CRRT Prescription Akash Deep Director - PICU King’s College Hospital London Chair Renal/CRRT Section European Society of Pediatric and Neonatal Intensive Care (ESPNIC)

Not necessarily a recipe Overview Vascath – Size , location Rates & Dose Blood flow Dialysis fluid Replacement fluid Ultrafiltration rate Anticoagulation Drug Dose Suggested Not necessarily a recipe

Is there a “typical” prescription? CRRT for AKI or Sepsis or Liver failure does the dose matter ? Modality : Do you do convective or diffusive or both , does it matter? Blood Flow rate: based upon the size of the child or what the vascular access can give you? Anticoagulation – Which, when, dose, mode of delivery Drug dosing – a perennial debate!!!!

Essential steps in CRRT Prescription Decide the Indication to start CRRT PRESCRIBE: VASCULAR ACCESS – Size Location Haemofilter and appropriate Sized Blood line set Priming Solution Blood Flow Modality /Dose – Replacement Fluid/Dialysis Fluid Prescribe Fluid loss rate Prescription of electrolyte corrections Anticoagulation – Dose,Modality, Monitoring Drug Dosing

Blood flow rate Qb Age & weight – based Promote circuit lifespan + patient stability: clots vs alarms Highly access-dependent Aim return access pressures ~ < 200 mmHg, no alarms Start lower and increase by about 10 minutes (?) – 50% of target and then go up 10% every 10 minutes till desired flow reached

Blood flow rate No set “perfect rates” From 3 to ~10 ml/kg/min, depending on age though we use minimum of 50 mls/min for newborns Examples: 0-10 kg: 25-50ml/min 11-20kg: 80-100ml/min 21-50kg: 100-150ml/min >50kg: 150-180ml/min Neonates 8 to 12 ml/kg/min Children 4 to 8 ml/kg/min Older 2 to 4 ml/kg/min. Most not > 200 ml/min: not dangerous just not necessary Based on previously most commonly used machine

Blood flow rate May need to modify: - Patient hemodynamics – initial and subsequent which might change with CRRT - Be aware of access and return pressure - Visually inspect filter for clots - Trans-membrane pressure – may need to increase blood flow

Treatment Dose

Dialysis and Replacement Fluid Rates: Clearance & Dose Clearance mostly a function of: Dialysis fluid flow rate (Qd) Replacement fluid flow rate (Qr) Molecular weight and sieving coefficient Higher rates = higher clearance for IEM, drug removal, severe high K = more middle molecule clearance (CVVH/CVVHDF) = more hypophosphatemia, kalaemia, magnesaemia = more amino acid losses = more drug clearance = more work to change bags, give electrolyte infusions Qd + Qr (CVVHDF)

Dialysis and Replacement Fluid Rates: Clearance & Dose No well-defined right “dose” of clearance. For CRRT: mostly expressed in terms of effluent (ml/kg) per hour “Standard” suggestion: Qd or Qr or Qd+Qr ~ 40-60 ml/kg/hour OR 2 to 2.5 liters/hr/1.73msq. Some do much higher: some machines as high as 8L/hour REALIZE: What you prescribe is not necessarily what the patient gets!! Time off circuit, microclots in filter over time, predilution Urea clearance ~ 30-40 ml/min/1.73msq

Prescribed and Delivered therapy dose Typically, therapy dose would be prescribed at 35 ml/kg/hr, in practice the delivered therapy dose was on average 8ml/kg/hr less. Prescription should exceed that calculated to be adequate because of the known gap. Why might we ‘lose’ significant amounts of therapy dose? Recirculation in vascular access High filtration fractions Filter clogging and clotting Troubleshooting skills Changing of circuits Filter down time Vesconi et al Delivered dose of renal replacement therapy and mortality in critically ill patients with acute kidney injury Crit care 2009 13 (2);r57

CVVH Qr = 300 ml/hour CVVHDF Qd = 150ml/hour Qr = 150 ml/hour 10 kg child: 30 ml/kg/hr “clearance” OR ~ 0.26 msq: 2L/1.73msq/hour = 300 ml/hour CVVHD Qd = 300 ml/hour

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

ATN Study

Randomised Evaluation of Normal vs Augmented Level Replacement (RENAL) Therapy ) 1500 critically ill adults CVVHDF 25 ml/kg/hour 40 ml/kg/hour Mortality at 28 days was similar in the higher-intensity and lower-intensity treatment groups (38.5% and 36.9%, respectively), and mortality at 90 days was the same (44.7%) in both groups.

Does the dose of solution exposure per unit of time matter These adult studies have failed to note a dose response curve of survival These studies are flawed for IHD vs CRRT was compared and CRRT was both convective and diffusive

So If you start with a standard prescription Eg BFR 5-10 mls/kg/min (access dependent) Membrane surface area proportional to patient body surface area Decision of convective or diffusive at approx 2000-3000/mls/hr/1.73m2

and If the marker of your clearance is not achieved E.g. inadequate clearance of Urea, Ammonia, intoxicant, lactate Then increase your solution exposure per unit of time Maximize convective clearance before adding diffusive clearance Consider increasing the BFR and increasing surface area of the membrane Filter downtimes to be minimised

Solutions CVVHD – dialysis fluid for diffusive clearance CVVH – replacement fluid: replacing fluid you are removing to achieve solute clearance by convection CVVHDF – both Priming solutions – Saline /blood prime Anticoagulant solutions Using these to correct metabolic abnormalities (remove) and prevent treatment-related metabolic abnormalities (replace).

Dialysis fluid? Replacement fluid? Personal suggestion: use the same solution If needed (e.g. alkalosis) can modify the replacement solution Regulatory issues may hinder: Replacement solution – saline, with additives

Solutions: watch for errors! Barletta et al, Pediatr Nephrol, 2006 Survey: ICU, Nephrology, CRRT 16/31 programs reported solution compounding errors with manually dispensed solutions 2 deaths 1 non lethal cardiac arrest 6 seizures (hypo/hypernatremia) 7 without complications

Ultrafiltration/fluid removal Rates 2323 Ultrafiltration/fluid removal Rates No Study has identified effective, safe UF rates in Children. General acceptance that 1-2ml/kg/hr is often safe (stable patient) Choose UF rate to: - balance input (e.g. boluses, citrate, calcium, etc) - remove excess fluid over time - “make room” for IV fluids and nutrition - Also provides solute clearance by convection

Ultrafiltration/fluid removal Rates Fluid removal should be safe AND effective – no need to sacrifice one for other: Frequent communication Frequent reassessment (MD), Hourly reassessment (RN) Know what the “usual hourly input is”: IV fluids Citrate & calcium Nutrition (give!!) Meds/infusions Provide “rules” for removing “intermittent fluids” Be aware of the “outs” (tubes, urine, diarrhea) Decide desired DAILY fluid removal based on: Haemodynamics TOTAL severity of Fluid Overload

SINGLE PASS Albumin dialysis -SPAD Removes protein bound small substances: e.g. copper/Wilson's, drugs, toxins of liver failure Albumin live a scavenger Dialysis: albumin-containing solution across highly permeable membrane 20% albumin NOT “added” to dialysis fluid bag- it sinks however it is mixed with normal dialysate via 3 way tap -it's “single pass” - bags are changed Shouldn't affect sodium – may affect (reduce) other electrolytes Collins et al, Pediatr Nephrol, 2008 Askenazi et al, Pediatrics, 2004 Ringe, Pediatr Crit Care Med, 2011

ANTICOAGULATION

ANTICOAGULATION-Points to consider Choice of anticoagulant Dose Route of delivery – systemic, into the circuit

Anticoagulation Heparin Citrate Prostacyclin

Dosing and Route Heparin – 10-20 U/kg/hour Prostacyclin – 2-8 ng/kg/min Citrate – separate protocol All anticoagulants to be used pre-filter with post filter monitoring ( ACT in heparin, ionised Ca in citrate)

Drug Dose Alteration Drug dosing- important ( antibiotics, anticonvulsants, sedation, inotropes) Hepatic failure + CRRT – Bigger issues Based on: Protein Binding Information Volume of Distribution Molecular Weight

Drug Prescribing in Renal Failure edited by George Aronoff et al Commonly carried text by pharmacists http://www.kdp-baptist.louisville.edu/renalbook/ New edition to come out soon Recommendations for new drugs IHD and CRRT recommendations Pediatric recommendations (T bunchman)

Summary Blood flow: balance access/circuit life with tolerability Solutions: Many choices Know their content, regional rules, CRRT type used Decide on desired flexibility Decide what's best for your institution (volume, expertise) Bicarbonate and calcium are most substantial differences Be aware of errors – can be life threatening Dialysis/replacement fluid rates: ie clearance dose Balance desired clearance with undesired losses 2-2.5 L/hour/1.73msq – suggested only Ultrafiltration rate: Frequent reassessment, team + targeted fluid removal decisions Safety AND efficacy are feasible

Acknowledgements T Bunchman pCRRT Foundation CRRT team at King’s