# Presentation: 015963

## Continuous Renal Replacement Therapy

**Gregory M. Susla, Pharm.D., F.C.C.M.**
**Associate Director, Medical Information**
**MedImmune, Inc.**
**Gaithersburg, MD**

## Definition of Terms

**Definition of Terms**

**SCUF - ****S****low ****C****ontinuous ****U****ltra****f****iltration**
**CAVH - ****C****ontinuous ****A****rterio****v****enous ****H****emofiltration**
**CAVH-D - ****C****ontinuous ****A****rterio****v****enous ****H****emofiltration  with ****D****ialysis **
**CVVH - ****C****ontinuous ****V****eno****v****enous ****H****emofiltration**
**CVVH-D - ****C****ontinuous ****V****eno****v****enous ****H****emofiltration with ****D****ialysis**

## Indications for Continuous Renal Replacement Therapy

**Indications for Continuous ****Renal Replacement Therapy**

**Remove excess fluid because of fluid overload**
**Clinical need to administer fluid to someone who is oliguric**
**Nutrition solution**
**Antibiotics**
**Vasoactive substances**
**Blood products**
**Other parenteral medications**

## Advantages of ContinuousRenal Replacement Therapy

**Advantages of Continuous****Renal Replacement Therapy**

**Hemodynamic stability**
**Avoid hypotension complicating hemodialysis**
**Avoid swings in intravascular volume**
**Easy to regulate fluid volume**
**Volume removal is continuous**
**Adjust fluid removal rate on an hourly basis**
**Customize replacement solutions**
**Lack of need of specialized support staff**

## Disadvantages of ContinuousRenal Replacement Therapy

**Disadvantages of Continuous****Renal Replacement Therapy**

**Lack of rapid fluid and solute removal**
**GFR equivalent of 5 - 20 ml/min**
**Limited role in overdose setting**
**Filter clotting**
**Take down the entire system**

## Basic Principles

**Basic Principles**

**Blood passes down one side of a highly permeable membrane**
**Water and solute pass across the membrane**
**Solutes up to 20,000 daltons **
**Drugs & electrolytes**
**Infuse replacement solution with physiologic concentrations of electrolytes**

## Anatomy of a Hemofilter

- <date/time>

**Anatomy of a Hemofilter**

**blood in**

**blood out**

**dialysate**
**in**

**dialysate**
**out**

**Outside the Fiber ****(effluent)**
**Inside the Fiber ****(blood)**

**Cross Section**

**hollow fiber membrane**

## Basic Principles

**Basic Principles**

**Hemofiltration**
**Convection**** based on a pressure gradient**
**‘****Transmembrane pressure gradient’**
**Difference between plasma oncotic pressure and hydrostatic pressure**
**Dialysis**
**Diffusion based on a ****concentration gradient**

## CVVHContinuous Veno-Venous Hemofiltration

**Blood In**

**Blood Out**

***to waste***

***(from patient)***

***(******to patient)***

***HIGH PRESS***

***LOW  PRESS***

**Repl.**
**Solution**

**CVVH****Continuous Veno-Venous Hemofiltration**

**(Convection)**

**Notes:**
Note that this schematic indicates the addition of a REPLACEMENT FLUID.  The replacement fluid-usually composed of approximate normal plasma values- enters the blood flow path as it circulates through the hemofilter.  This not only has a dilutional effect on the blood but enables us to remove large volumes of water into the waste without dehydrating the patient or causing other hemodynamic shifts.  Using the principles we discussed, pressures in the system can be adjusted to regulate ultrafiltrate volume. How much clearance of small/midsize molecules will be influenced both by the composition of the replacement fluid, and the amount of fluid we “replace” or force to cross the membrane into the waste collection.  Note that replacement fluids may be administered pre or post filter.  We will discuss these choices in a few moments.

## CVVHContinuous VV Hemofiltration

**Primary therapeutic goal:**
**Convective solute removal**
**Management of intravascular volume**
**Blood Flow rate = 10 - 180 ml/min **
**UF rate ranges 6 - 50 L/24 h (> 500 ml/h)**
**Requires replacement solution to drive convection**
**No dialysate**

**Notes:**
CVVH - Continuous veno-venous hemofiltration aims for maximizing convective removal of small and middle molecules.  Replacement solutions are used to drive this convective transportation.  This therapy can use 12-20 liters of fluid in a 24 hour period to achieve the desired clearance of solutes.

## CVVH Performance

**Continuous venovenous hemofiltration**
**“****In vitro” ultrafiltration with blood (post-dilution)**
**(values ± 15%) (Bovine blood at 37******** C, Hct 32%, Cp 60g/l)**

## CVVHDFContinuous Veno-Venous Hemodiafiltration

**Repl.**
**Solution**

**Dialysate**
**Solution**

**Blood In**

**Blood Out**

***to waste***

***(from patient)***

***(to patient)***

***HIGH PRESS***

***LOW  PRESS***

***HIGH CONC***

***LOW CONC***

**CVVHDF****Continuous Veno-Venous Hemodiafiltration**

**(Diffusion)**

**(Convection)**

**Notes:**
Describe flow paths on slide.  Note:  Point out again that ... Replacement fluids may be administered either pre or post filter.  We will discuss these options later in the program.

## CVVHDFContinuous VV Hemodiafiltration

**Primary therapeutic goal:**
**Solute removal by diffusion and convection**
**Management of intravascular volume**
**Blood Flow rate = 10 - 180ml/min **
**Combines CVVH and CVVHD therapies**
**UF rate ranges 12 - 24 L/24h (> 500 ml/h)**
**Dialysate Flow rate = 15 - 45 ml/min (~1 - 3 L/h)**
**Uses both dialysate (1 L/h) and replacement fluid (500 ml/h)**

**Notes:**
The next therapy for discussion is CVVHD - continuous veno-venous hemodialysis.  This therapy uses a dialysate on the fluid side of the filter to increase solute exchange by diffusion.  Replacement fluid is not administered with this therapy.  UF rates are lower than with CVVH therapy.  Dialysate is infused at 15-45 ml/min (1-3 L/ hour).  The blood flow rate is maintained between 10-180 ml/min.  This compares to intermittent HD that uses typical blood flow rates of 350-500 ml/min and dialysate flow rates of 500-800 ml/min.  Unlike intermittent HD it is the dialysate flow rate rather than the blood flow rate that will determine clearances.  The advantage of continuous therapies is that the 24 hour exposure to “renal replacement” makes up for the system efficiencies of the lower flows.  

## Pharmacokinetics of ContinuousRenal Replacement Therapy

## Basic Principles

**Basic Principles**

**Extracorporeal clearance (Cl****EC****) is usually considered clinically significant only if its contribution to total body clearance exceeds 25 - 30%**
**	****	****     ****Fr****EC**** = Cl****EC**** /  Cl****EC**** + ****Cl****R**** + Cl****NR**
**Not relevant for drugs with high non-renal clearance**
**Only drug not bound to plasma proteins can be removed by extracorporeal procedures**

## Determinants of Drug Removal by CRRT

**Determinants of ****Drug Removal by CRRT**

**Drug****	****	****	****	****Same as hemodialysis**
**                                             ****but increased MW range****	****	****	****	**
**Membrane****	****	****	****Permeability**
**	****	****	****	****	****Sieving Coefficient**
**Renal replacement****	****	****Convection **_**+**_** diffusion Cl**
**   ****technique****	****	****	****Flow rates**
**	****	****	****	****	****	****	****Blood, Dialysate, UF**
**	****	****	****	****	****	****Duration of CRRT**

## Sieving Coefficient (S)

**Sieving Coefficient (S)**

**The capacity of a drug to pass through the hemofilter membrane**
**	****	****	****	****S = C****uf**** / C****p**
**	****C****uf**** = drug concentration in the ultrafiltrate**
**	****C****p **** = drug concentration in the plasma**
**	****S = 1****	****Solute freely passes through the filter**
**	****S = 0****	****Solute does not pass through the filter**** **
**	****	****	****	****CL****HF**** = Q****f**** x S**** **

## Determinants of Sieving Coefficient 

**Determinants of Sieving Coefficient **

**Protein binding**
**Only unbound drug passes through the filter**
**Protein binding changes in critical illness**
**Drug membrane interactions**
**Not clinically relevant**
**Adsorption of proteins and blood products onto filter**
**Related to filter age**
**Decreased efficiency of filter**

## Relationship Between Free Fraction (fu) and Sieving Coefficient (SC)

**Relationship Between Free Fraction (*****fu*****) and Sieving Coefficient (*****SC*****)**

## Dialysate Saturation (Sd)

**Dialysate Saturation (S****d****)**

**Countercurrent dialysate flow (10 - 30 ml/min) is always less than blood flow (100 - 200 ml/min)**
**Allows complete equilibrium between blood serum and dialysate**
**Dialysate leaving filter will be 100% saturated with easily diffusible  solutes**
**Diffusive clearance will equal dialysate flow**

## Dialysate Saturation (Sd)

**Dialysate Saturation (S****d****)**

**	****	****	****	****S****d**** = C****d**** / C****p**
**C****d**** = drug concentration in the dialysate**
**C****p**** = drug concentration in the plasma**
**Decreasing dialysate saturation**
**Increasing molecular weight**
**Decreases speed of diffusion**
**Increasing dialysate flow rate**
**Decreases time available for diffusion**
**	****	****	****	****Cl****HD**** = Q****d**** x S****d**

## CVVHDF Clearance

**Continuous venovenous hemofiltration - post dilution**
**QB = 150 ml/min - QD = 2000 ml/h (in vitro saline)**

## Extracorporeal Clearance

**Extracorporeal Clearance**

**Hemofiltration clearance (Cl****HF**** = Q****f**** x S)**
**Q****f**** = Ultrafiltration rate**
**S = Seiving coefficient**
**Hemodialysis clearance (Cl****HD**** = Q****d**** x S****d****)**
**Q****d**** = Dialysate flow rate**
**S****d**** = Dialysate saturation**
**Hemodialfiltration clearance**
**	****	****     ****Cl****HDF**** = (Q****f**** x S) + (Q****d**** x S****d****)**

## Case History

**Case History**

**AP 36yo HM s/p BMT for aplastic anemia**
**Admitted to ICU for management of acute renal failure**
**CVVH-D initiated for management of uremia**
**ICU course complicated by pulmonary failure failure requiring mechanical ventilation, liver failure secondary to GVHD and VOD, and sepsis**

## Case HistoryAntibiotic Management on CRRT

**Case History****Antibiotic Management on CRRT**

**Gentamicin 180 mg IV q24h**
**Vancomycin 1 g IV q24h**
**Dialysis rate 1000 ml/hour**
**12 hour post gentamicin levels: 3 - 4 mg/L**
**12 hour post vancomycin levels: 20 - 23 mg/L**
**Dialysis rate increased to 1200 ml/hour**
**12 hour post gentamicin levels: < 0.4 mg/L**
**12 hour post vancomycin levels: < 4 mg/L**

## Dosage Adjustments in CRRT

**Dosage Adjustments in CRRT**

**Will the drug be removed?**
**Pharmacokinetic parameters**
**Protein binding < 70 - 80%**
**Normal values may not apply to critically ill patients**
**Volume of distribution < 1 L/kg**
**Renal clearance > 35%**
**How often do I dose the drug?**
** ****Hemofiltration: ‘GFR’ 10 - 20 ml/min**
**Hemofiltration with dialysis: ‘GFR’ 20 - 50 ml/min**

## Drug Removal During CRRT

**Drug Removal During CRRT**

**Recommendations not listed in PDR**
**Limited to case reports or series of patients**
**Different filter brands, sizes, flow rates**
**Limited information in many reports**
**Rarely report % of dose removed**
**Many journals will not publish case reports**
**Artificial models and predictions have no clinical value**

## Dosage Adjustments in CRRT

**Dosage Adjustments in CRRT**

**Loading doses **
**Do not need to be adjusted**
**Loading dose depends solely on volume of distribution**
**Maintenance doses**
**Standard reference tables**
**Base on measured loses**
**Calculate maintenance dose multiplication factor (MDMF)**

## Dosage Adjustments in CRRT

**Frequent blood level determinations**
**Aminoglycosides, vancomycin**** **
**Reference tables**
**Bennett's tables or the PDR recommendations require an approximation of patient's GFR**
**The CVVH ‘GFR’ is approximated by the ultrafiltrate rate (UFR), plus any residual renal clearance**
**Using Bennett's or the PDR’s tables, in most CVVH patients, drug dosing can be adjusted for a ‘GFR’ in the range of 10 to 50 ml/min**

## Supplemental Dose Based on Measured Plasma Level

**Supplemental Dose Based on Measured Plasma Level**

## Adjusted Dose Based on Clearance Estimates

**Adjusted Dose Based on Clearance Estimates**

**   **

## COMPARISON OF DRUG REMOVAL BY INTERMITTENT HD AND CRRT

**COMPARISON OF DRUG REMOVAL BY INTERMITTENT** **HD AND CRRT**