With IHD, CRRT or SLEDD there are limited data on what is ‘adequate’ intensity of dialysis. However, this concept should include maintenance of homeostasis at all levels,¹⁰ and better uraemic control may translate into better survival.^11,¹² An appropriate target urea might be 15–25 mmol/l, with a protein intake around 1.5 g/kg per day. This can be easily achieved using CRRT at urea clearances of 35–45 l/day depending on patient size and catabolic rate. If intermittent therapy is used, daily and extended treatment as described with SLEDD becomes desirable.¹³

MODE OF RENAL REPLACEMENT THERAPY

There is a great deal of controversy as to which mode of RRT is ‘best’ in the ICU, due to the lack of randomised controlled trials comparing different techniques. In their absence, techniques of RRT may be judged on the basis of the following criteria:

1 haemodynamic side-effects

2 ability to control fluid status

3 biocompatibility

4 risk of infection

5 uraemic control

6 avoidance of cerebral oedema

7 ability to allow full nutritional support

8 ability to control acidosis

9 absence of specific side-effects

10 cost

CRRT and SLEDD offer many advantages over PD and conventional IHD (3–4 h/day, 3–4 times/week),¹³ and whereas CRRT is almost exclusively used in some centres,¹⁴ only a minority of American ICU patients receive CRRT. Some salient aspects of CRRT, IHD and PD require discussion.

CONTINUOUS RENAL REPLACEMENT THERAPY

First described in 1977, CRRT has undergone several technical modifications. Initially, it was performed as an arteriovenous therapy (continuous arteriovenous HF: CAVH). The need to cannulate an artery, however, is associated with 15–20% morbidity. Accordingly, double-lumen catheters and peristaltic blood pumps have come into use (continuous venovenous HF: CVVH) with or without control of ultrafiltration rate. Ultrafiltration rates of 2 l/h yield urea clearances > 30 ml/min. Diagrams illustrating typical HF circuits are presented in Figures 41.1–41.3.

Figure 41.1 Diagrams illustrating a continuous venovenous haemofiltration circuit (CVVH).

Figure 41.2 Diagrams illustrating a continuous venovenous haemodiafiltration circuit (CVVHDF).

Figure 41.3 Diagram illustrating a continuous venovenous haemodialysis circuit (CVVHD).

In a venovenous system, dialysate can also be delivered countercurrent to blood flow (continuous veno-venous haemodialysis/haemodiafiltration) to achieve either almost pure diffusive clearance or a mixture of diffusive and convective clearance.

No matter what technique is used, the following outcomes are predictable:

1 continuous control of fluid status

2 haemodynamic stability

3 control of acid–base status

4 ability to provide protein-rich nutrition while achieving uraemic control

5 control of electrolyte balance, including phosphate and calcium balance

6 prevention of swings in intracerebral water

7 minimal risk of infection

8 high level of biocompatibility

However, CRRT mandates the presence of specifically trained nursing and medical staff 24 hours a day. Small ICUs often cannot provide such level of support. If CRRT is only used 5–10 times a year, the cost of training may be unjustified and expertise may be hard to maintain. Furthermore, depending on the organisation of patient care, CRRT may be more expensive than IHD. Finally, the issues of continuous-circuit anticoagulation and the potential risk of bleeding have been a major concern.

DOSE OF CRRT AND CIRCUIT ANTICOAGULATION

The optimal dose (expressed as effective effluent per kilogram per hour) of CRRT remains unknown. Several studies suggest that higher dose may translate into better outcome.^12,¹⁵ However such studies have been single-centre in nature and require confirmation in multicentre randomised controlled trials. Such trials are now under way (see below).¹⁶ It seems wise to wait for the results of larger studies before making any changes to the typical dose of approximately 25 ml/kg per hour currently delivered in Australia and New Zealand.

The flow of blood through an extracorporeal circuit causes activation of the coagulation cascade and promotes clotting of the filter and circuit itself. In order to delay such clotting and achieve acceptable operational lives (approximately 24 hours) for the circuit, anticoagulants are frequently used.¹⁷ However, circuit anticoagulation increases risk of bleeding. Therefore, the risks and benefits of more or less intense anticoagulation and alternative strategies (Table 41.2) must be considered.

Table 41.2 Strategies for circuit anticoagulation during continuous renal replacement therapy

No anticoagulation

Low-dose prefilter heparin (< 500 IU/h)

Medium-dose prefilter heparin (500–1000 IU/h)

Full heparinisation

Regional anticoagulation (prefilter heparin and postfilter protamine, usually at a 100 IU:1 mg ratio)

Regional citrate anticoagulation (prefilter citrate and postfilter calcium – special calcium-free dialysate needed)

Low-molecular-weight heparin

Prostacyclin

Heparinoids

Serine proteinase inhibitors (nafamostat mesylate)

In the vast majority of patients, low-dose heparin (< 500 IU/h) is sufficient to achieve adequate filter life, is easy and cheap to administer and has almost no effect on the patient’s coagulation tests. In some patients, a higher dose is necessary. In others (pulmonary embolism, myocardial ischaemia), full heparinisation may actually be concomitantly indicated. Regional citrate anticoagulation is very effective but requires a special dialysate or replacement fluid.¹⁸ Regional heparin/protamine anticoagulation is also somewhat complex but may be useful if frequent filter clotting occurs and further anticoagulation of the patient is considered dangerous. Low-molecular-weight heparin is also easy to give but more expensive. Its dose must be adjusted for the loss of renal function. Heparinoids and prostacyclin may be useful if the patient has developed heparin-induced thrombocytopoenia and thrombosis. Finally, in perhaps 10–20% of patients anticoagulation is best avoided because of endogenous coagulopathy or recent surgery. In such patients adequate filter life can be achieved provided that blood flow is kept at about 200 ml/min and vascular access is reliable.¹⁹

Many circuits clot for mechanical reasons (inadequate access, unreliable blood low from double-lumen catheter depending on patient position, kinking of catheter). Responding to frequent filter clotting by simply increasing anticoagulation without making the correct aetiological diagnosis (checking catheter flow and position, taking a history surrounding the episode of clotting, identifying the site of clotting) is often futile and exposes the patient to unnecessary risk. Particular attention needs to be paid to the adequacy or ease of flow through the double-lumen catheter. Smaller (11.5 Fr) catheters in the subclavian position are a particular problem. Larger catheters (13.5 Fr) in the femoral position appear to function more reliably.

CRRT TECHNOLOGY

The increasing use of venovenous CRRT has led to the development of a field of CRRT technology which offers different kinds of machines to facilitate its performance.²⁰ Some understanding of these devices is important to the successful implementation of CRRT in any ICU. One can a have simple blood pump with safety features (air bubble trap and pressure alarms) and use widely available volumetric pumps to control replacement or dialysate flow and effluent flow. Such adaptive technology is inexpensive, but is not user-friendly. Also, volumetric pumps have an inherent inaccuracy of about 5%, which, in a system exchanging up to 50 l/day, can cause problems. Various manufacturers have now produced custom-made machines for HF. These machines are safer and have much more sophisticated pump control systems, alarms and graphic displays. They are much more user-friendly, especially with the set-up procedure.

The choice of membrane is also a matter of controversy. There are no controlled studies to show that one confers a clinical advantage over the others. The AN 69 is the most commonly used CRRT membrane in Australia. The issue of membrane size is also controversial as no controlled studies have compared different membrane surface sizes. If high-volume haemofiltration is planned, however, the membrane surface needs to be in the 1.6–2 m ² range.

INTERMITTENT HAEMODIALYSIS

Vascular access is typically by double-lumen catheter, as in continuous HF. The circuit is also the same. Countercurrent dialysate flow is used as in CVVHD. The major differences are that standard IHD uses high dialysate flows (300–400 ml/min), generates dialysate by mixing purified water and concentrate and treatment is applied for short periods of time (3–4 hours), usually every second day. These differences have important implications. Firstly, volume has to be removed over a short period of time and this may cause hypotension. Repeated hypotensive episodes may delay renal recovery.⁴ Secondly, solute removal is episodic. This translates into inferior uraemic control²¹ and acid–base control. Limited fluid and uraemic control imposes unnecessary limitations on nutritional support. Furthermore, rapid solute shifts increase brain water content and raise intracranial pressure.²² Finally, much controversy has surrounded the issue of membrane bioincompatibility. Standard low-flux dialysing membranes made of cuprophane are known to trigger the activation of several inflammatory pathways, when compared to high-flux synthetic membranes (also used for continuous HF). It is possible that such proinflammatory effect contributes to further renal damage and delays recovery or even affects mortality. Given the minimal difference in cost between biocompatible and bioincompatible low-flux membranes, biocompatible membranes (polysulfone) are now preferred.

The limitations of applying ‘standard’ IHD to the treatment of ARF ⁹ has led to the development of new approaches (so-called ‘hybrid techniques’) such as SLEDD.¹³ These techniques seek to adapt IHD to the clinical circumstances and thereby increase its tolerance and its clearances.

PERITONEAL DIALYSIS

This technique is now uncommonly used in the treatment of adult ARF in developed countries.¹⁴ However, it may be an adequate technique in developing countries or in children where the peritoneal membrane has a greater relative surface or alternatives are considered too expensive, too invasive, or are not available. Typically access is by the insertion of an intraperitoneal catheter. Glucose-rich dialysate is then inserted into the peritoneal cavity and acts as the ‘dialysate’. After a given ‘dwell time’ it is removed and discarded with the extra fluid and toxins that have moved from the blood vessels of the peritoneum to the dialysate fluid. Machines are also available which deliver and remove dialysate at higher flows, providing intermittent treatment or higher solute clearances. Several major shortcomings make PD relatively unsuited to the treatment of adult ARF:

1 limited and sometimes inadequate solute clearance

2 high risk of peritonitis

3 unpredictable hyperglycaemia

4 fluid leaks

5 protein loss

6 interference with diaphragm function

There have not been any reports of the sole use of PD for the treatment of adult patients with ARF in the last 15 years. A randomised trial comparing PD to CVVH found that PD was associated with increased mortality.²³

OTHER BLOOD PURIFICATION TECHNIQUES

HAEMOPERFUSION

During haemoperfusion, blood is circulated through a circuit similar to one used for CVVH. However, a charcoal cartridge is perfused with blood instead of a dialysis membrane. In some cases an ion exchange resin (Amberlite) has been used. Charcoal microcapsules effectively remove molecules of 300–500 D MW, including some lipid-soluble and protein-bound substances. Heparinisation is necessary to prevent clotting. Attention must also be paid to changes in intravascular volume at the start of therapy because of the large priming volume of the cartridge (260 ml). Glucose absorption is significant and monitoring of blood glucose is necessary to avoid hypoglycaemia. Also thrombocytopenia is common, and can be marked. The role of haemoperfusion is controversial, as no controlled trials have ever shown it to confer clinically significant advantages. It may be useful, however, in patients with life-threatening theophylline overdose because it removes the agent effectively.

PLASMAPHERESIS OR PLASMA EXCHANGE

With this technique, plasma is removed from the patient and exchanged with fresh frozen plasma (FFP) and a mixture of colloid and crystalloid solutions. This technique can also be performed in an ICU familiar with CRRT techniques. A plasmafilter (a filter that allows the passage of molecules up to 500 kD) instead of a haemofilter is inserted in the CVVH circuit, and the filtrate (plasma) is discarded. Plasmapheresis can also be performed with special machines using the principles of centrifugation. The differences, if any, between centrifugation and filtration technology are unclear. Replacement (postfilter) will occur as in CVVH using, for example, a 50/50 combination of FFP and albumin. Plasmapheresis has been shown to be effective treatment for thrombotic thrombocytopenic purpura and for several diseases mediated by abnormal antibodies (Guillain–Barré syndrome, cryoglobulinaemia, myasthenia gravis, Goodpasture’s syndrome) in which antibody removal appears desirable. Its role in the treatment of sepsis remains uncertain.²⁴

BLOOD PURIFICATION TECHNOLOGY OUTSIDE ARF

There is growing interest in the possibility that blood purification may provide a clinically significant benefit in patients with severe sepsis/septic shock by removing circulating ‘mediators’. A variety of techniques, including plasmapheresis, high-volume HF, very-high-volume HF, coupled plasma filtration adsorption ²⁴^–²⁷ and large-pore HF,²⁷ are being studied in animals and in phase I/II studies in humans. Initial experiments support the need to continue exploring this therapeutic option. However, no suitably powered randomised controlled trials have yet been reported. Also, blood purification technology in combination with bioreactors containing either human or porcine liver cells is under active investigations as a form of artificial liver support for patients with fulminant liver failure or for patients with acute-on-chronic liver failure. Albumin-based dialysis has been developed to deal with protein-bound toxins in patients with liver failure. This system, known as MARS (molecular adsorption recirculating system), has shown benefits in patients with elevated intracranial pressure and/or acute-on-chronic liver failure, but not in patients with fulminant liver failure.²⁸

DRUG PRESCRIPTION DURING DIALYTIC THERAPY

ARF and RRT profoundly affect drug clearance. A comprehensive description of changes in drug dosage according to the technique of RRT, residual creatinine clearance and other determinants of pharmacodynamics is beyond the scope of this chapter and can be found in specialist texts.²⁹ Table 41.3 provides general guidelines for the prescription of drugs commonly used in the ICU.

Table 41.3 Drug dosage during dialytic therapy *

Drug	CRRT	IHD
Aminoglycosides	Normal dose q 36 h	50% normal dose q 48 h – 2/3 redose after IHD
Cefotaxime or ceftazidime	1 g q 8–12 h	1 g q 12–24 h after IHD
Imipenem	500 mg q 8 h	250 mg q 8 h and after IHD
Meropenem	500 mg q 8 h	250 mg q 8 h and after IHD
Metronidazole	500 mg q 8 h	250 mg q 8 h and after IHD
Co-trimoxazole	Normal dose q 18 h	Normal dose q 24 h after IHD
Amoxicillin	500 mg q 8 h	500 mg daily and after IHD
Vancomycin	1 g q 24 h	1 g q 96–120 h
Piperacillin	3–4 g q 6 h	3–4 g q 8 h and after IHD
Ticarcillin	1–2 g q 8 h	1–2 g q 12 h and after IHD
Ciprofloxacin	200 mg q 12 h	200 mg q 24 h and after IHD
Fluconazole	200 mg q 24 h	200 mg q 48 h and after IHD
Acyclovir	3.5 mg/kg q 24 h	2.5 mg/kg per day and after IHD
Gancyclovir	5 mg/kg per day	5 mg/kg per 48 h and after IHD
Amphotericin B	Normal dose	Normal dose
Liposomal amphotericin	Normal dose	Normal dose
Ceftriaxone	Normal dose	Normal dose
Erythomycin	Normal dose	Normal dose
Milrinone	Titrate to effect	Titrate to effect
Amrinone	Titrate to effect	Titrate to effect
Catecholamines	Titrate to effect	Titrate to effect
Ampicillin	500 mg q 8-hourly	500 mg daily and after IHD