisory Board: CytoPherx, Inc. Consultant: Sanofi-Aventis Research Support: Spectral Diagnostics, Inc.

5 Learning Objectives Describe the most commonly used RRT modalities. Discuss the evidence supporting use of Discuss the evidence supporting use of various RRT modalities.

6 Differences Between Renal Support in AKI and ESRD Time-frame days to weeks versus years Burden of concomitant illness Hemodynamic instability Recoverability of kidney function

7 Renal Replacement Therapy in Acute Kidney Injury What modalities can we use? When should RRT be initiated? How should RRT be dosed?

8 Renal Replacement Therapy in Acute Kidney Injury What modalities can we use? When should RRT be initiated? How should RRT be dosed?

9 Modalities of RRT Intermittent hemodialysis Continuous therapies Continuous hemofiltration Continuous hemodialysis Continuous hemodiafiltration ti Hybrid therapies Peritoneal dialysis

10 Continuous Renal Replacement Therapy Arteriovenous Therapies technical simplicity require large-bore arterial catheter blood flow dependent on MAP Venovenous Therapies no arterial line pump-assisted blood flow independent of blood pressure

11 CRRT Nomenclature Slow Continuous Ultrafiltration (SCUF) volume control; minimal solute clearance Continuous Hemofiltration ti (CH) convective solute removal Continuous Hemodialysis (CHD) diffusive solute removal Continuous Hemodiafiltration (CHDF) convective and diffusive solute removal

12 CRRT: Slow Continuous Ultrafiltration ti Q E = Q UF = Q Neg Q E

13 CRRT: Continuous Hemofiltration ti Q R Q E Q E = Q UF Q Neg = Q E -Q R

14 CRRT: Continuous Hemodialysis i Q D Q E Q Neg = Q UF = Q E -Q D

15 CRRT: Continuous Hemodiafiltration ti Q R Q D Q UF = Q E -Q D Q E Q Neg = Q E (Q D +Q R )

16 Convection vs. Diffusion i Ultrafiltrate Blood Flow Convection Diffusion Dialysate small molecular wt substances (< 1 kd) large molecular wt substances (5-50 kd)

17 Convection vs. Diffusion i Cle earance Diffusive Clearance Convective Clearance ,000 10,000 Molecular Weight

18 CVVHD Solute Clearance: Dialysate Flow Brunet et al: Am J Kidney Dis 1999; 34:

19 Convective Solute Clearance Troyanov S, et al: Nephrol Dial Trans 2003; 18:

20 Continuous Hemofiltration Pre-Dilution vs. Post-Dilution ti Pre-Dilution Q R Q E Post-Dilution ti Q R Q E

21 Continuous Hemofiltration Pre-Dilution vs. Post-Dilution ti Pre-Dilution Decreases filtration fraction Diminishes solute clearance by diluting blood reaching hemofilter Q B C B = C B x QB + Q R Post-Dilution No effect on filtration fraction Solute concentration within hemofilter unchanged from systemic concentration

22 Solute Clearance in CVVH Pre-Dilution vs. Post-Dilution ti Brunet et al: Am J Kidney Dis 1999; 34:

23 Solute Clearance in CVVH and CVVHDF With Pre-Dilution Fluids Troyanov S, et al: Nephrol Dial Trans 2003; 18:

24 ATN Study: Observational Cohort 100% 80% IHD CRRT Treatm ments 60% 40% 20% 0% Cardiovascular SOFA Score

25 CRRT vs. IHD in Acute Kidney Injury: Hemodiafe Study IHD CVVHDF (n=184) (n=175) Vasopressors 86% 89% Mechanical Ventilation 95% 98% Sepsis 69% 56%* SAPS II Crossovers 6 31 Duration of RRT (days) day survival 31.5% 32.6% # *p=0.01; # p=0.98 Vinsonneau C,, et al: Lancet 2006; 368:

26 CRRT vs. IHD in Acute Kidney Injury: Hemodiafe Study Vinsonneau C,, et al: Lancet 2006; 368:

27 Meta-analysis of Studies Comparing IHD to CRRT Bagshaw SM, et al. Crit Care Med 2008; 36:

28 CRRT vs. IHD in AKI: Recovery of Renal Function CRRT IHD Mehta, et al Manns, et al. Jacka, et al. N survived recovered N survived recovered Total %* 57.9%* *percentage of survivors Mehta R, et al: Kidney Int 2001; 60: Manns B, et al. Crit Care Med 2003; 31: Jacka MJ, et al. Can J Anesth 2005; 52:

29 CRRT vs. IHD in AKI: Recovery of Renal Function Mehta, et al Manns, et al. Jacka, et al. CRRT N survived recovered death or dialysis IHD N survived recovered death or dialysis Total %* 74.9%** 57.9%* 69.1%** *percentage of survivors **percentage of all patients Mehta R, et al: Kidney Int 2001; 60: Manns B, et al. Crit Care Med 2003; 31: Jacka MJ, et al. Can J Anesth 2005; 52:

30 Comparison of Fluid Removal with IHD vs CRRT Bouchard J, et al. Kidney Int 2009; 76:

31 Hybrid Therapies Extended Daily Dialysis (EDD) Sustained low-efficiency dialysis (SLED) Sustained low-efficiency daily diafiltration (SLEDD-f) The Genius system

32 Sustained Low-Efficiency Dialysis Comparision of Hemodynamic Parameters with CVVH Kielstein JT, et al. Am J Kidney Dis 2004; 43:

33 SLEDD-f versus CVVHDF Survival CVVHDF (n=30) SLEDD-f (n=30) P-value ICU discharge or day (70.0%) 26 (86.6%) 0.21 ICU discharge 20 (66.7%) 25 (83.3%) 3%) Hospital discharge 19 (63.3%) 25 (83.3%) 0.14 Recovery of kidney function All patients 18 (60.0%) 24 (80.0%) 0.16 Hospital survivors 16 (84.2%) 23 (92.0% 0.64 Abe M, et al. Artificial Organs 2010; 34:

34 SLEDD-f versus CVVHDF Abe M, et al. Artificial Organs 2010; 34:

35 Peritoneal Dialysis vs CVVH in AKI Phu NH, et al: N Engl J Med 2002; 347:

36 High-Volume PD vs Daily IHD in AKI Weekly Kt/V HVPD: 3.6±0.6 DHD: 4.7±0.6 Gabriel DP, et al. Kidney Int 2008; 73:S87-S93

37 High-Volume PD vs Daily IHD in AKI Gabriel DP, et al. Kidney Int 2008; 73:S87-S93

38 Renal Replacement Therapy in Acute Kidney Injury What modalities can we use? When should RRT be initiated? How should RRT be dosed?

39 Timing of Renal Replacement Therapy in AKI While there is increasing recognition of the value of earlier dialysis, the published consensus, and the practice in many centers at present, is still to apply dialysis to relatively ill rather than to relatively healthy patients -Teschan PE, et al: Ann Intern Med 1960; 53:

40 Indications for Renal Support in Acute Kidney Injury Volume overload Metabolic acidosis Hyperkalemia Uremic state encephalopathy pericarditis Azotemia without uremic manifestations Oliguria

41 Timing of CVVH in Post-Traumatic AKI 60% 50% 39 % Surv vival 40% 30% 20% 10% 0% 20 % BUN < 60 mg/dl BUN > 60 mg/dl (Mean: 42.6±12.9).9) (Mean: 94.5±28.3) n=41 n=59 Gettings LG, et al: Intensive Care Med 1999; 25:

42 Timing of CVVH in Post-Cardiac Surgery AKI 60% Elahi Demirkilic 55.5% 50% 43% Mortality 40% 30% 20% 10% 0% 22% 23.5% n=36 n=34 n=28 n=27 Early UOP < 100 ml for 8 hours BUN 84 mg/dl, Cr >2.8 mg/dl, or Potassium > 6 meq/l Late Cr >5.0 mg/dl, or Potassium > 5.5 meq/l Elahi MM, et al: Eur J Cardiothorac Surg 2004; 26: Demirkilic U, et al: J Card Surg 2004; 19: 17-20

43 Timing of RRT in AKI: PICARD Study Data BUN 76 mg/dl (n=122) BUN>76 mg/dl (n=121) Mean BUN 47.4 mg/dl mg/dl p< Mean Creatinine 3.4 mg/dl 4.7 mg/dl p< Failed Organ Systems 4 (IQR: 3-4) 3 (IQR: 2-4) p=0.008 Sepsis 37% 46% p=0.14 Initial RRT with CRRT 69% 43% p<0.001 Survival day 14 day 28 80% 65% 75% 59% p=0.09 Adjusted mortality risk adjusted for covariates 1.85 (95% CI: ) adjusted for propensity score 2.07 (95% CI: ) adjusted for both covariates and propensity 1.97 (95% CI: ) 20) Liu K et al. Clin J Am Soc Nephrol 2006; 1:

44 Timing i of RRT in AKI Patients with Early AKI Early RRT Late RRT Recover without RRT Die without RRT

45 Timing and Dose of CVVH in AKI ay Surviv val 28-D 100% 80% 60% 40% 20% 0% 74.3% 68.8% 75.0% n=35 n=35 n=36 SOFA SOFA SOFA 10.3± ±2.21± ±1.9 EHV ELV LLV Treatment Group Bouman CS, et al. Critical Care Med 2002; 30:

46 Sequelae of Fluid Overload Prowle JR, et al. Nat Rev Nephrol 2010; 6:

47 PICARD Study: Impact of Fluid Overload at Initiation of RRT Bouchard J, et al. Kidney Int 2009; 76:

48 Fluid Balance, Initiation of RRT and Mortality Underlying Disease Volume Overload Mortality

49 Fluid Balance, Initiation of RRT and Mortality Underlying Disease Volume Overload? Mortality

50 Renal Replacement Therapy in Acute Kidney Injury What modalities can we use? When should RRT be initiated? How should RRT be dosed?

51 What is Dose? Clearance of small solutes Urea Clearance of larger ( middle molecular weight) solutes Cytokines Time Volume management

52 Dosing Intermittent t Hemodialysis i Solute clearance per hemodialysis session Kt/V urea URR Frequency of hemodialysis sessions

53 Hemodialysis in AKI Dose of Dialysis i Paganini EP, et al: Am J Kidney Dis 1996; 28 (suppl 3):S81-S89

54 Frequency of Hemodialysis in Acute Kidney Injury Outcomes Alternate-Day Hemodialysis Daily Hemodialysis P value Mortality 46% 28% 0.01 Duration of ARF (days) 16±6 9± Schiffl H, et al. N Engl J Med 2002; 346:

55 Frequency of Hemodialysis in Acute Kidney Injury Characteristics of Dialysis Sessions Alternate-Day Hemodialysis Daily Hemodialysis Duration (hrs) 3.4± ±0.4 BFR (ml/min) 243±25 248±45 Dose (Kt/V) Prescribed Delivered Weekly 1.21± ± ±06 3.0± ± ± ±04 5.8±0.4 Schiffl H, et al. N Engl J Med 2002; 346:

56 Frequency of Hemodialysis in Acute Kidney Injury Comparison of Groups During Therapy Alternate-Day Hemodialysis Daily Hemodialysis Mean time-averaged BUN 104±18 mg/dl 60±20 mg/dl Mean UF per session 3.5±0.3 L 1.2±0.5 L % of sessions with hypotension 25±5% 5±2% SIRS/sepsis 46% 22% Respiratory failure 65% 35% GI bleeding 36% 15% Change in mental status 69% 38% Schiffl H, et al. N Engl J Med 2002; 346:

57 Dose of CRRT For most small solutes, concentration in ultrafiltrate approximates that of plasma water Since dialysate flow << blood flow, equilibration between plasma and dialysate is nearly complete The concentration of small solutes in the effluent is therefore close to that of plasma water Solute clearance therefore approximates effluent flow rate

58 Dose of CRRT As a convention, dose of CRRT is commonly normalized to body weight and expressed as ml/kg per hour If we assume that V D is 0.6 L/kg Dose (ml/kg gp per hour) Kt/V urea

59 Dose of CVVH in ARF Survival 100% 80% 60% 40% 20% 41% * p < v. 20 ml/kg/hr * * 57% 58% 0% 20 ml/kg/hr 35 ml/kg/hr 45 ml/kg/hr Ultrafiltration Rate Ronco C, et al: Lancet 2000; 356:26-30

60 Renal Replacement Therapy in AKI: Dose of CRRT Surv vival (%) CVVHDF* Q UF :24±6 ml/kg/hr Q D : 18±5 ml/kg/hr CVVH Q UF : 25±5 ml/kg/hr Survival time (days) *Adjusted HR: 0.59 ( ); p=0.008 Saudan P, et al. Kidney Int 2006; 70:

61 Timing and Dose of CVVH in AKI ay Surviv val 28-D 100% 80% 60% 40% 20% 0% 74.3% 68.8% 75.0% n=35 n=35 n=36 SOFA SOFA SOFA 10.3± ±2.21± ±1.9 EHV ELV LLV Treatment Group Bouman CS, et al. Critical Care Med 2002; 30:

62 Renal Replacement Therapy in AKI: Dose of CVVHDF 20 ml/kg per hour 35 ml/kg per hour Tolwani, A, et al. J Am Soc Nephrol 2008

63 RENAL Replacement Therapy Study: 90-Day Survival Bellomo R, et al. N Engl J Med 2009; 361:

64 RENAL Replacement Therapy Study: 90-Day Survival Subgroup Analysis Bellomo R, et al. N Engl J Med 2009; 361:

65 Hanover Dialysis i Outcome Study Treatment protocol Initial day: Target BUN : SED (n=75) 1 ED mg/dl IED (n=81) 2 ED <42 mg/dl P-value Treatments provided 7.7±8.17±8 13.3±10.23±10 < BUN at 48 hours 53.5±19.0 mg/dl Mortality Day 14 Day 28 Dialysis independence at day % 38.7% 31.9±11.5 mg/dl 29.6% 44.4% < /46 (63%) 27/45 (60%) 0.77 Faulhaber-Walter R, et al. Nephrol Dial Transplant 2009; 24:

66 VA/NIH Acute Renal Failure Trial Network (ATN) Study Hemodynamically Stable Patients Intensive Management Strategy Less-Intensive IHD* 6x/week 3x/week Hemodynamically Unstable Patients CVVHDF 35 ml/kg/hr 20 ml/kg/hr SLED* 6x/week 3x/week *target Kt/V: per treatment Palevsky PM, et al. N Engl J Med 2008; 359:7-20

67 VA/NIH Acute Renal Failure Trial Network (ATN) Study Odds Ratio: % CI: P=0.47 Intensive 53.6% Less-Intensive 51.5% Palevsky PM, et al. N Engl J Med 2008; 359:7-20

68 VA/NIH ATN Study: Subgroup Analysis of Mortality Palevsky PM, et al. N Engl J Med 2008; 359:7-20

69 VA/NIH ATN Study: Survival & Dialysis-Independence i d Survival, Intensive therapy Survival, Less-Intensive therapy Alive and dialysis independent, Intensive therapy Alive and dialysis independent, Less-intensive therapy survival Probabi ility 48.5% 46.4% 36.8% 34.6% dialysis-independence Time Since Randomization (Days)

70 RRT Dose and Survival Survival Dose Dependent Dose Independent RRT Dose

71 Drug-Induced Acute Kidney Injury (AKI) in the ICU Joseph F. Dasta, M.Sc., FCCM, FCCP Professor Emeritus The Ohio State University Adjunct Professor University of Texas

72 Confessions of a renal wanabee Not a card carrying renal expert I know a bunch of experts Looking through h the lens of an ICU person Focus on AKI in critically ill patients Every part of kidney function can be adversely affected by drugs Situation is made worse by critical illness I confess have to discuss costs of AKI

73 Epidemiology of drug-induced AKI Nephrotoxicity from drugs contributes to 8-60% of cases of in-hospital AKI In the ICU 104 patients with biopsy-documented acute-on- chronic kidney injury, had drug-related nephrotoxicity in 35% of cases Antibiotic-induced AKI, up to 36% of hospital cases Variable % due to variable definitions Crit Care Med 2010;38:S169

74 Use of nephrotoxic drugs in the ICU Reviewed the top 100 drugs at one hospital in 2004 ordered in the ICU Each drug was evaluated for nephrotoxic potential from Micromedex A total t of 41/182 (22.5%) drug or drug combinations were potentially nephrotoxic Crit Care Clin 2006;22:357

75 Use of nephrotoxic drugs in the ICU DRUG Acetaminophen 2751 Furosemide 2085 Aspirin 1935 Vancomycin 1890 Piperacillin/tazobactam 1258 Cefazolin 1083 Dopamine 512 # TIMES ORDERED Crit Care Clin 2006;22:357

76 Costs of drug-induced AKI Very few studies 2008 mean costs attributable to AKI $95,612 $56,095 $43,022 (survivors) $36,200 $3,300 uncomplicated AKI Not receiving ICU care and not requiring MV Different definitions of AKI and costs Management of acute kidney problems. Springer Publications, 2009 pp75-80

77 AKI cost in CABG patients 3741 CABG admissions AKI in 6.9% Total postoperative costs $37,674 in AKI patients $18,463 in matched control Costs by RIFLE score RIFLE-R $29,697 (1.6) RIFLE-I $38,924 (2.1) RIFLE-F F $52,618 (2.9) Nephrol Dial Transplan 2008;23:1970

78 KI 707 patients treated with non-lipid amphotericin from % developed acute AKI Mean increased LOS 8.2 days Adjusted additional costs averaged $29,823/patient Lipid-based product Lower incidence hence assumed lower cost Clin Infect Dis 2001;32:686

79 Shock and awe: Nesiritide-induced nephrotoxicity Nesiritide associated worsening renal function (SCr> 0.5 mg/dl) from meta-analysis of 1369 pts from 5 randomized trials (Sackner-Bernstein) 15% incidence in controls, 21% incidence in nesiritide patients Adjusted RR 1.54 ( ) Brought nesiritide to its knees As an aside J&J's Scios pleads guilty, pay $85M in Natrecor misbranding case (Sept 15, 2011) Circulation 2004;111:1487

80 Where did the nesiritide-induced nephrotoxicity i go? ASCEND-HF study July 7, 2011 NEJM 7141 hospitalized for AHF randomized to nesiritide or placebo plus standard of care Improved dyspnea but more hypotension with nesiritide No other benefit and no other ADE s Worsening renal function (>25% decrease ease in GFR) 31.4% vs. 29.5% (p=0.11) Study design, large sample size, other? New Engl J Med 2011;365:32

81 Risk factors for drug-induced AKI in ICU patients Long list of chronic diseases and risk factors Acute risk factors Sepsis/infection Low intravascular volume (from disease or drug) Hypotension (drug and disease induced) Acute decompensated heart failure Major surgery Trauma Mechanical ventilation (PEEP) Altered pharmacokinetics of nephrotoxins Kid Internat 2010; Dec. 1 (ahead of print) Pharmacotherapy: A pathophysiologic approach. Appleton & Lang, Eighth edition pp

82 Nephrotoxic drugs used in patients with acute and chronic risk factors An overview Sepsis Multiple organ failure Accounts for up to 50% of AKI in the ICU Systemic vasodilation and renal vasoconstriction Renal hypoperfusion Enhance toxicity of nephrotoxic drugs, i.e., aminoglycosides, amphotericin, NSAIDS Either underuse of over use of vasopressors Management of acute kidney problems. Springer Publications, 2009 pp

83 Acute heart failure Reduced kidney perfusion (pre-renal) renal) Cardio-renal syndrome Increased risk for NSAIDS, vasopressors, diuretics, radiocontrast agents Commonly used drugs in AHF Occurs in late sepsis Crit Care Med 2010;38:S169-74

84 Liver disease Systemic vasodilation and renal vasoconstriction Sepsis can cause shock liver NSAIDS Hydroxyethyl starch (less with low MW) IVIG(sucrose stabilizer) Radiocontrast dyes Crit Care Med 2010;38:S169-74

85 Pharmacokinetic changes in critical illness Disease states and associated treatments with mechanical ventilator, RRT Alterations in absorption, distribution, renal and hepatic clearance Renal failure reducing hepatic metabolism Predisposes nephrotoxic drugs to enhanced nephrotoxicity CPOE, CDS, and PharmD (live) can help Curr Opin Crit Care 2005;11:555

86 Easiest to Classify Based on Location 1. Pre-Renal or Impaired perfusion to kidneys 2. Glomerular Injury 4. Obstructive Injury 3. Tubular Injury

87 Hemodynamic mediated FIGURE 31-2 Drugs that alter renal hemodynamics by causing afferent arteriole vasoconstriction or efferent arteriole vasodilation. ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; CCBs, calcium channel blockers; COX-2, cyclooxygenase-2; NSAIDs, nonsteroidal anti-inflammatory drugs.

88 NSAIDS Parenteral NSAIDS (ketorolac, ibuprofen,?diclofenac) Also cause interstitial nephritis Can occur after a few days of therapy Particularly in high-risk patients Occurs in both COX-1 and COX-2 drugs In high-risk patients Consider using other drugs for fever and pain like a multimodal approach with acetaminophen, and/or local anesthetics ti for surgical patients, t and low-dose opioids id If NSAIDS are necessary, use lowest dose and shortest duration Crit Care Med 2010;38:S169-74

89 Easiest to Classify Based on Location 1. Pre-Renal or Impaired perfusion to kidneys 2. Glomerular Injury 4. Obstructive Injury 3. Tubular Injury

90 ATN by commonly used ICU drugs Aminoglycosides Amphotericin-B Radiocontrast t dyes Hydroxyethyl starch IVIG osmotic nephropathy by sucrose stabilizers Sulfa, ciprofloxacin - crystal-induced tubular injury

91 Drug-induced AIN accounts for 3-15% of all drug-induced AKI Hypersensitivity y reaction affecting tubules and interstitium Many drugs cause this but the most common include: antibiotics (beta-lactams, quinolones, sulfa-based), NSAIDS, PPI s, allopurinol Often self limiting once drug (s) discontinued, and recovery can take a few weeks or months Management of acute kidney problems. Springer Publications, 2009 pp

92 Specific examples I knew I could weave in ICU sedation into a kidney talk No-sedation sedation and renal risk Our old friend renal contrast dye Our even older friend the aminoglycosides

93 Analgesic-first sedation RCT of no sedation (analgesic-based) vs. sedative-hypnotic based revealed less time on the ventilator and shorter LOS in ICU and hospital Hypothesis: since no sedation group had improved hemodynamic stability, less vasopressors, less extra fluids, renal function could be improved Also 4.2 fewer MV d and 9.7 d shorter ICU LOS Lancet 2010;375:475

94 Analgesic-first sedation post hoc analysis Subset analysis of 103 patients from this RCT was performed Over the first 14 days, intervention group had a higher urine output (1.15 vs ml/kg/hr; p=.03) and fewer patients with renal impairment by RIFLE criteria (51% vs. 76%, p=.012) No difference in blood pressure or need for vasopressors seen Interesting hypothesis-generating study Crit Care 2011;15:R119

95 Aminoglycoside Nephrotoxicity Commonly used agents in ICU patients In-hospital incidence of AKI 10-25% ICU patients up to 58% Differences in AKI definitions, risk factors, and agent used Recent study of risk factors in SICU patients 11.5% developed nephrotoxicity (51% received concurrent nephrotoxins) Only vasopressors and vancomycin were independent predictors of nephrotoxicity OR 19.9 and 49.8, respectively Inter J Crit Ill Inj Sci 2011;1:17

96 Aminoglycoside Nephrotoxicity Typically seen in 5-10 days; often non-oliguric oliguric Gradual yet persistent decrease in CrCl Full recovery if drug is immediately discontinued Prevention strategies Use other antimicrobials in high-risk patients Avoid volume depletion, limit total dose, minimize concurrent nephrotoxins Use PK monitoring and extended interval dosing may not be optimal in all ICU patients Pharmacotherapy: A pathophysiologic approach. Appleton & Lang, Eighth edition pp

97 Contrast-induced AKI 3 rd leading cause of AKI in hospitalized patients Incidence can be as high as 50% in patients with multiple risk factors Usually self limited but up to 15% may require dialysis Increase in SCr of 0.5 mg/dl or a 25% increase in SCr at 48 hours Renal vasoconstriction and direct cellular toxicity Ideal therapy work on both mechanisms Circulation Dec 7;122(23):2451-5; Pharmacotherapy: A pathophysiologic approach. Appleton & Lang, Eighth edition pp

98 Risk factors CCl < 60 ml/min Diabetes Age > 75 years Volume depletion Heart failure Hypotension Cirrhosis Proteinuria Co-administration i ti of nephrotoxins > 100 ml of contrast Intra-arterial administration Drug-Induced Diseases, 2 nd edition, ASHP PP 853

99 What population does this look CCl < 60 ml/min (ICU) Diabetes (ICU) Age > 75 years (ICU) Volume depletion (ICU) Heart failure (ICU) Hypotension (C (ICU) Cirrhosis (ICU) Proteinuria (ICU) like? Co-administration of nephrotoxins (ICU) > 100 ml of contrast Intra-arterial administration

100 Prevention strategies that have been tried Stop nephrotoxins 72 hours before procedure in high-risk patients IV fluids, acetylcysteine, y bicarbonate, theophylline, statins, low-dose dopamine, loop diuretics, ascorbic acid, mannitol, ANP, prostaglandin E1 and captopril have been used to prevent AKI Remember fenoldopam? Circulation Dec 7;122(23):2451-5; Pharmacotherapy: A pathophysiologic approach. Appleton & Lang, Eighth edition pp

101 Strategies that may work Crystalloids ml/kg/hr for 3-12 hours before procedure and continued for 6-12 hours afterwards N-acetylcysteine (NAC) evaluated in 30 trials In 11 meta-analyses of trials, 7 found net benefit Significant heterogeneity in 10/11 analyses Benefit seen by lower SCr, however, NAC can cause a false lowering of the SCr Variable doses used, but 1200 mg po BID the day before and after procedure is common Hence, ultimate role is controversial Circulation Dec 7;122(23):2451-5; Pharmacotherapy: A pathophysiologic approach. Appleton & Lang, Eighth edition pp

102 So, now what do we do? And who should do it?

103 Close collaboration with a clinical i l pharmacist and applying fundamental pharmacokinetic principles to drug administration is required. This approach can go a long way in eliminating or reducing drug nephrotoxicity and other adverse end-organ drug effects Kid Internat t 2010; Dec. 1 (ahead of print)

104 Implementing CPOE and clinical decision-support systems along with an appropriately trained ICU pharmacist as part of the intensivist-led multidisciplinary critical care team provides the optimal approach to minimize medication errors and ADEs (including drug-induced nephrotoxicity) in critically ill patients Curr Opin Crit Care 2005;11:555

105 Summary and conclusion Kidney s take a hit in the ICU Nephrotoxins are commonly used Perfect storm for drug-induced d d AKI Minimize use of nephrotoxins and if needed provide optimal conditions to minimize kidney injury Be proactive Protect the kidney at all cost

106 PHARMACOKINETIC AND DRUG DOSING CONSIDERATIONS DURING RRT Mariann D. Churchwell, Pharm.D., BCPS Associate Professor University of Toledo College of Pharmacy and Pharmaceutical Sciences Toledo, Ohio

107 CONFLICT OF INTEREST No conflicts to disclose

108 PHARMACOKINETICS AND DRUG DOSING CONSIDERATIONS DURING RRT Objectives Discuss the pharmacokinetic alterations observed in patients with Acute Kidney Injury Identify important drug-related determinants of removal by renal replacement therapy Describe continuous renal replacement therapy Describe continuous renal replacement therapy specific properties that influence drug removal.

109 ACUTE KIDNEY INJURY Pre-Renal or Post-Renal Fluids Medications Intrinsic Acute Tubular Necrosis Multi-Organ Failure Post-Surgery Sepsis Shock

110 AKI AND PHARMACOKINETIC ALTERATIONS Absorption Distribution Metabolism Elimination i

111 ABSORPTION GI Motility Enteral Feedings Cations Residual Volume H 2 Blockers and PPI s Opioids and/or Sedation Bowel Edema Fluid resuscitation Hyperglycemia Impaired gastric emptying Catecholamine/Sympathetic Nervous System

112 DISTRIBUTION Increased Volume of Distribution Alterations in Protein Binding Capillary Leak Edema Tissue Edema Third Spacing Tissue Distribution Free-drug Bound-drug

113 DISTRIBUTION Two-Compartment Model? Assumes uniform distribution Critically-ill patients Non-uniform distribution Drug characteristics Protein Binding Tissue Affinity Tissue Perfusion Phase of Illness Sepsis Early versus Late AKI Initiation versus Recovery

114 100% Pre-renal Acute Kidney Injury Pre-Renal Initiation Extension Initiation Maintenance Recovery GFR Extension Recovery 0% Maintenance Days Adapted from Molitoris BA. J Am Soc Nephrol 2003;14:

115 METABOLISM Decreased Hepatic Flow Decreased first-pass effect CYP450 enzymes Inflammation Uremia Albumin α-1 acid glycoprotein Critical illness Early phase Late phase Co-morbidities

116 ELIMINATION Kidneys Filtrationti Secretion Renal Perfusion Quantify Serum Creatinine Blood Urea Nitrogen Urine Output Residual Renal Function Non Renal Elimination

117 PHARMACOKINETICS CHANGES EFFECT PHARMACODYNAMICS? Time Dependent Concentration Dependent Post-Antibiotic Effect Area Under the Curve

118 C Peak C Average AUC Trough Time (hrs) 13

119 DRUG-RELATED DETERMINANTS OF REMOVAL BY RENAL REPLACEMENT THERAPY Drug dialyze-ability Molecular weight Free drug Volume of Distribution Protein Binding Ionic Charge

120 COMPARTMENTS Compartment t Compartment t Compartment t Vasculature Organs and Tissue Adipose

121 DRUG CHARACTERISTICS Molecular Weight 500 Daltons 1450 Daltons Protein Binding >50% Volume of Distribution >0.75 L/kg Hydrophilic or lipophilic Ionic Charge Tian Q. AAC 2008;52(3): Lam PK. AAC 2010;54(2):963-4

122 ADSORPTION Ionic Charge may increase Adsorption Ionic interaction ti between Drug and Hemofilter Polyamide - no net charge Polysulfone - no net charge Polyacrylonitrile (PAN) - fixed negative charge Amikacin Gentamicin i Vancomycin Levofloxacin Tian Q. Int J Antimicrob Agents 2006;28: Tian Q. Artif Organs 2008;32(1):81-4 Tian Q. Antimicrob Agents Chemother 2008;52(3): Lam PK. Antimicrob Agents Chemother 2010;54(2):963-4

123 CRRT SPECIFIC PROPERTIES THAT INFLUENCE DRUG REMOVAL Renal replacement therapies Continuous CVVH vs. CVVHD vs. CVVHDF Intermittent SLED or EDD High Volume HVVH vs. HVVHD/F

124 Renal Replacement Therapies Common Abbrevi- ation Blood Flow Rate Qb (ml/min) Dialysate Flow Rate Qd (ml/min) Ultrafiltration Flow Rate Quf (ml/min) Sieving Coefficient SC Saturation Coefficient SA Intermittent Hemodialysis IHD Quf ~2-3L/session or maintain fluid balance N/A Fraction of drug removed Continuous CVVH N/A Quf - net fluid loss Fraction of N/A Venovenous Hemofiltration Fluid loss > IV fluids administered CVVHD Quf zero or maintains fluid balance IV fluids = UF removed fluid CVVHDF Quf set for a net fluid loss Fluid removal UF > IV fluids administered SLED/ Quf - set to SLEDD remove excess EDD fluid or maintain fluid balance drug removed Continuous CVVHD Quf = zero or N/A Fraction of Venovenous drug Hemodialysis removed Continuous Venovenous Hemodiafiltration Slow Low Efficiency or Extended Daily Dialysis N/A N/A Fraction of drug removed Fraction of drug removed Adapted from Churchwell MD. J Clin Pharmacol 2011 in press

125 CONVECTION Convection uses solvent drag to remove solutes and is enhanced by increasing the volume of ultrafiltrate produced A limited volume can be removed by ultrafiltration Filtration fraction CRRT techniques using convective clearance require the replacement of fluid removed to prevent dehydration Pre-filter Post-filter 9/14/2011 Palevsky PM. Clinical Dialysis.4th ed. 2005:

126 HEMODIALYZER CONVECTION Blood from patient 9/14/ Ultrafiltrate Bl d t Blood to patient

127 CONVECTION X X X X 9/14/ X X X X Blood Ultrafiltrate

128 DIFFUSION Molecules move down a concentration gradient by passing through pores in a dialysis membrane Solutes, drugs waste products move from an area of higher concentration to lower concentration The rate of diffusion of a solute is inversely related to its molecular radius Low-molecular weight drugs will diffuse faster than higher molecular weight drugs 9/14/2011 Golper TA. Contrib Nephrol 1991;93:110-6 Joy MS. Am J Kidney Dis 1998 Jun;31(6):

129 HEMODIALYZER DIFFUSION Blood from patient Ultrafiltrate or spent dialysate 9/14/ Dialysate Bl d t Blood to patient

130 DIFFUSION 9/14/ X X X X X Blood Dialysate

131 DIFFUSION CVVHD and CVVHDF Diffusion does NOT increase proportionally with increasing dialysate flow rate (Qd) Molecular weight Small versus Large molecular weight drugs Diffusion is membrane specific

132 Calculated Saturation Coefficient for the PMMA Membrane SA=0.62 SA=0.71 SA=0.52 SA=0.38 JOY MS, MATZKE GR, FRYE RF, PALEVSKY PM. 27 AJKD 1998;31:

133 HEMOFILTER Low Flux versus High Flux Porosity High Efficiency versus High Flux Surface area versus porosity Ultrafiltration coefficient (Kuf) Dialyzer permeability to water Function of membrane thickness and pore size Hemodialyzer performance over time Decrease in small MW drug clearance Blood protein and fibrin deposits develop a layer or secondary membrane which impede filtration Large MW solutes Pasko DA. Blood Purif. 2011;32:82-88 Röckel A. Kidney Int.1986;30(3):429-32

134 CONTINUOUS VENOVENOUS HEMOFILTRATION (CVVH) Convective Therapies Removes plasma water as it seeps through membrane No dialysate is used Removes es small and large molecules les easily Sieving coeffcient (SC) Solutes that can pass through the membrane Protein binding is important determinant MW <15,000 Da Drug removal easy to calculate SC is usually a function of protein binding Ultrafiltrate t concentration/plasma ti concentration ti 29

135 SIEVING COEFFICIENT &PROTEIN& BINDING Drug Reported SC Free Fraction Amikacin Imipenem Metronidazole Penicillin Ranitidine Vancomycin Valproic Acid

136 CONTINUOUS VENOVENOUS HEMODIALYSIS (CVVHD) Diffusive Therapies Dialysate Small solute removal (<500 Da) Diffusion rate inversely proportional to MW Efficiency of solute removal Blood flow Dialysate flow Filter type Solute molecular weight 31

137 PUBLISHED DOSING RECOMMENDATIONS Meropenem MW 437 Daltons PPB 2% Sieving coefficient 1.0 Vd ~21-30 Liters Adults: 1 g every 8 hours Dosing adjustment in renal impairment: Cr Cl ml/minute: Administer 1 g every 12 h Cr Cl ml/minute: Administer 500 mg every 12 h Cr Cl <10 ml/minute: Administer 500 mg every 24 h Prod Info Merrem(R) IV, 2005 Thalhammer F, et al AAC 1998;42:

138 PUBLISHED MEROPENEM CRRT REGIMENS CVVH: UFR ~1100 ml/hr, AN69 hemofilter * 500 mg Q 12 hrs Tegeder I, et al. CPT 1999;65:50-7 CVVH: UFR 3000 ml/hr, polysulfone (Amicon) European study hence high volume hemofiltration * 1000 mg Q 8 hrs Thalhammer F, et al AAC 1998;42: CVVHDF: AN69 hemofilter 750 ml/hr HD, 1250 ml/hr UF * 1000 mg Q 12 hrs Meyer M, et al AJKD 1999;4:

139 CEFEPIME MW ~ 500 Daltons Pb 16-20% Vd 0.3 liters/kg CRRT clearance of cefepime could reduce the drug s effectiveness Goal: Maximize the drug s exposure (time) above a minimum inhibitory concentration Bactericidal effect is most closely related to the time the serum concentration exceeds a threshold concentration Maxipime Prod Info Bristol-Myers Squibb 2005

140 CEFEPIME CLEARANCE DURING CVVHD Six patients - ICU, anuric and septic shock Cefepime 2 grams every 12 hours CVVHD/F - AN69 hemofilter (surface area 0.6m 2 ) Qb 150 ml/min Qd 1 liter/hr Quf - ~ ml/hr Quf was variable & replacement fluid was given post-filter PB~20% Vd 0.71 L/kg Cmax 53 mg/l within 60 min Cmin 17.7 mg/l at ~12 hrs Allaouchiche B. AAC 1997;41:

141 CEFEPIME CLEARANCE DURING CVVHD Pt Age Ht (in) Wt (kg) Sex Vd (L/kg) Ke (h-1) T 1/2Ke M 1.11± ± ± M 0.92± ± ± M 0.93± ± ± M 0.81± ± ± M 0.26± ± ± F 0.23± ± ±6.5 *Fraction of drug removed (Sc) 0.72 (range ) Dosing 2 grams every 12 hrs Allaouchiche B. Antimicrob Agents Chemother 1997;41:

142 CEFEPIME CLEARANCE DURING CRRT 12 patients - ICU CVVH n=5 and CVVHDF n=7 Hemofilter - AN 69 (M60) Qb 150 ml/min Qd 1 L/hr Quf ~1050 ml/hr (range ml/hr) CVVHDF patients Cefepime 2g IV q 24 hrs (4 pts) Cefepime 1g IV q 12 hrs (1 pts) Cefepime 1g IV q 24 hrs (2 pts) Malone RS. Antimicrob Agents Chemother 2001;45:

143 CEFEPIME CVVHDF PATIENTS 2g IV q 24 hrs 4 patients Sa 0.8±~0.08 Vd 0.28 L/kg Range t 1/2 9h hrs Cmax 76.6 mcg/ml Cmin 12.5 mcg/ml 1g IV q 12 hrs 1 patients Sa 0.92±0.02 Vd 0.35 t 1/2 8.3 hrs Cmax 36.2 mcg/ml Cmin 13.6 mcg/ml Malone RS. Antimicrob Agents Chemother 2001;45:

144 Cefepime elimination is significantly enhanced and t 1/2 is decreased by CRRT Malone et al recommendations for Cefepime dosing 2 grams IV q 24 hours or 1 gram IV q 12 hours Except for nosocomial or P. aeruginosa infections 2 grams every 12 hours Allaouchiche et al 2 grams every 12 hours Maintain concentration above MIC Malone RS. Antimicrob Agents Chemother 2001;45: Allaouchiche B. Antimicrob Agents Chemother 1997;41:

145 DAPTOMYCIN Lipopeptide MW Daltons Half-life life 8 hours (renal failure - 28 hrs) Protein Binding 90-92% Volume of Distribution 7 liters (0.1L/kg) Systemic Clearance 8.2 ml/hr/kg Renal Elimination 60% Dosing 4-6mg/kgIV q24h Dosing interval adjusted for renal disease (q48 hrs) Tedesco KL. Pharmacother 2004;24(1):41-57 Cubicin prod info Cubist 2010

146 CVVHD RESULTS SATURATION COEFFICIENTS Qd rate L/hour M ± ± ± ±0.007 Daptomycin SA F-160NR Daptomycin SA Daptomycin SA % difference between filters 0.15± ± ± ± % 30.8% 57.5% 97.0% p-value between filters for same solute (unpaired t test) Churchwell MD. Blood Purif 2006;24:

147 DAPTOMYCIN TRANSMEMBRANE CLEARANCE DURING CVVHD Daptomyc cin Cleara ance (ml/ /min) = P < Dialysate Flow Rate (ml/min) Daptomycin F-160NR Daptomycin M-100 Churchwell MD. Blood Purif 2006;24:

148 DAPTOMYCIN CLEARANCE DURING CVVHD Eight ICU patients received daptomycin ~8 mg/kg CVVHD - PS hemodialyzer (surface area 1.5m 2 ) Qb 200 ml/min Qd 33.3 ml/min Quf 11 ml/min Cmax 81.2±19.0 mcg/ml Cmin 5.5±2.6 mcg/ml PB ~82% Vd 0.7.6±2.9 L/kg t 1/2 20.8±16.5 hours SA 0.14 Optimize PK/PD parameters 8mg/kg every 48 hours Study limitation - single dose study Vilay M. Crit Care Med. 2011;39(1):19-25

149 CONSIDERATIONS Type of renal replacement therapy Hemofilter membrane Flow rates Patient specific parameters Illness (phase) Co-morbidities Drug side-effects Goal of therapy

150 FINAL THOUGHTS... Monitor the whole patient Urine output Fluid status Any sudden changes Monitor for drug toxicity Rash Confusion Abnormal laboratory values Potential toxicities Are we treating a medical condition or a toxicity from medications or supplements? 45