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

3. 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.

4. 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

5. 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 ?

6. 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

7. 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

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

9. 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

10. 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

11. 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

12. When to start and when to end?

13. 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?

14. 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

17. 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

18. 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

19. 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

20. 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

21. K-DIGO Guidelines
Initiate RRT emergently when life threatening situations exist-(Not Graded)
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)
Stop RRT when no longer required.

22. 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

23. 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

24. 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

25. 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

26. CONVINT trial
252 pts, randomized to 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

27. 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

28. 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

29. 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

30. 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 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

31. 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

32. 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 ml/min With QD 300 ml/min
QF variable, but never above 500ml/hr
Bicarbonate dialysate with bi-bags
Modified –UAMS & UCD & MHNZ data

33. 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

34. 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
3-4 mEq/L, mEq/L
mEq/L
Citrate is useful in hep free situations

35. 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

36. 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

37. 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, Alonso et al, 2008

38. Hemodialyser BIMC- F40-Polysulphone, HF, 0.7 sq m,
MSHH- F60S, HF, 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

39. 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

40. 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

41. Urea kinetics solute removal in HD in slow flow situations
DUN/BUN QD 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

42. Optimal Dose?

43. 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

44. VA/NIH/ATN Study
All pts received HD/PIRRT/CRRT as per hemodynamic status
randomly assigned to either Intensive dosing or Less intensive dosing of RRT.
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

45. 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

46. 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%

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

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

51. 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

52. 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 low dose schedule, many treatments without heparin

53. 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

55. Take home points