Pediatric AKI in Bad Pediatric CRRT is Hard

Pediatric AKI in Bad Pediatric CRRT is Hard David Askenazi MD, MSPH Professor of Pediatrics Director Pediatric and Infant Center for Acute Nephrology (PICAN)

Potential COI Speaker for Baxter, and the AKI Foundation

Objectives Review neonatal and pediatric AKI epidemiology Review neonatal and pediatric CRRT epidemiology Discuss the added challenges to Neonatal CRRT Provide a framework to determine which neonates and children should be offered CRRT

Despite overwhelming data from animals and bigger humans.there are still clinicians who will say they just happen to have AKI.It s part of the death process Show me some data Does this sound familiar? Do these conversations happen in your ICU s?

AWARE Epidemiology: Main Variables of interest Exposure: Severe AKI (Stage 2 or 3 KDIGO) Outcomes 28 day mortality (PRIMARY) PICU LOS Need for mechanical ventilation

26.9% of all patients 11.6% of all patients 3.5% of cohort died AKI patients make up 50% of all Deaths

26.9% children had AKI within 7 days 11.6% Severe AKI NEJM 2017

Supplementary Table S4a: AKI MAX-associated Risk with Mortality in Multivariate Logistic Regression Models to Adjust for Severity of Illness using PRISM-III, PIM-2 and PELOD Scores 3 AKI MAX associated-risk on mortality (Adjusted for PRISM-III as severity of illness score) N= 1263 AKI MAX associated-risk on mortality ( Adjusted for PIM-2 as severity of illness score) N= 1363 AKI MAX associated-risk on mortality ( Adjusted for PELOD as severity of illness score) N= 859 OR (95% CI) p OR (95% CI) p OR (95% CI) p AKI MAX 1 1.18 (0.50 2.47) 0.69 1.29 (0.37 1.86) 0.76 1.46 (0.56 3.34) 0.41 Severity Score 1.13 (1.09 1.17) <0.0001 1.06 (1.05 1.07) <0.0001 1.13 (1.09 1.16) <0.0001 AKI MAX 2 1.41 (0.34 3.79) 0.56 1.66 (0.57 3.99) 0.32 2.28 (0.45 42.00) 0.38 Severity 1.13 (1.09 1.17) <0.0001 1.06 (1.05 1.07) <0.0001 1.12 (1.09 1.16) <0.0001 Score AKI MAX 3 6.08 (2.70 13.01) <0.0001 8.21 (4.07 15.83) <0.0001 4.78 (1.77 11.83) 0.003 Severity 1.10 (1.06 1.14) <0.0001 1.06 (1.05 1.07) <0.0001 1.11 (1.07 1.15) <0.0001 Score Severe AKI MAX Severity Score 4.01 (2.01 7.72) 0.0001 5.12 (2.80 9.15) <0.0001 2.41 ( 1.00 5.36) 0.038 1.10 (1.06 1.15) <0.0001 1.05 ( 1.04 1.07) <0.0001 1.11 (1.07 1.15) <0.0001 Any AKI 1.87 (1.4 2.43) <0.0001 2.01 (1.59 2.54) <0.0001 3.91 (1.47 9.83) 0.007 Severity 1.10 (1.06 1.14) <0.0001 1.05 (1.04 1.07) <0.0001 1.11 (1.08 1.15) <0.0001 Score AKIMAX, Maximum acute kidney injury stage within 7 days of intensive care unit admission; Severe AKI MAX = AKI MAX Stage 2 or 3; OR, Odds Ratio; PELOD, pediatric logistic organ dysfunction; PIM-2, Pediatric Index of Mortality 2; PRISM-III, Pediatric Risk of Mortality-III.

Supplementary Table S4a: AKI MAX-associated Risk with Mortality in Multivariate Logistic Regression Models to Adjust for Severity of Illness using PRISM-III, PIM-2 and PELOD Scores 3 AKI MAX associated-risk on mortality (Adjusted for PRISM-III as severity of illness score) N= 1263 AKI MAX associated-risk on mortality ( Adjusted for PIM-2 as severity of illness score) N= 1363 AKI MAX associated-risk on mortality ( Adjusted for PELOD as severity of illness score) N= 859 OR (95% CI) p OR (95% CI) p OR (95% CI) p AKI MAX 1 1.18 (0.50 2.47) 0.69 1.29 (0.37 1.86) 0.76 1.46 (0.56 3.34) 0.41 Severity Score 1.13 (1.09 1.17) <0.0001 1.06 (1.05 1.07) <0.0001 1.13 (1.09 1.16) <0.0001 AKI MAX 2 1.41 (0.34 3.79) 0.56 1.66 (0.57 3.99) 0.32 2.28 (0.45 42.00) 0.38 Severity 1.13 (1.09 1.17) <0.0001 1.06 (1.05 1.07) <0.0001 1.12 (1.09 1.16) <0.0001 Score AKI MAX 3 6.08 (2.70 13.01) <0.0001 8.21 (4.07 15.83) <0.0001 4.78 (1.77 11.83) 0.003 Severity 1.10 (1.06 1.14) <0.0001 1.06 (1.05 1.07) <0.0001 1.11 (1.07 1.15) <0.0001 Score Severe AKI MAX Severity Score 4.01 (2.01 7.72) 0.0001 5.12 (2.80 9.15) <0.0001 2.41 ( 1.00 5.36) 0.038 1.10 (1.06 1.15) <0.0001 1.05 ( 1.04 1.07) <0.0001 1.11 (1.07 1.15) <0.0001 Any AKI 1.87 (1.4 2.43) <0.0001 2.01 (1.59 2.54) <0.0001 3.91 (1.47 9.83) 0.007 Severity 1.10 (1.06 1.14) <0.0001 1.05 (1.04 1.07) <0.0001 1.11 (1.08 1.15) <0.0001 Score AKIMAX, Maximum acute kidney injury stage within 7 days of intensive care unit admission; Severe AKI MAX = AKI MAX Stage 2 or 3; OR, Odds Ratio; PELOD, pediatric logistic organ dysfunction; PIM-2, Pediatric Index of Mortality 2; PRISM-III, Pediatric Risk of Mortality-III.

Urine trouble 3X higher than central line Must know: infections UOP-AKI 1 out of 3 dead ~20% missed 10X higher than catheter associated UTI NEJM 2017

AWAKEN Assessment Worldwide Acute Kidney Epidemiology Neonates Published on September 7 th, 2017 Lancet: Child and Adolescents - online first

AWAKEN methods Multi-center retrospective cohort study 24 level 2-4 NICUs NICU admissions from Jan 1 March 31, 2014 Inclusion criteria Admission during the study period Provision of at least 48 hours of IV fluids Exclusion criteria Admission at > 2 weeks of life Newborns requiring congenital heart disease repair < 7 days of life Death within 48 hours of admission Lethal chromosomal anomaly Severe, bilateral congenital kidney and urinary tract disease

Neonatal AKI definition Stage Serum Creatinine (SCr) Urine Output (UOP)** 0 No change in SCr or rise < 0.3 mg/dl > 1 ml/kg/hour 1 SCr rise 0.3 mg/dl within 48 hrs or SCr rise 1.5-1.9 X reference SCr* > 0.5 and 1 ml/kg/hour SCr rise 2 to 2.9 X reference SCr* > 0.3 and 0.5 ml/kg/hour 2 SCr rise 3 X reference SCr * or 3 SCr 2.5 mg/dl or Receipt of dialysis *reference value is lowest previous value **includes days #2-7 only (day of birth = day #1) 0.3 ml/kg /hour

AWAKEN: Breakdown of Screened vs. Enrolled

AKI Incidence in AWAKEN study All Enrolled Neonates 30% No AKI AKI 70%

AKI Incidence by GA 41% 14% 45% GA 22-29 (N=273) GA 29-36 (N=916) GA 36+ (N=833)

AKI incidence by GA GA 22-29 57% 43% 41% 14% 45% GA 22-29 (N=273) GA 29-36 (N=916) GA 36+ (N=833) No AKI AKI

AKI Incidence by GA GA 22-29 57% 43% 41% 14% 45% GA 22-29 (N=273) GA 29-36 (N=916) GA 36+ (N=833) No AKI AKI 18% GA 29-36 82%

AKI Incidence by GA GA 22-29 GA 36+ 57% 43% 63% 37% 41% 14% GA 22-29 (N=273) GA 29-36 (N=916) 45% GA 36+ (N=833) No AKI AKI 18% GA 29-36 82%

AKI Outcomes in AWAKEN study Enrolled Neonates Mortality Rates: AKI: 59/605 (9.7%) NO AKI: 20/1417 (1.4%) p<0 0001 70% 30% No AKI AKI

Outcomes by AKI status Crude p-value Adjusted p-value Mortality OR=7 5 (4 5 12 7 ) <0 0001 OR=4 6 (2 5 8 3)* <0 0001 Length of Stay (Days) Parameter Estimate 14 9 (11 6 18 1) < 0 0001 Parameter Estimate*** 8 8 (6 1 11 5) <0 0001 *Logistic model for mortality adjusted for Gestational Age, Mode of Delivery, Neonatal Intubation, Neonatal Chest Compression, Neonatal Saline Use, Admission for Respiratory Failure, Admission for Seizures, Admission for Hypoglycemia, Admission for Congenital Heart Disease, Neonatal Height, Neonatal Temperature, and Admission for Other Reasons **Linear model for LOS adjusted for Gestational Age, Birthweight, Neonatal Intubation, Neonatal Chest Compression, Admission for Prematurity, Admission for Respiratory Symptoms, Admission for Respiratory Failure, Admission for NEC, Admission for Omphalocele, Maternal Multiple Gestation, Maternal use of NSAIDs, Neonatal Height, Neonatal Head Circumference, Neonatal APGAR of 5 minutes, and Admission for Other Reasons

CRRT in little ones First infant treated with CAVH Claudio Ronco et.al Vicenza, Italy, circa 1980

ppcrrt manuscripts The prospective pediatric continuous renal replacement therapy (ppcrrt) registry: a critical appraisal. Sutherland SM, Goldstein SL, Alexander SR. Pediatr Nephrol. 2014 Nov;29(11):2069-76. doi: 10.1007/s00467-013-2594-5. Epub 2013 Aug 28. Review. Continuous renal replacement therapy for children 10 kg: a report from the prospective pediatric continuous renal replacement therapy registry. Askenazi DJ, Goldstein SL, Koralkar R, Fortenberry J, Baum M, Hackbarth R, Blowey D, Bunchman TE, Brophy PD, Symons J, Chua A, Flores F, Somers MJ. J Pediatr. 2013 Mar;162(3):587-592.e3. doi: 10.1016/j.jpeds.2012.08.044. Epub 2012 Oct 24. Continuous renal replacement therapy (CRRT) after stem cell transplantation. A report from the prospective pediatric CRRT Registry Group. Flores FX, Brophy PD, Symons JM, Fortenberry JD, Chua AN, Alexander SR, Mahan JD, Bunchman TE, Blowey D, Somers MJ, Baum M, Hackbarth R, Chand D, McBryde K, Benfield M, Goldstein SL. Pediatr Nephrol. 2008 Apr;23(4):625-30. doi: 10.1007/s00467-007-0672-2. Epub 2008 Jan 29. The effect of vascular access location and size on circuit survival in pediatric continuous renal replacement therapy: a report from the PPCRRT registry. Hackbarth R, Bunchman TE, Chua AN, Somers MJ, Baum M, Symons JM, Brophy PD, Blowey D, Fortenberry JD, Chand D, Flores FX, Alexander SR, Mahan JD, McBryde KD, Benfield MR, Goldstein SL. Int J Artif Organs. 2007 Dec;30(12):1116-21. Demographic characteristics of pediatric continuous renal replacement therapy: a report of the prospective pediatric continuous renal replacement therapy registry. Symons JM, Chua AN, Somers MJ, Baum MA, Bunchman TE, Benfield MR, Brophy PD, Blowey D, Fortenberry JD, Chand D, Flores FX, Hackbarth R, Alexander SR, Mahan J, McBryde KD, Goldstein SL. Clin J Am Soc Nephrol. 2007 Jul;2(4):732-8. Epub 2007 May 18. Evaluation of the PRISMA M10 circuit in critically ill infants with acute kidney injury: A report from the Prospective Pediatric CRRT Registry Group. Goldstein SL, Hackbarth R, Bunchman TE, Blowey D, Brophy PD; Prospective Pediatric Crrt Registry Group Houston. Int J Artif Organs. 2006 Dec;29(12):1105-8. The Prospective Pediatric Continuous Renal Replacement Therapy (ppcrrt) Registry: design, development and data assessed. Goldstein SL, Somers MJ, Brophy PD, Bunchman TE, Baum M, Blowey D, Mahan JD, Flores FX, Fortenberry JD, Chua A, Alexander SR, Hackbarth R, Symons JM. Int J Artif Organs. 2004 Jan;27(1):9-14. Review.

CRRT Outcomes in Newborns Underlying Diagnosis Survival (%) (n=84) Sepsis Renal disease (n=25) (n=5) 36% 80% Cardiac Inborn error disease of Metabolism (n=16) (n=13) 38% 62% Inborn Pulmonary error disease of Metabolism (n=5) (n=13) 62% 60% Hepatic Oncologic disease (n=9) (n=6) 50% Oncologic Cardiac disease (n=16) (n=6) 50% 38% Pulmonary Sepsis (n=25) disease (n=5) 60% 36% Renal Hepatic disease (n=5) (n=9) 80% Other (n=5) 75% Total cohort (n=84) - If > 10kg = 64% Highest survival in - Primary renal diseases - Inborn errors Lowest Survival in - Liver failure - Sepsis - Cardiac disease -Askenazi DJ, et. al.. Continuous Renal Replacement Therapy for Children 10 kg: A Report from the ppcrrt Registry. J Pediatr. 2012 Oct 23.

Smaller children in ppcrrt have lower survival 70% 60% 50% 40% 30% 20% 10% 0% <5 kg 5-10 kg <10 kg >10 kg Askenazi et al. Journal of Pediatrics 2013;162:587-92.

Small children are dialyzed differently! < 5kg > 5kg N = 170 N = 251 Anticoagulation Protocol Citrate 76 (45%) 155 (62%) Heparin 94 (55%) 96 (38%) <0.001 Prime <0.001 Blood 164 (96.5%) 202 (80%) Saline 5 (3%) 29 (12%) Albumin 1 (0.5%) 20 (8%) Blood Flow * (ml/kg/min) 12 (7.9-15.6) 6.6 (4.8-8.8) <0.001 Daily Effluent Volume* (ml/hr/1.73m 2 ) 3328 (2325-4745) 2321 (1614-2895) <0.001 Circuit LIfe 28 (11-67) 37 (16-67) 0.15 Askenazi et al. Journal of Pediatrics 2013;162:587-92.

What we are doing here? 4 kg infant Blood volume = 80 * kg 320 ml Blood flow = 50 ml/min = (12 ml/kg) Clearance flow rates = 3500 ml/1.73m 2 /hr = 400 ml/hr System HF 1000 BSA 1.1 m2 (5 times infant s BSA) Extracorporeal volume (ECV) = 165 ml % ECV = 165/320 50%

What if we did that to me 70 kg Blood volume = 70 * kg 5000 ml = 5 L Blood flow = 840 ml/min = (12 ml/kg) Clearance flow rates 7000 ml/ hr = 100/kg/hr System MEGA-25,000 BSA 8.6 m2 (5 times BSA) Extracorporeal volume (ECV) = 2.5 L % ECV = 2.5 L /5 L 50%

What about a 2 kg infant Blood volume = 80 * kg 160 ml Blood flow = 50 ml/min = (24 ml/kg) Clearance flow rates = 3500 ml/1.73m 2 /hr = 200 ml/hr System HF 1000 BSA 1.1 m2 (5 times infant s BSA) Extracorporeal volume (ECV) = 165 ml % ECV = 165/320 101%

What about a 1 kg infant

Circuit Priming for Neonatal CRRT

When Should a Blood Prime Be Considered? ECV: > 10% of TBV Extracorporeal RBC volume: If the drop of original RBC volume is greater than 30% or the patient is hemodynamically unstable, anemic, or at risk of organ ischemia. Kim,H. Therapeutic Pediatric Apheresis. Journal of Clinical Apheresis 15 (2000):129-157

Added Risk for PRBC prime Packed RBCs HYPOCALCEMIC Citrate HYPERKALEMIC LYSIS OF CELLS ACIDIC There are no Plts in packed prbc s Every prime you start CRRT you should expect for your plts count to drop Example: 4 kg infant (BV = 80 * kg = 320) HF 1000 (ECV = 160) Expect a drop in plts of 33% There are no coagulation factors in prbc s Every prime you start CRRT you should expect for your coagulation factor to drop.

Added Risk for PRBC prime Anticipate the need for plts, ffp for those with high ECV Protocols for initiation of CRRT use need to keep in mind that blood is acidotic (ph 7.0) and hypocalcemic (ica around 0.3) Reconstitute the blood like ECMO folks do and use it to prime Dialyze the Blood before you start Incorporate bicarbonate and calcium Just do it and be ready to give calcium and bicarbonate If you have a circuit running and need to change USE THE BLOOD in the current circuit for the second circuit

CRRT in small children So, lets acknowledge. Can be a complex puzzle Even with the best practices.this approach exposes the smallest children to added risk People (Nurses, Families, Doctors and Babies Get nervous when the BIG BLOOD MACHINE COMES INTO THE ROOM

When should you start CRRT In a small child? Ask the following questions What are we trying to accomplish? Why do neonatologist hate calling the nephrologist and the nephrologist hate the call from the neonatologist?

Do we agree on the following? Doctors shouldn t do things to their patients just because. Doctors have been trained (and are compensated) because they can make decisions? Starting insulin to gain control of blood glucose physiology Start Pressor to gain control of organ perfusion physiology Start antibiotic to gain control of Infectious disease physiology Intubate - to gain control of Pulmonary Physiology Put a bolt in someone s head to gain control of Brain Physiology

WHEN SHOULD A DOCTOR START A THERAPY? When your patient can benefit from it! When the natural course of events will likely lead the a worse place than the place your patient will be with your intervention. When what you have to offer will improve the chances for a good outcome 45

Does anyone with respiratory distress need to be intubated? NO that ridiculous! But sometimes you may have mild distress and you should intubate. (say in a trauma and you need an airway) And we intubate folks before they are in respiratory distress? (for elective surgery) WE INTUBATE A PATIENT WHEN WE NEED CONTROL OF THEIR PULMONARY PHYSIOLOGY 46

When to Start Renal Support Therapy? When your patient can benefit from it! WHEN WE NEED CONTROL OF THEIR KIDNEY PHYSIOLOGY When there is impending harm from the inability of the kidney to do its job. Clear waste products Manage electrolytes Maintain the fluid balance Including inability to nourish Why should this be different in children? in babies? 47

Conversation between DJA and neonatologist circa 2013. DJA: Whey didn t you call me before the patient was so fluid overloaded that we couldn t find his neck to put a catheter so that we can improve his fluid overload? imagine if you couldn t start insulin cause the glucose was too high You couldn t start pressors cause the blood pressure was too low You couldn t start antibiotics because the infection was too disseminated Dr. Dirk T. Diaper: It s a pain they call me all night long with issues My nurses are not really comfortable Patients always crash when you start It doesn t work well They have all these complication All the patients who go on your machines die

So, how do we swing the Pendulum? Education is big Quality improvement Process is huge Smaller circuits are the Humongous RISK Benefit

We addressed these concerns! Enhanced training Quarterly classes for NICU 57 nurses trained last year Enhance QI Yearly review of NICU specific patients Worked with Surgery to figure out how to put in optimal cathters 50

NICU Specific QI data Hypotension Requiring Intervention at Intervention 96% 1000 800 600 400 200 0 CRRT days in NICU by machine by year 2013 2014 2015 2016 2017 2018 aquadex Prismaflex 27% 73% no yes Non-Patient Issue Circuit Survival (>60 hrs) goal met goal not met system 51

Catheter complications (rate per 10 catheter days) Old approach (n=37) New approach (n=9) RR (95% CI) p-value All complications 3.39 1.91 0.96 (0.32-2.87) 0.95 Revisions 0.16 0.00 Undefined - Replacements 0.29 0.06 0.20 (0.06-0.70) 0.01 Bleeds 0.50 0.04 0.10 (0.02-0.43) <0.01 Infections 0.00 0.06 Undefined - Clots 0.26 0.10 0.38 (0.15-0.94) 0.04 tpa 0.74 0.43 1.88 (0.43-8.23) 0.40 * Estimated from a negative binomial model and in reference to the old" group 52

What if you had better tool? A Neonatal Specific Machine? Could use smaller access Could use smaller blood flows as the resistance of the tubing would be smaller Could avoid blood prime Even if you needed to blood prime A 50% blood prime is not as dangerous as a 12% blood prime

What if we all had a smaller circuit?