Improving outcomes in AKI and CRRT: Does Quality matter? Timothy E. Bunchman Professor and Director Pediatric Nephrology & Transplantation Timothy.bunchman@vcuhealth.org pedscrrt@gmail.com www.pcrrt.com

Overview What has occurred to improve the diagnosis and outcome in AKI in children What has occurred to improve the use of CRRT in children

How do you diagnosis AKI? Severity of illness score? Biomarkers? FO? Uremia?

Historically AKI diagnosis was synominous with the need for renal replacement therapy Uremia, hyperkalemia, metabolic acidosis In 2000 ADQI occurred and began to quantitate and measure markers of AKI

RIFLE Criteria

Modified Pediatric RIFLE Goldstein et al , KI 2007 Now validated in 3 additional Pediatric Studies

LIMITATIONS OF AKI CLASSIFICATION CRITERIA pRIFLE AKIN KDIGO inconsistency in application urinary output criteria often excluded → loss of additional cases exclusion of patients with elevated initial SCr UO and sCr are late markers Biomarkers…

AKI diagnosis: pRIFLE 51%, AKIN 37.3%, KDIGO 40.3%

AKI = 50% or greater increase in serum creatinine from baseline Urine NGAL as an Early AKI Biomarker after Cardiopulmonary Bypass AKI = 50% or greater increase in serum creatinine from baseline Mishra et al, Lancet 2005, 365:1231-1238

Dialysis Dose and Outcome Ronco et al. Lancet 2000; 351: 26-30 425 patients Endpoint = survival 15 days after D/C HF 146 UF rate 20ml/kg/hr survival significantly lower in this group compared to the others 139 UF rate 35ml/kg/hr p=0.0007 140 UF rate 45ml/kg/hr p=0.0013 Conclusions: Minimum UF rates should be ~ 35 ml/kg/hr Survivors had lower BUNs than non-survivors prior to commencement of hemofiltration

26.9% of all patients 11.6% of all patients 3.5% of all patients AWARE Investigators– submitted

So what! The diagnosis of AKI and the need for RRT are discreptent But If AKI at risk is 25% of all PICU admissions then attention to detail of nephrotoxins and fluid over load are needed to avoid the worsening of AKI

SPECIAL FIBERS AND FILTERS HAVE BEEN DESIGNED FOR SPECIAL CONDITIONS AND PATIENTS Minifilters Ronco C, et al Treatment of acute renal failure in newborns by Continuous Arterio-Venous Hemofiltration. Kidney International, 1984

1980s Following Ronco’s paper little was published except for a descriptive paper by Leone et al describing CAVH in children Early experience with continuous arteriovenous hemofiltration in critically ill pediatric patients. Crit Care Med. 1986 Dec;14(12):1058-63. Neonatal work by Zobel Continuous arteriovenous hemofiltration in premature infants. Crit Care Med. 1989 Jun;17(6):534-6.

1990s Equipment during this era was “adaptive” Solutions for convection or diffusion was pharmacy made or lactate based Latter part of 1990s industry began to market machines that did not take momentum until turn of the decade

1990s Important work on Access was presented by John Gardner RN describing the MAHURKAR™ Catheter that is now marked by Covidien “how to do it papers” Continuous arterial-venous diahemofiltration and continuous veno-venous diahemofiltration in infants and children. Pediatr Nephrol. 1994 Feb;8(1):96-102. Continuous venovenous hemodiafiltration in infants and children. Am J Kidney Dis. 1995 Jan;25(1):17-21. Out come paper by Smoyer et al on Determinants of survival in pediatric continuous hemofiltration. J Am Soc Neph 1995 Nov;6(5):1401-9. Comparison paper on CAVH vs CVVH by our group in Am J Kid Dis 1995 Maxvold and colleagues began comparison of modalities Management of acute renal failure in the pediatric patient: hemofiltration versus hemodialysis. Am J Kidney Dis. 1997 Nov;30(5 Suppl 4):S84-8.

1990s Evaluation of PICU needs and RRT beyond AKI began Parekh RS et al Dialysis support in the pediatric intensive care unit. Adv Renal Replac Therapy 1996 Oct;3(4):326-36. Quigley and associates on use of HD and hemofiltration in TLS Hyperphosphatemia in tumor lysis syndrome: the role of hemodialysis and continuous veno-venous hemofiltration. Peds Nephrol 1994, 8: 351-3

2000s This era exploded with advancements in Equipment FDA approval of bicarbonate based Solutions Nutrition in AKI/CRRT Avoidance of complications Anticoagulation protocols

2000s Gambro and B Braun (and soon to follow Baxter) came out with machines with commonality of warmer, accurate fluid control as well as blood flow and solutions controllers

2000s FDA approval of bicarbonate based Solutions by Dialysis Solution Inc and Walter O’Rourke Pediatric hemofiltration: Normocarb dialysate solution with citrate anticoagulation. Pediatr Nephrol 2002 17:150-4 Maxvold et al described Nutrition needs and losses in AKI/CRRT Amino acid loss and nitrogen balance in critically ill children with acute renal failure: a prospective comparison between classic hemofiltration and hemofiltration with dialysis. Crit Care Med 2000 28:1161-5

2000s Anticoagulation Protocols Pediatric acute renal failure: outcome by modality and disease. Pediatr Nephrol 2001, 16:1067-71 Pediatric convective hemofiltration: Normocarb replacement fluid and citrate anticoagulation. Am J Kid Dis 2003 42: 1248-52 Brophy et al Multi-centre evaluation of anticoagulation in patients receiving continuous renal replacement therapy (CRRT). NDT 2005 20:1416-21

Circuit survival censored for Seven ppCRRT centers 138 patients/442 circuits 3 centers: hepACG only 2 centers: citACG only 2 centers: switched from hepACG to citACG HepACG = 230 circuits CitACG= 158 circuits NoACG = 54 circuits Circuit survival censored for Scheduled change Unrelated patient issue Death/witdrawal of support Regain renal function/switch to intermittent HD

Heparin vs citrate prospective study Zaoral et al, Pediatric Critical Care Medicine. 17(9):e399–e405, SEP 2016 “ We showed in our study that citrate provided significantly longer circuit lifetimes than heparin for continuous venovenous hemodialysis in children. Citrate was superior to heparin for the transfusion requirements. Citrate was feasible and safe in children and infants”.

Convective Clearance CVVH Convective clearance Replacement Solutions Physiologic sterile solution that is either infused pre filter (NA) or post filter (outside of NA) that infused at a set rate (Qr)

Diffusive Clearance CVVHD/HD/PD Diffusive clearance Dialysate Physiologic sterile solution that is infused countercurrent to the blood flow rate (Qd)

Convective and Diffusive Clearance (? Confusion) CVVHDF/CAVHDF Convective clearance Replacement Solutions Diffusive clearance Dialysis solution

Stem Cell Transplant: ppCRRT 51 patients in ppCRRT with SCT Mean %FO = 12.41 + 3.7%. 45% survival Convection: 17/29 survived (59%) Diffusion: 6/22 (27%), p<0.05 Survival lower in MODS and ventilated patients Flores FX et al: Pediatr Nephrol. 2008 Apr;23(4):625-30

Prospective Pediatric Study 40 patients with Sepsis/ARF at 4 ppCRRT centers Randomized crossover design 24 hours of CVVH or CVVHD, then crossover 2500 ml/hr/1.73m2 clearance Dialysis/Replacement fluid with [HC03]=35mmol/l Citrate ACG Serum collection at 0,1, 24, 25 and 48 hours TNF-alpha IL-1 beta IL-6, IL- 8, IL-10, IL-18 Six hours of effluent for CK’s for clearance estimation

ppCRRT Sepsis Study 10 patients enrolled to date PELOD 6 male, 4 female Mean age 12 + 4.8 years Mean weight 44 + 21 kg PELOD Mean = 27 + 10 Median = 22 (range 11-42)

ppCRRT [Cytokine] % Change: Convection vs. Diffusion TNF-alpha -3.7 + 9.6 3.9 + 9.1 0.08 IL-1 beta -2.8 + 14.8 1.4 + 12.9 0.46 IL-6 32.7 + 102.8 -2.6 + 18.4 0.21 IL-8 -29.1 + 26.0 - 8.3 + 17.2 0.018 IL-10 -44.6 + 29.0 3.1 + 45.0 0.007 IL-18 -13.6 + 17.9 16.9 + 24.7 0.002 PELOD -22 + 34 -6 + 30 0.26

Leaders in the Field Stu Goldstein began the ppCRRT and now the ppAKI study groups that have balanced research, QI with advancements

Has RRT improved out come? All modalities of RRT have changed from adaptive to newer products for children of all ages In the 90’s reports of 45 % survival rates have been replaced by current 65% survival rates in sepsis AKI

Has RRT improved out come? In the 90’s reports of 17 % survival rates have been replaced by current 53% survival rates in liver AKI as reported by Deep and Colleagues

Conclusion QI and Research have improved the diagnosis of AKI and the use of RRT Since the beginning of this time, patients have more co-morbidities and are more complicated

Future Areas primed for prospective and future research/QI include Optimal med dosing Optimal nutrition delivery Non dialytic options of treatment of AKI Science around starting and stopping RRT