1. 20 years of PCRRT: changing indications and diagnoses ? Ekkehard Ring Department of Pediatrics Medical University of Graz Austria

2. Historical background of pediatric continuous renal replacement therapy (PCRRT) 1977 Kramer et al. Klin. Wochenschr.1977 Kramer et al. Klin. Wochenschr. –First report of arteriovenous hemofiltration (CAVH) in adult patients 1986 Ronco et al. Kidney Int.1986 Ronco et al. Kidney Int. –Four critically ill neonates with ARF and successful CAVH-treatment Starting point for intensified development in PCRRTStarting point for intensified development in PCRRT

3. In Graz: first CAVH 05/1985 Diabetic coma, rhabdomyolysis

4. Development of pediatric continuous renal replacement therapy (PCRRT) „Self-made“ arteriovenous devices and circuits (CAVH), partially with suction support„Self-made“ arteriovenous devices and circuits (CAVH), partially with suction support Addition of dialysate countercurrentAddition of dialysate countercurrent –Hemodiafiltration (CAVHDF)

5. Development of pediatric continuous renal replacement therapy (PCRRT) Pump-assisted veno-venous devicesPump-assisted veno-venous devices –CVVH, CVVHDF –Initially leading to hemodynamic instability –Inaccuracies of blood flow and ultrafiltration

6. Development of pediatric continuous renal replacement therapy (PCRRT) Improvement ofImprovement of –Vascular catheters, hemofilters, blood lines –Accuracy of pumps for blood flow and UF –Replacement solutions (bicarbonate) –Anticoagulation (regional, citrate) Minimizing bleeding risk

7. Development of pediatric continuous renal replacement therapy (PCRRT) Nowadays High sophisticated automatic devices enabling the optimal technical support for critically ill children and neonates with ARF and need for RRT Further development needed –Devices for neonates and prematures –Optimal dosage of HF, HDF

8. Method of choice for acute RRT ? Questionnaire survey among nephrologistsQuestionnaire survey among nephrologists „...CRRT will soon be used at virtually all pediatric centers“.„...CRRT will soon be used at virtually all pediatric centers“. European GuidelinesEuropean Guidelines –Strazdins et al. Pediatr Nephrol 2004; 19:199 –„choice of dialysis depend upon clinical circumstancies, location of the patient, and expertise available... Hemofiltration increasingly employed in the intensive care situation“ CRRTPDHD Belsha 1995 18%45%38% Warady 1999 36%31%33%

9. Indications for RRT Acute renal failure (ARF) PD, HD, HF availableAcute renal failure (ARF) PD, HD, HF available –Primary renal disorders (isolated ARF) Extremely low mortality rate (HUS as most frequent diagnosis)Extremely low mortality rate (HUS as most frequent diagnosis) –ARF as part of multiple organ system failure (MOSF) Chronic renal failure (CRF)Chronic renal failure (CRF) –PD, HD, intermittent use of CRRT (HDF) ? –At least 2 of 3 modalities needed in large pediatric clinics –Cost effectiveness of HD-Units in smaller centers –CRRT being established in an open pediatric ICU –HF (HDF) as treatment for CRF to be considered A time for rediscovery: chronic hemofiltration for end-stage renal disease. McCarthy et al. Semin Dial (2003) 16:199A time for rediscovery: chronic hemofiltration for end-stage renal disease. McCarthy et al. Semin Dial (2003) 16:199

10. Non-renal indications for CRRT Metabolic crisis - inborn errors of metabolismMetabolic crisis - inborn errors of metabolism –Organic acidurias, Urea cycle disorders (hyperammonemia) –Rapid elimination of toxic metabolites –Disease specific treatment CVVHDF treatment of choice (Highest clearance rates)CVVHDF treatment of choice (Highest clearance rates) –Outcome correlates with rapid elimination rate »Schäfer et al. NDT 1999; 14:910 –Outcome correlates with coma duration before CRRT »Picca et al. Pediatr Nephrol 2001; 16:862 Intoxications with drugsIntoxications with drugs SepsisSepsis –With or without ARF, HF-dosage, removal of mediators....

11. Non-renal indications for CRRT Liver support in fulminant hepatic failureLiver support in fulminant hepatic failure –Molecular Adsorbents Recycling System (MARS) –Promising results –Open for discussion Tissieres et al. Liver support for fulminant hepatic failure: is it time to use the molecular adsorbents recycling system in children? Pediatr Crit Care Med 2005; 6:616Tissieres et al. Liver support for fulminant hepatic failure: is it time to use the molecular adsorbents recycling system in children? Pediatr Crit Care Med 2005; 6:616 Tumor lysis syndromeTumor lysis syndrome –Significant cause of morbidity and mortality in oncology –Continuous, massive release of intracellular solutes –CRRT is the method of choice –„preventive CRRT“ in high-risk patients

12. Outcome after CRRT Change of overall mortality rate ? 9 publications (1x 1995), 2000-05 and own data9 publications (1x 1995), 2000-05 and own data Mortality rates 32% - 89% (21 – 226 children)Mortality rates 32% - 89% (21 – 226 children) 416 / 834 non-survivors = mortality rate 50%416 / 834 non-survivors = mortality rate 50% Data divided by 3 time-periods of patient samplingData divided by 3 time-periods of patient sampling No. of patients Non-survivors Mortality rate 1985-1994247150 61 % 1992-1998277138 50 % 1995-2004310128 41 %

13. Long-term surveys of ARF / RRT Trends in diagnoses and outcome Just 1 single-center studyJust 1 single-center study –Williams et al. Arch Pediatr Adolesc Med (2002) 156:893 Retrospective examination 1979 – 1998Retrospective examination 1979 – 1998 divided in 2 periods 1979-1988 and 1989-1998divided in 2 periods 1979-1988 and 1989-1998 228 children with ARF228 children with ARF –Admission to PICU: n = 154 (68%) Acute RRT: n = 93 (41%) [60% of PICU admission]Acute RRT: n = 93 (41%) [60% of PICU admission] ARF-mortality rate 27% (no difference between decades)ARF-mortality rate 27% (no difference between decades) –Mortality rate of 67% in patients with RRT

14. Long-term surveys of ARF / RRT Trends in diagnoses and outcome Study of Williams et al. Arch Pediatr Adolesc Med (2002) 156:893Study of Williams et al. Arch Pediatr Adolesc Med (2002) 156:893 CRRT starting in the second decade (14% of RRT)CRRT starting in the second decade (14% of RRT) Unchanged between decades:Unchanged between decades: –HUS as leading diagnosis with favourable outcome (2% mortality) –Young age < 1 y represents 57% of non-survivors Changes between decades:Changes between decades: –Cardiac surgery main and increasing cause of death (27% >> 44%) –Decreasing mortality rate in sepsis and burns –Oncologic complications increasing No death with tumor lysis syndrome in the second decadeNo death with tumor lysis syndrome in the second decade Complications with bone marrow transplantation as new diseaseComplications with bone marrow transplantation as new disease

15. 20 years of PCRRT in Graz (1985 – 2004) Retrospective analysis of 115 consecutive childrenRetrospective analysis of 115 consecutive children Two periods (1985-1994 and 1995-2004)Two periods (1985-1994 and 1995-2004) Decreasing incidence of CRRT in the second decadeDecreasing incidence of CRRT in the second decade Decreasing mortality rate aside from infantsDecreasing mortality rate aside from infants 1985-19941995-2004Total Patients (mortality rate) 87 (45%) 28 (39%) 115 (43%) Age < 1y 42 (38%) 8 (88%) 8 (88%) 50 (46%) 50 (46%) Age 1-6 y 24 (42%) 14 (29%) 38 (37%) 38 (37%) Age 6-18 y 21 (62%) 6 ( 0%) 6 ( 0%) 27 (48%) 27 (48%)

16. 20 years of PCRRT in Graz (1985 – 2004) Underlying disorders [No. of patients (mortality rate)]Underlying disorders [No. of patients (mortality rate)] 1985-19941995-2004Total primary renal disease 8 (12%) 8 (12%) 5 (0%) 5 (0%) 13 (8%) cardiac surgery 39 (43%) 10 (60%) 10 (60%) 49 (47%) sepsis 14 (43%) 6 (50%) 6 (50%) 20 (45%) oncologic 13 (92%) 2 ( 0%) 2 ( 0%) 15 (50%) metabolic 7 (14%) 7 (14%) 2 (50%) 2 (50%) 9 (25%) 9 (25%) burns 3 (0%) 3 (0%) 0

17. 20 years of PCRRT in Graz (1985 – 2004) Changes of CRRT techniqueChanges of CRRT technique –Period 1: 75% treated with CAVH or CVVH –Period 2: 75% treated with CVVHDF –No influence of CRRT-modality on outcome of patients Cardiac failure after cardiac surgeryCardiac failure after cardiac surgery –Leading cause of secondary ARF in both decades –Increasing mortality rate (neonates !) –Responsible for 46% of non-survivors Decreasing number of patients withDecreasing number of patients with –Sepsis, oncologic disease –No CRRT after burns Young age < 1 year highest mortality rateYoung age < 1 year highest mortality rate –46% of non-survivors are infants and neonates

18. 20 years of PCRRT in Graz (1985 – 2004) Evaluation with scores (scoring systems)Evaluation with scores (scoring systems) –Number of organ failures –Pediatric Risk of Mortality (PRISM-score)

19. 20 years of PCRRT in Graz (1985 – 2004) Ventilation and vasopressor supportVentilation and vasopressor support –Associated with high mortality Non-resolving MOSF is the leading cause of deathNon-resolving MOSF is the leading cause of death –Period 1: 67% died within 3 to 7 days of CRRT –Period 2: 55% died after more than 7 days of CRRT Our data seem to indicateOur data seem to indicate –Advances in intensive care treatment –Advances in diagnosis and treatment of underlying disorders –High sophisticated CRRT modalities –Leading to slowly decreasing mortality of critically ill children –Specific local situations to be considered

20. Determinants of non-survival after CRRT Age (body weight)Age (body weight) –Technical complications decreasing –Worse survival < 3 kg compared to 3-10 kg –Symons et al. Am J Kidney Dis 2003; 41:984 Hemodynamic instabilityHemodynamic instability –Vasopressor support –Low mean arterial pressure (MAP) –Smoyer JASN 1995; 6:1401 –Bunchman et al. Pediatr Nephrol 2001; 16:1067 PRISM score: good prognostic capacityPRISM score: good prognostic capacity –Zobel et al. Child Nephrol Urol 1990; 10:14 –Fernandez et al. Pediatr Nephrol 2005; 20:1473

21. Determinants of non-survival after CRRT Dialytic modality Development of 20 years should be of importance No systematic review available No influence of RRT modality was found –Bunchman et al. Pediatr Nephrol 2001; 16:1067 –Goldstein et al. Kidney Int. 2005; 67:653 We did a good job even in the early years Underlying disorders of importance

22. Determinants of non-survival after CRRT Underlying disorder Cardiac surgery 35% of non-survivors (Williams 2002)Cardiac surgery 35% of non-survivors (Williams 2002) Postop. Cardiac surgery 42% of CRRT (Fernandez 2005)Postop. Cardiac surgery 42% of CRRT (Fernandez 2005) Left-heart hypoplasia 80% mortality (Smoyer 1995)Left-heart hypoplasia 80% mortality (Smoyer 1995) Causes leading to CRRTCauses leading to CRRT Cardiogenic shock (20%)Cardiogenic shock (20%) Sepsis (39%)Sepsis (39%) Organ Tx (Liver, Bone marrow) 22%Organ Tx (Liver, Bone marrow) 22% (Goldstein 2005) (Goldstein 2005)

23. Determinants of non-survival after CRRT Degree of fluid overload (%FO) %FO = (Fluid in – Fluid out)/PICU admission weight x 100%FO = (Fluid in – Fluid out)/PICU admission weight x 100 Foland et al., Crit Care Med 2004; 32:1771Foland et al., Crit Care Med 2004; 32:1771 –Survival associated with lower PRISM-score and lower %FO Goldstein et al., Kidney Int 2005; 67:653Goldstein et al., Kidney Int 2005; 67:653 –First report of the Prospective Pediatric CRRT Registry Group –116 patients, PRISM higher in non-survivors –%FO higher in non-survivors 25.4% vs 14.2% in survivors –Patiens with 20% %FO may serve as an important parameter for fluid status%FO may serve as an important parameter for fluid status Guidance of fluid managementGuidance of fluid management Timing of CRRT (early initiation)Timing of CRRT (early initiation)

24. Conclusions 20 years of PCRRT – a story of success20 years of PCRRT – a story of success Development of high sophisticated equipmentDevelopment of high sophisticated equipment Changing indicationsChanging indications –Timing of CRRT in established indications –New indications even without ARF Changing diagnosesChanging diagnoses –Decreasing and increasing incidence of disease –„New“ disorders like BMT Slowly decreasing mortality ratesSlowly decreasing mortality rates Prospective Pediatric CRRT Registry Group (Data)Prospective Pediatric CRRT Registry Group (Data) Intensive care treatment is always on the border-lineIntensive care treatment is always on the border-line