Renal replacement therapy Dr . Ashish Moderator : Dr. Muralidhar www.anaesthesia.co.in anaesthesia.co.in@gmail.com

Epidemiology of AKI Prospective epidemiology survey of AKI was conducted in ICU patient who were either treated with RRT or had ARF(U.O< 200ml /12hr or BUN>30mmol/l) Of 29269 critical ill pts. 5.7% pt. had AKI during ICU stay including 4.3% who were t/t with RRT BEST study(Beginning and ending supportive therapy for the kidney investigators Acute renal failure in critically ill patients JAMA 294;813-818,2005)

Overall hospital mortality was 60.3% Most common contributing factor was septic shock in 47.5% At hospital discharge 86.2% survivors were independent from dialysis BEST study(Beginning and ending supportive therapy for the kidney investigators Acute renal failure in critically ill patients JAMA 294;813-818,2005)

Introduction Term RRT is used to describe all the currently available approaches to artificial mechanical support of renal function Includes traditional intermittent hemodialysis,peritoneal dialysis and variety of other intermittent and continuous therapy, and renal transplant

Indications to start and stop RRT There is no consensus as to indication for initiation of RRT Common indications are azotemia , anuria, and complications of AKI , including pulmonary edema, severe fluid overload ,hyperkalemia and uncontrolled metabolic acidosis

Routine clinical practice is to adequately control fluid balance and to maintain a serum urea <30 mg/dl, creatinine < 2mg/dl and normal electrolyte values

Indications of RRT Anuria – oliguria(diuresis <200 ml in 12 hr) Severe metabolic acidosis(pH<7.10) Hyperazotemia(BUN> 80mg/dl) or creatinine >4mg/dl Hyperkalemia K >6.5mEq/l Clinical signs of uremic toxicity

Indications of RRT Severe dysnatremia Na<115 or Na>160mEq/l Hyperthermia (>40 deg.C without response to medical therapy) Anasarca or severe fluid overload Multiple organ failure with renal dysfunction and /SIRS, sepsis, or septic shock with renal dysfunction

Technique and modalities All RRT consist of blood purification by having the blood flow through SPM. Blood flow into hollow fibers composed by porous biocompatible synthetic materials

Technique and modalities Wide range of substances( water , urea,and low, middle and high mol.wt. solutes)allow the blood across such membranes by diffusion (solutes) and by convection(solute and water)

Diffusion Solute move from blood across membrane to reach same concentration on each side of membrane Leads to passage of solute from compartment with highest conc. to lower compartment with lowest conc.

Factors affecting rate of diffusion – Thickness and surface of membrane, Temperature of blood Diffusion coefficient

Dialysis occur when solution flows through semi- permeable conduit countercurrent to blood, allowing maximal solute diffusion, because solute conc. is lower in solution than blood

Diffusion

Diffusion During diffusion , solute flux (Jx) is function of solute concentration gradient(dc)between two sides of SPM, temp(T), diffusivity coefficient(D), membrane thickness(dx)and surface area(A) Jx=D.T.A(dc/dt)

Convection During convection , movement of solute across a SPM occurs with significant amount of ultrafiltration( water transferring across the membrane)

Convection As the solvent (water in plasma) is pushed across the SPM in response to TMP(transmembrane pressure) by UF, solutes are carried with it, as long as porosity of membrane allows the molecules to be sieved from blood

Convection

The process of ultrafiltration is governed by UF rate (Qf), membrane UF coefficient(Km) and TMP gradient generated by pressure on both sides of hollow fiber Qf= Km.TMP

TMP= Pb-Pd-Blood oncotic pressure Pb: Blood hydrostatic pressure Pd:Hydrostatic pressure on UF side of SPM

Hydrostatic pressure in blood compartment dependent on blood flow(Qb) Greater the Qb , greater the TMP Modern RRT machine , UF is maximised by applying a pump, which generates control of UF rate

As blood is processed , membrane fiber get soiled and a negative pressure become necessary to maintain a constant Qf Molecules cleared during convection are physically dragged to UF side , but this function is limited by protein layer that progressively develops and closes fiber pores during convective treatments

As UF proceeds over time, plasma water and solutes are filtered from blood, hydrostatic pressure within filter is lost And oncotic pressure is gained as blood concentrates and Hct rise

The fraction of plasma water that is removed from blood during UF is called Filtration Fraction F.F. is kept ~20-25% to prevent hemoconcentration within filtering membrane

Replacing plasma water with a substitution solution completes the hemofiltration(HF) and returns the purified blood to patient Post dilution HF - Replacement fluid infused after the filter Pre dilution HF - Replacement fluid infused before the filter

Post dilution HF allow urea clearance equivalent to therapy delivery(2L/hr) While pre dilution l/t prolonged circuit lifespan by reducing hemoconcentration and protein caking effect

Conventional HF is performed with highly permeable membrane with surface area of about 1sq.mt, steam sterlized with cutoff point 30kD

Difference b/n volume of ultra filtered plasma water and reinfused substitution solution is Net UF Net UF is fluid finally removed from patient

Prescriptions for net UF are based on individual patient need Range from >1L/hr(pulmonary edema pt. with CHF who is resistant to diuretic) To zero net UF ( sepsis with catabolic state with increased creatinine levels)

Net UF rate must be added to dialysis to achieve fluid balance during diffusion that do not allow water movement

Most common techniqe utilised for CRF IHD Most common techniqe utilised for CRF Diffusive t/t in which blood & dialysate are circulated in countercurrent manner & usually low permeability,cellulose membrane is employed Dialysate must be pyrogen free but not necessarily sterile, as blood contact does not occur

IHD UF rate is equal to scheduled weight loss This t/t can be typically performed 4 hrs thrice weekly or daily Qb :150-300ml/min , Qd:300-500ml/min

PD Diffusive t/t in which blood circulating along capillaries of peritoneal membrane , is exposed to a dialysate Peritoneal catheter allows abdominal instillation of dialysate

PD Solute & water movement achieved by means of variable concentration and tonicity gradients generated by dialysate Can be done continuously or intermittently

Dose and prescription for RRT During continuous t/t in ICU goal – deliver urea clearance of 2 l/hr Evaluation of chronic dialysis in ESRD described by fractional clearance of given solute = Kt/v K: dialysis clearance t: time for dialysis treatment v : solute marker volume of distribution Kt/v urea of 1.2 currently recommended

Dose reciept of more dialysis improve patient outcome?

Prospective study on 425 patients - 3 groups: Effects of different doses in CVVH on outcome of ARF - Ronco & Bellomo study. Lancet . july 00 Prospective study on 425 patients - 3 groups: Study: survival after 15 days of HF stop recovery of renal function 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.

Effects of different doses in CVVH on outcome of ARF - Ronco & Bellomo study. Lancet . july 00 100 90 80 70 60 50 40 30 20 10 Group 1(n=146) ( Uf = 20 ml/h/Kg) Group 2 (n=139) = 35 ml/h/Kg) Group 3 (n=140) = 45 ml/h/Kg) 41 % 57 % 58 % p < 0.001 p n..s. Survival (%) This is a another way to visually see the outcome from Dr. Ronco’s study. Group 1 is what we consider conventional delivery with poor patient outcome. Group 2 and 3 prove that a higher dose improves patient survival. Group 2 and 3 showed very little difference in survival therefore, the new dosing standard was announced that a dose of 35 mL/hr/kg improved patient outcome.

Continuous Renal Replacement Therapy (CRRT) Is an extracorporeal blood purification therapy intended to substitute for impaired renal function over an extended period of time and applied for or aimed at being applied for 24 hours a day. * Bellomo R., Ronco C., Mehta R, Nomenclature for Continuous Renal Replacement Therapies, AJKD, Vol 28, No. 5, Suppl 3, November 1996 CRRT is the blanket term which encompasses all continuous therapies. It has been defined as…. Read the slide. Make sure to note the proof source.

A central double-lumen veno-venous hemodialysis catheter Requirements for CRRT CRRT requires: A central double-lumen veno-venous hemodialysis catheter An extracorporeal circuit and a hemofilter A blood pump and a effluent pump. With specific CRRT therapies dialysate and/or replacement pumps are required. In order, to initiate CRRT there are some essential items you will need. CRRT requires a functioning vascular access, which is usually a central double-lumen catheter, and extracorporeal circuit, a hemofilter, a blood pump, and a effluent pump. In some CRRT therapies dialysate and/or replacement pumps are required.

SCUF- Slow Continuous Ultrafiltration Ultrafiltration CRRT Modalities SCUF- Slow Continuous Ultrafiltration Ultrafiltration CVVH- Continuous Veno-Venous Hemofiltration Convection CVVHD- Continuous Veno-Venous Hemodialysis Diffusion CVVHDF- Continuous Veno-Venous Hemodiafiltration Diffusion and Convection 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.

SCUF Blood driven through highly permeable filter via extracorporeal circuit in venovenous mode UF produced during membrane transit is not replaced so it correspond to wt. loss Used only for fluid control in overloaded pt. (CHF pt not responding to diuretic t/t) Qb :100-250 ml/min &Quf:5-15ml/min

SCUF-Ultrafiltration Slow continuous ultrafiltration: Requires a blood and an effluent pump. No dialysate or replacement solution. Solute control is not goal of this therapy Fluid removal up to 2 liters/hr can be achieved. Primary Goal Safe management of fluid removal Large fluid removal via ultrafiltration SCUF (slow continuous ultrafiltration) when using this therapy, significant amounts of fluid are removed from the patient. No dialysate or replacement fluid is used because solute control is not a goal of this therapy. Ultrafiltration can be adjusted to cause dramatic fluid shifts. SCUF treatment utilize UFR’s of up to 2L/hr in some cases. The only pumps needed for this therapy is a blood pump and an effluent pump.

SCUF Return Pressure Air Detector Return Clamp Syringe pump Blood Pump Patient Hemofilter Filter Pressure Access Pressure Effluent Pressure BLD Effluent Pump Pre Blood Pump This slide depicts the SCUF (slow continuous ultrafiltration) is a therapy that uses no dialysate or replacement solution.On the right hand side of the screen you see a Pre-blood pump that could deliver anticoagulation solution at the patient access. The there is really only 2 pumps that are required for this therapy: Blood pump, Effluent pump, and if desired the Pre-blood pump. Plasma water is removed by ultrafiltration.

CVVH(Continuous venovenous hemofiltration) Blood driven through highly permeable membrane via extracorporeal circuit in venovenous mode UF produced during membrane transit is replaced in part or completely to achieve blood purification & volume control Pre or post dilution hemofiltration based on replacement fluid delivery before or after filter

CVVH-Convection Continuous veno-venous hemofiltration Requires blood, effluent and replacement pumps. Dialysate is not required. Plasma water and solutes are removed by convection and ultrafiltration. CVVH (continuous veno-venous hemofiltration) aims for maximizing convective removal of middle to large molecules. Replacement solutions are used to drive convective transport. When performing CVVH the following pumps are used: The blood pump, replacement pump and the effluent pump.

CVVH Return Pressure Air Detector Syringe Pump Return Clamp Patient Hemofilter Filter Pressure Access Pressure Post Effluent Pressure Pre Post Replacement Pump Pre Blood Pump Effluent Pump Replacement Pump This slide depicts the CVVH flowpath for both blood and fluid. As you, can see there are several points that replacement solution can enter the circuit. On the right hand side of the slide the replacement solution is entering pre-blood pump. Delivering the replacement solution Pre-blood pump will allow for greater hemodilution of the access line, and better solute clearance before the blood comes in contact with the filter. The first purple bag from the right hand side delivers the replacement solution Pre-filter, which means that as the blood enters the filter it is mixed with replacement solution. Pre-filter offer greater hemodilution of the filter, which increases filter life. Unfortunately, about 15% of the replacement solution is lost over the filter, thus decreasing solute clearance. The purple bag on the left hand side of the slide is delivering replacement Post-filter, which means as the blood is returning to the patient replacement solution is added. Delivering replacement post-filter allows better solute clearance, but may decrease filter life due to the hemoconcentration of the blood in the filter.

CVVHD Continuous venovenous hemodialysis Blood driven through low permeability dialyzer via extracorporeal circuit in venovenous mode and countercurrent flow of dialysate delivered in dialysis compartment UF produced during membrane transit correspond to wt. loss Solute clearance is mainly diffusive & efficiency limited to small solutes only Qb :100-250ml/min & Qd :15- 60ml/min

CVVHD-Diffusion Continuous veno-venous hemodialysis Requires the use of blood, effluent and dialysis pumps. Replacement solution is not required. Plasma water and solutes are removed by diffusion and ultrafiltration. CVVHD (continuous veno-venous hemodialysis) is a therapy that uses dialysate solution on the fluid side of the filter to increase solute exchange by diffusion. Replacement solution is not required for this therapy. The pumps required for this therapy are as follows: Blood, dialysate and effluent pump. Plasma water and solutes are removed by diffusion and ultrafiltration.

CVVHD Return Pressure Air Detector Return Clamp Syringe Pump Blood Pump Patient Hemofilter Filter Pressure Access Pressure Effluent Pressure BLD Dialysate Pump Pre Blood Pump Effluent Pump This schematic depicts a CVVHD flowpath. Describe the blood flowpath through the hemofilter and back to the patient. Then show green dialysate entry into the hemofilter (counter-current flow) and effluent removal through the yellow line/bag. Prismaflex allows use of the Pre blood pump fluid/anticoagulant infusion. The white bag on the right-hand side of the slide can deliver anticoagulation solution. We really want to focus on the green bag on the left hand side of the slide. This is the dialysate solution that is going to be delivered to the fluid side of the filter. The dialysate solution enters at the top of the filter and travels counter-current of the blood. The counter-current flow increases solute removal.

CVVHDF Continuous venovenous hemodiafiltration Blood driven through highly permeable dialyzer via extracorporeal circuit in venovenous mode and countercurrent flow of dialysate is delivered in dialysate compartment UF produced during membrane transit is in excess of pt. desired wt. loss

CVVHDF Continuous veno-venous hemodiafiltration Requires the use of a blood, effluent, dialysate and replacement pumps. Both dialysate and replacement solutions are used. Plasma water and solutes are removed by diffusion, convection and ultrafiltration. CVVHDF (continuous veno-venous hemodiafiltration) combines the benefits of CVVH and CVVHD using both convective and diffusive transport mechanisms. Replacement and dialysate fluids are both employed. The pumps required for this therapy are as follows: A blood, dialysate, replacement and effluent pumps.

CVVHDF Removal of small molecules by diffusion through the addition of dialysate solution. Removal of middle to large molecules by convection through the addition of replacement solution. The use of both diffusion and convection transport mechanism create a therapy called hemodiafiltration. This specific therapy combines dialysate solution to create diffusive clearance of small molecules, and replacement solution to create convective clearance of middle to large molecules.

SLEDD(Slow low efficiency daily dialysis) Hybrid therapy that try to match physiological advantage of CRRT Involves use of blood & dialysate flows less than in IHD Qb : 100-200ml/min & Qd :< 300ml/min T/t time extended to 6-12hr every day

SLEDD(Slow low efficiency daily dialysis) Result slower solute clearance & fluid removal & result in hemodynamic stability comparable to CRRT.

Removal of sodium & water cannot be dissociated when using diuretic & some RRT Diuretics l/t natriuresis whereas dialysis may result in hypotonia or hypertonia Depending on effect of dialysis on diffusion & on removal of molecules , including urea & other electrolyte

Water removal is always a/w removal of other solutes & its amount depend on technique used UF from SCUF is iso-osmotic & and isonatremic because Na elimination is linked to Na conc. in plasma Best evidence to date support RRT dose of 35ml/kg/hr for CVVH, CVVHD, IHD

UNLOAD trial(UF versus i.v. diuretics for acute decompensated CHF) First RCT comparing Diuretic versus HF in hypervolemic pt. Principal Findings Ultrafiltration l/t greater wt. & fluid loss Reduction in rate & duration of subsequent hospitiliztions in pt with volume removal by UF Benefits from short term use of UF over 90 days was achieved without significant adverse effects

Vascular Access A veno-venous double lumen hemodialysis catheter or two single lumen venous hemodialysis catheters may be used. A patient will need a veno-venous double lumen catheter or two single lumen venous hemodialysis catheter. One side of the lumen will deliver blood from the patient to the filter, and the other lumen will return the blood back from the filter to the patient.

Access Location Internal Jugular Vein Primary site of choice due to lower associated risk of complication and simplicity of catheter insertion. Femoral Vein Patient immobilized, the femoral vein is optimal and constitutes the easiest site for insertion. Subclavin Vein The least preferred site given its higher risk of pneumo/hemothorax There are three access locations that are used some may be preferred over others. Internal jugular vein is the primary choice due to the simplicity of catheter insertion. Femoral vein is a great access when a patient is immobilized, and is also considered an easy site for insertion. Subclavin is the least preferred and often used if no other sites are available. A Subclavin has a high risk of pnemo/hemothorax and is associated with central stenosis.

Result in clotting of filter or circuit Anticoagulation Blood contact to circuit tubing in CCRT l/t activation of coagulation cascade Result in clotting of filter or circuit Quantity & duration of anticoagulation changes depending on schedule of RRT Anticoagulation necessary for CRRT where blood – artificial surface interaction is maximum

Vascular access adequate size Kinking of circuit tubing avoided Circuit set up optimisation Vascular access adequate size Kinking of circuit tubing avoided Blood flow rate should exceed 100ml/min Plasma filtration fraction < 20% When possible predilution hemofiltration considered

Unpredictable bioavailibility Unfractionated heparin Dose 5-10 IU/kg/hr Regional heparinization in 1:1 ratio with protamine ( 150IU Of UFH per mg protamine) Problems : Unpredictable bioavailibility Necessity for AT III levels for optimal use Heparin induced thrombocytopenia

LMWH Alternative to UFH Prospective studies hav not shown it superior to UFH in prolonging life of RRT circuit Better bioavailibility Lower incidence of HIT Cost 10% > than UFH

Prostacyclin (PGI2) Potent inhibitor of platelet aggregation with short half life Infusion dose 4-8ng/hr with or without addition of low dose UFH Problems: Very short circuit life span Hypotension

Citrate Citrate chelates calcium which prevents clot formation Drawbacks : Risk of hypoalcemia Metabolic alkalosis

Complications as/w hemodialysis Hypotension – MC d/t osmolar shift & ultrafiltration- induced volume depletion Hypotensive episode may reflect myocardial ischemia,dysarrythmias or pericardial effusion with cardiac tamponade T/t – slowing rate of ultrafitration and/or i.v fluids

Hypersensitivity reaction to ethylene oxide used to sterlize dialysis machine d/t specific membrane material polyacrylonitrile MC in pt. receiving ACE inhibitors This reaction d/t bradykinin release which is degraded by kinases but ACE inhibitors block this response

Progressive renal failure,catabolism,&anorexia l/t loss of lean body mass but fluid retention mask this may l/t wt. gain Between t/t wt. gain of 3%-4% of body mass is appropriate

Increased chances of ischemic heart disease in ESRD pt Increased chances of ischemic heart disease in ESRD pt. on hemodialysis d/t Systemic HTN Anemia Hyperlipidemia Hyperhomocystemia Accelerated atherosclerosis Impaired oxygen delivery to myocardium d/t uremic toxin

Pericarditis with pericardial effusion d/t inadequate hemodialysis T/t - Intensive heparin free dialysis Persistent effusion - pericardiocentesis

Bleeding tendency d/t altered platelet function , partially correctable by hemodialysis Heparin free dialysis or administration of DDAVP , sufficient to correct bleeding tendency

At risk of infection d/t impaired phagocytosis & chemotaxis T.B in pt on hemodialysis is extrapulmonary and atypical symptom mimicing inadequate dialysis Vaccinated against pneumococcal and hepatitis B

Summary Mechanism in RRT based on principles of water & solute transport via diffusion & convection These mechanism applied lead to different techniques & modalities Clinical effects on critically ill pt. depend on selected RRT strategy & on severity/ complexity of patients clinical picture

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