Folyamatos vesepótló kezelések az intenzív osztályon Prof. Dr. Balla József tanszékvezető egyetemi tanár Debreceni Egyetem Belgyógyászati Intézet Nephrológiai Tanszék, FMC Extracorporalis Szervpótló Centrum, Debrecen

József Balla University of Debrecen Hungary AKI – CRRT József Balla University of Debrecen Hungary

AKI: Acute Kidney Injury/Impairment The shift of terminology from ARF to AKI has been well received by the research and clinical communities AKI as defined by the RIFLE criteria is now recognized as an important syndrome Kidney Disease: Improving Global Outcomes (KDIGO), 2012

AKI: Acute Kidney Injury/Impairment There is a need for a single definition for practice, research, and public health Stage 1 (RIFLE-Risk) Serum creatinine increased 1.5-1.9 times baseline (known or presumed to have occurred within the prior 7 days) or Serum creatinine increase > 27 μmol/l (within 48 hours) Urine volume < 0.5 ml/kg/h for 6-12 hours Kidney Disease: Improving Global Outcomes (KDIGO), 2012, MANET

AKI: Acute Kidney Injury/Impairment Stage 2 (RIFLE-Injury) Serum creatinine increased 2.0-2.9 times baseline Urine volume < 0.5 ml/kg/h for more than 12 hours Kidney Disease: Improving Global Outcomes (KDIGO), 2012

AKI: Acute Kidney Injury/Impairment Stage 3 (RIFLE-Failure) Serum creatinine increased > 3.0 times baseline or Serum creatinine > 354 μmol/l with an abrupt rise of at least 44 mmol/l Initiation of renal replacement therapy Urine volume < 0.3 ml/kg/h for more than 24 hours anuria for more than 12 hours Kidney Disease: Improving Global Outcomes (KDIGO), 2012

RRT sügősségi indikációk Renális Nonobstruktív oliguria (vizelet kiválasztás < 200 mL/12 h) vagy anuria Progresszív azotaemia, még klinikai jelek nélkül (serum urea > 36 mmol/L) Hyperkalaemia, (K+ > 6,0 mmol/L, vagy gyorsan emelkedő) gyógyszeres terápiára refrakter Metabolikus acidózis, (pH ≤ 7,15) Uraemia, szervi tünetek megléte, encephalopathia, myopathia, pericarditis, uraemiás diathesises vérzés Progresszív súlyos hyper-/hyponatraemia (Na+ > 160 vagy < 115 mmol/L)

RRT sürgősségi indikációk Renális Folyadékretenció, diuretikum rezisztens oedema (pl. tüdő-oedema) AKI megléte esetén Nem renális Mérgezés, dializálható  hemofiltrálható exogén toxinok (gyógyszer, méreg) Endogén toxinok, dializálható és/vagy hemofiltrálható toxinok kalcium > 3-4 mmol/L, magnézium > 4 mmol/L, ammónia, immun globulin könnyűlánc Hyperthermia (mag hőmérséklet > 39,5 °C)

„The optimal timing of RRT for AKI is not defined.” Kidney Disease: Improving Global Outcomes (KDIGO), 2012

Maintaining fluid homeostasis Fluid overload in critical illness and AKI is associated with adverse outcomes. Payen D, de Pont AC, Sakr Y, et al. A positive fluid balance is associated with a worse outcome in patients with acute renal failure. Crit Care 2008;12: R74. Foland JA, Fortenberry JD, Warshaw BL, et al. Fluid overload before continuous hemofiltration and survival in critically ill children: a retrospective analysis. Crit Care Med 2004; 32: 1771–1776. Gillespie RS, Seidel K, Symons JM. Effect of fluid overload and dose of replacement fluid on survival in hemofiltration. Pediatr Nephrol 2004; 19:1394–1399. Goldstein SL, Currier H, Graf C, et al. Outcome in children receiving continuous venovenous hemofiltration. Pediatrics 2001; 107: 1309–1312. Goldstein SL, Somers MJ, Baum MA, et al. Pediatric patients with multiorgan dysfunction syndrome receiving continuous renal replacement therapy. Kidney Int 2005; 67: 653–658. Hayes LW, Oster RA, Tofil NM, et al. Outcomes of critically ill children requiring continuous renal replacement therapy. J Crit Care 2009; 24:394–400. Sutherland SM, Zappitelli M, Alexander SR, et al. Fluid overload and mortality in children receiving continuous renal replacement therapy:the prospective pediatric continuous renal replacement therapy registry.Am J Kidney Dis 2010; 55: 316–325. Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluidmanagement strategies in acute lung injury. N Engl J Med 2006; 354:2564–2575.

Underlying disease When to start RRT Type and severity of the underlying disease ANCA vasculitis Brockmann et al: Proteinase-3 as the major autoantigen of c-ANCA is strongly expressed in lung tissue of patients with Wegener's granulomatosis. Arthritis Res. 2002;4(3):220-5.

Timing of initiation of RRT on outcome early vs. late initiation Observational studies: A prospective multicenter observational cohort study Program to Improve Care in Acute Renal Disease (PICARD) 243 patients, adjusted for age, hepatic failure, sepsis, thrombocytopenia, and SCr Conclusion: initiation of RRT at higher BUN [blood urea > 27.1 mmol/l] was associated with an increased risk of death (RR 1.85; 95% CI 1.16–2.96) Liu KD, et al. Timing of initiation of dialysis in critically ill patients with acute kidney injury. Clin J Am Soc Nephrol 2006; 1:915–919.

Timing of initiation of RRT on outcome early vs. late initiation Observational studies: A prospective multicenter observational study (54 ICUs in 23 countries) Stratified into ‘‘early’’ or ‘‘late’’ by median urea at the time RRT started (24.2 mmol/l) Also categorized temporally from ICU admission into early (less than 2days), delayed (between 2–5 days), or late (more than 5 days). Conclusion: - timing by serum urea showed a tendency but no significant difference in mortality - in relation to ICU admission, late RRT was associated with greater crude mortality Bagshaw SM, et al. Timing of renal replacement therapy and clinical outcomes in critically ill patients with severe acute kidney injury. J Crit Care 2009; 24: 129–140.

Timing of initiation of RRT on outcome early vs. late initiation Observational studies: A prospective multicenter observational study Major abdominal surgery AKI early or late start of renal replacement therapy defined by simplified RIFLE early start: sRIFLE-0 or Risk; late start: sRIFLE -Injury or Failure Shiao CC, et al. Late initiation of renal replacement therapy is associated with worse outcomes in acute kidney injury after major abdominal surgery. Crit Care 2009; 13: R171.

Late initiation of renal replacement therapy is associated with worse outcomes in acute kidney injury after major abdominal surgery. Shiao CC, et al. Crit Care 2009; 13: R171. indications for RRT Underscore the importance of predicting prognoses of major abdominal surgical patients with AKI by using RIFLE classification

AKI – RRT Modality of renal replacement therapy for patients with AKI Use continuous and intermittent RRT as complementary therapies in AKI patients. (Not Graded) Kidney Disease: Improving Global Outcomes (KDIGO), 2012

Modality of renal replacement therapy for patients with AKI We suggest using CRRT, rather than standard intermittent RRT, for hemodynamically unstable patients (2B). In non-septic AKI, 20-25 ml/kg/h remains optimal. We suggest using CRRT, rather than intermittent RRT, for AKI patients with acute brain injury or other causes of increased intracranial pressure or generalized brain edema. (2B). Kidney Disease: Improving Global Outcomes (KDIGO), 2012

AKI – RRT Modality of renal replacement therapy for patients with AKI Until the IVOIRE trial becomes available, septic AKI should be treated by continuous veno-venous hemofiltration at 35 ml/kg/h. Honoré PM, Jacobs R, Boer W, Joannes-Boyau O, De Regt J, De Waele E, Van Gorp V, Collin V, Spapen HD. New insights regarding rationale, therapeutic target and dose of hemofiltration and hybrid therapies in septic acute kidney injury. Blood Purif. 2012;33:44-51 CVVHD-CiCa: BW = 70 kg, 24 x 2,4L = 35 ml/kg/h

Hemodialysis

Hemofiltration

Renal Replacement Therapies University of Debrecen AKI (221) – RRT (112) Hybrid form IHD (39) SLED (5) CRRT (72) CVVHDF (31) + CRRT (41) HD (15) + HDF (25) CVVHD (29) + CVVH (12) CVVHD-LMWH/Hirudin (17/3) + CVVHD-CiCa (9) Alternate (27), Daily (9), Extended (3) University of Debrecen; March, 2013

Anticoagulation CI – CA

23

Ci-Ca CVVHD: Concept & Application, Univ. of Debrecen, Hungary, R. Pohlmeier

Ci-Ca CVVHD: Scheme and typical flows Blood flow: 100 ml/min Citrate flow: 180 ml/h Calcium flow: 35 mL/h (91 mmol/L Ca) Dialysate flow: 2000 mL/h Effluent flow: ca. 2300 mL/h depending on the net-UF 5 flows selectable  5 treatment goals achievable Ci-Ca CVVHD: Concept & Application (R. Pohlmeier)

multiFiltrate Screen during citrate anticoagulation Blood and Dialysate flow => Selection of CVVHD-efficacy => Adjustment of the acid-base status Citrate dose => Adjustment of the regional anticoagulation Ca-Dose => Adjustment of the Ca balance Ci-Ca CVVHD: Concept & Application (R. Pohlmeier)

Examplary monitoring schedule under stable conditions Ci-Ca CVVHD: Concept & Application (R. Pohlmeier)

Ci-Ca Treatment: Prescription of the citrate dose General approach Prescription of the citrate dose Start with an appropriate initial value Initial citrate dose: 4.0 mmol/l Measure the effect on a regular basis* Check the post-filter ionised calcium concentration every ≈ 8 h* Continue during the treatment Change the prescription if needed Change the citrate dose in steps of 0.1 mmol/l if needed *: if clinically indicated, additional measurements should be done Ci-Ca CVVHD: Concept & Application (R. Pohlmeier)

Initial choice and adjustment of the citrate dose Initial citrate dose: ca. 4.0 mmol/L Monitoring of the post-filter ionised Ca (venous / blue sampling side) 1. Measurement shortly after start of the treatment (about 5 min) to ensure that citrate and calcium solutions have not been mixed up Thereafter regular measurements (e.g. every 8 h) Adjust the citrate dose according to the table Ci-Ca CVVHD: Concept & Application (R. Pohlmeier)

Ci-Ca Treatment: Prescription of the calcium dose General approach Prescription of the Ca-dose Initial calcium dose: 1.7 mmol/L Start with an appropriate initial value Check the systemic ionised calcium concentration every ≈ 6 h* Measure the effect on a regular basis* Continue during the treatment Change the calcium dose in steps of 0.2 mmol/l if needed Change the prescription if needed *: if clinically indicated, additional measurements should be done Ci-Ca CVVHD: Concept & Application (R. Pohlmeier)

Initial choice and adjustment of the calcium dose Initial Ca-dose: ca. 1.7 mmol/L Monitoring of the systemic ionised Ca Preferably blood sample from arterial catheter Alternative: slowly taken sample from the “arterial” / red sampling side while the blood pump is running; risk of falsely low Ca measurements in case of reversely connected catheter due to recirculation and possible contamination with citrate In stable patients, regular measurements every 6 h usually are sufficient, but additional samples in unclear clinical situations recommended Adjust the calcium dose according to the table Ci-Ca CVVHD: Concept & Application (R. Pohlmeier)

University of Debrecen

CVVH, HVHF, CVVHD, CVVHDF

„Prometheus” Németh Csilla Palotai Ilona

Modality of renal replacement therapy Acute Kidney Injury (AKI ) Renal Replacement Therapies (RRT) Intermittent (IHD) Continuous (CRRT) Slow Low Efficiancy Dialysis (SLED) Akut vesekárosodás (AVK) Vesepótló kezelés Intermittáló Folyamatos vesepótló kezelés Alacsony hatékonyságú elnyújtott, tartós

The treatment of AKI with RRT has the following goals to maintain fluid and electrolyte, acid-base, and solute homeostasis to prevent further insults to the kidney to permit renal recovery; and iv) to allow other supportive measures (e.g., antibiotics, nutrition support) Kidney Disease: Improving Global Outcomes (KDIGO), 2012

The optimal timing of dialysis for AKI = Indications for RRT Initiate RRT emergently when Life-threatening changes in fluid electrolyte acid-base balance uremic complications: pericarditis, pleuritis, encephalopathy, coagulopathy Kidney Disease: Improving Global Outcomes (KDIGO), 2012, MANET

Renal Replacement Therapies (RRT) Akut vesekárosodás (AVK) Acute Kidney Injury (AKI ) Renal Replacement Therapies (RRT) Intermittent (IHD) Continuous (CRRT) Slow Low Efficiancy Dialysis (SLED) Akut vesekárosodás (AVK) Vesepótló kezelés Intermittáló Folyamatos vesepótló kezelés Alacsony hatékonyságú elnyújtott, tartós

IV/1 Az akut vesekárosodás megelőzése Vérzéses sokk nélküli manifeszt vagy fenyegető akut vesekárosodás (AVK) esetekben a kezdeti volumen expanzióra nem kolloid (albumin vagy keményítő), hanem izotóniás krisztalloid oldatok használata javasolt. (2B) 4. Ajánlott, hogy a kritikus állapotú betegek inzulin kezelésének plazma glükóz céltartománya 6.1-8.3 mM közötti legyen. (2C) 5. Ajánlott, hogy a teljes energiabevitel az akut VK bármely szakaszában 20-30 kcal/kg/nap között (achieving) legyen. (2C)

IV/1 Az akut vesekárosodás megelőzése 6. Nem ajánlott a fehérjebevitel korlátozása a vesepótló kezelés (RRT = VPK) igény (initiation) esetleges megelőzésének vagy késleltésének indokával. (2D)) 7. Fehérjebeviteli ajánlás a - nem-katabol, nem dializált AVK betegeknek 0.8-1.0 g/kg/nap (2D), - VPK-ben részesülő AVK betegek számára 1.0-1.5 g/kg/nap (1D), - folyamatos vesepótló kezelésben (FVPK=CRRT) részesülő és hiperkatabol betegeknek maximum 1.7 g/kg/nap 8. Az AVK betegek táplálását döntően enterális úton ajánlott megoldani. (2C)

IV/1 Az akut vesekárosodás megelőzése 9. Nem javasolt diuretikumok alkalmazása az AVK megelőzésére. (1B) 10. Nem ajánlott diuretikumok használata az AVK kezelésére, kivéve a túltöltéssel járó állapotokat (volume overload). (2C)

IV/1 Az akut vesekárosodás megelőzése 11. Nem javasolt a kisdózisú (’vese-dózisú’) dopamin, vagy fenoldopam használata az AVK megelőzésére vagy kezelésére. (1A) 12. Nem ajánlott pitvari natriuretikus peptid (ANP) az AVK megelőzésére (2C) vagy kezelésére (2B). 14. Nem javasolt a rekombináns humán IGF-1 (rh-IGF1) az AVK megelőzésére vagy kezelésére (1B)

IV/1 Az akut vesekárosodás megelőzése 20. Az amfotericin-B hagyományos formái helyett a szer lipid-komplex készítményeinek használata ajánlott. (2A) 23. Nem ajánlható a NAC (N-acetil cisztein) haszálata AVK megelőzésére a hipotóniás, kritikus állapotú betegekben (2D) 24. Nem ajánlható a NAC per os vagy iv. alkalmazása a posztoperatív AVK megelőzésére. (1A)

Kontrasztanyag nefropátia 25.5. Kontrasztanyag-AVK kockázatnak kitett betegekben a lehető legkisebb kontrasztanyag mennyiséget használandó. (NG) 25.6. A nagy ozmolaritású jódos kontrasztanyagok helyett izo-ozmoláris vagy alacsony ozmolaritású kontrasztanyag használata javasolt. (1B) 25.7. Fokozott kontraszt-AVK kockázatú betegekben iztonóniás Na-kloriddal vagy Na-bikarbonáttal történő volumen-expanzió javasolt. 25.8. Fokozott kontraszt-AVK kockázatú betegekben a csak-per os folyadékpótlás nem javasolható. (1C)

Kontrasztanyag nefropátia 25.9. Fokozott kontraszt-AVK kockázatú betegekben a per os NAC és iv. izotóniás krisztalloid oldatok együttes használata javasolt. (2D) 25.10. Kontraszt-AVK megelőzésére a teofillin használata nem ajánlható. (2C) 25.11. Nem ajánlható a fokozott kontraszt-AVK kockázatú betegek számára az intermittáló hemodialízissel (IHD) vagy hemofiltrációval (HF) történő profilaktikus kontrasztanyag eltávolítás. (2C) MANET

AKI: Acute Kidney Injury/Impairment The optimal timing of dialysis for AKI is not defined Kidney Disease: Improving Global Outcomes (KDIGO), 2012

AKI: Acute Kidney Injury/Impairment Only one RCT has evaluated the effect of timing of initiation of RRT on outcome Kidney Disease: Improving Global Outcomes (KDIGO), 2012

Timing of initiation of RRT on outcome early vs. late initiation Bouman et al. Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: a prospective, randomized trial Randomized 106 critically ill patients with AKI to early vs. late initiation of RRT The early initiation group started RRT within 12 hours oliguria (30 ml/h for 6 hours, not responding to diuretics or hemodynamic optimization) or CrCl < 20 ml/min The late-initiation group started RRT when classic indications were met Conclusion: did not find differences in ICU or hospital mortality, or in renal recovery among survivors Bouman CS, Oudemans-Van Straaten HM, Tijssen JG, Zandstra DF, Kesecioglu J. Crit Care Med 2002; 30: 2205–2211. Department of Intensive Care, Academic Medical Center, Amsterdam, The Netherlands

Timing of initiation of RRT on outcome early vs. late initiation Observational studies: in the 1960 s and 1970 s (Conger JD. J Trauma 1975; 15: 1056–1063, Fischer RP. Surg Gynecol Obstet 1966; 123: 1019–1023, Kleinknecht D. Kidney Int 1972; 1: 190–196) blood urea or BUN were used to distinguish early vs. late start of dialysis. However, these studies mostly combined early start with more-intensive dialysis and late start with less-intensive dialysis. Not conclusive

Timing of initiation of RRT on outcome early vs. late initiation Observational studies: Single-center observational studies that were restricted to AKI after trauma (HD) and coronary artery bypass surgery (CVVHDF, CVVH) early starters - BUN 15 mM, late starters - BUN 33 mM early starters – urine output is less than 100 mL/8 hours time between the operation and the initiation Conclusion: Suggested a benefit (survival ) to RRT initiation at early start (at lower BUN concentrations) Gettings LG, Intensive Care Med 1999; 25: 805–813., Demirkilic U, J Card Surg 2004; 19: 17–20. Elahi MM, Eur J Cardiothorac Surg 2004; 26: 1027–1031.

Timing of renal replacement therapy initiation in acute renal failure: a meta-analysis early vs. late initiation Meta-analysis of randomized trials, early RRT was associated with a nonsignificant 36% mortality risk reduction (RR, 0.64; 95% confidence interval, 0.40 to 1.05; P = 0.08) In cohort studies, early RRT was associated with a statistically significant 28% mortality risk reduction (RR, 0.72; 95% confidence interval, 0.64 to 0.82; P < 0.001). Seabra VF, Balk EM, Liangos O, Sosa MA, Cendoroglo M, Jaber BL. Am J Kidney Dis. 2008;52:272–284

Timing of renal replacement therapy initiation in acute renal failure: a meta-analysis Meta-analysis suggests that early initiation of RRT in patients with ARF might be associated with improved survival. calling for an adequately powered randomized controlled trial to address this question Seabra VF, Balk EM, Liangos O, Sosa MA, Cendoroglo M, Jaber BL. Am J Kidney Dis. 2008;52:272–284

Maintaining fluid homeostasis Patients receiving RRT predominantly for solute control experienced better outcomes than those predominantly treated for volume overload. Payen D, de Pont AC, Sakr Y, et al. A positive fluid balance is associated with a worse outcome in patients with acute renal failure. Crit Care 2008;12: R74. Foland JA, Fortenberry JD, Warshaw BL, et al. Fluid overload before continuous hemofiltration and survival in critically ill children: a retrospective analysis. Crit Care Med 2004; 32: 1771–1776. Gillespie RS, Seidel K, Symons JM. Effect of fluid overload and dose of replacement fluid on survival in hemofiltration. Pediatr Nephrol 2004; 19:1394–1399. Goldstein SL, Currier H, Graf C, et al. Outcome in children receiving continuous venovenous hemofiltration. Pediatrics 2001; 107: 1309–1312. Goldstein SL, Somers MJ, Baum MA, et al. Pediatric patients with multiorgan dysfunction syndrome receiving continuous renal replacement therapy. Kidney Int 2005; 67: 653–658. Hayes LW, Oster RA, Tofil NM, et al. Outcomes of critically ill children requiring continuous renal replacement therapy. J Crit Care 2009; 24:394–400. Sutherland SM, Zappitelli M, Alexander SR, et al. Fluid overload and mortality in children receiving continuous renal replacement therapy:the prospective pediatric continuous renal replacement therapy registry.Am J Kidney Dis 2010; 55: 316–325. Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluidmanagement strategies in acute lung injury. N Engl J Med 2006; 354:2564–2575.

Maintaining fluid homeostasis Patients dialyzed for control of both azotemia and volume overload experienced the worst outcome. Payen D, de Pont AC, Sakr Y, et al. A positive fluid balance is associated with a worse outcome in patients with acute renal failure. Crit Care 2008;12: R74. Foland JA, Fortenberry JD, Warshaw BL, et al. Fluid overload before continuous hemofiltration and survival in critically ill children: a retrospective analysis. Crit Care Med 2004; 32: 1771–1776. Gillespie RS, Seidel K, Symons JM. Effect of fluid overload and dose of replacement fluid on survival in hemofiltration. Pediatr Nephrol 2004; 19:1394–1399. Goldstein SL, Currier H, Graf C, et al. Outcome in children receiving continuous venovenous hemofiltration. Pediatrics 2001; 107: 1309–1312. Goldstein SL, Somers MJ, Baum MA, et al. Pediatric patients with multiorgan dysfunction syndrome receiving continuous renal replacement therapy. Kidney Int 2005; 67: 653–658. Hayes LW, Oster RA, Tofil NM, et al. Outcomes of critically ill children requiring continuous renal replacement therapy. J Crit Care 2009; 24:394–400. Sutherland SM, Zappitelli M, Alexander SR, et al. Fluid overload and mortality in children receiving continuous renal replacement therapy:the prospective pediatric continuous renal replacement therapy registry.Am J Kidney Dis 2010; 55: 316–325. Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluidmanagement strategies in acute lung injury. N Engl J Med 2006; 354:2564–2575. Mehta RL, McDonald B, Pahl M, et al. Continuous vs. intermittent dialysis for acute renal failure in the ICU: Results from a randomized multicenter trial (abstract). J Am Soc Nephrol 1996; 7: 1456.

Maintaining fluid homeostasis Analysis of a multicenter observational cohort showed that mean daily fluid balance in AKI patients was significantly more positive among nonsurvivors than survivors. Payen D, de Pont AC, Sakr Y, et al. A positive fluid balance is associated with a worse outcome in patients with acute renal failure. Crit Care 2008;12: R74. Survivors had lower fluid accumulation at dialysis initiation compared to nonsurvivors (8.8% vs. 14.2% of baseline body weight; P=0.01 adjusted for dialysis modality and severity score). PICARD: Liu KD, et al. Timing of initiation of dialysis in critically ill patients with acute kidney injury. Clin J Am Soc Nephrol 2006; 1:915–919.

Indications for RRT fluid homeostasis Massive volume overload resulting from volume resuscitation may be an indication for RRT even in the absence of significant elevations in BUN or SCr. – not RRT but renal support

Modality of renal replacement therapy for patients with AKI We suggest using CRRT, rather than standard intermittent RRT, for hemodynamically unstable patients (2B). In non-septic AKI, 25 ml/kg/h remains optimal. We suggest using CRRT, rather than intermittent RRT, for AKI patients with acute brain injury or other causes of increased intracranial pressure or generalized brain edema. (2B). In non-septic AKI, 25 ml/kg/h remains optimal. Until the IVOIRE trial becomes available, septic AKI should be treated by continuous veno-venous hemofiltration at 35 ml/kg/h. Kidney Disease: Improving Global Outcomes (KDIGO), 2012

30 90 15 60 CKD. St. V IV III II I