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Salon b 13 kasim 15.45 17.00 yusuf savran-ing
1. CRRT(Continuous Renal Replacement Therapy)
with Case Reports
(Timing,treatment modalities,general settings)
Assist. Prof. Dr.Yusuf Savran
Dokuz Eylul University Internal Medicine ICU
2. Case- 1
58 years-old male with diagnosed Type 2 Diabetes
mellitus, hypertension and COPD
Sepsis secondary to pneumonia
Multiorgan failure including oliguric acute renal
insufficiency
Mechanically ventilated
0.15μg/kg/dk norepinephrine infusion needed to
resume systolic blood pressure > 60 mmHg
3. Case - 2
35 years-old male
Crash injury in earthquake
Splenic rupture, splenectomy performed.
Perop. 10 units erythrocyte suspension
Bilateral fasciothomy applied to both lower extremity due to
compartment syndrome
Severe rabdomyolisis , ARF (CK: 10000,Creatinin:12 mg/dl)
Severe metabolic acidosis
TA:85/50 mmHg despite inotropic support (Dopamin10 mcg/kg/dk)
4. Case-3
50 years-old female with no comorbidity
Multilobar pneumonia
ARDS,Septic shock and MOF development 24 hours
after initiation of antibiotherapy
Metabolic acidosis
Mechanical ventilation
NE: 0.5 mcg/kg/dk infusion needed to resume
MAP >60 mmHg
5. Case - 4
70 years-old male operated for left femur neck fracture
Discharged - Acute respiratory distress 1 weeks later
TA:70/40 mmHg, ABG:ph:7.25 pO2:60 pCO2:20
HCO3:12 Sa02:88%
Thorax BT Angiography:Massive PTE
Oliguric
Creatinine:3.5 mg/dl (creat:1.0 mg/dl 1 week ago)
6. Case - 5
40 years-old female
Bipolar disorder on Lithium treatment
Commits suicide by 50 tablets Lithium ingestion
Unconscious TA:70/40 mmHg Glasgow score :6
Severe arrythmias (+)
Aspiration pneumonia (+)
MOF (anuric ,elevated liver enzymes and coagulation
parameters)
7. Case - 6
72 years-old female with past history of CHD (3 vessel CABG) and CRF (low
clearance) admitted to Emergency service unconscious
TA:80/40 mmHg, N:160/dk arrythmic,ventilation superficial,intubated
ABG Ph:7.25 PO2:58 mmHg Pco2:70 mmHg HCO3:26 SaO2:%86
Chest X-ray: Acute pulmonary edema
EKG:AF with high ventricular response
Cranial CT: İschemic stroke
Mechanically ventilated
Echo: EF:35%,PAP:35 mmHg,LV Global hypokinetic
ARF on CRF(creat:1.6 mg/dl 3.2 mg/dl)
8. Acute renal injury in ICU
Unstabile
Continuous drug replacement
Mechanically ventilated
Unconscious
Accompanying findings : Sepsis or MOF
Which RRT ?
10. Disadvantages of iHD
Sudden declines in plasma osmolarity
UF in limited time
İncrease in body temperature
Inability to remove cytokines
So how shall we treat ???
11. Why CRRT ?
Similar to normal physiology: rate slow, period enhanced
Better tolerance especially in hemodynamic instability
Allows removal of great amounts of fluid
Efficient clearance
Medium and large sized solutes can be cleared more efficiently
Inflammatory mediators cleared more effectively
Allows supplementary replacement fluid delivery
13. The technique and timing as well as the type
of renal replacement therapy used may affect patients’
survival and recovery of renal function.
Palevsky PM et al., Curr Opin Crit Care. 2005;11:548-554.
Demirkilic U, J Card Surg. 2004;19:17-20.
Swartz RD et al., Am J Kidney Dis. 1999; 34:424-432.
23. Convection
Hydrostatic pressure causes water movement through the membrane.During this movement
Pressure
1. 2. 3.
time
Concurrent water and solute movement
Driving force: pressure gradient
FMC Pazarlama Departmanı 2011
Medium and large sized molecules
removed
water also drags the molecules that can not be diffused .
24.
25. The concentration gradient between the sides of the membrane causes the solutes to move
from the dense concentration to less dense concentration.
Different concentrations
(effective for small molecular sizes) Solute concentration equals on both sides
1. 2. 3.
Driving force: concentration gradient
FMC Pazarlama Departmanı 2011
time
Diffusion
26.
27. SCUF (Slow continuous ultrafiltration)
In case of fluid overload
6-7 L/day ultrafiltrate
Blood flow rate <100 ml/dk
No dialysate fluid
No Replacement fluid
İnconvenient for uremics
and hyperkalemia
Convenient for CHF UF
28.
29. Hemofiltration
Solute removal via convection
Blood flow rate: 200-300 ml/min
UF rate: 12-20 L/24 saat
Replacement fluid necessary
No dialysate fluid
Clearance of urea 22 L/day
Time > 24 hours
PreD
PostD
UF
RF
30. CVVHD (Hemodialysis)
Solute clearance by diffusion
UF rate 2-7 L/day
Flow rate of dialysate fluid:
15-45 ml/dk
Blood flow rate:
100-200 ml/dk
No replacement fluid
Clearance of urea: 24-30 L/day
Dial
UF
31. CVVHDF(Hemodiafiltration)
Blood flow rate:
100-200 ml/min
Flow rate of dialysate fluid:
15-45 ml/dk
High removal rate of solutes (clearance of urea:
30-60 ml/min.)
Clearance of solutes:
% 75 dialysis
% 25 hemofiltration
Dial
UF rate 12-20 L/day
Replacement fluid in need. UF
RF
32. Principles of CRRT clearance
• CRRT clearance of solute is dependent on the following:
The molecule size of the solute
The pore size of the semi-permeable membrane
33.
34.
35.
36. Principles of CRRT clearance
• Small molecules easily pass through a membrane
driven by diffusion and convection.
• Middle and large size molecules are cleared primarily
by convection.
• Semi-permeable membrane remove solutes with a
molecular weight of up to 50,000 Daltons.
• Plasma proteins or substances highly protein—bound
will not be cleared.
37. Membrane types and characteristics
• Hemofilter membrane are composed of:
High flux material
Synthetic/biocompatible material
• Structural design is characterized by:
High fluid removal
Molecular cut-off weight of 30,000-50,000
Daltons.
38. Semi-permeable Membrane
• The semi-permeable membrane provides:
An interface between the blood and dialysate
compartment.
• Biocompatibility minimizes:
Severe patient reactions
Decreases the complement activation
39. The decision of the type of RRT is influenced
by many factors:
• Availability
• Experience
• Catabolic state
• Hemodynsmic stability
• Primary goal ?
Removal of excess fluid ?
Removal of excess solutes ?
Both?
40. Decision of modality
If the primary goal is removal of excess fluid :
SCUF, CVVHF
In catabolic state and excess low molecular size solutes :
CVVHD
If the primary goal is removal of excess inflammatory mediators:
CVVHDF
46. Effect of BUN at CVVH Initiation on Survival
80
70
60
50
40
30
20
10
0
Survivors Non Survivors
p < 0.01
Group 1 Group 2 Group 3
Blood Urea Nitrogen (mg/dl)
p < 0.01 p < 0.01
47. Conclusions:
An increased treatment dose from 20 ml/h/kg to 35 ml/h/kg
significantly improved survival.
A delivery of 45ml/kg/hr did not result in further benefit in
terms of survival, but in the septic patient an improvement
was observed.
Our data suggest an early initiation of treatment and a
minimum dose delivery of 35 ml/h/kg improve patient
survival rate.
48. EIHF vs Conventional
45mL/Kg/hr for 6 hours then 20mL/Kg/hr vs 20mL/Kg/hr
28-day Survival: 55% vs 27.5%
56. Randomized
(Post-dilution CVVH)
1508
Low dose
(25ml/Kg/hr)
761
High dose
(40ml/Kg/hr)
747
Lost to follow up = 1
Consent withdrawn = 2
Consent not obtained = 23
Analyzed
722
Lost to follow-up = 0
Consent withdrawn = 2
Consent not obtained = 16
Analyzed
743
57. RENAL Study
High
Intensity
Low
Intensity
90-days mortality 44.7% 44.7%
28-days mortality 38.5% 36.5%
58. What have we learned about doses ?
Before the ATN trial
CRRT: 35mL/kg/hr
Daily iHD
After the ATN trial
SOFA 0-2: 3x/week iHD (Kt/V 1.2)
SOFA 3-4: CRRT 20 mL/kg/hr or SLED 3x/week
59. In Summary
Decide on the treatment modality
according to the primary goal
Start treatment as early as possible
Decide on the dose for every patient
individually
-By a group of expert from ADQI ( Acute Dialysis Quality Initiative ) to propsoed graded definition of RIFLE criteria in 2002
-RIFLE correlated with prognosis in a number of studies
-Limitation:
--Serum Cr were strong predictors of ICU mortality but not UO criteria, remember to use the least favorable RIFLE strata
--Change in Serum Cr not directly correlate with changes in GFR
--Baseline CR is necessary to calculate the change
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This is the first study attempting to validate the RIFLE system with respect to its ability to predict mortality in critically ill ARF patients. In this retrospective study, mortality over a six month period in 223 CRRT-treated patients was assessed. Overall, acuity of illness in the patient population was quite high, with 85% of patients receiving mechanical ventilation and 78% receiving vasopressor support. The RIFLE classification effectively stratified patients according to mortality risk, with a significant survival difference observed between patients with an “R” or “I” designation and patients with a “F” and “L/E” designation. If the RIFLE approach is validated clinically in prospective studies, it will address a major shortcoming in the field of ARF and should allow for more timely and accurate diagnosis of ARF.
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-Modification of the RIFLE criteria by Acute Kidney Injury Network
-Both diagnostic and staging system
-Diagnostic criteria
--abrupt in onset within 48 hrs
--Absolute increase in serum Cr &gt;=0.3mg/dL or 26.4 mmol/L or % increase of Cr &gt;=50% or oliguric for &gt;=6 hrs
--After volume status optimised and urinary tract obstruction excluded
-Staging system
--RIFLE Loss and ESRD removed
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CRRT modalities contains four therapies, and we will begin by talking specifically about each therapy. CRRT is well-known by all the acronyms. Each acronym describes the therapy being performed in treating the patient. History has shown us that there are many ways to perform each therapy. However, each therapy does carry is own basic concept.
SCUF- modality is only removing patient plasma water. Does not require replacement or dialysate solution.
CVVH- modality requires replacement solution. This replacement solution drives convection.
CVVHD- is continuous form of hemodialysis and requires dialysate solution to create a concentration gradient for diffusion.
CVVHDF- hemodiafiltration requires the use of dialysate and replacement solution and uses both transport mechanisms of convection and diffusion.
Let’s take a look at the transport mechanisms related to each individual therapy.
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This visual will provide you with a better understanding of how convection works. From the picture you can see a faucet which represents replacement solution. The top faucet is an example of pre-filter dilution, which means that the replacement solution mixes with the blood as it enters the filter. The bottom faucet is an example of post-filter dilution and is delivered as the blood is returning to the patient.
Now the effluent pump is removing ultrafiltration (just like SCUF), or patient plasma water and replacement solution.
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The patients blood contains a high concentration of unwanted solutes that can be effectively removed by diffusion. Diffusions key mechanism is to move a solute from a higher concentration gradient to a lower concentration gradient.
For example, let us assume the blood in the filter has a high concentration of potassium molecules and on the fluid/dialysate compartment has a low concentration of potassium. The potassium gradually diffuses through the membrane from the area of a higher potassium concentration to the area of a lower potassium concentration until it is evenly distributed.
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Here is a visual example of how ultrafiltration works. On the blood side of the hemofilter you have a positive pressure gradient. on the fluid side of the hemofilter you have a negative pressure gradient. The effluent pump applies pressure on the membrane causing the fluid to move from the positive pressure gradient to the lower pressure gradient.
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CRRT solute clearance is dependent on the following: The size of the molecule and the pore size of the semi-permeable membrane. The best way to drive solute clearance is to increase the ultrafiltration removal rate ( combination of replacement solution and patient plasma water).
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Remember the transport of a molecule through a membrane is governed largely by its molecular weight. Generally, the more a molecule weighs, the larger it is in size and the more resistant it is to transport. The chart gives an indication of relative molecular weights for some of the common molecules that we are concerned with in CRRT. Molecular weights are measured in units called Daltons.
Small molecules &lt;300 Daltons, e.g. urea, creatinine, Na+, electrolytes
Intermediate or middle molecules 500-5000 Daltons e.g. B12
Large molecules 5000-50000 Daltons e.g. LMW proteins, beta 2 micro globulins, cytokines, myoglobin
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Molecular size: Both molecule size and pore size determine the solute flow through the semi-permeable membrane. As you can see from this picture we have a membrane with small pores. The pink molecule represent Urea molecules, which are considered small size molecules. The green molecules represents cytokine molecules, which are considered a middle size molecules. The (pink molecule) Urea easily passes through the small pores, but the (green molecule) Cytokines are to large to move across the membrane therefore they remain in the blood.
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This picture depicts a membrane that has large pore size. As you can see from this picture we have a membrane with large pores. Again, we will say the pink molecule represent Urea molecules, and the green molecules represent a cytokine molecules. The Urea easily passes through the large pores, and the Cytokines also move across the membrane therefore they are removed from the blood.
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Back to the basic CRRT transport principles: the combination of diffusion and convection allow small molecules to easily pass through the membrane, and middle and large molecules to be driven across the filter by convection. The semi-permeable membrane allows removal of solutes with a molecular weight of up to 50,000 Daltons. Keep in mind that anything that is protein-bound will not be cleared.
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Membrane types and characteristics are other important technical considerations. Hemofilters are composed of a membrane that consists of high flux material (porous). The membrane material is usually synthetic, but very biocompatible to the patient.
Here are a few examples of high-flux membrane material:
Polysulfone (PS)
Polyamide (PA)
Polyacrylonitrile ( PAN)
AN69
The structural design of a high flux membrane is characterized by high fluid removal and typically has a molecular cut-off weight of 55,000 Daltons.
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The hemofilter contains a semi-permeable membrane that provides an interface between the blood and dialysate compartment. This interface creates a barrier so that the blood and dialysate never come in contact with each. Biocompatibility is an important feature, because the membrane’s chemical properties minimize blood’s reaction I.e. thrombocytes and/or complement activation and immune system response (allergic reaction).
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Dr. Ronco set forth to study answer the question “What is the adequate dose for the ARF patient?” thus began the journey to find this dose. The origin of ARF was mostly post surgical with the other causes from medical and trauma related. Sepsis was also prevalent throughout the study participants. Dr. Ronco selected 492 patients for the study, but 67 of those patient were excluded. Some of the 425 patients were actually randomized into the study, and assigned to one of the three doses: 20ml/kg/hr, 35ml/kg/hr, and 45ml/kg/hr. The study was conducted using only convection therapy. All replacement solution was delivered post-filter, and UFR was used to measure dosing.
Why did he use UFR to measure dosing. Well, it is known that solute movement across the membrane is proportional to UFR. For example, Urea has a sieving coefficient of 1 it is then assumed that it is equal to UFR. Therefore, ultrafiltration rate corresponds with clearance, and can be used as a surrogate treatment dose.
-Landmark study by Ronco in a single-centre randomised trial: survival at 15 days was improved by increasing CRRT dose from 20 to 35 ml/Kg/hr
-Concern about this study:
Unblined single-centre, took 5-years to complete
Sepsis contribute to 15% vs 50-60% incidence worldwide
Cost assoc with intensifying the therapy and it is post-dilution technique
Small sample size ( 425 patients)
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At least three different studies have shown a benefit for early initiation of therapy. Ronco’s study also suggests that patient’s with significantly lower BUN at the time of CVVH initiation had better survival rates whereas the patient with high BUN’s at the time of CVVH initiation had poor survival rates. This demonstrates a powerful effect of timing of treatment initiation on outcome.
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So based on the previous slides we can conclude that a dose of 35ml/h/kg is very appropriate in a CRRT setting and in the meantime is widely accepted as a golden standard.
Besides the dose this study also indicates that TIMING seems to be another important influencing factor from an outcome perspective.
Again you should point out the quality of the study and that there is not ONE single study available at the same level. So if you want to prescribe therapy and you feel comfortable to use a widely accepted guideline… this is one!
Published in early 2008 in J Am Soc Nephrol
-Primary outcome is survival to ICU discharge or 30-days survival: 49% ( high dose arm ) vs 56%( standard dose arm) (P=0.32)
-Among survivor, recover renal fx : 69% ( high dose arm) vs 80% (standard-dose arm)
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-Schiff_NEJM_2002: daily dialysis is better than second daily dialysis
-Two modality of treatment included and allow patient transition provided that they stick to the dose of dialysis
-Hemodynamic stable: SOFA cardiovascular score of 0-2
-For IHD/SLED: treatment intensity is adequate –up to Kt/V of 1.2-1.4
-For the CVVHDF: different from Ronco in which they use the HDF instead of HF and it is pre-dilution instead of post-dilutuion
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-Primary outcome: 60-days mortality is 53.6% ( intensive therapy) vs 51.5% ( less-intensive therapy) ( OR=1.09, P=0.47)
-No difference between the two groups in
--duration of RRT or
--rate of recovery of kidney function or
--nonrenal organ failure
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-RENAL: Randomised Evaluation of Normal versus Augmented Level Replacement Therapy Study
Different from the ATN study
--Older patient with lower incidence of sepsis, but higher CVS and Resp SOFA
--Not RRT before randomization
--Mean time from ICU admission to randomization: 50 hrs vs 150 hrs
--Use post-dilution CVVH and only 314 session of IHD
--lower rate of dialysis dependence in this study by 28 and 90 days ( 15.8% vs 45.2% & 5.6 % vs 24.6% ( 60-days))
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