Clinical review: Use of renal replacement therapies in special groups of ICU patients

Acute kidney injury (AKI) in ICU patients is typically associated with other severe conditions that require special attention when renal replacement therapy (RRT) is performed. RRT includes a wide range of techniques, each with specific characteristics and implications for use in ICU patients. In the present review we discuss a wide range of conditions that can occur in ICU patients who have AKI, and the implications this has for RRT. Patients at increased risk for bleeding should be treated without anticoagulation or with regional citrate anticoagulation. In patients who are haemodynamically unstable, continuous therapies are most often employed. These therapies allow slow removal of volume and guarantee a stable blood pH. In patients with cerebral oedema, continuous therapy is recommended in order to prevent decreased cerebral blood flow, which will lead to cerebral ischemia. Continuous therapy will also prevent sudden change in serum osmolality with aggravation of cerebral oedema. Patients with hyponatraemia, as in liver failure or decompensated heart failure, require extra attention because a rapid increase of serum sodium concentration can lead to irreversible brain damage through osmotic myelinolysis. Finally, in patients with severe lactic acidosis, RRT can be used as a bridging therapy, awaiting correction of the underlying cause. Especially in ICU patients who have severe AKI, treatment with RRT requires balancing the pros and cons of different options and modalities. Exact and specific guidelines for RRT in these patients are not available for most clinical situations. In the present article we provide an update on the existing evidence.

and continuous PD was comparable with daily HD or CVVHDF in AKI [6][7][8]. An important limita tion of these last studies is that they excluded patients who died on day 1 after randomisation, thereby rendering a more favourable outcome.
Each of these RRT modalities has specifi c charac teristics with implications for their use in specifi c ICU patient groups.

Patients with increased risk for haemorrhage
Most modalities of RRT, with the exception of PD, need anticoagulation to prevent clotting in the extracorporeal circuit, thereby increasing the circuit life and dose of RRT and containing the cost for replacement of a new fi lter and tubin. Th e downside of the use of anticoagulants is the increased risk for haemorrhage. Th e most frequently used anticoagulant in ICU patients is unfraction ated heparin, followed by low molecular weight heparin and regional citrate anticoagulation [9].

No anticoagulation
In most patients, a 2-hour dialysis session can be performed without anticoagulation; but in patients with thrombocytopaenia and coagulation disorders, even longer sessions up to CRRT can be performed without clotting. Th e use of heparin-coated membranes facilitates this session extension. Intermittent fl ushing with saline can also postpone clotting. If haemofi ltration is applied, predilution is preferred to prevent haemoconcentration in the circuit. In addition, in postdilution mode, the fi ltration fraction -calculated as effl uent rate/plasma fl ow rate -should be below 20 to 25%.
If no anticoagulation is allowed, catheter locks used to fi ll up dialysis catheters between dialysis session should be heparin-free as leakage of heparin through the side holes is demonstrated. For that purpose, citratecontaining solutions can be used as a catheter lock.
In the absence of contraindications, such as diverti culitis or recent abdominal surgery, PD in theory can be an alternative RRT modality in patients at high risk for bleeding.

Regional anticoagulation with citrate or with heparin/protamine
Regional anticoagulation with citrate is based on its binding with calcium. Citrate, infused into the aff erent bloodline, binds ionised calcium and hence blocks coagulation [10][11][12]. Th e removal of citrate is dependent on the dialysate fl ow and/or ultrafi ltration rate. Citrate may enter the systemic circulation and can induce hypocalcaemia, resulting in cardiac problems. Calcium substitution with a systemic calcium infusion is therefore nearly always necessary, especially in CRRT. Th e removal of citrate per minute is greater in dialysis compared with CVVH. Citrate anticoagulation is therefore theoretically safer in intermittent haemodialysis compared with CVVH, whereby less citrate is removed. Many diff erent citrate schemes are used for predilution and postdilution CVVH, continuous venovenous haemodialysis (CVVHD) and CVVHDF, and we would like the reader to refer to specifi c texts on this topic [11,12]. Haemodialysis with citrate can be performed with calcium-containing dialysate or with calcium-free dialysate, preferred for short and long sessions, respectively. In continuous modalities, and when using calcium-free dialysate, ionised calcium must be measured rigorously and calcium needs to be re-infused to prevent hypocalcaemia. Citrate accumulation can be monitored by the total to ionised calcium ratio. When this is above 2.5, the citrate dose should be decreased and calcium reinfused. In patients with reduced citrate metabolism, such as in liver failure and in patients with pre-existing hypocalcaemia and/or hypomagnesaemia, extra caution is warranted.
Regional citrate anticoagulation is increasingly used, and is currently recommended by the Kidney Disease: Improving Global Outcomes consensus group as the preferred anticoagulant for CRRT both in patients with and without increased bleeding risk (level of evidence 2B and 2C, indicating a suggestion based on low quality of evidence) (data not yet published; M Schetz, personal communi cation). Several studies have demonstrated the feasibility of this technique with diff erent protocols. Regional citrate anticoagulation resulted in an increased fi lter life in some studies, less bleeding complications, and in one study was even associated with increased survival when compared with low molecular weight heparin, although this could not be confi rmed in another study where unfractionated heparin was the comparator [13-17].
Although regional anticoagulation was originally described with unfractionated heparin and protamine  [18,19], its use has decreased in parallel with the increasing popularity of citrate. Protamine has several side eff ects such as anaphylaxis, hypotension, cardiac depression, leukopaenia and thrombocytopaenia. Further, there is risk for a rebound anticoagulant eff ect, due to the shorter half-life of protamine compared with heparin. Regional anticoagulation with heparin-protamine is therefore no longer recommended [20].

Other anticoagulation strategies
Prostaglandins and the synthetic protease inhibitor nafamostat mesilate inhibit platelet aggregation and adhesion. In CRRT, prostaglandin I 2 and prostaglandin E 1 administered in a fi xed dose resulted in less fi lter clotting and less bleeding complications in a small prospective randomised study (n = 50 patients) [21]. Prostaglandin I 2 has also been successfully used in patients with combined AKI and acute liver failure, who were at increased risk for bleeding [22]. Prostaglandin induces vasodilation and therefore hypotension, however, and may also lead to increased intracranial hypertension and decreased cerebral perfusion pressure [23]. Th ese side eff ects and the cost of this anticoagulation strategy hindered its widespread introduction and use.

Patients with heparin-induced thrombocytopaenia type II
When heparin-induced thrombocytopaenia type II is suspected or confi rmed, the administration of un fraction ated heparin and low molecular weight heparin is contraindicated. In that respect, catheter locks, rinsing solutions, dialyser membranes, catheters, and so forth, must also be heparin free. Besides regional citrate anticoagulation (or prostacyclin), the following anticoagulants could be used in patients with heparin-induced thrombocytopaenia type II. Argatroban, a direct thrombin inhibitor, is mainly hepatically metabolised with a short half-life of 35 minutes in patients with end-stage kidney disease (ESKD). Th e activated clotting time and the activated partial thromboplastin time can be used for monitoring. Only minor extracorporeal clearance with high-fl ux membranes is demonstrated. Argatroban, due to its short half-life, is a safe anticoagulant in patients with renal failure without hepatic impairment. In patients with multiple organ failure, however, one-tenth of the usual dose without an initial bolus is recommended, depending on hepatic function [24].
Diff erent argatroban dosing regimens have been described for diff erent RRT modalities. A proposed dose in chronic haemodialysis patients is a 250 μg/kg bolus followed by continuous infusion of 2 μg/kg/minute [25]. In ICU patients treated with CRRT, it is recommended to administer a loading dose of 100 μg/kg argatroban followed by a maintenance infusion rate (μg/kg/minute) that is adjusted for severity of illness (measured by either 2.15 -0.06 × Acute Physiology and Chronic Health Evaluation II score, or by 2.06 -0.03 × Simplifi ed Acute Physiology Score II) and liver function, assessed by the indocyanine green disappearance rate (-0.35 + 0.08 × indocyanine green disappearance rate) [26]. For ICU patients treated with predilution intermittent venovenous haemodialysis, recommendations are a loading dose of 75 μg/kg followed by a continuous infusion of 0.4 to 0.6 μg/kg/minute until 20 minutes before termination of RRT [27].
Despite clinical use of argatroban in RRT, it should be mentioned that this is an off -label use for this drug.
Fondaparinux is a synthetic heparin analogue that can be used in patients with heparin-induced thrombo cytopaenia type II. In the absence of renal function, a single intravenous dose of 2.5 mg can maintain dialysis circuit patency provided that low-fl ux membranes are used [28]. Owing to its renal clearance, therapeutic anti-factor Xa activity is still demonstrated 48 hours after administration of 2.5 mg fondaparinux. Removal of fondaparinux is enhanced by the use of high-fl ux membranes. In ICU patients, caution is recommended for this anticoagulant considering its long half-life and the high bleeding risk, and/or the frequent need for surgical intervention or invasive procedures. Also, heparin-induced thrombocyto paenia is an off -label indication for fondaparinux.
Lepirudin, or recombinant hirudin, is a direct thrombin inhibitor and can also be used in patients with heparininduced thrombocytopaenia type II. In dialysis patients, a single intravenous dose of 0.08 mg/kg is recommended [29]. Because of its renal clearance, this dose results in sustained anticoagulation. Dialyser clearance depends on the membrane characteristics. High-fl ux membranes allow fi ltration of lepirudin, with the highest sieving coeffi cient for polysulfone (0.97) and lesser sieving coeffi cients for polymethylmethacrylate and polyarylethersulfone (0.75 and 0.73, respectively). Low-fl ux membranes do not fi lter lepirudin [30]. Dependent on the dialysis frequency, the dialysis membrane, and the activated partial thromboplastin time, measured before the start of the dialysis session, a reduced dose should be used from the second dialysis. Because of its prolonged half-life (52 hours), lepirudin is not an anticoagulant of choice in the intensive care patient with AKI.

Patients with severe haemodynamic instability
Haemodynamically unstable patients should be treated carefully, which can be achieved either by CVVH(D), sustained low-effi ciency daily dialysis or continuous HD. In many haemodynamically unstable patients, HD can be performed when specifi c precautions are taken [31,32]. Th ese precau tions include: less aggressive ultrafi ltration, increasing the treatment time in CRRT and daily treatment in intermittent HD, eventually using blood volume measure ments to guide ultrafi ltration; increasing dialysate sodium and calcium concentrations to respectively 145 mmol/l and 1.5 mmol/l; adapting the dialysate temperature to obtain isothermic dialysis; connecting aff erent and eff erent bloodlines simultaneously at the start of the procedure; using low blood fl ow (<150 ml/ minute) and low dialysate fl ows; using biocompatible membranes; and using (ultra)pure water [31].
An argument in favour of CRRT in haemodynamically unstable patients is that solute control is more constant. Th is factor may be of particular benefi t in patients with severe lactic acidosis, where RRT may help to stabilise the haemodynamic status by correction of blood pH. In patients with severe lactic acidosis, intermittent therapy will only off er a temporal improvement of blood pHbetween treatments there will be recurrent acidosis, with its untoward haemodynamic consequences.
In summary, patients with severe haemodynamic instability are best treated with CRRT in order to allow removal of extravascular fl uid and to maintain a stable blood pH.
A more elaborate discussion on the choice between CRRT and HD is presented in another publication in this topic series [33].

Patients with intracranial hypertension or cerebral oedema
Patients with cerebral oedema or intracranial hyper tension have decreased or absent autoregulation of cerebral blood fl ow. A decrease in systemic blood pressure, as may occur during RRT, will therefore lead to decreased cerebral blood fl ow and to cerebral ischaemia, which will consequently lead to more oedema [34]. Continuous arteriovenous haemofi ltration has been proven to better maintain cerebral blood fl ow in patients with acute liver failure and cerebral oedema compared with intermittent dialysis [35,36]. Th ese fi ndings have been extrapolated to treat ment recommendations for patients with other causes of cerebral oedema and to newer modalities of CRRT such as CVVH or CVVHD [37,38].
Another argument in favour of a low effi cient CRRT is that this therapy will seldom be complicated with acute and important tonicity changes of the systemic circulation. Because intermittent HD is a very effi cient RRT modality, these changes may occur after a session of HD. A decrease in serum osmolality will subsequently lead to water uptake by the cells, and to development of cellular oedema [39]. Intracranial pressure may therefore increase after HD.
If a patient is also at increased risk for intracranial haemor rhage, such as after traumatic brain injury, RRT should be administered without anticoagulation or with regional citrate anticoagulation. Th eoretically, PD can be considered as an alternative. Concerns on this modality are the effi cacy and the eff ects on intra-abdominal pressure. Th e intra-abdominal pressure may increase secon dary to infusion of PD fl uid in the abdominal cavity, which may have diverse eff ects on intracranial pressure and cerebral perfusion [40,41]. Increased abdominal pressure may translate into increased intracranial pressure. Further, intra-abdominal hypertension may also decrease systemic preload and increase afterload, leading to lower blood pressure and decreased cerebral perfusion pressure.

Patients with hyponatraemia
When chronic hyponatraemia is corrected rapidly, patients may develop osmotic demyelination syndrome [42,43], a condition with most irreversible brain damage. Th erefore, in asymptomatic patients with chronic hyponatraemia, the sodium concentration should be increased slowly, with a maximum increase of 10 to 12 mmol/l during the fi rst 24 hours and of 18 mmol/l during the fi rst 48 hours of treatment [44]. High serum urea concentration may protect the brain against the development of osmotic demyelination [45,46]. An explanation for this may be the slow diff usion of urea over the blood-brain barrier. Dialysis will decrease serum urea rapidly, but urea that has accumulated in brain cells will decrease only slowly. Th is diff erence will create a blood-brain gradient of urea, and will lead to accumulation of water in brain cells and a slower decline of cell volume, which is the mechanism that leads to osmotic demyelination. Low-effi ciency RRT such as CVVH is recom mended in these patients.
Some authors have recommended the use of replacement fl uid with reduced sodium concentration. Th is can be established by adding sterile water to the replacement fl uid bag [47]. Diluting replacement fl uid will also result in decreased potassium and bicarbonate concentrations, and therefore may induce hypokalaemia and acidosis. Th ese patients therefore need frequent follow-up of sodium and potassium concentrations and blood pH. During treatment, increasing plasma sodium concentrations may require less diluted replacement fl uid; patients may also have need for additional potassium or bicarbonate infusion. Because this procedure is poten tially error prone, and may lead to contamination of sterile replacement fl uid, an alternative strategy is intravenous infusion of hypotonic fl uid (for example, 5% glucose).

Patients with high serum urea concentration
When serum urea is high (typically >175 mg/dl) patients are at risk for developing dialysis disequilibrium syndrome, a neurological condition characterised by nausea and headache. Th e exact mechanism of dialysis disequilibrium is uncertain. A sudden decrease of serum osmo lality and slower decrease of (brain) cell osmolality with resultant increase of cellular water content is the most probable cause. A change in intracellular pH and accu mulation of organic osmolites are also mentioned as a possible cause for this condition. Preventive measures include initiation RRT with ultrafi ltration followed by dialysis, which will increase plasma osmolarity and so prevent development of cerebral oedema and dialysis disequilibrium. Decreasing the dose of dialysis will also prevent important changes of urea concentration, and so prevent dialysis disequilibrium. Th is can be achieved by shortening the fi rst RRT session when intermittent modalities are used (2 hours), decreasing blood fl ow (<200 ml/minute), using a small less effi cient dialyser, or using low-dose CVVH (for example, ultrafi ltration rate <20 ml/kg/hour). A urea reduction ratio of 0.4 to 0.45 or a urea clearance over time of the dialysis session corrected for volume of distribution (Kt/V) of 0.6 to 0.7 has been proposed. Administration of osmotic agents such as mannitol (1 g/kg intravenously per dialysis session) may also be of help. Finally, an increased dialysate sodium concentration (143 to 146 mmol/l) is also recommended in patients at risk [48][49][50].

Patients with acute or acute on chronic liver failure
Th ere are several aspects that deserve special attention in patients with liver failure and AKI.

Encephalopathy and cerebral oedema
Patients with acute liver failure and encephalopathy are very likely to have cerebral oedema, especially when the time between occurrence of jaundice and encephalopathy is short; for example, as in fulminant liver failure, defi ned by a time delay between icterus and encephalopathy of less than 2 weeks [37,51]. Th ese patients are at increased risk for increased intracranial pressure and brain stem herniation. One should therefore apply the principles for prevention of deterioration of intracranial pressure as described above. In summary, CRRT with special attention for haemo dynamic stability and maintenance of cerebral perfusion pressure is warranted.

Hyponatraemia
Patients with liver failure often experience chronic hyponatraemia. Hence, special attention should be given to a slow increase of serum sodium, as discussed above.

Hepatorenal syndrome
Patients with acute and acute on chronic liver failure may develop AKI as a consequence of hepatorenal syndrome. Especially in patients with acute on chronic liver failure this is an end stage of the process of water retention and increased catecholamine stress, characterised by hyponatraemia and ascites [52].
A small prospective randomised study suggests that treatment with artifi cial liver support may improve survival in these patients [53]. Th is study was underpowered (n = 13 patients), however, and the control popu lation was not treated with vasopressin analogues, which is currently the standard of care. A large prospective randomised study comparing the standard of care for liver dialysis with that of the Prometheus liver dialysis system (Fresenius Medical Care, Bad Homburg, Germany) in patients with acute on chronic liver failure recently found in subanalysis that patients with hepatorenal syndrome treated with Prometheus liver dialysis had better survival [54]. Th is study is currently only presented as an abstract, so we can only discuss preliminary results.
Th ere are no data that support the use of one specifi c RRT modality above another for hepatorenal syndrome, although generally less aggressive modalities such as sustained low-effi ciency daily dialysis or CRRT will be used most.

Coagulation abnormalities
Patients with liver failure have decreased production of coagulation factors II, V, VII, IX, X and XI, thrombocytopaenia and decreased thrombocyte function [55,56]. Th is will lead to decreased coagulation. Many patients with severe liver failure can therefore undergo RRT without anticoagulation. However, decreased production of protein C, protein S and antithrombin III, increased concentrations of factor VIII, von Willebrand factor and heparin cofactor II, and a decreased concentration of plasminogen will lead to increased coagulation, despite abnormal coagulation tests. Coagulation tests can therefore be misleading and, despite abnormal tests, fi lter clotting may occur. Monitoring the coagulation status with func tional haemostasis monitoring devices such as thrombo elastography or Sonoclot (Sienco Inc., Arvada, Colorado, USA), which measure the individual contribution of coagulation by platelets and coagulation factors, and fi brinolysis may be of help to better understand the coagulation status of these patients.

Patients with severe lactic acidosis
Th e treatment for lactic acidosis should be aimed at correcting the cause. However, as severe acidosis may in itself lead to profound systemic hypotension, RRT is sometimes used as a bridge until correction of the underlying cause, especially in patents who also have AKI [57]. RRT may correct blood pH, by removing lactic acid and through administration of bicarbonate from the dialysate. Con tinuous modalities are preferred to prevent intra dialytic rebound, and dialysis is more effi cient in removing small molecules as lactate [58,59].

Patients with congestive heart failure
Patients with decompensated heart failure and diuretic resistance, without AKI, can benefi t from isolated ultrafi ltration [60,61]. When these patients are haemodynamically unstable, the ultrafi ltration rate should be limited by increasing the treatment time. Th is limitation can be achieved by CRRT or hybrid therapy. PD is also used for fl uid removal in patients with congestive heart failure and ESKD. However, fl uid removal is less predictable com pared with extracorporeal ultrafi ltration [62,63].
Special attention should be given to patients with congestive heart failure and (chronic) hyponatraemia (see the discussion on hyponatraemia above).

Patients with burn injury
On average, 3% of patients with severe burn injury are treated with RRT for AKI [64]. Patients with burn injury and AKI often have large wounds and repetitive surgical interventions with increased risk for bleeding.
Another issue in burn patients is accumulation of iodine. Burn patients treated with topical povidoneiodine may have elevated iodine concentrations, secondary to increased absorption in combination with hampered renal excretion. Th is can lead to metabolic acidosis, AKI, and heart conduction abnormalities, eventually leading to heart block. Th e molecular weight of iodine is 253; hence the dialyser clearance during highfl ux dialysis is comparable with that of small solutes such as urea. Intercompartmental clearance is low, however, so long treatment times are mandatory [65]. Protracted high-fl ux haemodialysis or haemodiafi ltration, with high blood and dialysate fl ow, is therefore the treatment of choice to remove iodine.

Patients with accidental hypothermia
Consensus exists about cardiopulmonary bypass as the treatment of choice in cases of severe accidental hypothermia with cardiac arrest. In settings where cardiopulmonary bypass is not available, or in haemodynamically stable patients, HD is a valuable alternative [66]. Setting dialysate fl ow and temperature to their maximum optimises the effi ciency of warming. Blood fl ow and the membrane surface should also be optimised. HD can be started without exogenous anticoagulation because hypothermia is associated with coagulopathy.

Patients with intoxications
Th e use of RRT in the treatment of intoxicated patients has decreased over recent years. Reasons for this decline are diverse. Some intoxications, such as with paraquat and theophyllin, are nowadays less frequent in the western world. Other intoxications, such as with methanol and ethylene glycol, are often treated with fomepizole. At present, the most frequently encountered intoxications treated with RRT are caused by lithium, methanol, ethylene glycol and iodine. Rare intoxications that should in special indications be treated with haemodialysis include valproic acid, isoniazid and metformin [67]. Th e mainstay for treatment of salicylate intoxication remains alkalinisation of blood and urine. In patients with severe salicylate intoxication and in patients presenting with severe fl uid overload and/or pulmonary or cerebral oedema, however, HD should be used to eff ectively remove salicylate from blood [68,69].
With the introduction of high-fl ux membranes and haemo diafi ltration, haemoperfusion with charcoal cartridges has lost importance.
Th e lack of residual endogenous clearance, sometimes caused by the intoxication itself, will accelerate the decision to start dialysis. Examples include AKI in patients with lithium, iodine or ethylene glycol intoxications. If the molecular weight of a toxin is low and protein binding is limited, dialyser clearance is expected to be high. Th is is a prerequisite for effi cient removal. Th e body clearance depends on the compartmental behaviour. If the distribution is multicompartmental, with slow equili bration between the diff erent compart ments, rebound can ensue. In these cases, long dialysis times are necessary. Because of this latter reason and because of the availability of alternative treatment (digoxin-specifi c Fab fragments), digoxin intoxications are seldom treated by haemodialysis.
Our preference is to apply haemodialysis (mostly high fl ux) with high blood fl ow (250 to 300 ml/minute) and high dialysate fl ow (500 ml/minute) and a long treatment time or even continuously in order to optimise both dialyser and body clearance. For larger solutes, protracted or continuous online haemodiafi ltration is more effi cient. CVVH or CVVHD results in much less dialyser clearance because of absent or limited dialysate fl ow. Patients with lithium intoxication without renal failure should preferably not be treated with a single-pass batch system, as premature mixing of dialysate has been documented in the absence of uraemic solutes [70]. In these patients, haemodialysis with a conventional haemodialysis machine is recommended.

Chronic haemodialysis patients admitted to the ICU
Chronic haemodialysis patients represent a minority of ICU patients. In a tertiary care centre in the USA, 3.7% of ICU patients were chronic haemodialysis patients [71]. Other studies found that 11 to 12% of all patients treated with RRT in the ICU are chronic dialysis patients [72,73]. Th e main reasons for ICU admission are sepsis and cardiovascular complications, which are com parable with AKI patients [72,73]. Instead of the regular outpatient dialysis schedule of 4 hours of dialysis three times weekly, RRT during the ICU stay should be adapted towards the current needs of the patient. Daily, protracted dialysis can easily be performed through the arteriovenous fi stula. Staff should be extremely vigilant in keeping this arteriovenous fi stula patent. Th ey should therefore be advised against using the arm with the arteriovenous fi stula for blood sampling, arterial line insertion or noninvasive blood pressure measurement. Needling of this arteriovenous fi stula should only be performed by an experienced dialysis nurse. A temporary dialysis catheter is preferred when a continuous technique is applied.

Renal replacement therapy during surgery
Occasionally, haemodialysis is performed during surgery. Because liver transplantation in patients with renal impair ment can be associated with severe hyperkalaemia, especially during reperfusion, intraoperative dialysis should be considered. Unstable patients with acidosis and persistent electrolyte disturbances may also benefi t from a continuation of the dialysis in the operation room. Special attention should be paid to the temperature of the dialysate, to avoid cooling of the patient. If no water treatment is available in the operation room, haemodialysis can be performed with a single-pass batch system. Anticoagulation is mostly contraindicated, or in the case of liver transplantation is not needed. If necessary, a heparin-coated membrane can be used [74]. During liver transplantation, citrate may accumulate when regional citrate anticoagulation is used. Th e citrate load is often already elevated in these patients due to the adminis tration of fresh frozen plasma and packed cells. We therefore do not recommend citrate anticoagulation in these patients.

Continuous venovenous haemofi ltration
Two prospective randomised studies evaluated the use of standard CVVH compared with the standard of care in patients with severe sepsis [75,76]. Th e rationale was that infl ammatory mediators were removed at a constant rate in the CVVH intervention group, and that the infl am matory process could therefore be halted. Neither study could demonstrate that CVVH led to decreased serum concentrations of mediators, or to improvement of organ dysfunction. In fact, the most recent study was discontinued after an interim analysis on 76 patients demonstrated more organ dysfunction and more severe organ dysfunction in patients randomised to CVVH compared with the standard of care [76].

High-volume haemofi ltration
Observational data by Ratanarat and colleagues and by Honore and colleagues demonstrated that short-term high-volume haemofi ltration -6 to 8 hours of CVVH at 85 ml/kg/hour followed by 16 to 18 hours of CVVH at 35 ml/kg/hour [77], and ultrafi ltration of 35 l during a 4-hour period followed by conventional CVVH [78] was associated with better outcomes than compared with historic controls [77,78]. In the High Volume on Intensive Care (IVOIRE) study, septic study patients were randomised to high-volume haemofi ltration (70 ml/kg/hour for 96 hours) or to standard-dose CVVH (35 ml/kg/hour). Th e study was recently stopped after interim analysis, but was not yet published at the time of this review. Th e results will inform us on the exact place of this technique for treatment of sepsis patients.

Polymyxin-B haemoperfusion
Polymyxin-B bound to a membrane is a compound that effi ciently binds endotoxin, a component released from the cell membrane of Gram-negative bacteria. Endotoxin is a crucial component in the infl ammatory cascade follow ing Gram-negative infection. Several smaller studies that were bundled in a meta-analysis and a recent small prospective randomised study in patients with intraabdominal sepsis demonstrated that binding endotoxin with polymyxin-B haemoperfusion may improve haemodynamics and organ function at 72 hours, and may improve short-term (28-day) mortality in sepsis patients [79,80]. Th ese results are promising, but the dataset is still too small to adopt this therapy in routine practice.

Coupled plasma fi ltration and absorption combined with haemodialysis.
Coupled plasma fi ltration and absorption also targets diminishing the infl ammatory process, by removing infl ammatory mediators through absorption. For this technique, blood is fi ltered by a plasma fi lter. Plasma that is produced by the plasma fi lter is run through an absorption fi lter, reinfused into the circuit, and subsequently fi ltered by a high-permeable polysulfone haemofi lter. Results from a small pilot crossover study in 10 patients with severe septic shock demonstrated that this technique improved haemo dynamics during the 10-hour plasma fi ltration and absorption session compared with CVVHDF [81]. Responsiveness of white blood cells to stimulation with lipopolysaccharide was also normalised after treatment with coupled plasma fi ltration and absorption. A prospective randomised study on this technique was concluded in Italy recently, but the results have not yet been published.

Conclusions
Especially in ICU patients who have severe AKI, treatment with RRT requires balancing the pros and cons of diff erent options and modalities. Special groups of ICU patients that deserve extra consideration are, for example, patients with coagulation abnormalities or with increased risk for bleeding, such as after surgery, patients with severe haemodynamic instability, liver failure patients and patients with hyponatraemia. Exact and specifi c guidelines for RRT in these patients are not available for most clinical situations.