Renal Replacement Therapy – help or hindrance?! #FOAMed #FOAMcc

Written by Dr Richard Pertwee (Clinical Fellow ITU)

Edited and reviewed by Dr Jonny Wilkinson

Renal replacement therapy is a commonly administered treatment in Intensive Care. It is also a therapy / aspect of critical care that creates a large air of confusion amongst many, from nursing staff to medical staff alike.

>5% of the ICU population will require it during their journey. When the decision for renal replacement therapy (RRT) is made, internal dialogue begins and various questions need addressing:

  • What modality – CVVH/CVVHDF/CVVHD??
  • What flow rate – 25, 35 or >35ml/kg/hr?
  • What fluid – lactate containing, bicarbonate containing?
  • What pre / post dilution?
  • Fluid status – removal, neutral?
  • What anticoagulant – citrate, heparin or prostaglandin?

To many people, the good old Prismaflex machines are simply ‘voodoo’ boxes, with their array of tubes, spinning wheels and dangling bags of fluid which the nurses seem to periodically change when alerted to do so by the shrill bleeps of the machine.

So, the aim of this brief blog is to demystify the topic of renal replacement therapy in Critical Care.

 

What is renal replacement therapy (RRT)?

Renal replacement therapy (RRT) replaces the non-endocrine function of the kidney in patients with kidney failure and is also sometimes used in some forms of poisoning.

There are 3 ,Ain broad categories to think about:

  1. Peritoneal dialysis (PD)
  2. Intermittent haemodialysis (IHD)
  3. Continuous renal replacement therapy (CRRT)

IHD and CRRT are both effective methods of renal support for patients with acute kidney injury. However, discussions about whether IHD and CRRT is the preferred modality for RRT has continued for decades. Generally, nephrologists prefer IHD and intensivists favour CRRT. For this reason, continuous therapies are the prevailing mode of delivering renal support in Intensive Care Units in the UK.

A major reason for this is the fact that as critically ill patients tend to be haemodynamically unstable, the rapid fluid shifts caused by intermittent haemodialysis and the resulting periods of hypotension may adversely affect any remaining renal function that the patient may have and potentially delay recovery of renal function.

 

Indications

The conventional criteria for initiating renal replacement are:

  1. Hyperkalemia – refractory to medical treatment
  2. Metabolic acidosis – controversial if this is caused by the process of SIRS / Sepsis
  3. Rapidly climbing Urea and Creatinine
  4. Uraemia
  5. Oligo/Anuria
  6. Fluid overload
  7. Removal of drugs/Toxins
  8. Temperature control
Screenshot 2017-05-22 15.04.18.png
Baker & Green – andrewkellasbaker@doctors.org.uk

 

Modes of action

The main aims of RRT are to remove water and solutes and so correct electrolyte imbalances and acid-base disturbances.

The two main physical processes employed in RRT that cause the movement of solutes and fluids across a semipermeable membrane are haemofiltration and haemodialysis.

Haemofiltration

In haemofiltration, a positive pressure is generated in the blood compartment of the dialyser. This sets up a hydrostatic pressure gradient across the semipermeable membrane that drives water across the membrane as ultrafiltrate. Through this convective process, solutes are also ‘dragged’ across the membrane within the stream of water. Molecules <50,000 Daltons are small enough to be dragged across the membrane with the water by the process of convection. This process essentially mimics the function of the glomerulus. The filtered fluid (ultrafiltrate) is discarded and a replacement fluid is added in an adjustable fashion according to the desired fluid balance.

Haemodialysis

Haemodialysis on the other hand, involves diffusion of water and solutes down a concentration gradient.  To achieve this, blood is passed over a semi-permeable membrane separating it from an electrolyte solution flowing in the opposite direction. This counter current flow mechanism ensures that the solute concentration is always lower on the dialysate side of the membrane and so a concentration gradient is maintained along the entire length of the membrane. When removal of water is required the pressure on the blood-side of the membrane has to be increased forcing water molecules to pass into the dialysate.

The main distinction between haemofiltration and haemodialysis is the driving force for the movement of water and solutes across the semi-membrane. In haemofiltration, it is the transmembrane pressure while in haemodialysis, it is the concentration gradient.

Choose your site

There is no real perfect site to place a line, but the table below has some considerations

Screenshot 2017-05-22 16.23.25.png
Baker & Green – andrewkellasbaker@doctors.org.uk

 

Methods available

The methods available for continuous renal replacement therapy employ either of the physical processes or a combination of the two.

Continuous veno-venous haemodialysis (CVVHD)

In this circuit, blood passes through a haemodialyser with a semi-permeable membrane, with the dialysate solute solution flowing in the opposite direction to the blood. Solutes pass from the blood into the dialysate solution down a concentration gradient by diffusion

Continuous veno-venous haemofiltration (CVVHF)

In this circuit, blood passes through a haemofilter within which a positive pressure is generated on the blood compartment side, setting up a transmembrane pressure that drives water and with it solutes across the semi-permeable membrane to form ultrafiltrate on the opposite side.

Continuous veno-venous haemodiafiltration (CVVHDF)

As the name suggests, this particular mode combines the two processes of diffusion and convection by adding a counter-current flow of dialysate into a haemofilter, on opposite side to the blood compartment, ultimately forming a haemodiafilter.

Screenshot 2017-05-22 15.15.24.png
Baker & Green – andrewkellasbaker@doctors.org.uk

 

To Anticoagulate or not??

You have to optimise conditions for blood to flow, which often means adding in a bit of ‘thinner! You don’t have to do this if:

  • Pre-existent coagulopathy
    • INR > 2-2.5
    • APTT > 60 seconds
    • platelet count < 60 x 103.mm-3
  • High risk of bleeding

Unfractionated or low molecular weight heparins

Unfractionated heparin (UFH) [5-30kDa] is the most commonly used anticoagulant in the UK and a typical regime involves a 40-70 U/kg bolus followed by a pre-filter infusion at 5-10 U/kg./hr. It is the most cost effective anticoagulant and is fully reversible with protamine. The APTT should be monitored to avoid excessive anti-coagulation but there is no evidence that elevating the APTT prolongs filter life. Anticoagulate the filter..not the patient is the aim, so aiming for APTTR just >2 is fine

Prostaglandins

Prostaglandins (prostacyclin or prostaglandin E2) inhibit platelet function and can either be used on their own or in combination with heparin whereby they have a synergistic effect. Prostaglandins have a short half life (several minutes) so are administered as an infusion (2.5 – 10 ng/kg/min). The anticoagulant effect stops within 2 hours of discontinuing the infusion making them a useful alternative to heparin in patients at high risk of bleeding.

The main side effect is vasodilation which may include a reduction in hypoxic pulmonary vasoconstriction leading to hypoxemia. The other downside is that they are expensive and so are only used as second line therapy

 

Sodium Citrate

Regional citrate anticoagulation is an effective therapy especially when there is an increased risk of bleeding. It is often used as an alternative to heparin in the USA but it is rarely used in the UK.

Sodium citrate is infused into the circuit pre-filter which chelates calcium and inhibits clot formation. The calcium citrate complex is freely filtered so a calcium infusion is required post-filter. This form of anticoagulation is limited by the metabolic derangements that it can cause: Hypocalcaemia, hypomagnesaemia (Mg2+ is also chelated), hypernatraemia (sodium load in sodium citrate), metabolic alkalosis (citrate is metabolised to bicarbonate), metabolic acidosis (caused by the citrate especially if the body`s citrate handling is impaired e.g. liver failure

What Fluid?

Bicarbonate Vs Lactate containing; there is no evidence to suggest that the choice of replacement fluid has an impact on survival or renal recovery.

Replacement fluid can be added pre- or post-filter in varying ratios. The benefit of adding some of the replacement fluid pre-filter is that it lowers the haematocrit of the blood which reduces the likelihood of the filter clotting. The downside is that pre-dilution reduces solute clearance and a compensatory increase in flow rates should be considered. (15% for ultrafiltration rates of 2l/hr and up to 40% for rates of 4.5l/hr)

  • Use solutions without potassium if serum potassium is high but switch to potassium containing solutions as serum potassium normalises.
  • Use a bicarbonate-based buffer rather than a lactate-based buffer if there are concerns about lactate metabolism or if serum lactate >8mmol/l

Essentially, remain on a neutral balance if your patient is euvloaemic, or if overloaded, work out by how much and divide this by 24 to give you your removal rate per hour.

Screenshot 2017-05-22 16.20.45.png
Baker & Green – andrewkellasbaker@doctors.org.uk

 

Solute Clearance and Mode??

The aim of any renal replacement therapy is to remove water and solutes of varying sizes from blood. Think of it as ‘cleaning’ the blood in situations where a patient’s renal function is lacking.

For simplicity, you can classify the substances removed from blood plasma into four categories:

  • Small molecules / electrolytes – <500 Daltons
    • Examples: Urea, creatinine, K+, H+
  • Middle molecules – 500 – 5000 Daltons
    • Examples: Large drugs e.g. vancomycin, vitamin B12, inulin
  • Low molecular weight proteins – 5000 – 50000 Daltons
    • Examples: β2 microglobulin, cytokines, complement
  • Water – 18 Daltons

With this classification in mind, the next thing to consider is which mode – haemofiltration (convection) or haemodialysis (diffusion) clears a certain solute more effectively.

  • Small molecules are cleared equally effectively by convection (haemofiltration) and diffusion (haemodialysis)
  • Middle molecules are removed more effectively by convection than by diffusion
  • Low molecular weight proteins are cleared by convection
  • Water is cleared more effectively by convection than by diffusion

So, from this, it seems that the convective process provided by haemofiltration on balance, is better as it clears each type of solute.

However, it seems that there is still a lot of controversy as to which mode of RRT is best. This is primarily due to the lack of randomised controlled trials comparing different techniques.

The study below (click image) was a prospective cross over study in a cohort of critically ill patients. It compared small (urea and creatinine) and middle (β2 microglobulin) molecular weight solute clearance, filter lifespan and membrane performance over a period of 72 hours during 15 continuous CVVHD and 15 CVVH sessions.

Screenshot 2017-05-22 13.58.54

The headlines were

  • Median urea time weighted average (TWA) clearances were not significantly different p=0.213
    • CVVH – 31.6 ml/minute, (IQR) 23.2 to 38.9
    • CVVHD – 35.7 ml/minute, (IQR) 30.1 to 41.5
  • Median creatinine TWA clearances were not significantly different p=0.917
    • CVVH – 38.1 ml/minute, (IQR) 28.5 to 39
    • CVVHD – 35.6 ml/minute, (IQR) 26 to 43
  • Median β2 microglobulin TWA clearance was higher in convective, but not significantly p=0.55
    • Convective – 16.3 ml/minute, (IQR) 10.9 to 23
    • Diffusive – 6.27 ml/minute, (IQR) 1.6 to 14.9
  • Filter lifespan was longer during CVVHD with significance p=0.03
    • CVVHD – 37 hours, (IQR) 19.5 to 72.5
    • CVVH – 19 hours, (IQR) 12.5 to 28

So, maybe there really is no difference in solute clearance between haemofiltration and haemodialysis.

Polyacrylonitrile filters during continuous hemofiltration and continuous hemodialysis delivered at 35 ml/kg/h are comparable in little and middle size solute removal. CVVHD appears to warrant longer CRRT sessions. The capacity of both modalities for removing such molecules is maintained up to 48 hours.

Outcome Data?

Then, the next question – is there any difference in clinical outcomes when comparing haemofiltration and haemodialysis for acute kidney injury?

A systematic review examined the effect of renal replacement therapy (RRT), delivered as haemofiltration vs haemodialysis, on clinical outcomes in patients with acute kidney injury (AKI).

Screenshot 2017-05-22 14.15.41

19 RCTs (10 parallel-group and 9 crossover) were included, although the study quality was variable.

The headlines were

  • No mortality difference
    • (RR) 0.96, 95% CI 0.73 to 1.25, P = 0.76
    • three trials, n = 121 (primary analysis); RR 1.10, 95% CI 0.88 to 1.38, P = 0.38
    • eight trials, n = 540 (sensitivity analysis)
  • No difference in secondary outcomes
    • RRT dependence in survivors
    • vasopressor use
    • organ dysfunction
  • Haemofiltration appeared to shorten time to filter failure
    • mean difference (MD) -7 hours, 95% CI (-19,+5), P = 0.24
    • two trials, n = 50 (primary analysis); MD -5 hours, 95% CI (-10, -1), P = 0.01
    • three trials, n = 113 (including combined hemofiltration-hemodialysis trials comparing similar doses) MD -6 hours, 95% CI (-10, -1), P = 0.02
    • five trials, n = 383 (sensitivity analysis)

Data suggested that haemofiltration increased clearance of medium to larger molecules, including inflammatory cytokines, compared to haemodialysis, although almost no studies measured changes in serum concentrations.

Data from small RCTs do not suggest beneficial clinical outcomes from hemofiltration, but confidence intervals were wide. Hemofiltration may increase clearance of medium to larger molecules. Larger trials are required to evaluate effects on clinical outcomes.

Dose of continuous renal replacement therapy (CRRT)

The dose of CRRT can be thought of as the volume of blood ‘cleaned’ per unit time. In practice, the dose of CRRT is expressed as effective effluent/kg/hour. Standard doses of CRRT are 25-45ml/kg/hr.

The optimal dose remains controversial.

You could argue that with higher doses of CRRT, you would ‘clean’ a patient’s blood (i.e. remove accumulated solutes and water) more rapidly and so the patient would get better quicker.

The VA/NIH Acute Renal Failure Trial Network study sought to elucidate the optimal intensity of renal-replacement therapy in critically ill patients with AKI.

Screenshot 2017-05-22 14.25.42

1124 critically ill patients with acute kidney injury and failure of at least one non-renal organ or sepsis were randomly assigned to receive intensive or less intensive renal-replacement therapy.

  • Intensive treatment RRT arm had either
    • Intermittent haemodialysis (IH) six times per week – if haemodynamically stable
    • Sustained low-efficiency dialysis (SLED) six time per week or CVVHDF at 35 ml/kg/hr – if haemodynamically unstable
  • Less-intensive RRT arm had either
    • IH (three times per week) – if haemodynamically stable
    • SLED (three times per week) or CVVHDF at 20 ml/kg/hr – if haemodynamically unstable

The headlines were

  • Intensive therapy – mortality at day 60 was 53.6%
  • Less intensive therapy – mortality at day 60 was 51.5%
    • odds ratio, 1.09;
    • 95% CI, 0.86 to 1.40
    • P = 0.47

Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure as compared with less-intensive therapy involving a defined dose of intermittent hemodialysis three times per week and continuous renal-replacement therapy at 20 ml per kilogram per hour.

The Randomized Evaluation of Normal versus Augmented Level (RENAL) Replacement Therapy Study randomly assigned 1508 critically ill patients with acute kidney injury to either CVVHDF at 40 ml/kg/hr (higher intensity) or at 20 ml/kg/hr (lower intensity).

Screenshot 2017-05-22 14.40.06.png

The headlines were

  • Higher intensity group – 322 patients dead at 90 days
  • Lower Intensity group – 332 patients dead at 90 days
    • mortality of 44.7% in each group
    • odds ratio, 1.00
    • 95% CI, 0.81 to 1.23
    • P=0.99
  • 6.8% of survivors in the higher-intensity group still receiving RRT
  • 4.4% of survivors in the lower intensity group still receiving RRT
    • odds ratio, 1.59
    • 95% CI, 0.86 to 2.92
    • P=0.14

In critically ill patients with acute kidney injury, treatment with higher-intensity continuous renal-replacement therapy did not reduce mortality at 90 days.

 

Have a look at…

ICS RRT Guidelines

Renal Replacement Therapy playlist (click the top left icon in the box to display all)

What TBL said about big trials (click the pics)

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