Consulting Renal Physician, Dialysis in Sepsis Dr. Tushar Dighe M.D.(Medicine), D.M.(Nephrology) Consulting Renal Physician, Pune.

Dialysis in Sepsis Sepsis with AKI - reason for nephrologist in ICU Incidence & mortality of AKI in ICU remains unchanged over the years Probably means more sick pts rather than failure of critical care & nephrology When prevention & conservative treatment fails, we initiate RRT in ICU.

Sepsis and AKI Sepsis- > 50% of cases of AKI in the intensive care unit1. Septic AKI- renal replacement therapy in 2–3% of all ICU patients2. Mortality > 50% in patients of RRT3. 1 Uchino et al, 2005, 2 Bagshaw et al, 2007, 3 Palevsky et al, 2008

Goals of RRT in ICU Maintain cardiovascular stability When UOP low, must achieve ultrafiltration to enable daily infusion of obligatory fluid load Maintain excellent solute control even in presence of severely catabolic patients. But, How to attain this ?

The Options Continuous renal replacement -CRRT Intermittent hemodialysis- IHD Hybrid therapies - Prolonged intermittent renal replacement therapy-PIRRT Sustained low efficiency daily dialysis & diafiltration –SLEDD & SLEDD-f Extended daily & slow continuous dialysis EDD & SCD

Scope of the Talk Overview of RRT in sepsis Optimum modality Early vs late initiation of RRT PIRRT Various trials & our data Technical considerations of PIRRT Limitations Take home message

Will not be covering Early goal directed therapy protocols CRRT in all its glory Details of nomenclature CRRT machines Technical aspects of CRRT ECMO

Overview of Dialysis in Sepsis Continuous hemodialysis in ICU was initially described as an arteriovenous technique CAVHD Followed by CVVHD Both used equipment of HD Then came specialized equipment like filters, dialysate solutions & automated pumps & safety measures

Overview Continues These advances came with its price Specialized machinery Nursing needs Procedural complexities Increased costs of specialized replacement fluids & dialysate fluids All resulting high costs esp. in resource sensitive environment

Overview still Continues Thus intensified efforts to use & adapt the available batch & single pass intermittent hemodialysis equipment Since 1980s Now, several groups are using a variety of modifications to get optimal results Along with advantages of logistics & cost similar to IHD

When to start and when to end?

Early vs Late Initiation of RRT Accepted urgent indications of RRT Refractory fluid overload Hyperkalemia Uremic signs & Symptoms Severe metabolic acidosis Certain alcohol& drug intoxications We all like to start before such life threatening issues, but how early?

19th June 2008; AJKD Study Design: meta-analysis 23 studies (5 randomized or quasi-randomized controlled trials, 1 prospective and 16 retrospective comparative cohort studies, and 1 single-arm study with a historic control group). Conclusion: meta-analysis suggests that early initiation of RRT in patients with AKI might be associated with improved survival

Early vs Late Three RCTs evaluated whether early initiation of RRT and mortality1-3 were related. Bouman et al. found that late initiation or early initiation did not improve mortality and dialysis dependence1. 1 Bouman et al, 2002, 2 Sugahara et al, 2004, 3 Combes et al 2015

Early vs Late The largest prospective cohort study showed timing of RRT failed to influence outcomes in critically ill patients with severe AKI1. No differences in mortality observed between the early and late groups stratified by serum urea levels1. 1 Bagshaw et al, 2009

Early vs Late Systematic review and meta-analysis Early initiation of RRT in critically ill patients with AKI may have beneficial impact on survival compared with late initiation in specific situations1. 1 Karvellas et al, 2011

Early vs Late Initiation of RRT Optimal timing for initiating RRT is controversial. RCTs comparing strategies of Early v/s Late initiation of RRT in absence of clear indications have yielded conflicting results IDEAL-ICU & STARRT-AKI trials are underway & may allow more clear picture

K-DIGO Guidelines 5.1.1- Initiate RRT emergently when life threatening situations exist-(Not Graded) 5.1.2- Consider broader clinical context, conditions that can be modified with RRT & trends of laboratory investigations rather than single value when making decision of initiating RRT. ( Not Graded) 5.1.3- Stop RRT when no longer required.

Optimal Modality Number of modalities available for RRT IHD/ CRRT/SLED/Peritoneal dialysis Data do not support superiority of one mode over other Thus, local factors matter in majority Expertise/staff/equipment decide choice Selected patient population - more feasible for one mode over other e.g. cardiac surgery AKI & CRRT

HemoDiasafe study Vinsonneau c et al Lancet 2006 368:379 Prospective multicentric randomized controlled French trial 360 pts AKI & MODS, Randomly assigned to IHD or CVVHDF Survival at 60 days Similar severity of illness Good protocol adherence, low crossover, same dialysis membrane

HemoDiasafe study At 60 days, survival SAME in both groups, IHD -32 % vs CVVHDF 33% Similar hypotension & bleeding Even in subgroup of hemodynamically unstable pts Showed that it’s possible to perform IHD in practically all pts with AKI, given that complication rates were similar in both

CONVINT trial Schefold JC et al-Crit Care2014; 18;R11 Clinical Trial Comparing Continuous versus intermittent Hemodialysis in Intensive Care Patients- CONVINT Single center randomized controlled German trial

CONVINT trial 252 pts, randomized to CVVH @ 35 Ml/Kg/Hr or Daily Hemodialysis 19% of IHD pts shifted to CVVH 45% of CVVH shifted to IHD BOTH shifts due to complications IHD for severe hypotension/ vol mgt CVVH for filter clot/bleed/metabolic control/platelets/ mobilization

CONVINT Survival 14 days after stopping RRT IHD- 39.5% V/S CVVH 43.9% NO difference in in-hospital mortality NO difference in mortality at 30 day No difference in recovery of kidney function Overall, NO SURVIVAL BENEFIT to either CVVH or IHD

Hybrid therapies CRRT - convective & diffusive both CRRT-superior clearance of middle & large mol wt. molecules , than IHD which utilizes only diffusive clearance There are NO studies clearly showing improved clinical outcomes with CRRT Survival & recovery of kidney similar K-DIGO- complementary & not adversial

PIRRT Zhang L et al – EDD V/S CRRT in AKI ; A Meta Analysis. Am J Kidney Dis 2015;66;322 7 RCT & 10 Observational studies comparing PIRRT with CRRT NO DIFFERENCE with EDD V/S CRRT In mortality Or recovery of kidney function

Our data-Preliminary unpublished Retrospective chart analysis over last 12 months at our center ( 01/03/16 to 28/02/17) 72 bed in toto, Use EDD & CRRT ICU Adm-4599 pts 23914 pt-days of ICU stay RRT in ICU – 138 pt, 588 sessions(1-27) Sepsis as cause for AKI needing RRT-97 pts EDD- 86 pts, 561 sessions (1-27) CRRT-11 Pts, 27 sessions(1-3) Survival as discharge from hospital- 37 pts

Sustained Low efficiency extended daily dialysis SLEDD/EDD Multiple program all across world Use SLEDD in a varying pattern Beth Israel Medical Center- BIMC Univ of Arkansas- UAMS Univ of California-UCD Medical School Hannover, Germany- MSHH Middlemore Hosp Auckland New Zealand-MHNZ Univ of Parma, Parma Italy-UPI

The EDD prescription we use Fresenius 4008 B /S machine Fresenius F8 Polysulfone low flux dialyzer, Kuf 12 ml/hr for each mm of Hg 8 hrs daily treatment QB 100-200 ml/min With QD 300 ml/min QF variable, but never above 500ml/hr Bicarbonate dialysate with bi-bags Modified –UAMS & UCD & MHNZ data

Hemodialysis machine Available equipment 4008 B/S/Next Gen Some centers have modified the machines to deliver low dialysate flow Being in a corporate set up, I have not tried to modify the machine for the fear of losing the manufacturers guarantee on equipment!! So, dialysate flow at 300 ml/min , fixed

Dialysate We use bi-bag system by Fresineus Use the part A as available Have tried dextrose containing Dialysate in a few recently, but too little experience Composition of fluids varies K @ 3-4 mEq/L, Bicarb @ 24-32 mEq/L Ca @ 1.5-3.5 mEq/L Citrate is useful in hep free situations

Blood flow & anticoagulation Widely believed-lower blood flows = less hemodynamic issues. But very low blood flows = circuit clotting very often Citrate dialysate useful in preventing circuit clotting in heparin free HD Unfractionated heparin - gold standard Regional citrate anticoagulation is reportedly useful, but no personal experience

Ultrafiltrate rate Over 8 hrs, PIRRT prescription to remove UF about not more than 500 ml/hr As higher UF is always associated with higher rates of hypotension In a majority - heparin free dialysis, Thus necessitating NS flushes periodically, which need to be accounted for when deciding UF goal

Membrane? Systematic review of seven RCTs comparing mortality - use of BICM should be avoided1 Recent inclusive meta analysis by Cochrane Collaboration, nine RCTs and quasi-RCT in 1062 patients, failed to show that BCM resulted in lower mortality2. 1 Pannu et al, 2008 2 Alonso et al, 2008

Hemodialyser BIMC- F40-Polysulphone, HF, 0.7 sq m, MSHH- F60S, HF, 1.25 sq m UAMS- F8, LOW FLUX,1.8 sq m MNZ- AV600S, HF 1.4 sq m ARMC- AV600S, HF, 1.4 sq m UCD- Torray 1 , HF, polymethyl methacrylate, UPI- F7HPS, LOW FLUX, 1.6 sq m, Our data- F8, LF, 1.8 sq m

Anticoagulation Majority sessions heparin free Need NS flush periodically Other use low dose heparin 1000 unit bolus followed by 500 unit per hr infusion LMWH not used by us Regional citrate not used by us

Vascular access Acute setting, so Double/ triple lumen cath Right jugular followed by Left jugular then Right femoral then Left femoral Subclavian rarely Now started using tunneled cuffed catheters in selected pts with anticipatory need of RRT for prolonged period Arrow/ joline cath, QB 250 ml/min

Urea kinetics solute removal in HD in slow flow situations DUN/BUN ratio @ QD 30-50 ml/min is almost 100% implying complete saturation of dialysate with urea. With increasing blood & dialysate flow, the curve flattens. So, when QD is fixed as in our situations, suggested to keep QB maximum tolerated by catheter & pt

Optimal Dose?

Optimal Dose & survival ? The optimal dose of RRT for critically ill patients with AKI remains unclear. Study by Ronco et al. found survival at 15 days after discontinuation of CRRT was lower in the lowest dose(20 ml/kg/hr) than in intermediate (35 ml/kg/hr) and highest (45 ml/kg/hr) groups1. 1 Ronco et al 2000

VA/NIH/ATN Study All 1124 pts received HD/PIRRT/CRRT as per hemodynamic status randomly assigned to either Intensive dosing or Less intensive dosing of RRT. Death @ day 60- same for both Duration of RRT& Recovery- same More hypotention in intensive arm So, more intensive RRT does NOT improve survival as compared to standard dosing

RENAL study Randomized Evaluation of Normal versus Augmented Level of replacement therapy Australia & New Zealand, 1508 pt, randomly assigned to CVVHDF to either 40ml/kg/hr.( Augmented) or 25 ml/kg/hr. ( Normal) Mortality at 90 days same in both arms Renal recovery same Normal as good as Augmented RRT

DO-RE-MI study Dose Response Multicentric International Collaborative study Looked at actual dose delivered of RRT Median dose delivered was only 27 ml/kg/hr. as against prescribed 34.3 ml/kg/hr. Suggested to prescribe higher dose than desired delivered dose by factor of 20%

K-DIGO guidelines- dose of RRT 5.8.1- Dose of RRT should be prescribed before starting each session of RRT- (Not Graded) Frequent assessment of actual dose delivered to adjust prescription (1B)

K-DIGO guidelines- dose of RRT 5.8.2 provide RRT to achieve goals of electrolyte, acid-base, solute & fluid (Not Graded) 5.8.3- Kt/V of 3.9 per week for PIRRT (1A) 5.8.4-Effluent volume of 20-25 ml/kg/hr for CRRT in AKI (1A)

Take Home Points Acute RRT should be based upon local availability of resources & persons handling RRT matter. PIRRT & SLEDD – durable RRT in ICU Can be delivered to almost all category of patients Has advantages of CRRT & cost and feasibility advantages of IHD

Take home points Machine – Fresenius 4008 , dialysate standard QD- as per machine specifications, 300 ml/min in most settings Hemodialzer & tubing standard Uf need as per clinical setting & hemodynamics Anticoagulation unfractionated heparin most common @ low dose schedule, many treatments without heparin

Operational charachteristics Should achieve Kt/V of at least 1.2 per Rx Large solute control & drug clearance intermediate between IHD & CRRT & hence drug dosage modification individualised Fluid removal optimal Electrolyte & nutritional goals well met Outcomes comparable to CRRT

Take home points