Treatment of Acute Renal Failure Freseniu with Continuous Renal Replacement Procedures

8/12/2019 Treatment of Acute Renal Failure Freseniu with Continuous Renal Replacement Procedures

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Acute Therapy Systems

Treatment of Acute Renal Failurewith Continuous RenalReplacement Procedures

Freseniu.i_wv/Vs Medical Care


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ContentsTreatment of ARF - continuous or intermittent therapy?lndications for renal replacement therapyPrinciples of renal replacement therapyContemporary continuous proceduresHaemofiltration fluidsEffectiveness of treatmentNecessary intensity of renal replacement treatment in ARFVascular access for renal replacement therapyAnticoagulation

Frequent occlusion of the extracorporeal circuitNutritionDrug dosage in CRRTConclusionsGlossary

LiteratureBalancing protocol

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Treatment of ARF - continuous orintermittent theraoy"Effective treatment of ARF and survival of anuricpatients first became fundamentally possible withthe introduction of the first classical blood purifi-cation procedure, intermittent haemodialysis(iHD). For many decades, iHD remained the onlyavailable treatment for ARF. Following thepioneer work of Kramer (28-31) in the eighties,CRRT became available as an alternative to iHD.Since then, intensive care physicians and nephrol-ogists have debated (sometimes heatedly)about the advantages and disadvantages of thetwo procedures (8). A key controversy in this dis-cussion was whether differences in patient mor-tality could be demonstrated with the differentprocedures. A number of retrospective studiesdid indeed report reduced mortality in CRRT(3,39), while the only prospective, randomisedstudy published to date could find no difference(41). However, this study is methodologically pro-blematic as almost two thirds of the patientsrecruited were not randomised. Furthermore, al-though a randomisation procedure was per-formed, the patients of the CRRT group had a sig-nificant disadvantage (higher APACHE ll score,greater proportion of patients with additional liverfailure). ln addition, patients with severe hypoten-sion (who would benefit most from a CRRT pro-cedure) were excluded from the beginning.A recent meta-analysis of 13 studies with about1,4OO patients revealed a reduced mortality ratefor continuous renal replacement therapy com-

pared to iHD when patients with similar degreesof illness were compared (24). However, a limit-ing factor here which must be mentioned is thatmost of the studies analysed were not prospec-tive or randomised. Neveftheless, this carefullyconducted meta-analysis, because of the highpatient numbers, clearly indicates a superiorityof continuous renal replacement therapy. ln themeanwhile it has become generally acceptedthat CRRT, because of its particular characteri-stics, has clear advantages over iHD, particular-ly for critically ill and haemodynamically unstableintensive care patients. Therefore, CRRT is nowthe procedure of choice, at least in Europe, forthe treatment of ARF in lCUs (55). For organisa-tional reasons, iHD is often still preferred in theUSA, despite the now recognised disadvantagesof this procedure (40,55). The advantages anddisadvantages of CRRT and iHD procedures willbe discussed below.

Haemodynam ic stabi I ityA number of prospective (some also randomised)studies have proven that haemodynamic stabilityis undoubtedly significantly greater during conti-nuous renal replacement treatment than iHD; thisconstltutes an impoftant advantage of continuoustherapy (10,47,59). The haemodynamic effects ofiHD were studied by Schortgen et al. (57), forexample. Between 1995 and 1997, 33 o/o dfid 68 o/o


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Treatment of ARF - continuous orintermittent therapY"of patients suffered hypotensive episodes whichrequired medical intervention at the beginning ofand during dialysis treatment, respectively. Theintroduction of a strict treatment algorithm in thefollowing years reduced the incidence of initialblood pressure drops to 21 o/o, but the occurrenceof hypotensive episodes during dialysis couldstill not be avoided in over half the patients. About10 o/o of patients cannot be treated with iHD at alldue to their haemodynamic instability, and around8-10 % of all iHD treatments must be ended pre-maturely for this reason, meaning that the pre-scribed dialysis dose cannot be attained (47).Davenport et al. (1O) treated 32 patients with acuteliver and kidney failure with CBRT and iHD. Duringthe 4-hour iHD, the afterial blood pressure fell sig-nificantly, accompanied by a reduction in cardiacoutput and oxygen supply to the peripheral tissue.These changes were accompanied by an increasein intracranial pressure during iHD which, togetherwith the fall in blood pressure, can negatively affectcerebral perfusion, particularly in patients with liverfailure and increased risk for cerebral oedema. lnCRRT, haemodynamics and intra cranial pressureremained stable, and there were no fatal cases ofcerebral complications, while brain oedema wasthe cause of death in 60 % of iHD patients. Con-sequently, patients with combined liver and renalfailure should preferably be treated with CRFIT.To date only one prospective, randomised studyfound haemodynamic stability to be comparable

in CRRT and iHD (63). However, the patients inthis study were generally less ill than those in allother studies, which can explain why they tole-rated iHD so well. lntensive care physicians andnephrologists nowadays agree that continuousprocedures are preferable for haemodynamical-ly unstable patients.

Fluid and electrolyte balanceContinuous therapies facilitate a gentle removal ofeven large volumes of fluid and an effective fluidstatus control during treatment, as removal takesplace over the course of the whole day. The mini-mum fluid requirement of intensive care patients isabout 3 l/d, as enteral and parenteral nutritionalone constitute a volume of around 2 l/d. Fufther-more, a negative fluid balance is often requiredfor patients with heart failure or restricted pulmo-nary function. ln circulatory-unstable, catechola-mine-dependent patients, the removal of suchvolumes during a typical four-hour iHD often cau-ses significant decreases in blood pressure whichmust be corrected by an increased catechola-mine dose. Even short episodes of hypotensionreduce renal circulation in such patients, asautoregulation is lost in ARF and perfusion is pure-ly on a passive-pressure basis. Therefore, residu-al renal function is often negatively affected in iHD,while this is maintained in CRRT (38).The practically unlimited fluid supply possible


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with CBRT facilitates an adequate nutritionaltherapy, so that the already unavoidable catabol-ic state of these patients is not further enhancedby an insufficient supply of substrate. Bellomo etal. (3) could show that adequate parenteral nutri-tion was possible in 93 o/o of all CRRT patients butonly in 53 o/o of iHD patients due to the necessaryfluid restrictions.

Metabolic stabilit andhomeostasislndependent from an effective and steady con-trol of fluid balance, CRRT also facilitates a gen-tle and even reduction of those substances nor-mally excreted by urine (figure 2). ln iHD, urea

levels are reduced within 4 hours, and this isassociated with a corresponding shift in serumosmolality which leads to an enhanced influx offluid into the interstitium. This can result in adeterioration in pulmonary gas exchange andenhanced oedema of the brain, as has beendetected in computer tomographical studiesconducted by Ronco and co-workers (53).CRRT results in a somewhat slower, but stead-ier, reduction of those substances obligatorilyexcreted by urine, and the 'saw-tooth' profileobserved in iHD does not develop (figure 2).Thus disequilibrium syndrome can be avoided.Metabolic acidosis and electrolyte imbalancescan be corrected in the same gentle manner,making CRRT preferable also in this aspect (4).

1503E6I too)

Time (days)

Fig. 2: lnfluence of therapy choice on serum urea levels.ThL concentration profile of uraemic toxins in serum depends on the form of therapy. Serumlevels fall quickly during the typical 4-hour intermittent haemodialysis (iHD) treatments, andincrease again quickly after the treatment. This causes significant changes in the serumosmolality and a typical saw-tooth urea profile (continuous line). The abrupt fall in serum urea,particularly during the first treatment, can result in a disequilibrium syndrome and an addition-al fluid shift into the extravascular space. The serum urea levels fall more slowly, but contin-uously, during continuous renal replacement therapy, and can be maintained at a constant, lowlevel ldashed curve). Shifts in osmolality and the development of a disequilibrium syndromecan be avoided.


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lndications forRenal Replacement TheraPYBenal indicationsClassical indications for renal replacement therapyare oliguria or anuria, diuretic-resistant hyperhydra-tion, severe electrolyte disturbances (padicularlyhyperkalaemia), metabolic acidosis and uraemia-associated complications, such as pericarditis (table1a). There is some debate concerning the levels forthose substances normally excreted by urine abovewhich renal replacement treatment should be stad-ed. Older recommendations specify an upper limitfor urea of 200 mg/dl. ln the meanwhile, the ten-dency is to start treatment at urea levels under thattargeted during therapy. Many nephrologists thentalk about urea levels of 1O0 mg/dl.Gettings et al.(16) investigated whether an earlytreatment start for ARF is of advantage for trau-ma patients. Early begin was defined as startingCRRT treatment at serum urea levels below 1OOmg/dl. lndependent of the later applied dialysisdose, i.e. the intensity of treatment, early treat-ment start alone resulted in a significantly highersurvival rate compared to late treatment startRenal indications:Di u retic-resistant hyperhyd rationSevere electrolyte imbalances (especiallyhyperkalaemia)Metabolic acidosisUraemic complications (e.9. pericarditis)

Table 1a:Exemplary indications for renal replacementtherapy.

(39 % versus 20 Yo). Cardiac surgery patientsalso benefited from an early treatment start forARF: the mortality rate of 40 7o observed whenrenal replacement therapy was started 2.4 daysafter surgery and at urea levels of just 155 mg/dlwas significantly lower than expected (66 %) (6)'It follows that renal replacement therapy must nowbe initiated much earlier than a few years ago. Asthere is no consensus regarding absolute limits asyet, indications for renal replacement therapy mustbe individually defined. The development of ARFplays a decisive role here. Should kidney functiondeteriorate continuously (based on daily creatinineclearance measurements, for example), or shoulddiuresis decrease (in relationship to the dose ofloop diuretics), then it doesn't now appear sensi-ble to delay renal replacement treatment until cer-tain upper limits are reached. Fudhermore, referralto renal replacement therapy is made eadier whenother symptoms (e.9. hyperthermia which is diffi-cult to manage or pulmonary oedema) are presentwhich could be alleviated by the treatment.Treatment start tends to be delayed when theExtrarenal indications:SIRS (systemic inflammatory response syndro-me)SepsisAcute pancreatitisARDS (adult respiratory distress syndrome)Rhabdomyolysis

Table 1b:Potential indications for continuous haemofil-tration.


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risk of bleeding is enhanced or when, despiteenhanced urea levels, the rate at which bloodIevels increase is decreasing and a stabilisationat a high level and with adequate diuresis can beexpected. However, urea levels in excess of 18Omg/dl are generally no longer tolerated.

Etrarenal indications -septic shockSIRS (systemic inflammatory response syn-drome) and septicaemia or septic shock are pre-sently under discussion as extrarenal indicationsfor the application of CRRT (table 1b). Despitemany advances in intensive care medicine, sep-tic shock accompanied by multiorgan failure stillhas a fatality rate of over 50 7o, so that numeroustherapy forms which target an improvement inoutcome are considered. The main subject ofdebate concerning the application of CRRT pro-cedures is whether meaningful quantities oftoxins, inflammatory mediators or cardiac-depressive factors can be removed by convec-tive blood purification procedures, and whethersuch a removal would improve prognosis.Fact is, many studies have reported an improve-ment in haemodynamic stability, a reduction inthe dosage of catecholamines (2O,23) and a bet-ter pulmonary gas exchange (27) in septic shockpatients at the beginning of CRRT. Fudhermore,inflammatory mediators were detected in the

ultrafiltrate of patients with septicaemia (5,2O),although a significant reduction in cytokine plas-ma levels has not yet been attained (at least withconventional haemofiltration). One should notethat, in addition to these inflammatory mediators,their soluble receptor antagonists and numerousanti-inflammatory mediators may also be elimi-nated; thus the effect of CRRT procedures on thebalance between pro- and anti-inflammatoryprocesses remains unclear. The observed improve-ment in the clinical condition of the patientsstudied may not, therefore, be the result of theelimination of mediators, but may be the conse-quence of some other, non-specific effects, suchas improved blood circulation due to more effectivecontrol of blood temperature and fluid manage-ment (7). However, it is interesting to note thatcytokines can be adsorbed by the filter mem-brane and so be removed from the blood in away which is independent of convective removal.Consequently, filters of larger sur-face area and amore frequent filter change can possibly be ofadvantage when targeting cytokine elimination.ln summary, the present state of knowledgedoes not justify the use of CRRT to eliminatecytokines in patients suffering from septicaemiaand without ARF. Should, however, kidney func-tion become impaired, then a continuous renalreplacement therapy of adequate dialysis intensi-ty (perhaps also with frequent filter changes)should be initiated at an early stage (7).

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Principles of renalreplacement therapyThe haemofilter (figure 3) is the centrepiece ofthe renal replacement procedure as here sub-stances to be removed are transported out of

Fig.3:Schematic design of a haemofilter.

the blood. Contemporary haemofilters arealmost exclusively produced from syntheticmaterials (e.g. polysulfone, polyamide,polyacrylonitrile). These are highly biocompa-

810121416182022Haemodialysis treatments (number)

tible, whereby biocompatibility is defined as alow activation of the complement system and ofproteolytic enzymes (figure 4). Modern filterspossess large pores and are permeable for sub-stances of middle and high molecular weight.The so-called cut-off (precise definition seebelow) indicates the molecular weight up towhich substances can pass through the filterand is nowadays typically around 20 - 40 kDa.Blood entering the filter is usually pumped froma central vein (veno-venous procedure) via alarge lumen catheter (Shaldon catheter). Arterio-venous procedures have the advantage ofrequiring less technical equipment, but are nowrarely employed due to the higher morbidityassociated with arterial cannulae. Fufthermore,the effectiveness of arterio-venous blood purifica-tion procedures is highly sensitive to the patient'sactual systemic blood pressure. Adequate

Fig. 4: lnfluence of dialy-ser type on the durationof ARF.Revival of renal function isdependent on the type ofdialysis membrane em-ployed.Use of dialysers containingsynthetic, biocompatiblemembranes is associatedwith revival of renal functionin more patients and afterfewer dialysis treatmentsthan when bioincompatiblemembranes, e.g. ones madefrom cellulose, are used.Nowadays, biocompatiblemembranes are almost ex-clusively used for the treat-ment of ARF. Figure adaptedfrom (22).

Dialysis fluid flow outsidethe capillaries

A Blood flowI

] .., .--:il ,,,,: Dialysis: fluid flow.a:

I Dialysis. fluid flow,. :il:illl I Blood flow

Blood flow withe capillaries

100o.2dEloioE^^oouclEEo-Lno'5o'; 20oCo([^ U

Biocompatible membranes (64 %)

-Bioincompatible membranes (43 %

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blood flows may be difficult to attain, especiallyin patients suffering from hypotension andshock, so that the resultant dialysis dose is insuf-ficient. As opposed to afterio-venous procedures,the blood flow provided by pump-controlledveno-venous procedures is constant and inde-pendent of the patient's arterial blood pressure.This is an important prerequisite for a continuousand effective blood purification. ln the presentlycommercially available devices, the separatepumps for blood, ultrafiltrate, dialysis fluid and,/orsubstitution fluid are automatically controlled in apre-specified manner. Easy and safe use is faci-litated by automatic balancing and menu-orien-tated operation.A key task of renal replacement therapy, i.e. theremoval of fluid, is a direct function of two para-meters, namely the permeability of the dialyserfor water and the pressure gradient across thedialysis membrane (the transmembrane pres-sure). The transmembrane pressure is not an inputparameter in modern machines: here fluid removalis measured volumetrically or gravimetricallyand deviations from target values are correctedby appropriate changes to the speeds of thepumps. The transmembrane pressure is thus setautomatically in such modern machines. Conse-quently, measurements of pressure are notnecessary for fluid balancing; these are never-theless conducted at various points in the extra-corporeal circuit in order to identify disturbances

in blood flow or the beginning of a system occlu-sion, e.g. as the result of clotting in the haemo-filter.ln principle, removal of substances dissolved inplasma water occurs via the two mechanisms'convection' and 'diffusion'. The contribution ofeach of these to blood purification differs ac-cording to the treatment set-up: the mechanismis purely convection in haemofiltration, while dif-fusion dominates in haemodialysis.

Oonvective blood purification- haemofiltrationln convective blood purification (haemofiltration),an amount of plasma water which correspondsto the prescription entered into the machine isforced through the haemofilter membrane. Thisprocess mirrors in principle the production ofprimary urine by glomerular filtration in the kid-ney. lnsofar as the membrane is permeable forthem, all plasma water constituents, includingdrugs, will be present in the filtrate in the sameconcentration as in the unfiltered plasma water(figure 5). As opposed to diffusion, the elimina-tion of smaller solutes is not better than that oflarger ones: substances with molecular weightsup to the cut-off of the membrane will be re-moved as long as they are not protein-bound.The permeability of the membrane for a particu-lar substance is described by its sieving

1''


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Principles of renalreplacement therapycoefficient. The sieving coefficient is defined asthe ratio of the concentration in ultrafiltrate tothat in plasma. A sieving coefficient of 1 meansthat the substance can freely pass through thehaemofilter, and that the concentration of thissubstance in the ultrafiftrate is then the same asthat in plasma. The membrane is totally imper-meable for solutes with a sieving coefficient of O.The membrane cut-off is the molecular weightcorresponding to a sieving coefficient of O.O5. lnhigh-flux filters, this cut-off lies between 20,OOOand 4O,OOO Daltons. However, the sieving coef-ficient is not a fixed constant: the sieving coeffi-

cient decreases with increasing treatment time,particularly for large solutes. This is because thepermeability of a filter is reduced during use due toprotein deposition and blockage of pores by celldebris, blood clots or thrombocyte aggregations.ln addition to the molecular weight of a sub-stance, other factors influence its passagethrough the membrane, for example charge,lipophilicity and other physicochemical characte-ristics.The sieving coefficients of commonly usedmembranes for drugs are available in referencetables.

Fig. 5: Blood purification by convection.Convection is the transport of solutes with solvent through the membrane. When fluid is forced through adialysis membrane, the concentration of solutes in the filtrate primarily depends on the characteristics ofthe membrane as the pore size of the filter constitutes the main limiting factor for this transport process.The membrane cut-off describes the maximum size of molecules which can pass through the filter and isin the region of 20 - 40 kDa in modern haemofilters. For small molecular weight solutes the concentrationin the filtrate is more or less equal to that in the plasma.

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Blood purification by diffusion- haemodialysisW':a=,.:'::...:'"|':ln blood purification by diffusion (haemodialysis),sterile dialysis fluid is directed countercurrentlyto the blood flow along the outside of thehaemofilter capillaries. Substances diffuse fromblood to dialysis fluid according to the concen-tration difference between the blood and dialy-sate compartments (figure 6). This concentra-tion gradient is the basis of diffusion. Diffusivetransport processes depend on molecular size:the concentration gradient for smaller solutes is

annihilated more quickly. This size-dependencyis of little significance for low molecular weightsubstances, i.e. typical fluid exchanges in con-tinuous haemofiltration and haemodialysis aresuch that urea elimination is more or less identi-cal. Diffusive transport of larger uraemic toxinsinto the dialysate is, however, much slower, sothat haemofiltration provides a higher middlemolecule clearance. Higher molecular weightsubstances, such as cytokines, cannot be re-moved by haemodialysis.

ffi

p" Fig. 6: Blood purification by diffusion.The concentrations of solutes in two fluid compaftments will equalise in a time-dependent manner as longas solute transport between the compartments is possible. The rate of equalisation depends on the poresize of the membrane and the molecular weights of the solutes. Concentrations of smaller. solutes willthen equalise more quickly. Consequently, diffusive processes are best suited for the removal of low mole-cular weight substances (e.9. electrolytes, urea, creatinine).

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Gontempo rary continuous proceduresHeParin

fll}'arterial'ra--)-

CWHHeParin

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CWHD

Substitution fluid

(UF)

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haemofi ltration (OWFI)

-VUltrafiltrate

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CWHDF Dialysis fluid,in'

Oonti nuous veno-venous

ln veno-venous haemofiltration (figure 7), bloodis pumped through a highly permeable, largepore membrane (so-called 'high-flux' mem-brane) and the ultrafiltered plasma water is dumpedwith all its solutes. The transport principle is, there-fore, convection. A certain volume of substitutionfluid must be supplied in accordance withthe targeted fluid removal; the composition ofthis should be similar to that of physiologicalplasma water, albeit lower in potassium or eventotally free of potassium. Should no fluid removal

Fig. 7t Simplified set-ups of various contin-uous renal replacement therapies: contin-uous veno-venous haemofiltration (CWH),continuous veno-venous haemodialysis(CWHD), continuous veno-venous haemo-diafiltration (CWHDF).lndependent of the chosen procedure, blood istaken from a central vein through a double-lumencatheter and pumped at a typical rate of 15O - 2o0mL/min through a haemofilter. Anticoagulation isconducted in the 'arterial' arm of the circuit bet-ween blood pump and filter in order to attain high-est values prior to blood entry into the filter'Following passage through the filter, the blood isreturned to the patient via a venous air trap. Sub-stitution fluid is generally added here in CWH andCWHDF procedures (postdilution mode)' ln amodified set-up, substitution fluid can be addedbefore blood entry into the f ilter (predilutionmode). This reduces the effectiveness of theblood purification, but can extend filter use due tothe lower haemoconcentration within the filter'The figure shows that three pumps (P) are suffi-cient for the conduction of CWH and CWHD,while a fourth pump is required for CWHDF. Diffu-sive and convective transport are combined inCWHDF, facilitating the effective clearance of bothlow and high molecular weight substances'

be desired, e.g. in cases of sustained sponta-neous diuresis, then the volume of substitutionfluid should be exactly the amount of fluid ultra-filtered.Substitution fluid can be added to the extracor-poreal circuit either before or after the filter. Typi-cally, haemofiltration is conducted in the post-dilution mode, i.e. the substitution fluid is addedbehind the filter. ln such a set-up, the concentra-tion of substances normally obligatorily removedin the urine which are now removed in the ultra-filtrate is identical to that in the plasma water' Thisprocedure is very effective but haemoconcentra-tion within the filter is also high, especially whenonly moderate blood flows are reached' A high

d)V--{-l-)'r"nor"'-1 ---d)VDialysate+ UF'out'

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degree of haemoconcentration in the filter canreduce both filter permeability and filter life'Experience has taught us that the filtration frac-tion, i.e. the percentage of total plasma waterflow which is filtered per specified time interval,should not exceed 25 o/o. Plasma water flow isproportional to blood flow, QB, and is sensitive tohaemocrit; it can be estimated using the formulaQp = Qg * 1t- ttcU'lOO) x O-94-The factor 0.94 takes the plasma protein contentroughly into account, a more detailed calculation isusually considered unnecessary for clearance cal-culations. The effectiveness of CWH in postdilu-tion mode is then highly dependent on blood flow'

Calculation of the effectiveness of GWHin postdilution mode (Clearance)Realisticblood flow: 150 mUminHaematocrit: 30 %Plasmawater flow:Max.filtration fraction: 25 %

= 9000 mUh

= 6000 mUh= '1500 mUh

Maximalclearance: 1500 mUh:60 min = 25 mL /minln predilution haemofiltration, the substitutionfluid is added to the blood before it enters the fil-ter; the concentration of the substances whichare to be removed is then reduced by this dilutionbefore the filtration process begins' The effec-tiveness of predilution CWH is therefore reduced

compared to that of postdilution CWH whencomparable amounts of fluid are ultrafiltered' Onthe other hand, filter use can be extended due tothe lower haemoconcentration. ln cases wherefilter life spans are generally short, e.g. in patientswith enhanced bleeding risk who receive onlymoderate anticoagulation, predilution filtration isan alternative to avoid frequent filter changes.

Oonti n uous veno -venoushaemodialysis (OWHD)During dialysis, blood is pumped along a semi-permeable membrane within a haemofilter (fig-ure 7). Dialysis fluid, which is free of those soluteswhich are to be removed from the blood (e'9.urea, creatinine), flows countercurrently alongthe other side of the membrane. The predomi-nant transpoft mechanism here is diffusion:according to the concentration gradient, urae-mic toxins pass from the compartment with ahigher concentration (the blood) to that with alower concentration (the dialysis fluid).Negative fluid balance in CWHD is attained byapplying an ultrafiltration rate, i.e. the fluid to beeliminated is removed by convection in the haemo-filter. Nowadays high-flux filters which arepermeable for high molecular weight moleculesare also becoming popular for CWHD. ln prac-tice, a certain degree of internal filtration / back-filtration also occurs during CWHD due to the

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Gontempo rary continuous procedureshigh permeability of these filters and the blood-to dialysate-side pressure gradients within them,i.e. dialysate enters the blood compartment andplasma water is forced into the dialysis fluidcompartment. Therefore, a small amount ofconvective blood purification also takes place inCWHD, and the differences between CWH andCWHD now are not as great as they were whenfilters with a low permeability were used'When blood flow is adequate, clearance in CWHDis the product of dialysate flow and degree of satu-ration. The clearance can then be easily calculatedwhen the dialysate is fully saturated, e'g' with urea:

Calculation of the effectiveness ofCWHD (Clearance):Blood flow: 150 mUminDialysate flow: 2000 mUhClearance at100 % dialysatesaturation: 2000 mUh:60 min =33.3mUmin

Oontinuous veno-venoushaemod iafi ltration (OWH DF)Convective and diffusive transpott mechanismsare combined in CWHDF (figure 7). Ultrafiltrate isdrawn through a highly permeable haemofilterwhile dialysis fluid simultaneously flows along thefilter capillaries in a direction countercurrent to theblood flow. Typically one half of the fluid turnover is

specified as filtrate and the other as dialysis fluid,whereby other relationships are possible depend-ing on the blood flow attainable. The degree ofhaemoconcentration in the filter is dependent onthe ultrafiltration alone, and can be reduced in thecase of short filter life spans by increasing the dia-lysis fluid fraction in favour of ultrafiltration.Postdilution CWHDF is therefore a good alter-native to postdilution CWH when the treatmenteffectiveness must be increased but the filtrationrate may not exceed 20-25 %o due to inadequateblood flow and the associated high haemo-concentration. The addition of a dialysate com-ponent facilitates a further increase in clearance'

Galculation of the effectiveness ofpostdilution GWHDF (Clearance):Realisticblood flow: 150 mUminHaematocrit: 30 %Plasmawater flow:Max. filtration

= 9000 mUh

= 6000 mUhfraction: 25 % = 1500 mUhMaximalconvectiveclearance: 1500 mUh : 60 min = 25 mUmin

PLUSDialysate (diffusive component a|100 %saturation): 1500 mUh : 60 min = 25 mUminTotalclearance: 3000 muh :60 min = 50 mL/min

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The effectiveness of continuous renal replace-ment therapy can, therefore, be significanilyenhanced with postdilution CWHDF (figure 8),without increased haemoconcentration causingmore blood trauma or reducing filter life span. lt isnoteworthy that large solute clearance increasesless with the addition of a dialysis componentthan small solute clearance. Effective clearanceof low molecular weight substances and, conse-quently, excellent control of urea is still possible.The particular significance of an intensive renalreplacement therapy regarding the prognosis ofARF patients will be discussed later.

ln the past, all commercially available machinesused to contain only three pumps (for blood,substitution fluid and ultrafiltrate). ln order toconduct CWHDF with this equipment, a fourth,external, pump (usually in the form of an infusionpump) had to be attached for the dialysis fluid.Automatic fluid balancing was no longer possibleas the external dialysis fluid pump was not includ-ed in the measurement system. Fluid balancingwas then much more difficult. ln the meantime,some dlalysis equipment manufactures offermachines which have solved this problem by theintegration of a fourth pump or by coupling blood

850E)540ooEeo(uc)o20

100 1000Molecular weight (Daltons) ]0000 100000Fig. 8:Clearance in renal replacement therapy as a function of molecular size and procedure.The data shown were calculated for a high-flux polysulfone filter with a surface area of 1.4 m2, and for ablood flow of 120 ml/min.Clearance of low molecular weight substances (e.g. urea and creatinine) by CWHD or postdilution CWHwith the same fluid turnovers is practically identical and, in practice, is generally limited by the volumesused (here 2 L/t1, corresponding to a clearance of 33 ml/min). Higher molecular weight substances aremore effectively removed in postdilution CWH.The effectiveness of the treatment is further improved in CWHDF by introducing dialysis fluid flow in addi-tion to the standard convective transport; this increases the clearance of low molecular weigh solutesespecially (for example,2 L/h filtrate plus 2 L/h dialysate).ln predilution CWH, the toxins to be eliminated are diluted prior to entering the filter; this significanlyreduces clearance compared to postdilution CWH. However, haemoconcentration and the associatedtendency towards enhanced clotting in the system is avoided, so that filter use can be extended.

High{lux PolysulfoneQe = 120 mUmin

41at


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Oontemporary continuous procedures:i ri$\ ::i@ \ .,15ffi'i

Fig. 9: GENIUS', a modification of a systemused in chronic dialysis therapy whichallows conduction of long (up to 18 h),and gentle daily dialysis treatments inacute renal failure patients.

and dialysis fluid flows via a single pump. As aresult, the conduction of CWHDF is now as sim-ple and unproblematic as CWH or CWHD.

OutlookThe differences between iHD (typically 4 hours)and CRRT (almost 24 h a day) have recentlybecome less distinct. Machines used in chronicdialysis therapy are employed for the contin-uous-like treatment of acute renal failurefollowing some small technical modifications.One short-coming of this approach is that someinfrastructure for water treatment and supply isnecessary. However, it also has the advantageof offering a highly effective treatment which,given a high number of applications, is cost-effective due to the lower running costs involved.One example is the GENIUS' System; here atank is filled with 90 litres of dialysis fluid at a cen-tral filling station (figure 9). This whole system istransported to the patient and allows a veryeffective dialysis of up to 18 hours, whereby nobag changes are necessary. The spent dialysateis later deposited at the filling station, the ma-chine is serviced, refilled and is ready for thenext treatment. Preliminary data indicate a high-ly effective blood purification and excellent bloodpressure stability, also in ICU patients with acuterenal failure (37).

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.\,.:lEr t -J,-rf -: t,=;TB.L''d*..,.,.: ;;i.Fn .,.:ri


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Haemofiltration fluidsThe composition of fluids used in CRFIT shouldbe similar to that of physiological plasma water.Of course, substances targeted for removal,such as urea and creatinine, are not included. Avariety of electrolyte concentrations, especiallypotassium concentrations, are available, and thechoice depends on the desired change in elec-trolyte levels. Generally potassium must be in-fused when potassium-free haemofiltration (HF)fluids are employed. ln addition to the use of HFfluid as substitution fluid in CWH, it is alsoemployed as dialysis fluid in CWHD andCWHDF.The prescribed dialysis dose must be taken intoconsideration when choosing the appropriateHF fluid: not only is the removal of uraemic wasteproducts enhanced with increasing fluid turn-over, but the elimination of potassium and theaddition of buffer is also augmented. Potassiumremoval increases significantly in intensified treat-ment, so a substitution solution can be chosenhere which contains potassium (2 to 4 mmol/L)in order to avoid having to infuse large quantities

SodiumPotassiumCalciumMagnesiumChlorideBicarbonateLactateGlucose

140 mmol/L0 to 4 mmol/L

1.5 mmol/L0.5 mmol/L109 to 1 13 mmol/L

35 mmol/L0 mmol/L5.6 mmol/L

of it. ln contrast, large quantities of buffer will beadded to the plasma during intensified treat-ment, and the appropriate fluid here should thenhave a relatively low concentration thereof.The choice of buffer substance is of significantimportance in continuous renal replacementtherapy. Many patients with ARF have a highalkali requirement due to renal acidosis. All HFfluids which were commercially available up to ashort time ago contained lactate as buffer. Thisis converted 1:1 to bicarbonate, mainly in theliver. Lactate metabolism is frequently disturbedin seriously ill intensive care patients and in pa-tients with impaired liver function, so the additionof large quantities of lactate can result in hyper-lactataemia, especially when the treatment isintensified. Acidosis can even be enhancedduring CRRT with lactate fluids when lactatemetabolism is impaired, as endogenous bicar-bonate is simultaneously removed (11).It is well known that persistent acidosis negative-ly affects the prognosis of patients with ARF(19), therefore, the use of bicarbonate buffer

Table 2: Composition of typical bicarbo-nate-based HF fluids.

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p < 0.0121 out of 56Patients

15 o/o 38 o/o

Haemofiltration fluids

Bicarbonate Lactate Bicarbonate

0.8 -C0)E(Enn 9^-" .==fstcoC*;X6)0.4 .9 l:ooo>o: 19oou.z oI

ocO/1zo.oo-ioE --=oo(.9l20(Eo==c rno rwF((L

in substitution fluids appears wise. Until recently,production problems posed a hindrance to theclinical application of such fluids: it was not phar-macologically possible to produce bicarbonatesubstitution fluids which were stable in plasticbags and could be stored for the required times'Bicarbonate solutions have meanwhile becomeavailable where the electrolyte and buffer com-ponents are separated in a two-chambersystem. These components are mixed shortlybefore use - similar to the combination bagsused for parenteral nutrition - and can be usedfor up to 24 hours thereafter.Data from recent prospective, randomised stu-dies have proven that use of bicarbonate fluids is

Fig. 'lO: Buffer selection in con-tinuous renal rePlacement thera-py: comparison of bicarbonateand lactate solutions.A prospective, randomised multicen-tre study (2) reported a statisticallysignificant reduction in the frequencyof cardiovascular complications whenbicarbonate buffer was employed inthe substitution fluids (data on theleft). This was especially true for thefrequency of hypotensive episodes(data on the right); these should beavoided in patients with ARF at allcosts because of their disturbedautoregulation of renal perfusion.Substitution fluid with bicarbonate asbuffer will therefore be preferred inthe future.

associated with fewer hypotensive episodes andother cardiovascular complications compared touse of lactate fluids (figure 1O). Mortality of pa-tients with a history of cardiovascular illness alsotended to be lower when bicarbonate was usedas buffer (2). These results clearly show thatpreference should be given to this 'physiological'buffer in future. ln addition to electrolytes andbuffer, HF fluids also contain glucose, usually inconcentrations of '1OO mg/dl (5.6 mmol/L); this isto avoid the otherwise undesired loss of thissubstrate. The composition of some commer-cially available bicarbonate HF fluids is given intable 2.

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Effectiveness of treatmentThe clearance approximations for the variouscontinuous renal replacement therapies pre-sented earlier in this work provide an idea of thedialysis dose received by the patient. However,calculation of exact clearance values can bemuch more complex. One prerequisite for anadequate treatment is a good blood flow whichshould, ideally, reach 2OO ml/min. Theoretically,the total daily clearance attainable cannotexceed the sum of HF fluid used and net ultrafil-tration. One should note that the volume of fluidAverage urea clearance

used cannot simply be calculated from the cho-sen substitution rate multiplied by 24 h - instead,the actual treatment running time must be used,as each interruption of treatment (e.9. due totransporting the patient or due to frequent filterchanges) reduces the dialysis dose receivedthat day. lt is therefore important that treatment-free intervals are kept as short as possible, orare taken into consideration during the dialysistreatment prescription by the specification ofhigher filtrate or dialysis fluid flows.

CWHDF CWH CWHDF CWHPostdilution Postdilution Predilution Predilution

32.1 31 .7 27.0 22.6Qe = 100 mUmin, Qo = 2000 mUmin

Table 3: Average urea clearances in 40 patients with post-surgery ARF treated witheither predilution or postdilution continuous veno-venous haemofiltration (CWH) or contin-uous veno-venous haemodiafiltration (CWHDF)-1O patients with post-surgery ARF were treated with each of the above continuous renal replacement the-rapies using a commercially available acute dialysis machine. 6-8 hours after connection of the patient tothe machine, urea elimination by the haemofilter was measured during clinical routine, and the urea clear-ance was calculated. Always 48 litres of fluid per day were exchanged at a blood flow of 1OO ml/min; thiswas in the form of pure ultrafiltrate in CWH and half ultrafiltrate, half dialysate in CWHDF. The table showsthe average urea clearances of 1O patients. Postdilution procedures achieved the best results. There is nodifference in the effectiveness of urea removal between postdilution CWH and postdilution CWHDF. Asatisfactory control of serum urea levels can usually be attained with urea clearance values of over 30ml/min, even in catabolic ICU patients. Compared to these, the predilution procedures are significantlyless effective. While the clearance of 27 ml/min attained with predilution CWHDF may be sufficient formost patients, values for predilution CWH are probably too low to provide sufficient reductions in urea formany catabolic patients. However, haemoconcentration within the filter is significantly higher in postdilu-tion procedures, and this can lead to reductions in filter life spans.(Kindgen-Milles et al., lntensive Care Medicine, 1998, abstract).

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Effectiveness of treatmentThe effectiveness of the various procedures canbe calculated using different formulae. Undernormal clinical conditions, the small solute (e.9.urea and creatinine) clearances actually attainedin postdilution CWHD or CWH(D)F are usually ingood agreement with the theoretically attainabledaily value (amount of HF substitution fluid used+ volume of fluid removed). Preconditions for thisare, firstly, that the blood flow is at least twice theso-calculated clearance and, secondly, that thehaemofilter used has an adequate performanceprofile and size. The effect of blood dilution dueto the addition of substitution fluid before the fil-ter must be taken into consideration in predilu-tion CWH. The clearance K of a plasma water

solute with a sieving coefficient of 1 (e.9. creati-nine) can then be calculated from the plasmawater flow Qp, the net ultrafiltration rate Qgp andthe substitution rate QsLlg using the formula:K = (Qsub + Qgp) x Qp / (Qsub + Qp).The plasma water flow is proportional to theblood flow, whereby the haematocrit has a signi-ficant influence. ln practice, as explained above(p. 15), the plasma water flow can be approxi-mated using this formula:Glp = Qg * (1- HcVIOO) x O'94.For demonstration purposes, urea clearancesattained in clinical practice by various CRRT pro-cedures using commercially available machinesare shown in table 3.

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Necessary intensity ofrenal replacement treatment in ARFPrescriptions for renal replacement therapymust specify the procedure and the necessarydialysis or substitution fluid flow, i.e. the daily turn-over volume.Treatment of chronic renal failure has taught usthat patient prognosis is improved when dialysistreatment intensity is increased. However, untilrecently, it was unclear whether such a rela-tionship also exists between treatment intensityand moftality in ARF.As early as 1991, Storck et al. (60) showed thatpatients with ARF have a higher rate of survivalwhen the fluid volume is increased. However,these patients were all inadequately dialysedaccording to present views, and the fluid turn-over above which prognosis is no longer ex-pected to improve remained unclear. A little later,Paganini et al. (46) demonstrated in a large,retrospective study that there is a clear correla-tion between applied dialysis dose and survival inintensive care patients with ARF.

The decisive work regarding a connection bet-ween intensity of continuous renal replacementtreatment and moftality in intensive care patientswith ARF was published in 2OOO by Ronco et al.(54). This can justifiably be termed a milestonepublication and it will certainly influence the fu-ture treatment of ARF in the lCU. In the scope ofa prospective, randomised study, three differentdoses of HF fluid were employed for the post-dilution CWH treatments of a total of 425 patientswith anuric ARF. The lowest dose (2O mUkg/h)reflected standard practice prior to the begin-ning of the study (fluid turnovers of about 1.O to1.5 L/h). HF fluid turnovers of 35 ml/kg/h and 45mUkg/h were studied in two other treatmentgroups. The three groups were well balanced;specifically the degree of illness was compara-ble. ln the low-dose group however, 59 % of thepatients died, while only 42 o/o ?nd 43 o/o of thosein the two other more intensive treatmentgroups did (figure 11).

8070

^60s CUoE+oE.2 soLJ^^azu

100 20 35 45Exchange rate (mUkg/h)

Fig. 11: Probability of survival with diffe-rent CWH doses.A prospective, randomised study involving 425patients with anuric ABF revealed an increasedprobability of survival which was statisticallysignificant and clinically relevant when the haemo-filtration dose (as measured on the basis offluid turnover) was increased from 20 mL/kg/hto 35 mllkg/h. A further increase in dose didnot improve the prognosis any more. Patientswith septicaemia particularly benefit from amore intensive renal replacement treatment(54). Consequently, the 'dose' of a renal replace-ment treatment should be significantlyincreased in future, and should take the cha-racteristics of the individual patients intoaccount, i.e. body weight must be considered.

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Necessary intensity ofrenal replacement treatment in ARFAugmented treatment intensity appeared to beparticularly beneficial for patients suffering fromsepticaemia. A target turnover volume of 35mL/kg/h is equivalent to a daily turnover of about67 L in an 8O kg patient. Such therapies placehigh demands on the staff and equipment inintensive care units. However, considering theproven reduction in mortality, such intensive treat-ments of ARF are indispensable in the futureand are readily achievable with the presentequipment (figure 12).An important new point which became clear inthis study is that the dialysis dose must be pre-scribed for each patient individually, especiallytaking his or her body weight into consideration.Standardised HF fluid turnovers for all patientsirrespective of their body weights are no longerstate-of-the-art.Schiffl et al. (56) repofted similar results in theyear 2OO2. They treated ARF patients with inter-mittent haemodialysis rather than with a con-tinuous renal replacement procedure. From thetwo patient groups which were randomly formed,one was dialysed daily and the other wasdialysed every other day (as was once typical).Moftality was found to be significantly lower in thegroup receiving the more intensive treatment (28 o/ovs. 46 o/o), and the duration of ARF was also sig-nificantly shorter (treatment times of 9 vs. 16days).Therefore, these two studies provide sufficient

scientific evidence (through prospective, rando-mised studies with appropriate numbers of pati-ents) that ARF patients profit from a more inten-sive renal replacement therapy in the sense thatmodality is reduced.

Fig. 12: multiFiltrate, a modern machine forcontinuous renal replacement therapy.

:, _::ri.t

i+::a ril*itr: i.:

24


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Vascular access forrenal replacement therapyAccess sitesExperience has taught us that a number ofcatheter changes are necessary during a long,intensive treatment, so that various central veinsare punctured in turn. Reviews of the variouspossibilities and risks associated with centralvein puncture are provided elsewhere (49,50).ln principle, however, the right internal jugularvein has the advantage of being easy topuncture, and allows a relatively straight position-ing of the catheter in the upper vena cava, thusfacilitating high blood flows (figure 13). Punctureof the subclavian vein is somewhat more com-plicated, but here the catheters have a lower riskof infection, especially in patients with tracheo-stomies. Access via the femoral vein is also fun-damentally possible. However, due to theenhanced risk of infection and thrombosis, thisaccess site should be avoided if at all possible.This was impressively confirmed by Merrer et al.(45) in a prospective, randomised comparison offemoral and subclavian vein punctures.

OathetersNumerous double-lumen catheters from variousmanufacturers are available which differ in form,length, configuration of the tip, number and posi-tion of perforations for the aspiration of blood,material and sufface coating. Considering the

Fig. 13: Central venous puncture.There are a number of possible puncture sitesfor dialysis catheters. Puncture of the rightinternal jugular vein is easy from a technicalpoint of view, and has the advantage of allowinga straight catheter positioning which minimisesblood flow problems. The distal tip of the cathe-ter should be positioned slightly above theconnection between the V. cava superior andthe right atrium.

necessary intensity of treatment, the cathetersmust be sustainably capable of blood flows of2OO mUmin. ln order to avoid blood trauma,these rates should be attainable with a minimumof pressure.lndependent from acute complications due tothe puncture itself, catheter-associated long-term complications must be avoided. Catheterocclusions and thrombosis can be reduced byadequate anticoagulation and the avoidance of'no flow' phases (stops of the blood pump dueto machine alarms). Vascular thrombosis/steno-sis affects the puncture site and vascular regions

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Vascular access forrenal replacement therapyadjacent to the catheter. Consequently, the sub-clavian vein is, due to its curved nature, padicu-larly susceptible to problems following infraclavi-cular puncture.Catheters made from polyurethane have be-come popular in routine clinical practice (figure 14).The risk of thrombosis with these is low and theybecome relatively flexible at body temperaturewhich, in turn, reduces vessel damage. Due totheir surface characteristics and high flexibility,catheters made from silicon appear to be besttolerated. However, these are extremely expen-sive and not usually necessary for short termuse.ln the meanwhile it has been proven that anti-microbial coating of central vein catheters cansignificantly reduce the risk of catheter infectionand catheter-associated septicaemia (68). Useof these somewhat more expensive catheters isalso economically attractive considering the high

Fig. 14:Typical position of a central venous cathe-ter.

costs involved in even a single incidence ofcatheter-associated septicaemia (69). Nowa-days antimicrobiotic- and anticoagulant-coateddialysis catheters are available which can possi-bly reduce the risk of catheter-associated infec-tions and thrombosis.The position of the catheter must be verifiedbefore beginning CRRT. A position approxi-mately 2 cm above the connection between theV. cava superior and the right atrium is usuallyrecommended. Lesions in the tricuspid valvecan result from a position which is too low, whilea short insertion of catheters can cause aspira-tion problems and reduced blood flow. Measure-ments of the negative (suction) pressure in the'arterial' catheter segment (which should neverexceed 3OO mmHg) provide an indication foraspiration problems. One should remember that,with increasing use, resistance is slightly en-hanced due to the fibrin/protein coating of thecatheter.Recirculation (expressed as percentage of theblood flow) takes place in every catheter, i.e. aporlion of the blood returning from the haemo-filter (so-called venous blood) is drawn back intothe filter through the arterial lumen of the cathe-ter, without having circulated through the pa-tient. This reduces the efficiency of the treat-ment. The recirculation rate is reduced withincreasing distance between the arterial aspira-

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tion and venous outflow points, and is enhancedat high blood flows. lndependent of these fac-tors, recirculation is always higher in femoralaccesses because blood flow in the femoral veinis lower than that in central veins (36). Recircu-lation is particularly high (20 o/o - 40 7o) wheneverthe roles of the different catheter lumens areexchanged (the venous lumen becomes the

afterial lumen, and vice versa, figure 15). This issometimes done intentionally to avoid the changeof the catheter when blood cannot be reliablyaspirated from the arterial lumen, but can ren-der the whole treatment ineffective. Recircula-tion is totally avoidable when blood is withdrawnand returned at different points (two-cathetertechnique).

Fig. 15:Connection of a double-lumen catheter.During connection of the double-lumen catheter to the extracorporeal circuit, care must be taken toensure that the distal lumen is connected with the venous end, and the proximal lumen with the arterialend. Otherwise significant recirculation can take place, i.e. blood which is already purified can be drawninto the extracorporeal circuit again, decreasing the effectiveness of the treatment.

Wrong posiiioning of the Iumen

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AnticoagulationContinuous renal replacement therapy generallydemands a continuous and effective anticoagu-lation in order to facilitate sufficiently long filterusage and to avoid activation processes withinthe extracorporeal circuit (table 4). The target isan effective anticoagulation in the extracorpore-al circuit with minimal effect on coagulation in thesystemic circulation. Therefore, anticoagulationin continuous therapies should be conducted ata point before the haemofilter in the extracor-poreal circuit.Nowadays unfractionated heparin is usuallyused as an anticoagulant, although some cen-tres employ prostacyclin or a combination of thisand heparin. The increase in heparin-intolerancein recent years, particularly the heparin-inducedthrombocytopenia type ll (HlT-ll), has lead to anAnticoagulantHeparin, heparinoids

HirudinCitrate

ProstacyclinCoumarin-li ke anticoagulants(only when indicated)

intensive search for treatment alternatives. Hiru-din and citrate are discussed as possible alter-natives.

Standard anticoagulation withunfractionated hepari nThe most common form of anticoagulation todayis that with heparin. This may be done by apply-ing a standard scheme involving weight-relateddoses, e.9., an initial heparin bolus of 50 lU/kgbody weight followed by 5 - 20 lU/kg/h. However,heparin action can be controlled more exactlyand safely using measurements of activatedclotting time (ACT, Hemochron@) and/or aPTT.ACT measurements are easily to perform, can bedone so at the bedside and can be repeated at

FunctionAccelerate the function of anti-thrombin lll (AT lll) whichforms complexes with activated clotting factors and soinactivates them. Protamine is available as an antidote.lnactivates thrombin. No antidote presently available.Forms complexes with calcium so that no free calciumis available for some of the enzymatic clotting steps. Theeffect can be cancelled by adding calcium to the sys-tem.I nhibits thrombocyte aggregationHas an antagonistic effect on vitamin K andinhibits the hepatic production of some clotting factors.Vitamin K is available as an antidote.

Table 4: Possible anticoagulants for use in dialysis and their function.Of course one should also ensure that blood-air contact and stagnation of blood flow is avoided wheneverpossible. SurJaces which come into contact with blood should be made from non-thrombogenic materials'

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shorl intervals; they thus allow speedy adapta-tions of the heparin dose and this is particularlyimpoftant for patients with enhanced bleedingrisks. Recommendations of an ACT of 14O - 18Oseconds for post-surgery patients are found inthe literature. Values of around 2OO - 25Oseconds have been mentioned for patients whodon't suffer from enhanced bleeding risks. Filteruse is certainly reduced significantly with ACTtimes of under 12O seconds (58,67). ln additionto these bedside procedures, an analysis ofsystemic coagulation should be conducted onceor twice a day. Target aPTT values have beenspecified in the range of 40 - 80 seconds (52).One should be aware that adequate antithrom-bin-lll (AT-lll) levels are necessary for heparinfunction, so these levels should also be measureddaily and, if necessary, replenished. ln cases offrequent occlusions in the extracorporeal circuitduring heparin anticoagulation, coagulation analy-sis in the venous segment provides informationon whether a further increase in heparin dosewould be advantageous. This is not the case foraPTT values in excess of 60 seconds.One side-effect of heparin which is diagnosedmore and more often is the development ofheparin-induced thrombocytopenia (HlT). Onedistinguishes between type I HIT (usually abbre-viated as HIT-I or 'heparin-associated throm-bocytopenia', HAT) and type ll HIT (abbreviatedas HIT-ll). Usually HIT-l has a mild clinical course

and is indicated by moderate reductions inthrombocyte counts. No special therapy, apaftfrom close observation, is necessary. HIT-ll hasan immunological cause, being based on theformation of antibodies. lt is accompanied by asignificant fall in the number of thrombocytesand often results in severe to fatal thromboem-bolic complications. Heparin use should be dis-continued immediately when HIT-ll is suspected,and an alternative form of anticoagulation mustbe substituted. Other heparins or heparinoidsshould also be avoided due to frequent cross-reactions. Thrombocyte counts are generallyclosely monitored during continuous renal replace-ment therapy anyway, so such complicationscan be identified in their early stages.

Anticoagulation withprostacyclinBlood contact with foreign surfaces and trauma-tisation of cellular constituents within the extra-corporeal circuit not only activates the plasmaticclotting system, but also the thrombocytesthemselves. This leads to increased plateletadhesion and aggregation, and the release ofmediators which further sustain activation pro-cesses in the clotting cascade. These steps canbe inhibited by prostaglandins. Usually prostacy-clin (Pgl2) is used. Recommended doses are inthe range of 5 - 10 ng/kg/min (33). Filter use is

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Anticoagulationnot extended with prostacyclin compared toheparin alone. The drop in thrombocyte num-bers is, however, clearly reduced. The inhibition ofthrombocyte function by prostacyclin is reversiblewithin minutes, as opposed to inhibition byacetylsalicylic acid, so that prostacyclin is suita-ble for post-surgery use.Side-effects of prostacyclin stem from its vaso-dilatory effects; hypotension, flushing and anincrease in intrapulmonary shunting have beenobserved, depending on the dose and form ofapplication. Accidental bolus applications (e.9.following restarting of the blood pump after priorstop due to a machine alarm) must be avoided.The high price of prostacyclin is a significant dis-advantage.

Anticoagulation with heparinand prostacyclinOptimal anticoagulation should inhibit both plas-matic and thrombocytic coagulation activation.Consequently, some clinics use a combination oflow doses of heparin and prostacyclin. Someauthors have observed increases in filter life (33),while others could not confirm these findings.Fear of prostacyclin side-effects and its high costhas stopped this combination from becomingwidely used until now, but the additional applica-tion of prostacyclin in cases of frequent filter clot-ting can significantly extend filter life.

Anticoagulation with hirudinAnticoagulation in cases of HIT-ll can now alsobe conducted using recombinant hirudin. Use ofhirudin for anticoagulation in CRRT has, however,only scarcely been investigated, so that it is notyet possible to offer general recommendationsregarding dose. lt is also uncertain whether hiru-din should best be given as a bolus or contin-uously in this situation. An increased risk ofbleeding was found in a study involving the con-tinuous dosing of hirudin, but hirudin levels couldnot be monitored (25). Sources of concern arethe long half-life of the substance (especially inrenal insufficiency), the lack of an antidote, andthe associated enhanced risk of bleeding incases of overdose. Hirudin is eliminated by high-flux but not by low-flux membranes. Therefore,higher hirudin requirements are to be expectedwith the use of high-flux haemofilters and parti-cularly during intensified renal replacement pro-cedures (15). Consequently, regular control ofthe therapy is mandatory. Hirudin dosage can becontrolled using Ecarin Clotting 11me (ECT) or bydirect determination of hirudin levels.Hirudin and heparin anticoagulation during CRRTwere compared in a recent study (67). The sub-stances were found to be comparable regardinganticoagulation success (filter life). Both proce-dures were safe, in principle, although bleedingcomplications were observed in some patients

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following long exposure to hirudin whereby, sur-prisingly, the plasma hirudin concentrationalways was below the therapeutic levels and theECT was prolonged only moderately. As theaffected patients already suffered from clottingproblems, the authors suspected the maincause to lie therein; however, a possible involve-ment of hirudin could not be excluded with cer-tainty.ln summary, effective anticoagulation in CRRT incases of proven HIT-ll can be achieved with hiru-din, although dosage must be adjusted carefully,and the hirudin blood levels or the ECT and thecoagulogram must be closely monitored. Ourpersonal experience of intensified renal replace-ment therapy involving daily fluid turnovers of 40mUkg/h and using high-flux polysulfone filters isthat 10 to 3O mg hirudin are necessary daily toachieve filter life spans of over 24 hours withouta recognisable increase in bleeding risk.

Reg ional anticoagu lationwith citrateThe aim of regional anticoagulation is coagula-tion inhibition exclusively in the extracorporealcircuit with appropriate antagonism in thevenous segment prior to return of blood to thepatient. This has the advantage of maintaining alow bleeding risk in operative intensive caremedicine.

The principle behind regional citrate anticoagula-tion is the inactivation of coagulation by the bind-ing of calcium (1 ,48): citrate ions infused into theblood before it enters the haemofilter bind thecalcium needed for coagulation activation. TheHF fluid used here is, unlike those commonly used,free of calcium so that anticoagulation is not can-celled too early in the extracorporeal circuit. Thebound calcium is replaced in the venous segmentof the extracorporeal circuit or via an infusion intoa separate central venous catheter. The citrate-bound calcium in the returning blood is releasedagain following citrate metabolism in the liver.However, one should be aware that citrate meta-bolism can be significantly reduced in caseswhere liver function is impaired (43,44). There arethree difficulties associated with this approach:1. The citrate added to the blood is metabolised

to bicarbonate in the liver and can so causemetabolic alkalosis.

2. Sodium is usually added to the blood alongwith the citrate, and this can lead to hyperna-traemia.

3. ln order to maintain the patients' ionised cal-cium levels within a normal range, calciumsupplementation must be conducted exactlyand closely monitored. Changes in citratemetabolism can cause difficulties here: re-duced degradation of citrate due to liverimpairment can result in a significant drop inionised calcium levels.

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AnticoagulationVarious systems for citrate anticoagulation aredescribed in the medical literature. Most authorsuse a tri-sodium-citrate solution or ACD-A (amixture of tri-sodium-citrate and citric acid andglucose which was originally developed in trans-fusion medicine), sometimes together with a HFfluid which is appropriately modified in composi-tion (9,42,44,66). A different approach is basedon the procedure described by Palsson & Niles(48) involving a special citrate-buffered HF fluid:calcium is bound directly by the HF fluid which,consequently, must be added to the system inthe predilution mode. Due to the composition ofthe fluid, the risk of hypernatriaemia or develop-ment of metabolic alkalosis is not any higherthan in conventional CRRT. Citrate anticoagula-tion is still not a widely accepted procedure dueto the lack of appropriate commercially availablefluids and easy application patterns; however,considering the increasing prevalence of hepa-rin-associated thrombocytopenia, it is certainly apromising procedure for the future.

Begional anticoagulation withheparin and protamineAlthough heparin anticoagulation and titratedantagonism with protamine has long been usedin cardiac surgery, this procedure has not be-come popular in CRRT. Reasons are the very poorcontrol possible, the side-effects of protamine

(hypotension, the intrinsic anticoagulatoryeffect) and the incalculability of a procedurewhich is conducted continuously over a periodof days - the significantly different half-lives ofthe two substances involved is a contributoryfactor here (1).

Anticoagulation in patientswith increased bleeding riskln general, the bleeding risks associated withanticoagulation in CRRT must be weighed upagainst the possible advantages of CRRT. Hepa-rin coated systems for CRRT are not yet widelyavailable. Should regional anticoagulation not bepossible, then low dose heparinisation or hepa-rin-free treatments must be conducted. Prerins-ing of the extracorporeal circuit with a heparinsolution is recommended for heparin-free treat-ment, e.g. 5,OOO IU heparin in the rinsing fluidwhich is dumped prior to connecting the patient.Tan et al. (64) conducted heparin-free predilu-tion CWH in patients with enhanced bleedingrisks, and achieved filter usages of up to 32 h.lntermittent rinsing of the extracorporeal bloodcircuit with HF fluid (or isotonic NaCl solution) issometimes suggested to extend the filter life.The obvious assumption that the filter lives areextended due to this intervention could not beconfirmed clinically (51). The other alternative is aswitch to iHD, or even heparin-free iHD.


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Frequent occlusion ofthe extracorporeal circuitCcclusion of the extracorporeal circuit is definedas being frequent when filter life-span is less',han 18-24 hours, depending on the author. Ifthese short filter life-spans are not the result ofintentional low anticoagulation in patients withncreased risk of bleeding, then the reasonsmust be investigated. A common cause is adisturbance in blood flow due to catheter pro-blems, e.g. following a partial catheter thrombo-sis. Blood clots are more often found in the airtraps (particularly the venous drip chamber) thanin the haemofilter itself. Attention must be paid toremoving as much air as possible when filling theextracorporeal circuit, as coagulation activationoccurs at blood-air boundaries.Clotting can be caused by excess haemocon-centration within the filter due to a high ultrafil-tration fraction in postdilution CWH. Possiblecountermeasures are an increase in blood flow,a reduced filtration fraction and a switch fromthe postdilution to the predilution mode. Haemo-

concentration and, consequently, coagulationtendency can also be reduced by switching fromhaemofiltration to haemodiafiltration while main-taining, or even increasing, the treatment inten-sity.Despite these measures, early system occlusionstill occurs in a small number of patients. Onepossible reason is then a tendency towardsthrombocyte aggregation. In such cases, thiscan be alleviated by the addition of prostacyclin.Should filter life still not be increased to normaltimes, then one must contend with setting upthe system anew or with switching to iHD. Anelaborate coagulation analysis or the advice of ahaemostasis expert should be sought if neces-sary. Simply increasing the anticoagulation canbe dangerous: when aPTT is over 60 seconds inthe venous segment of the extracorporeal cir-cuit, a further increase in heparin dose willincrease the risk of bleeding but will not lengthenthe filter life.

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Nutritionlntensive care patients with ARF are usually in acatabolic state which is independent of the meta-bolic influences of ARF and due, rather, to theseverity of their illness. The metabolic changesassociated with the underlying illness are in theforeground, in particular in cases of multi-organfunctional dysfunction syndrome or septicaemia.Consequently, nutritional therapy must be orien-tated more towards the particulars of the under-lying illness than towards specific issues in ARF.Present opinion is that the nutrition of critically illpatients with ARF should not generally differfrom that of other intensive care patients withthe same underlying illness who don't have ARF(14). Enteral nutrition should be staded as soonas possible as even small quantities of enteralsubstances maintain intestinal integrity and func-tion.Restricted dosage of amino acids (AA) in pa-tients with ARF is no longer targeted. Such a dietis recommended in the predialysis phase ofchronic renal insufficiency as it may slow downthe progression of the underlying renal disease.It remains unclear whether special 'kidney solu-tions' for patients with ARF are of clinical advan-tage or not. The composition of AA solutions ispresently under discussion, although use of nor-mal AA solutions appears to be also possible forpatients with ARF. AA solutions containing onlyessential amino acids should not be used (14).The fact that 'kidney solutions' are usually potas-

sium-free while many conventional AA solutionscontain 20 - 40 mmol/L potassium is frequentlyoverseen. This can lead to significant increasesin serum potassium levels in cases where hyper-kalaemia is difficult to control and when theCBRT is interrupted.Only very small amounts of lipids are eliminatedin CRRT, while glucose and AA are removed inquantities which depend on their plasma con-centration. Approximately 40 - 80 g glucose and6 - 15 g AA are lost daily for fluid turnovers of24 - 4A L/d (13). Glucose balance in CRRT can bekept neutral by using HF fluids which contain aphysiologic amount of glucose (e.g. 1 g/L); it isthen not necessary to change the enteral orparenteral glucose supply. As HF fluids contain-ing AA are not available, AA losses during CRRTmust be taken into consideration when planningthe parenteral or enteral nutrition, i.e. more AAmust be supplied. About O.25 g AA are lost perlitre of ultrafiltrate produced in postdilution CWH(13). ln other CRRT procedures, the clearancecalculated with simplified formulas (table 5) canbe used instead of the ultrafiltrate volumebecause of the low molecular weight of AA toestimate the loss of AA. With fluid turnovers of4A L/d (or 2 L/h) and a net ultrafiltration volume of4 Ud (negative balance), an additional require-ment of about 13 g a476 is calculated. For a pa-tient weighing 70 kg, this corresponds to anincrease in AA supply of about O.2 g/kg body

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r/eighvd compared to a patient with the sameolinical picture who is not undergoing renal'eplacement therapy. AA supply must be appro-priately increased in more intensive treatmentsnvolving higher fluid turnovers.ln contrast to chronic dialysis where hyperphos-phataemia is usually a problem, inadequatephosphate levels in CRBT patients is frequentlyan issue due to the continuous nature of thetreatment (65). For this reason, phosphate levelsshould be measured daily along with the usuallaboratory controls. Regular phosphate substitu-tion is necessary in intensified renal replacementtherapy.

Drug dosage in CRRTTotal body clearance of any drug is the sum ofits individual regional clearances. Drug dosagesonly have to be altered in ARF whenever renalclearance constitutes a relevant portion of thetotal body clearance. Apart from being a func-tion of the filtration rate and the sieving coeffi-cient, the elimination of a substance in CRRT isparticularly determined by its distribution vol-ume (VD) and its plasma protein binding (PPB).Substances which have a high VD are only pre-sent in the 'central compartment', blood, to asmall extent. Correspondingly, only very small

Water-soluble vitamins are eliminated in contin-uous renal replacement procedures in quantitieswhich depend on the chosen treatment effec-tiveness. Adequate substitution must be madevia parenteral nutrition. We double the daily doseof water-soluble vitamins from fluid turnovers of4A Vd upwards. Trace elements and fat-solublevitamins are not effectively removed due to thesmall amount which is not bound, so en-hanced substitution of these substances is notnecessary (61).

quantities of these have access to the extra-corporeal circuit, and even total removal herewould not constitute significant elimination.Substances with high PPB are also not effec-tively eliminated, as only the free, unbound por-tion can be removed. Drug PPB can be alteredin critically ill patients and in patients with ARF -influencing factors are, for example, pH value,bilirubin levels, dlsplacement by other drugsand heparin.Drug molecular weight (MW) is of very little sig-nificance when high-flux membranes with cut-

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Drug dosage in CRRToffs of over 2O,OOO Da are used, as most drugshave molecular weights of under 1,5OO Da.Vancomycin, with a molecular weight of 1,449Da, is the largest drug prescribed in clinical rou-tine.Drug clearance in the different CRFIT proce-dures can be calculated using the formulaegiven in table 5. Such approximations of clea-rance may be considered roughly equal to theGFR, so that dose alterations can be estimatedfor all those drugs for which a dose reductionaccording to GFR are known.ln addition to filtration/dialysis across the mem-brane, adsorption can be of significance in some

ProcedurePostdilution CWHPredilution CWHCWHDPostdilution CWHDFPredilution CWHDF

Glearance(simplified formulae)Qur+Qsuo

Qp(Qur+Qsun) * 1q-r*o.*)Qur+QoiaQur+Qsuo+Qoia

Qp(Qur+Qsuo+Qoir)x ,tOr+Orrn)

cases. ln particular, the negatively chargedpolyacrylonitrile membrane (PAN, AN 69) canremove significant quantities of drugs from theblood by adsorption, whereby these sub-stances are not detected in the filtrate.A number of tables and lists are available whichfacilitate adaptations to the dosage of nume-rous drugs in CRRT (51). An extensive collec-tion of literature and formulae is available onthe internet under the address:Vrrww. uni-heidelberg. de/med/klinpharm.These allow a calculation of drug dose independence on residual renal function or renalreplacement procedure.

Table 5: Calculation of drug clearancefor various CRRT procedures.The clearance can be calculated using a sim-ple formula which applies when the drug inquestion has a molecular weight of under2OOO, an efficient high-flux haemofilter isused, and the HF fluid flow (i.e. dialysis fluid +substitution fluid flow) is significantly lowerthan the blood flow. This estimation of drugclearance is not exact but is nevertheless suf-ficient for clinical purposes.Qgp net ultrafiltration (= negative fluid bal-ance), Qsun substitution fluid flow, Qdia dialysateflow, Qp plasma water flow.

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Conclusions- rumber of good clinical studies conducted in'ecent years have yielded important new facts,', rrch demand a change in the present common:-actice of treating acute renal failure. ARF in^tensive care units is frequently manifested in^-l;lti-organ dysfunction syndrome or multi-crgan failure. Although patient prognosis is thencrimarily related to the underlying illness, ARF^evertheless constitutes an independent morta-ty factor and effective treatment can improve:he prognosis. Thus early treatment start, inde-cendent of its intensity, reduces mortality in pa-t ents developing ARF. For these reasons, indica-tions for the start of extracorporeal blood purifi-cation techniques are now given much earlierthan they were a few years ago. One now tendsto stad treatment when the retention valueshave reached the levels normally targeted undertreatment. Here a serum urea limit of around 1OOmg/dl is gaining more and more acceptance.Two prospective, randomised studies haveproven that a more intensive treatment with in-creased dialysis dose can reduce mortality, inde-pendent of the underlying disease. Here filtrationvolumes of about 35 ml/kg/h are necessary inhaemofiltration. Daily treatment should be target-ed in the case of intermittent haemodialysis, asthis was shown to significantly reduce mortalitycompared to treatment every other day.Intensifying renal replacement therapy demandsappropriate personnel resources and equip-

ment. Modern machines for continuous renalreplacement treatment have an easy technicalset-up, reliable automatic fluid balance control,and menu-assisted operation instructions whichallow even medical staff who are not specialisedin nephrology to conduct renal replacementtreatment in accordance with the guidelinesgiven above.Regarding the choice of substitution fluid forhaemofiltration treatment, the advantages ofbicarbonate-buffered fluid have been clearlydemonstrated. ln addition to a more effectivecorrection of metabolic acidosis, haemodynamicstability was shown to be improved.These new developments have resulted in high-er demands on the quality and quantity of renalreplacement therapy on intensive care wards inrecent years. Coupled with a possible extensionof the indications for CRRT, this will lead to a sig-nificant increase in the application of CRRT inICUs. Transfer of patients to large specialisedcentres for such treatments will become moredifficult due to capacity and financial problems,so that this technology must also be available insmaller intensive care units. The continuousrenal replacement procedures described hereare effective and easy to perform. They will,therefore, become an indispensable paft of thestandard repertoire in good intensive care medi-cine in future.

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Amino acidsActivated clotting timeActivated partial thromboplastin timeAdult respiratory distress syndromeAcute renal failureAntithrombin lllContinuous arterio-venoushaemofiltrationContinuous arterio-venoushaemodiafiltrationContinuous renal replacement therapyContinuous veno-venous haemofiltrationContinuous veno-venous haemodialysisContinuous veno-venoushaemodiafiltrationGlomerular filtration rateHaemodialysis

HaemodiafiltrationHaemofiltrationHeparin-induced thrombocytopeniaType IHeparin-induced thrombocytopeniaType llHigh volume CWHlntensive Care Unitlntermittent haemodialysisMulti-organ dysfunction syndromeMulti-organ failureProstacyclin (prostaglandin 12)Plasma protein bindingSystemic inflammatory resPonsesyndromeTumor necrosis factorDistribution volume

HDFHFHIT-IHtT-ilHV-CWHtcuIHDMODSMOFPg'2PPBSIRSTNFVD

Hamilton G, Roder G, Germann P C),tokine patterns in patients who undergo hemofiltration for treatment of multip e organ failurediscussion 448

GlossaryAAACTaPTTARDSARFAT IIICAVHCAVHDCRRTCWHCWHDCWHDFGFRHD

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Treatment of Acute Renal Failure Freseniu with Continuous Renal Replacement Procedures

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