1. Continuous Renal Replacement Therapy
Kelly Monaghan, DVM
Small Animal Internal Medicine
August 28, 2009

2. Indications Toxins/drugs Leptosporosis Oliguric/anuric renal failure
Acute kidney injury that is not responsive to traditional management
Acute kidney injury in critically ill patients
SIRS, sepsis?
Pull papers on use w/ SIRS/Sepsis

3. Benefits More closely approximates normal kidney function
Slower blood and dialysate flow rates
Smaller patients
Less dramatic changes/shifts
Cage-side system
Less maintenance required for machine
Less dramatic and abrupt changes in renal values

4. Basic Principles Blood is diverted from the patient to the unit
Anticoagulants are added to the blood before the filter
Uremic toxins are removed and electrolytes normalized
Blood is returned to the patient
Delete slide??

5. Diffusion
BUN and creatinine diffuse freely into dialysate through semipermeable membrane
Limited by the size of the membrane pores
Substances in dialysate also diffuse into blood
Movement of molecules in a solution from an area of high concentration to an area of low concentration
Dialysate solutions must be sterile and balanced and free of toxins, metals, etc (can be used to correct acidosis)

6. Convection
Blood traveling within semipermeable membrane is exposed to a positive transmembrane pressure
Pressure pushes fluid out of the blood (with toxins and electrolytes) and across the semipermeable membrane
Ultrafiltrate is removed from the dialyzer and disposed of as effluent
Larger molecules are more effectively cleared by this process than by diffusion
Can dehydrate patient or result in electrolyte imbalances if fluids/electrolytes are not replaced

7. Adsorption
Molecules adhere to the dialysis membrane and are removed from circulation
May be of benefit for SIRS/sepsis
Potentially requires more frequent filter changes
Membrane

8. The Machine Dialyzer Four pumps
Blood pump
Dialysis solution pump
Replacement solution pump
Effluent pump
Solutions are continuously weighed by machine

9. Filtration = Convection
Modes of Operation
SCUF
CVVH
CVVHD
CVVHDF
Filtration = Convection
Dialysis = Diffusion

10. SCUF Slow Continuous UltraFiltration
Least complex and most rapid (few hours)
Purely convection
Ultrafiltrate is not replaced in this modality
Congestive heart failure, fluid overload
No replacement solution
Aims to remove fluid, not solutes

11. SCUF

12. CVVH Continuous Veno-Venous Hemofiltration
Similar to SCUF (convection) but removed fluids are replaced with sterile, balanced electrolyte replacement solution to prevent hemoconcentration
Effective at removing uremic toxins through convection only
Purely convective w/ replacement solution
Best for middle sized molecules

13. Pre / Post Filter Replacement
Pre-filter Replacement
Replacement solution mixed with blood before passing through the filter
Decreased risk of filter clotting due to hemodilution
Decreased overall efficiency
Post-filter Replacement
Replacement solution is mixed with blood leaving the filter
Higher risk of filter clotting due to relative hemoconcentration within the filter
Improved efficiency
Pre-filter dilution
Instills replacement solution into blood b/f entering filter so dilutes out patient’s blood in the filter
Decreased filter clotting
Decreased efficiency
Lower risk of hypotension
Post-filter dilution
Replacement solution mixes w/ blood after blood has passed through the filter
Blood going through filter is more hemoconcentrated
Increased risk of filter clotting
Increased risk of hypotension since using patient for source of volume that ultrafiltrate will be drawn
More efficient
Not likely to be too efficient if doses are calculated beforehand
LSU uses this modality and reports low incidency of clotting and hypotension

14. CVVH

15. CVVHD Continuous Veno-Venous HemoDialysis Primarily diffusive therapy
Similar to intermittent hemodialysis
Toxins diffuse across membrane into dialysate
Beneficial substances diffuse into blood from dialysate
Purely diffusive
Most like IHD
Removes small molecules

16. CVVHD

17. CVVHDF Continuous Veno-Venous HemoDiaFiltration
Primary modality for our patients
= CVVH (convection) + CVVHD (diffusion)
Diffusion guides movement of uremic toxins and electrolytes
Convection causes movement of fluid and molecules out of blood

18. CVVHDF

19. Pathophysiology (Ronco and Ricci. Intensive Care Med 2008)
CRRT requires continuous contact of patient’s blood with foreign surfaces which activates the coagulation and complement cascade, leukocytes, and platelets
Activated leukocytes release inflammatory mediators and induce oxidative stress, transforming lipids and proteins and contributing to endothelial injury
Activated platelets aggregate and stimulate thrombin generation
Bio-incompatibility of RRT materials potentially enhances coagulation and inflammation pathways that are already triggered in the critically ill patients and that RRT is used to treat

20. Complications Clotting of dialyzer/circuit (blood loss) Hemorrhage
Thromboembolic events
Sepsis
Dialysis dysequilibrium (not reported in CRRT)

21. Anti-coagulation HEPARIN CITRATE Requires systemic anti-coaulation
Less intensive monitoring required
Reported shorter filter life (Kutsogiannis et al. Kidney Intl. 2005)
Heparin-induced thrombocytopenia (people)
Decreased risk of hemorrhage
Requires calcium supplementation
Risk of iatrogenic hyper/hypocalcemia
Risk of metabolic alkalosis as it is metabolized
More intensive monitoring
Human medicine debates this issue regularly and the literature seems to favor citrate due to lack of systemic anti-coagulation and prolonged circuit life
However, citrate associated w/ much more intense monitoring of acid/base and calcium as well as ACT; thereby increasing cost
Heparin Dosing
Remember: must enter into machine as ml/hr
LSU aims for ACT ~200s
Start of therapy
In the absence of coagulopathy (ACT >150) give 25 u/kg hep bolus
Recheck ACT. If <180 repeat bolus (max of 3 total boluses)
During CRRT
Start heparin infusion 20u/kg/h
If ACT<180, increase heparin by 1 u/kg/hr
If ACT>220, decrease heparin by 1 u/kg/hr
If ACT<150, bolus 15 u/kg heparin and increase CRI
Monitor ACT q30min after any change
Monitor ACT q1-2 hr once stable

22. Veterinary Literature
Only one paper by Diehl et al. JVECC 2008
Retrospective on 17 dogs and 16 cats that received CVVHDF
Regional citrate anticoagulation was performed
Median duration of CRRT in dogs was 16.3 hours and in cats was 11.5 hours (until values normalized)
UOP was not consistently monitored and therefore not reported
Complications: hypokalemia, CNS signs, hyper/hypocalcemia, hypothermia, alkalosis, filter clotting, chronic kidney disease
41% of dogs and 44% of cats survived to discharge
Patients received CRRT for ARF and A on CRF over 4 years
All patients failed standard medical management prior to RRT3 dogs,
2 cats died before collection of recheck labwork; all others showed improvement in the degree of azotemia
2 dogs and 1 cat developed hypotension (1 dog and the cat arrested)
10 dogs and 15 cats developed hypothermia
pRBC transfusion was required in 4 dogs and 4 cats
4 cats and 5 dogs developed iatrogenic metabolic alkalosis
Citrate anticoagulant:
4 dogs and 2 cats developed iatrogenic hypercalcemia
15 dogs and 13 cats developed hypocalcemia during CRRT (4 of each were clinical)
CNS
1 dog developed twitching and vocalization which resolved w/ mannitol (6.1% URR over 12.5 hrs)
1 cat developed nystagmus, head tremors, and facial fasciculation which resolved with mannitol (2.6% URR over 31.5hrs)
1 cat developed hyperexcitability, twitching, and anxiety which spontaneously resolved in 48 hours (9.2% URR over 9.5hrs)
1 cat with an 8 year seizure history developed progressive obtundation, convlusions, coma and arrested (4.8% URR over 16.5 hrs)
9 filters failed due to clotting In 6 dogs and 9 failed in 7 cats; 4 dogs had concurrent catheter clotting
Complications
Hypokalemia in 71% of dogs and 47% oc cats due to low potassium in dialysate
CNS signs in a cat with chronic hypernatremia due to rapid decrease in the sodium (not clear if this was the cause of death in this patient)
Total hypercalcemia and ionized hypocalcemia due to citrate anticoagulation
Metabolic alkalosis also possible b/c the citrate is metbolized to bicarb by the liver
Filter clotting
Significant hypothermia
CNS signs
May have been due to ionized hypocalcemia, cerebral infarct, cerebral vasospasmm, cerebral hypoxia, systemichypertension, intracranial hemorrhage, or dialysis disequilibrium syndrome as a result of an excessively rapid lowering of solutes from the extracellular fluid relative to the intracellular space resulting in cerebral edema
Recommended URR in IHD is 25-50%
DDS has never been reported in CRRT in humans!
Incidence of induction of CKD was 6% in cats while no dogs developed CKD

23. Intermittent HD versus CRRT
Which is the better choice for our patients?

24. Evidence-Based Medicine
No veterinary studies in this area
Several human papers that try to compare
To date, there is no clear answer

25. Theory of Practice Intermittent HD CRRT
Research in humans has failed to identify a difference in outcome/mortality b/t the two modalities
Felt in human medicine that CRRT is more appropriate for the cardiovascularly unstable and many comparison papers are biased in that theses patients are commonly in the CRRT group
CRRT more common in human medicine but tends to be more expensive

26. Literature Ricci and Ronco. Crit Care Med 2008 Review article
80% of centers use CRRT, 17% use IHD
Studies comparing the modalities have found conflicting results
Surviving Sepsis Campaign concluded that they should be considered equivalent in AKI
Problem in all of the studies is that despite attempts at randomization, CRRT population has significantly greater severity of illness scores and despite improved fluid balance and azotemia control, still had higher mortality in some studies
Metaanalysis by Kellum et al in 2002 found that after stratifying 1400 patients according to disease severity, CRRT was associated with a significant decrease in the risk of death when similar patients were compared
Metaanalysis by Tonelli et al in 2002 found no difference between the techniques
Concluded that the most important point with either is achieving an adequate dose
CRRT may be better in terms of total water and solute removal over 24 hours and hemodynamic tolerance, but IHD can remove much more water and solute per hour and it does not require continuous anticoagulation or complete immobilization
the question of superiority of a modality for renal support may be artificial
Reasonable to transfer a patient from CRRT to IHD as their clinical status changes or vice versa

27. Literature Bell et al. Intensive Care Med 2007
Concluded that there was better renal recovery for patients receiving CRRT than those that got IHD but no difference in mortality
Study does not discuss dose, time on machine, or severity of illness for each population
Metha et al 2001 had similar results

28. Literature Lins et al. Nephrol Dial Transplant (2009)
Randomized controlled trial stratified for disease severity
No difference between IHD and CRRT was observed in duration of ICU stay or hospitalization
Renal recovery at the time of discharge was comparable between groups
No difference in mortality between groups
Cross-over was allowed between groups
Cross-over of treatment was allowed and reasons included coagulation problems (CRRT to IHD) and hemodynamic instability (IHD to CRRT)
54% of patients were not randomized for medical reasons (hemodynamic instability or coagulation problems) or non-medical (availability of procedure, time)
Seems that these patients were included in final analysis though difficult to say for sure based on how paper is written)
No differences were noted in randomized or non-randomized groups
Randomized patients were overall younger and had lower severity scores

29. Literature Rauf et al. Intensive Care Med (2008)
Evaluated costs and outcomes associated with each modality
Patients in CRRT group had higher severity scores, higher incidence of sepsis and respiratory disease
Significantly longer hospitalization stays
Less likely to have chronic renal insufficiency
RRT method did not affect the likelihood of renal recovery, in-hospital survival, or survival during 1 year follow-up
Mean adjusted cost through hospital discharge was $93,611 for IHD patients and $140,733 for CRRT patients

30. How do we apply this?
General consensus that CRRT may be better for cardiovascularly unstable patients
Veterinary dialysis patients tend to correlate with the most critically ill and often, cardiovascularly unstable human patients

31. Future Directions IHD for toxins, transient insults
CRRT for critical patients and follow-up IHD if needed
Consider use in septic AKI

32. Use in Sepsis / SIRS Ronco et al. Artificial Organs (2003)
Peak-concentration theory: cutting peaks of soluble mediators
CRRT non-selectively removes peak concentrations of pro- and anti-inflammatory mediators
Non-selective adsorption produced in excess may improve survival
May require higher doses of CRRT as compared with renal injury alone
Peng et al. Burns (2005)
CVVHDF given to burn patients with sepsis
Plasma level of endotoxin, TNF-α, IL-1β, IL-6, and IL-8 significantly lower than pre-treatment or control
Endotoxin not present in effluent
No significant differences in median hospitalization or mortality
Joannidis M. Seminars in Dialysis (2009)
Review
Use of standard CRRT in absence of AKI did not demonstrate changes in levels of cytokines or complement at standard doses (DeVriese et al 1999)
High adsorption hemofiltration (changing filter q3h in CVVH) showed significant reduction in IL-8 and IL-10 as well as faster reduction in vasopressor requirements (Haase et al 2007)
High volume hemofiltration used to increase convection and adsorption utilizing filtration rates up to 215ml/kg/h showed improved hemodynamic stability and survival

33. Cost ~$1100 per day for treatment Estimate $10,000-15,000
Owner should be prepared for at least hours of treatment

34. For More Info or Questions
Anyone on dialysis team
Happy to consult, talk with owners or RDVMs
Personal contact info
Pager: (508)
Cell: (225)
Home: (508)

35. QUESTIONS?