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Role of CRRT in Sepsis. Dr Apoorva Jain Agra. SEPSIS: BACKGROUND. Severe Sepsis and Septic Shock are the primary causes of Multiple Organ Dysfunction Syndrome (MODS) [of which Acute Renal Failure-is part of] One of the most common cause of mortality in the ICU setting.

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role of crrt in sepsis

Role of CRRT in Sepsis

Dr Apoorva Jain

Agra

sepsis background
SEPSIS: BACKGROUND
  • Severe Sepsis and Septic Shock are the primary causes of Multiple Organ Dysfunction Syndrome (MODS) [of which Acute Renal Failure-is part of]
  • One of the most common cause of mortality in the ICU setting
sepsis background1
SEPSIS: BACKGROUND
  • Variety of Water soluble mediators with Pro & Anti- Inflammatory Activities play a strategic role in Septic Syndrome including (but not limited to):

TNF, IL-6,IL-8 and IL-10, Kinins, Thrombins, heat shock proteins

sepsis background2
SEPSIS: BACKGROUND
  • Stimulus –Receptor coupling sets off the signal transduction cascade resulting in exacerbated generation of; Platelet activating factor, cytokines, leukotrienes, Arachidonic acid derivatives etc.) and activation of the complement cascade and coagulation pathways.
sepsis pathophysiology
SEPSIS: Pathophysiology
  • Dysfunctional homeostatic balance results in increased biological activity of sepsis associated mediators and loss of control over these by specific inhibitors-cell hypo-responsiveness
  • This excessive anti-inflammatory counterpart to SIRS has been coined “CARS- Compensated Anti-inflammatory Response Syndrome”
    • Bone et al. Chest 112:235-43, 1997
goals of treatment are hemodynamic and relate to outcome
Goals of Treatment are hemodynamic and relate to outcome
      • Early Goal-Directed Therapy in the treatment of Severe Sepsis and Septic Shock. Rivers E, N Engl J Med 2001;345:1368-1377.
  • RCT 130 adults randomized to aggressive care In First few hours
  • Results: In Hospital Mortality 30.5% vs 46.5% in Controls
  • Early goal directed therapy improves shock outcome(Han Y. 2000 Pediat Res 47:108a. Ceneviva G. Pediatrics 1998;102:e19.)
outline
OUTLINE
  • 1 CRRT for Sepsis - associated AKI
  • 2. CRRT as Immunomodulatory therapy
crrt for sepsis associated aki
CRRT for Sepsis-associated AKI

• Role & Indications

• Dosing

• Alternative therapies

crrt for sepsis associated aki1
CRRT for Sepsis-associated AKI
  • Dialysis allows:

– Correction of acid-base status

– Correction of electrolyte abnormalities

– Clearance of toxins

– Control of fluid balance

crrt for sepsis associated aki2
CRRT for Sepsis-associated AKI
  • Advantages of using CRRT
    • Suitable for use in hemodynamically unstable patients
    • Precise, adaptable, volume control
    • Very effective control of uremia, PO4, K
    • Rapid control of metabolic acidosis
    • Improved nutritional support (full protein diet)
    • Available 24 hours a day
    • May have an effect as an adjuvant therapy in sepsis
crrt for sepsis associated aki3
CRRT for Sepsis-associated AKI
  • Disadvantages of using CRRT
    • Expense – more than IHD, due to fluids
    • Continuous anticoagulation may be required
    • Risk of line disconnection
    • Hypothermia
    • Severe depletion of electrolytes (K and PO4), nutrients
crrt for sepsis associated aki4
CRRT for Sepsis-associated AKI
  • Dosing of dialysis in AKI
    • 425 patients randomized
    • Post-dilution CVVH mode
    • only 12% had sepsis

Ronco et al, Lancet 2000; 355: 26

crrt for sepsis associated aki8
CRRT for Sepsis-associated AKI
  • Dosing of dialysis in AKI
    • 206 patients randomized
    • 60% sepsis
    • CVVH versus

CVVH + added D

Saudan et al, Kidney Int 2006; 70:1312

crrt for sepsis associated aki9
CRRT for Sepsis-associated AKI
  • Negative dosing studies
    • 200 patients
      • CVVHDF 20 v 35 ml/kg/hr
      • No difference

Tolwani et al J Am Soc Nephrol 2008; 19:1233

    • 1124 patients, multicentred (NIH ATN study)
      • Intensified (35ml/kg, 6x/wk IHD) versus
      • Standard (20ml/kg, 3x/wk IHD)
      • No difference

Palevsky et al N Engl J Med 2008; 359:7.

crrt for sepsis associated aki10
CRRT for Sepsis-associated AKI
  • Reasons for differences
    • Delayed initiation of RRT in Tolwani and ATN studies: 6 to 8 days
    • No clear separation of dose delivered when combining CRRT and IHD dosing (ATN study)
    • Majority (65%) enrolled after initial dialysis
    • Dosing was not actually achieved in the ATN study
crrt for sepsis associated aki11
CRRT for Sepsis-associated AKI
  • RENAL study
    • 1508 patients, approx 50% sepsis
    • 48-54 hr in ICU before randomisation
    • Prescribed dose achieved: 84 – 88%
    • CVVHDF, postdilution (1:1 dialysate:filtration)
      • Low intensity: 25 ml/kg/hr
      • High intensity: 40 ml/kg/hr
    • No difference in mortality

N Engl J Med Oct 22nd, 2009.

crrt for sepsis associated aki12
CRRT for Sepsis-associated AKI
  • Alternative therapies
  • IHD
    • mortality higher in many CRRT studies
    • 5 RCT’s: no difference in mortality
    • 7 meta-analyses: no differences
crrt for sepsis associated aki13
CRRT for Sepsis-associated AKI
  • Alternative therapies

Kellum et al. Intensive Care Med 2002; 28:29

crrt for sepsis associated aki14
CRRT for Sepsis-associated AKI
  • Alternative therapies

Bagshaw et al, Crit Care Med 2008; 36:610

crrt for sepsis associated aki15
CRRT for Sepsis-associated AKI
  • Alternative therapies
  • IHD
    • mortality higher in many CRRT studies
    • 5 RCT’s: no difference in mortality
    • 7 meta-analyses: no differences
  • SLED: sustained low efficiency dialysis
    • safe, effective, cheaper than CRRT
    • limited comparative data

Berbece & Richardson, Kidney Int 2006; 70:963

epidemiology of aki
Epidemiology of AKI
  • BEST Kidney study:
    • 23 countries, over 30,000 patients, 2001
    • 1738 developed acute renal failure
    • Dialysis
      • CRRT 80% ---
      • IHD 17%
      • SLED/PD 3%
    • Hospital mortality 60%

CVVH 53%

CVVHD 13%

CVVHDF 34%

Uchino et al, JAMA 2005; 294:813

Uchino et al, Intensive Care Med, 2007 33:1563

crrt as immunomodulatory therapy
CRRT as Immunomodulatory therapy
  • Background & rationale
  • Studies supporting this hypothesis
  • Clinical studies
  • Variations on standard CRRT
crrt as immunomodulatory therapy1
CRRT as Immunomodulatory therapy
  • Rationale – Removal of “Bad Humours”
crrt as immunomodulatory therapy2
CRRT as Immunomodulatory therapy
  • Rationale – Removal of “Bad Humours”
crrt as immunomodulatory therapy4
CRRT as Immunomodulatory therapy

Ronco et al. Artiforgans 2003; 27:792

crrt as immunomodulatory therapy5
CRRT as Immunomodulatory therapy

Ronco et al. Artiforgans 2003; 27:792

crrt as immunomodulatory therapy6
CRRT as Immunomodulatory therapy
  • Mechanism of cytokine removal
    • Convective
      • High flux membranes cut-off 30 – 40 kD
      • Should remove many cytokines (17 – 30 kD)
      • Is removal rate significant given high production?
    • Adsorption
      • Filter dependent: higher with polyacrylonitrile (AN69) than with polysulfone membranes
crrt as immunomodulatory therapy7
CRRT as Immunomodulatory therapy
  • Convective therapy can:
    • Remove cytokines
      • In some, but not all studies
      • Adsorption important
      • Frequent filter changes
      • Plasma levels unchanged
    • Improve hemodynamics
      • In animal studies
      • In open clinical studies

Heering et al Intensive Care Med. 1997;23:288

crrt as immunomodulatory therapy8
CRRT as Immunomodulatory therapy
  • 15 pts, sepsis, AKI
    • first 24 hr hemofiltration
    • AN69 filter

De Vriese et al. J Am Soc Nephrol 1999;10:846-853

crrt as immunomodulatory therapy9
CRRT as Immunomodulatory therapy

Morgera et al. Crit Care Med 2006; 34:2099

crrt as immunomodulatory therapy10
CRRT as Immunomodulatory therapy

Morgera et al. Crit Care Med 2006; 34:2099

crrt as immunomodulatory therapy12
CRRT as Immunomodulatory therapy
  • Ronco study

Ronco et al, Lancet 2000; 355: 26

crrt as immunomodulatory therapy14
CRRT as Immunomodulatory therapy
  • CRRT without AKI
    • Sepsis, no renal failure
    • CVVH, 2L/hr, AN69 filter
    • No significant reduction in

cytokines

    • No clinical benefit

Cole et al, Crit Care Med 2002; 30:100

crrt as immunomodulatory therapy15
CRRT as Immunomodulatory therapy
  • Outcome studies
    • 80 patients, early CVVH 25ml/kg/hr or control
    • High flux polysulfone filter

Payen et al Crit Care Med 2009; 37:803

crrt as immunomodulatory therapy16
CRRT as Immunomodulatory therapy
  • Outcome studies
    • 80 patients, early CVVH 25ml/kg/hr or control
    • High flux polysulfone filter
    • No benefit, deleterious?

Payen et al Crit Care Med 2009; 37:803

crrt as immunomodulatory therapy17
CRRT as Immunomodulatory therapy
  • Outcome studies
    • 80 patients, early CVVH 25ml/kg/hr or control
    • High flux polysulfone filter
    • No benefit, deleterious?

Payen et al Crit Care Med 2009; 37:803

crrt as immunomodulatory therapy18
CRRT as Immunomodulatory therapy
  • Outcome studies
    • 80 patients, early CVVH 25ml/kg/hr or control
    • High flux polysulfone filter
    • No benefit, deleterious?
  • Can’t expect a mortality benefit

with the wrong intervention in the

wrong dose

Payen et al Crit Care Med 2009; 37:803

variations on standard crrt
Variations on standard CRRT
  • High volume hemofiltration
  • High cutoffhemofiltration
  • Plasmafiltration
  • Cascade filtration
  • Coupled plasma filtration adsorption