Continuous Renal Replacement Therapy -CRRT Other types of RRT- Haemodialysis and PD

Classical ‘renal’ indications for starting renal replacement therapy (RRT) are: Rapidly rising serum urea and creatinine or the development of uraemic complications Hyperkalaemia unresponsive to medical management Severe metabolic acidosis Diuretic resistant pulmonary oedema Oliguria or anuria

‘Non renal’ indications for starting RRT are: Management of fluid balance e.g. in cardiac failure Clearing of ingested toxins Correction of electrolyte abnormalities Removal of inflammatory mediators in sepsis? Rhabdomyolysis Rhabdomyolysis results from skeletal muscle injury and cell lysis with the release of myoglobin and other muscle breakdown products. Myoglobin is freely filtered by the kidneys and is directly toxic to the tubular epithelial cells particularly in the setting of hypovolaemia and acidosis. There are a number of causes including trauma, burns, compartment syndrome and drugs (cocaine, ecstasy, statins). aggressive fluid resuscitation and alkalinisation of the urine.nFluid resuscitation with 0.9% sodium chloride is preferred at a rate of 10-15ml/kg/hr to achieve high urinary flow rates (>100ml/hr), with the cautious addition of sodium bicarbonate 1.4% to maintain urinary pH> 6.51. Mannitol is still used because of its properties as an osmotic diuretic and free radical scavenger by many centres although there is little clinical data to support its use. Inappropriate use of mannitol can precipitate pulmonary oedema particularly if used with hypertonic sodium bicarbonate. It has been shown that many, if not all of the septic mediators can be removed by CVVH however the benefit on clinical outcome is less clear (ICS standards and safety, 2009). A variable degree of adsorption occurs on to the membrane and it is thought that this may lead to the removal of some inflammatory mediators. adsorption may or may not be clinically significant as membranes reach saturation relatively quickly

Diffusion- movement of solutes across a semi permeable membrane through a concentration gradient Good for smaller sized molecules

Convection- movement of fluid across a semi permeable membrane creating a solute drag. Good for smaller and middle sized molecules

When to start RRT Conventional starting criteria for RRT should be used Treatment should be started before complications develop- Earlier the better! The rate of change of urea and creatinine is more significant than their absolute levels, however in most cases RRT should be started before urea is 20 – 30 mmol/L. Initiation of RRT on the basis of fluid balance, urine output, potassium level or degree of acidosis will be dependent on the patient’s clinical condition. ? What constitutes early -levels of urea and creatinine or urine output. Renal Society (2008) start RRT if serum urea>30mmol/l; met acidosis<or= 7.1; UO< 0.3ml/kg/24hrs or absolute anuria . RRT was started significantly earlier when oliguria, rather than solute levels was used as a trigger, and an early start was associated with reduced hospital mortality. In many circumstances, starting RRT well before urea rises to these levels may well be justified.

What type of RRT SCUF CVVH CVVHDF CVVHD SLED(D) CVVHDF- more complicated as addition of dialysate fluid. Given both intermittent and continuous therapies have their own potential benefits, hybrid therapies such as slow low efficiency daily dialysis (SLED(D)) have been developed as a ‘best of both worlds’. These therapies aim to provide haemodynamic stability over a time period short enough to avoid the complications of continuous anticoagulation, allowing time for therapeutic interventions/diagnostic imaging, but over a period long enough to gain good solute and fluid control. Slow low efficiency daily haemodiafiltration (SLEDD-f) can be used to combine the beneficial effects of diffusion with convection. There is little doubt that in terms of solute control they are comparable to other forms of RRT, but so far there is no evidence that hybrid therapies are superior to either CRRT or IHD. A need for a dialysis machine, water supply and trained nursing staff may also limit its widespread use.

Ultrafiltration-UF Hydrostatic pressure gradient between blood and filtrate creates pressure gradient that forces fluid out of blood (ultrafiltration and along with it goes molecules (convection)

CVVH When considering CRRT, continuous may not indeed be continuous, and patients may receive inadequate solute control. One retrospective review found that only 68% of patients received their prescribed dose of CRRT where as in the study by Ronco et al, over 85% of prescribed dose was delivered. Even with intermittent therapies, it has been found that the delivered dose may be up to 30% lower than the prescribed dose.

CVVHDF a blood pump provides solute removal by diffusion and convection simultaneously. It offers high volume ultrafiltration using replacement fluid which can be administered pre-filter/ post-filter. Simultaneously, dialysate is pumped in counter flow to blood. By increasing hydrostatic pressure (prefilter dilution) increase hydrostatic pressure

CVVH v CVVHDF There is no evidence to suggest that CVVH is superior to CVVHDF in terms of patient outcome or renal outcome (or vice versa). With CVVHDF -UF flow rates may be reduced therefore larger molecule removal by convection is decreased If adequate UF rates cannot be achieved using CVVH due to machine limitations, then CVVHDF should be considered. A predominantly convective mode of clearance may be considered in severe sepsis

Solute clearance- depends on Blood flow Recirculation Membrane characteristics- type of filter Filter clotting- aim for 85% of prescribed dose Pre/post dilution The removal of potassium, correction of acidosis or the removal of fluid may have just as much of an impact on patient outcome as solute clearance. Pre-dilution CRRT reduces solute clearance and an increase of 15% for ultrafiltration rates of 2 L/h and up to 40% for rates of 4.5L/h or more should be considered. When considering CRRT, continuous may not indeed be continuous, and patients may receive inadequate solute control. One retrospective review found that only 68% of patients received their prescribed dose of CRRT where as in the study by Ronco et al, over 85% of prescribed dose was delivered. Even with intermittent therapies, it has been found that the delivered dose may be up to 30% lower than the prescribed dose. Pre-dilution lowers the haematocrit of blood passing through it and has been used as an adjunct to anticoagulation (61). As discussed in the previous section, pre-dilution leads to a reduction in solute clearance. There is no evidence to suggest that CVVH (convection) is superior to CVVHDF (convection plus diffusion) in terms of patient outcome or renal outcome (or vice versa). If adequate ultrafiltration rates cannot be achieved using CVVH due to machine limitations, then CVVHDF should be considered. A predominantly convective mode of clearance may be considered in severe sepsis dose.

Pre filter dilution

Post filter dilution

Ultrafiltration flow rates Moves towards higher UF rates Too low reduces clearance of solutes Too high- affect membrane performance Filtration fraction <25%

Ultrafiltration Rates Ronco et al (2000) large prospective study Suggestion that a higher level of solute clearance was beneficial at higher UF rates. (35 mls/kg/hr) American Acute Renal Failure Trials Network (ATN study, 2008), did not find any difference in survival, rate of renal recovery or nonrenal organ failure in ‘intensive’ versus ‘less-intensive’ renal support. The Australian/NZ RENAL study (Randomised Evaluation of Normal vs. Augmented Level of renal replacement therapy in ICU, 2009) compared 40 ml/kg/h to 25 ml/kg/h of ultrafiltrate production in CVVHDF. No difference in terms of outcome. ? 25-30ml/kg/hr in hopes of achieving 19ml/kg/hr (ATN study) and 22mls/kg/hr RENAL study)

Points for consideration Replacement fluid Membrane Anticoagulation Flow rates- vascular access Temperature management Drug dose adjustment

Replacement fluid Composition similar to normal serum electrolytes Bicarbonate/lactate buffer. The individual components of filtration fluid vary but phosphate and potassium supplementation is often needed. Bicarbonate may trigger inflammatory mediators, an undesirable side effect in the critically ill and could theoretically be harmful. Bicarbonate may induce nitric oxide synthase activity, increase cyclo-oxygenase activity and increase proapoptotic protein in the extracorporeal circuit, an undesirable side effect in the critically ill and could theoretically be harmful. Standard bicarbonate or lactate bags cannot be used if citrate anticoagulation is used; modified replacement and dialysate fluid should be used in such circumstances. If lactate levels extreme or liver failing opt for lactate free fluid but need to add bicarb separately as unstable in mix Hyperosmolar HONKC & neuro patients. Avoid risk disequilibrium syndrome change between osmolarity of extracellular and intracellular osmolarity (urea) Causes neuological effects….fitting. Less likely with CRRT than IHD because slower speeds and volumes make better control.

Membranes High surface area Used to be cellulose, now synthetic biocompatable Pore size affects solute transfer Phosphates are lost at the same rate as urea Doesn’t clear protein bound molecules eg midazolam Doesn’t secrete toxins like a tubular cell Removes glucose Future ? Bioartificial kidney with human tubular cells lining hollow fibers A variable degree of adsorption occurs on to the membrane and it is thought that this may lead to the removal of some inflammatory mediators. PAN and PA membranes appear to have greater adsorptive properties than PS membranes (68) but membrane adsorption may or may not be clinically significant as membranes reach saturation relatively quickly. Alter drug dosages Protein bound drugs will accumulate Drugs that are actively secreted by tubular cell ( or their metabolytes) will accumulate eg ranitidine, digoxin, opiates, benzodiazipines, aminiglycosides and other antibiotics.

Historically, cellulose dialysis membranes in chronic haemodialysis showed that they caused complement and leukocyte activation as blood came into contact with the membrane surface. Leukocyte activation is associated with increased expression of adhesion molecules leading to leukocyte retention in the lungs, renal parenchyma and other organs, thus resulting in further organ damage. Biocompatibility refers to this activation of inflammatory pathways, with more biocompatible membranes causing less activation. Synthetic membranes are more biocompatible and they cause less leukocyte activation; however leukocyte activation is only reduced with these membranes but never completely abolished

Anticoagulation

Anticoagulation No anticoagulation UFH unfractioned heparin LMWH low molecular weight heparin-Fragmin Prostacyclin Citrate Others Clotting of filter is significant source of underdelivery of CRRT Air/blood interface; hypercoaguable state of crit ill pts. Tech factors Non laminar flow within vas access; blood membrane interactions; haemoconc from high UF vols in CVVH/CVVHDF

No Anticoagulation Increased risk of clotting Increased consumption of clotting factors and platelets Short circuit life Preventative Measures Pre-dilution High Flow Aim for Filtration fraction of 25% or less Filtration fraction=turnover l/h divided by pump speed (mls/min) x 60 divided by1000 Disad as need for increase UFR = risk of filter rupture and additional nursing workload

Heparin Occurs naturally in human mast cells within the connective tissue of the blood vessels, liver and lungs. Results seen instantly with a half-life of 30 minutes – 2hours reversal with protamine sulphate but Fresh Frozen Plasma remains the definitive treatment. Heparin induced Thrombocytopaenia (HIT) Keeling, D (2006) The management of heparin-induced thrombocytopenia British Society for Haematology 133: p259-269

Heparin Used in patients with normal coagulation profile, normal platelet count and not at risk of bleeding The most commonly used anticoagulation for CVVH. Its cheap, effective and well tolerated. APTT and platelet counts routinely measured (no consensus on the frequency of testing -APTT does not always reflect the anticoag effect of heparin) (There is no correlation between increasing APTT and filter life) APTT does not always reflect the anticoag effect of heparin

Fragmin No evidence that it is superior to Unfractioned heparin in terms of efficacy or risk of side effects Extended half life Less risk of HIT lack of reliable predictors of bleeding and antithrombotic activity The true incidence of HIT type II is unknown, but for patient receiving prophylactic UFH HIT type II occurs in 2.6% of cases compared with 0.2% of cases when LWMHs are used (77). In the intensive care setting HIT type II has been reported in around 1-5% of patients treated with heparin for more than 5 days (78). The development of HIT type II may be associated with repeated clotting of the extracorporeal circuit (78).

Epoprostenol (prostacyclin, Flolan®) Considerable use in IHD and CVVH Inhibits platelet aggregation Can use in thrombocytopenia 50% reduction in bleeding therefore beneficial with high risk of patients Short half life of 3 minutes IHD= intermittant haemodialysis

Epoprostenol (prostacyclin, Flolan®) Common concerns Expensive and has powerful vasodilator properties Side effects of hypotension, flushing and headache. There is no reliable laboratory test to quantify the anticoagulation effect Its not effective for filter membrane fouling due to fibre clotting

Citrate Citrate binds with calcium and makes it unavailable for clotting cascade so need to -monitor serum calcium and give calcium infusion -monitor sodium and acid-base status as citrate to bicarbonate. Suggestion that citrate prolongs CRRT time and reduces need for blood transfusions and/or haemorrhage

Others Danaparoids; Fondaparinux- little experience of use in CVVH; monitor anti Xa levels Recombinant hirudin and argatroban are direct thrombin inhibitors. Experience with these drugs is limited, but increasing and they may have pharmacological advantages.

Vascular access Usually double D or D/O x section >11FG for blood flows >200-250ml/min Polyurethane- 3 weeks Jugular -Right side less recirculation ? subclavian Femoral catheters shorter than 20cm associated with increase recirculation Femoral replace weekly basis as infection and fem vein thrombosis

Hypothermia Do the following have any place in preventing hypothermia ? Wrap circuit Fluid warmer Systemic warming

Hypothermia Do the following have any place in preventing hypothermia ? Wrap circuit NO Fluid warmer Systemic warming the only available option

Blood Requests Due to the high volumes of filtration fluid with the increased pump speed and UF rates we need to monitor phosphate and calcium daily Bloods for U & E, FBC, Clotting- minimum daily

TROUBLE SHOOTING Connections top/bottom filter! Air detector Heparin infusion pump Vascular access Alarms

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