Renal replacement therapy
Transcript of Renal replacement therapy
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Dr Peter SherrenSpecialist trainee
Anaesthesia and Intensive Care
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ObjectivesObjectives
RRT Indications Modes and principles Dosing Replacement solutions Anticoagulation Special Circumstances
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AKI / CKD vs ARF / CRF
RIFLE
Renal failure - is the cessation of renal function with or without changes in urine volumes.
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Anaesthesia UK. Acute renal failure. Renal replacement therapy on ITU
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“Renal tubular cell injury after a toxic or ischaemic insult results in sloughing of tubular debris and cells into the tubular lumen with eventual obstruction of tubular flow, increased intra-tubular pressure and back leak of glomerular filtrate out of the tubule and into the interstitium and renal venous blood”1
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Renal: Symptomatic Uraemia Nephrogenic Pulmonary Oedema Severe Hyperkalaemia Severe metabolic acidemia Relative Urea/Creatinine levels
Non Renal: SIRS/sepsis Fluid balance Rhabdomyolsis * Overdose/Drug accumulation Renal protection pre/post contrast, CIN Temperature control Plasmapheresis/Exchange (immune complexes) Severe acute liver failure with molecular adsorbent
re-circulating system (MARS, PROMETHEUS) as bridge to transplant
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Early or late initiation of RRT (UO and Urea)
The answer to whether early initiation of RRT is beneficial with regards to survival and/or renal recovery is not clear. Why?
Getting et al 19992. Urea 15.2 vs 33.7 conferred
survival benefit.
Ronco et al 20003 and Saudan et al 2006
4 both
dose/outcome studies suggested an early start.
Liu et al 20065 observational PICARD study (Urea 27)
suggested an early start
Not all agree, Bouman et al 20026 RCT no benefit in
early initiation of RRT. CvvHF
Recommendation?
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Intermittent vs continuous
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.
Patients with AKI as part of MODS are less likely to tolerate Fluid shifts CVS instabiltiy (hyovolaemia and hypotension) Secondary renal insult
In MODS, CRRT is certainly better tolerated in terms of drop in CVP/CO/SVR/MAP7-9.
Likely benefits in for CRRT in SIRS/SEPSIS & cytokine clearance over IHD10.
Many papers advocating the benefit of CRRT in patients with raised ICP12-13.
In terms of survival and renal recovery the benefit of either is still to be demonstrated in all AKI requiring RRT. Recent Cochrane Database review 2007 demonstrated important haemodynamic effects but little survival benefits11.
So is there a place for IRRT?
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Ultrafiltration - movement of fluid across a pressure gradient,via hydrostatic forces.
Convection - The movement of solutes with a water flow or “Solvent drag”
Diffusion - Movement of solute from an area of high concentration to an area of low concentration viaosmosis across a semi-permeable membrane
Adsorption - Surface adsorption where the molecules are too large
to permeate and migrate through the membrane; however can adhere to the membrane
Bulk adsorption within the whole membrane when molecules can permeate it
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• Beta 2 Microglobulin (11,800) 2
• Inulin (5,200)
• Vitamin B12 (1,355)
• Aluminum/Desferoxamine Complex (700)
• Glucose (180)
• Phosphate (80)
• Urea (60)
• Phosphorus (31)
• Sodium (35)
•Potassium (23)
100,000
50,000
10,0005,000
1,000
500
100
50
10
50
molecular weight, daltons
}
}}
“small”
“middle”
“large”
•Albumin (55,000 - 60,000)
• Creatinine (113)• Uric Acid (168)
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Intermittent RRT HD most commonly Peritoneal dialysis
CRRT• SCUF - Slow Continuous Ultrafiltration
Ultrafiltration - fluid removal• CVVHF - Continuous Veno-Venous Hemofiltration
Convection - Small, medium and some large size molecules MW <30000 Daltons
• CVVHD - Continuous Veno-Venous Hemodialysis Diffusion - Small molecules <500 Daltons
• CVVHDF - Continuous Veno-Venous Hemodiafiltration Diffusion and Convection- small and medium sized
molecules
Niche techniques Plasmapheresis/exchange Haemoperfusion
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Method Peritoneal catheter Instil 1-2 litres dialysis fluid
under gravity
Dialysis Fluid Similar composition to ECF Variable Tonicity Variable K+ and glucose
content
Advantages Technically simple Safer than haemodialysis if:
high risk of systemic bleeding
circulatory instability vascular access difficult
Indicated in some cases of pancreatitis
Disadvantages Pain Bowel perforation Bleeding Infection/Peritonitis/SP/SEP Metabolic
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Requires AV shunt or Percutaneous catheter.
Removal of solutes by diffusion (mainly small sized molecules) via conc gradient.
Ultrafiltration, via hydrostatic gradient. Very effectively (1-2L/HR)
High blood flow rates required (350-400ml/min +)
Semi permeable membrane is used for selected diffusion. Dialysate is used to create a concentration gradient across a semi permeable membrane.
Need dialysate flow +/- countercurrent. The counter-current flow increases solute removal by maintaining gradient along filter (flow rate 15-45ml/min, 1-3L/Hr)
No replacement fluid
Minimal Adsorption
AKI without sepsis or CVS instability.
S
Access
Return
Effluent
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Advantages Rapid correction of volume overload Better solute clearance than
PD/CRRT Intermittent hence mobility
Disadvantages Specialist nurses, water tanks etc Vascular access complications Anticoagulation CVS instability NO medium/large molecule
clearance.
Dialysate Out
Dialysate In
Blood In
Blood Out
to waste
(from patient)
(to patient)
HIGH CONCLOW CONC
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Primary therapeutic goal:
Safe management of fluid removal
UF rate ranges up to 2 L/Hr via hydrostatic forces.
No dialysate
No replacement fluids
Large fluid removal via ultrafiltration
Minimal solute clearance
Blood In
Blood Out
to waste
(from patient)
(to patient)
HIGH PRESSLOW PRESS
Fluid VolumeReduction
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Primary therapeutic goal:
Convective solute removal
Management of intravascular volume (pressure gradient)
Blood Flow rate = 10 - 180 ml/min, newer machines 300ml/min.
UF rate ranges 6 - 50 L/24 h (> 500 ml/h) GFR 10-20%.
Replacement solution can help to drive convection
Removal of small and medium sized molecules
No dialysate
AccessAccess
ReturnReturn
EffluentEffluent
ReplacementReplacement
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Advantages Better at removal of middle sized MW
molecules >500-1000 daltons Use for Cytokine adsorption and CVS
instability in intractable septic shock10,16
Accurate control of ultrafiltered volume
CAVH self-regulating CVVH requires no arterial access
Disadvantages Complex equipment Worse clearance/diffusion of small MW
solutes. NA/K/Ur/Creat CAVH blood-pressure dependent Access site complications (esp CAVH)
Blood In
Blood Out
to waste
(from patient)
(to patient)
HIGH PRESSLOW PRESS
Repl.Repl.SolutionSolution
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Primary therapeutic goal:
Solute removal by diffusion and convection
Management of intravascular volume
Blood Flow rate = 10 - 180ml/min, again newer machines capable of 300ml/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). Countercurrent flow
Uses both dialysate (1 L/h) and replacement fluid (500 ml/h+)
Dialysate
AccessAccess
ReturnReturn
EffluentEffluent
ReplacementReplacement
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Advantages Better clearance of small solutes
over HF, K/Na/Ur/Creat Less limited by poor access and
hypotension Benefits in ARF & MOF4
Small/medium/large molecule removal to a degree
Disadvantages Not as efficient adsorption and
middle molecular clearance Solute and drug clearance less
predictable Fluid balance complicated Complicated equipment Clotted filter may be disguised
Repl.Repl.SolutionSolution
DialysateDialysateSolutionSolution
Blood In
Blood Out
to waste
(from patient)
(to patient)
HIGH PRESSLOW PRESS
HIGH CONCLOW CONC
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Studies in patients with end stage kidney disease (ESKD) requiring IHD have led to well defined targets for what constitutes adequate clearance17
In AKI the dosing/clearance/filtrations rates are not nearly so clear.
IHD fractional clearance Kt/V well used.
In post filter dilution CvvHF Ultrafiltration volume acts as a surrogate for clearance in the critically ill16.
Ultrafiltration volume in ml/kg/hr represents the filtered fraction of patient’s blood.
Remember that HDF incorporates diafiltration plus ultrafiltration to give total filtration.
Recent studies have described dose of CRRT in terms of ml/kg/h of ultrafiltrate production.
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Ronco et al 20003 used this approach (ml/kg/hr) to demonstrate survival benefits of 35 over 20ml/kg/hr.
Kellum et al 200718 pooled 4 recent dose/outcome to demonstrate very large effect on survival in favour of an augmented dose.
Landmark multicentre RCT in America (AKI study19) and Australasia (RENAL study20) showed that a high renal dosing regime in RRT conferred no benefit.
The ideal dose for CRRT is not known or universally agreed upon; however 35 ml/kg/h of ultrafiltrate production is recommended as a minimum for CVVH (post-dilution) and CVVHDF16.
Maybe room for Short term High volume isovolaemic haemofiltration (STHVH) doses of up to 100ml/kg/min or ~8-9L/Hr exchange for severe SIRS/sepsis10,18.
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Cellulose Low flux Poor at removing middle MW
molecules Used in end ESRF. Cause more complement and
leukocyte activation16
Leukocyte retention in the lungs, renal parenchyma and other organs, thus resulting in further organ damage.
Not desirable in the critically ill patient.
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Synthetic Polysulphone (PS), Polyamide (PA), Polyacrylonitrile (PAN),
Polymethyl methacrylate (PMMA).
High flux membranes.
Flux being a measure of ultrafiltration capacity and based on the membrane ultrafiltration coefficient.
High flux membranes are highly water permeable.
Allowing convective therapy and the removal of middle MW molecules.
Better biocompatibility, less complement/leucocyte activation and end organ disfunction16.
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Adjusted based on pt. clinical need
Help drive convective transport
Administered pre or post filter
Must contain:
Sodium Calcium (except with citrate) Base (bicarbonate, lactate or citrate)
May contain:
Potassium Phosphate Magnesium
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Contents Lactasol Hemosol
BO mmol/L mmol/L
Sodium 140 140 Potassium 1 0 Calcium 1.63 1.75 Magnesium 0.75 0.5 Chloride 100 109.5 Lactate 45 3 Glucose 10 - pH 5 – 6.5 7.4 Bicarb - 32
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Patients with Liver dysfunction, profound hypoperfusion and pre-existing Lactic acidaemia are at risk of lactate intolerance.
Some studies have suggested better control of acidaemia with bicarbonate solutions14 this has not universal though16
Improved cardiovascular stability have also been reported14
To date though use of either base has not demonstrated any survival or renal outcome benefits14-16
Conflicting views, as always! Bicarbonate in theory has some potential benefits but currently no data to clearly advocate one or the other16
Indications for bicarbonate buffer16
A rise of lactate of greater or equal to 5 mmol/L (from base-line) associated with a worsening metabolic acidosis suggests lactate-intolerance.
Severe pre-existing lactic acidosis pH <7.2 with associated lactate of ≥ 8 mmol/L. Severe liver dysfunction.
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Factors affecting filter life: Access, Anticoagulation, Pre/Post dilution,
Hyperlipidemia, Sepsis
Pre-Dilution Increases filter life Increases convective transport Reduced solute clearance Some of delivered replacement fluid lost by
hemofiltration Lower anticoagulation requirements Higher UF required given loss of replacement fluid
through filter
Post-Dilution No solute dilution, improved diffusion and solute
clearance Increased hemoconcentration Higher delivered dose of hemofiltration
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Heparin Intermittent bolus or continuous
infusion Disadvantages
Haemorrhage Anti-thrombin III deficiency Thrombocytopaenia
Regional heparinisation
Low molecular weight heparin Less effect on platelet function
Direct Thrombin Inhibitors
r-Hirudin
Argatroban
Prostacyclin (PGI2)
Inhibits platelet aggregation Reduced risk of haemorrhage Disadvantage
vasodilation and hypotension
Citrate Complexes ionised calcium Ca infused in efferent limb Citrate metabolised Liver, renal and
skeletal muscle. Some evidence for prolonged filter life
and less bleeding events22. Disadvantages
Low Ca++, Low Mg++ Hypotension and tetany Acidaemia in renal/hepatic impairment
as a result of reduced citrate metabolism.
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Principles Same equipment as haemofiltration Larger pores in filter To remove pathogenic material (IgG/M, paraproteins etc) in plasma Replace with equal volume of substitute
HAS, FFP
Often rebound antibody synthesis and may need immunosupression
Indications Multiple Myeloma/Waldenström macroglobulinemia and hyperviscocity
syndrome (HVS) Poisoning SIRS in conjunction with HF, early days Acute Guillian-Barre syndrome TTP and HUS Goodpastures Meningococcal sepsis
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Techniques used for extracorporeal drug removal
Haemodialyis Haemoperfusion Continuous haemofiltration Continuous haemodiafiltration
Factors effecting clearance
Molecular size (<500 daltons desirable) Steric hindrance Polarity Volume of distribution, Water/lipid solubility Protein binding, in particular in HD Rate of Endogenous clearance Rate of redistribution
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Substances for which haemodialysis may be used
Salicylates clearance doubled over UA (seizures/coma/pH/AKI/absolute level/paeds)
Lithium Alcohols:
- ethylene glycol, methanol, ethanol, isopropanol
Theophylline HP better Metformin (Bromide)
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HPF was first used in toxicology in the 1960s for barbiturate poisoning
Since these initial reports HPF has been attempted in the treatment of a number of other poisonings
A standard haemofiltration / haemodialysis pump can be used
The only special equipment required is the perfusion column
Blood is pumped (150 - 250 mL/min) through a column containing an adsorbent, usually activated charcoal, coated with a biocompatible ultrathin membrane
Characteristics of compound removed
Adsorbed by charcoal
Vd and endogenous clearance factors similar to previous
Protein binding, water solubility & molecular size are not such limiting factors as with haemodialysis as blood in direct contact with adsorbent
NO prospective controlled studies looking at the effect of HPF on outcome in poisoned patients
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Carbamazepine Causes significant and prolonged toxicity
(T1/2 19-32 hrs)
Problem of enterohepatic recirculation
Binds activated charcoal
MDAC vs HP have similar clearance
iIeus often limits MDAC/whole bowel irrigation
Reserved for life threatening seizure, cardiotoxicity, impaired gut motility or deteriorating despite MDAC treatment.
Theophyllines Both acute & chronic theophylline
poisoning can cause significant morbidity and mortality
Better clearance than MDAC
Applications in severe OD with dysrrthmias and seizures
Phenobarbitone Both MDAC and HPF increase
phenobarbitone clearance, HP to a greater extent
life-threatening toxicity & deterioration despite full supportive care
Others TCA, Digoxin, Paraquat, Na valporate
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A common ‘non-renal’ indication for CRRT is in the management of severe sepsis.
It has been shown that many, if not all of the septic mediators can be removed by CVVHF16.
Cytokines (IL 1/6/8, TNF, complement, bradykinins, beta-2 microglobulin).
Due to the MW of inflammatory mediators it has been shown that CvvHF is particularly effective in their clearance and adsorption16.
Due to high generation rate, studies have concentrated on the use of ‘high dose’ or ‘high volume’ haemofiltration.
High volume haemofiltration has also been used as ‘rescue therapy’ for patients with severe septic shock unresponsive to other treatments, with encouraging results for cardiovascular stability/outcomes3,10,21,23,24.
Ultrafiltration doses as high as 40-85ml/kg/Hr were shown to improve 28 day mortality in septic shock23,24.
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Any Questions?
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Initiation of RRT should be started earlier rather than later particularly when -
AKI is unlikely to be reverse early
Patient had normal renal function prior to insult
CRRT
Appears to offers some benefits over IHD but no Grade A evidence.
Generally agreed that it is better tolerated in the critically ill.
Modality
No clear benefits for one modality over another when addressing the diverse group that is AKI
However, there are encouraging results for the use of certain modalities in specific subgroups (Septic shock ± AKI, ICP, OD, Rhabdomyolysis, Pulmonary oedema, Solute issues, Immunological conditions etc)
Correct modality for the correct patient
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Dose No clear evidence on dosing and outcome benefit for all AKI However 35 ml/kg/h of ultrafiltrate production is recommended as a minimum for CVVH
(post-dilution) and CVVHDF Higher rates for Cytokine clearance and adsorption in unresponsive septic shock shows
some promise
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 should be considered.
Lactate-based replacement fluids are as effective as bicarbonate-based fluids except in conditions where liver function is compromised but there is little evidence that either kind of fluid has survival advantage.
Synthetic membranes for CRRT
UFH, LMWH and prostacylin are most commonly used, but Citrate may offer some interest for the future.
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1. Allen R. Nissenson (1998)Kidney International Vol. 53, Suppl. 66
2. Gettings LG et al. Outcome in post-traumatic acute renal failure when continuous therapy is applied early vs late. Intensive Care Med 1999;25(8):805-813
3. Ronco C et al. Effects of different doses on continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial. Lancet 2000; 356(9223): 26-30.
4. Saudan P et al. Adding dialysis dose to continuous haemofiltration increases survival in patients with acute renal failure. Kidney Int 2006; 70(9): 1312-1317.
5. Liu KD et al. Timing of initiation of dialysis in critically ill patients with acute kidney injury. Clin J Am Soc Nephrol 2006; 1(5): 915-919.
6. Bouman CS et al. Effects of early high volume continuous veno-venous haemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: prospective , randomised trial. Crit Care Med 2002: 30(10): 2205-2211.
7. Davenport A et al. Improved cardiovascular stability during continuous modes of renal replacement therapy in critically ill patients with acute hepatic and renal failure. Crit Care Med 1993; 21(3): 328-338.
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8. Augustine JJ et al. Randomised controlled trial comparing intermittent with continuous dialysis in patients with ARF. Am J Kidney Dis 2004; 44(6): 1000-1007.
9. John S et al. Effects of continuous haemofiltration Vs intermittent haemodialysis on haemodynamics and splanchnic regional perfusion in septic shock patients: A prospective randomised clinical trial. Neprol Dial Transplant 2001; 16(2): 320-327
10. Patrick M et al. Prospective evaluation of short-term , high volume isovolemic hemofiltration on the hemodynamic course and outcome in patients with intractable circulatory failure resulting from septic shock. Crit Care Med 2000. Vol 28(11) 3581-3586
11. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD003773
12. Davenport A et al. Changes in ICP during haemofiltration in oliguric patients with grade IV hepatic encephalopathy. Nephron 1989; 53(2): 142-146
13. Ronco C et al. Brain density changes during renal replacement in critically ill patients with acute renal failure: Continuous versus intermitent haemodialysis. J Nephrol 1999; 12(3): 173-178.
14. Barenbrock M et al. Effect of Bicarbonate and Lactate buffered replacement fluids on cardiovascular outcome in CvvHF patients. Kidney Int 2000; 58 (4): 1751-1757.
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15. Thomas AN et al. Comparison of bicabonate or lactate buffered haemofiltration fluid; use in critically ill patients. Nephrol Dial Transplant 1997; 12 (6): 1212-1217.
16. Standards and Recommendations for the provision of renal replacement therpy on intensive care units in the UK. Intensive Care Society standards and Safety. 01/2009.
17. http://www.kidney.org/Professionals/kdoqi/
18. Kellum JA. Renal replacement therapy in critically ill patients with acute renal failure: does a greater dose improve survival? Nature Clin Pract Nephrol 2007; 3(3):128-129.
19. VA/NIH Acute Renal Failure Trial Network. Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med 2008; 359(1):7-20.
20. The RENAL Replacement Study Investigators. Intensity of Continuous Renal-Replacement Therapy in Critically Ill Patients. N Engl J Med 2009; 361 (17): 1627-38.
21. Ratanarat et al. Pulse high-volume haemofiltration for treatment of severe sepsis: effects on hemodynamics and survival. Critical Care 2005, 9:R294-R302
22. Monchi M et al. Citrate vs. heparin for anticoagulation in continuous venovenous haemofiltration: a prospective randomised study. Intensive Care Med 2004; 30(2):260-265.
23. Honore PM et al. Prospective evaluation of short-term, high volume isovolemic haemofiltration on the haemodynamic course and outcome in patients with intractable circulatory failure resulting from septic shock. Crit Care Med 2000; 28(11): 3581-3587.
24. Ratanarat R et al. Pulse high-volume haemofiltration in critically ill patients: A new approach to patients with septic shock. Seminar Dial 2006,19(1):69-74.