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Acute renal support in the ITU
Acute Renal Support in the ITU
D. W. Jacobson and A. R. W e b b
With mortality in excess of 90%, acute renal failure was largely untreatable until 1944 when Willem Kolff successfully dialysed a patient with sulphonamide induced acute renal failure. 1 Since that initial treatment a plethora of renal replacement devices and procedures have reduced the current mortality of uncomplicatedacute renal failure to around 8%. 2 The mortality of acute renal failure in the ITU patient, however, remains high, increasing with the number of other failed organs; often assumed to be 100% with two other major organ system failures, z
The poor membrane technology and lack of suitable anticoagulant (heparin was not clinically available until 1933) limited the application of their discovery. After the Second World War much work was done on dialysis machine design, anticoagulation, dialysate composition, vascular access, and crucially, membrane technology. Manipulation of the physiological principles was also explored. In the 1950s Alwall described experiments in Sweden using semipermeable membranes as isolated ultrafilters. 4 This process, which became known as haemofiltration, was initially envisaged as a method of fluid removal, but after much refnement it now forms the basis of the majority of the support offered to critically ill patients with acute renal failure.
History Although of various designs and with confusing nomenclature, all the extracorporeal renal replacement therapies currently available rely on the same two physiological principles that Kolff's early machine employed; ultrafiltration and diffusion. Kolff's original device was a 40m length of cellulose sausage skin wrapped in a spiral around a drum which was half submerged in a bath of dialysate, x Blood was propelled along the tube by the Archimedes' Screw principle when the drum was rotated. Solute removal was by diffusion across the primitive membrane and fluid was removed by what little ultrafiltration the system provided. This cellulose membrane was considerably more successful, however, than the collodion membrane used 30 years earlier by Abel et al. 3 who had passed rabbit blood through collodion tubes and obtained a filtrate in which salicylate, previously fed to the animals, was detectable. This process, which Abel termed 'vividiffusion' was the first successful treatment of a living animal by dialysis.
Haemofiltration (Fig. 1) The limiting factor in the early haemofiltration designs was the poor solute removal. Haemofiltration is ultrafiltration of blood, ultrafiltration being the passage of fluid, under pressure, across a semipermeable membrane. Solutes are carried along with the fluid by solvent drag, that is convection. In practice this driving pressure is the hydrostatic pressure difference on either side of the membrane, the
Mr D. W. Jacobson, RGN Charge Nurse (ITU), Dr A. R. Webb, MB MRCP Consultant Physician (ITU), Bloomsbury Department of Intensive Care, The Middlesex Hospital, Mortimer Street, London W1N 8AA, UK Current Anaesthesia and Critical Care
© 1992LongmanGroupUK Ltd
(1992)3, 150-155 150
ACUTE RENAL SUPPORT IN THE ITU Blood flow in
7
Filtrate flow
ation
151
correct such patients' pH was associated with a high mortality.5 The efficiency of the process is limited by the volume of plasma filtrate removed and replacement fluid reinfused. The bulk movement of fluid and solutes by ultrafiltration is affected by the pressure difference across the membrane, the transmembrane pressure. The positive pressure on the blood side of the membrane can be maximised by increasing the blood flow speed with a mechanical pump, or by optimising the patient's blood pressure in an arterio-venous circuit. Limiting pressure drop across the arterial line in an AV circuit can be achieved by keeping this line as short as possible, reducing the resistance it exerts on blood flow. Conversely, a longer venous line will provide more resistance post-filter, increasing hydrostatic pressure, and thus ultrafiltration, inside the filter itself.
Dialysis and haemodiafiltration (Fig. 2) e membmne
~
Blood flow out
Fig. 1 - - Schematic diagram of haemofiltration.
transmembrane pressure (TMP). To increase the TMP (and thus the amount of filtrate) the pressure difference must also be maximised, either by increasing the pressure on the blood side of the membrane, or be decreasing it on the filtrate side. Thus, to maximise TMP the speed of blood flow can be increased (assuming no change in circuit dimensions), or the filtrate pressure can be reduced by using a pump to apply a negative pressure to the plasma filtrate. Alwall described lowering the filtrate collection vessel of his haemofilter out of a window to maximise the pressure difference between the membrane and the vessel. 4 He commented that this system did not work in the Swedish winter, as the filtrate froze! As the plasma solutes are removed stoichiometrically, large volumes of ultrafiltrate need to be produced to significantly affect the uraemic patient's blood chemistry, in practice 400- 600 ml/h. In the catabolic, often septic ITU patient, it may be difficult to remove enough of the ever-increasing amounts of uraemic metabolites, or to correct the ensuing acidaemia. Wendon et al. showed that this inability to
Adding a diffusive element to this process of ultrafiltration increases the efficiency of solute removal while, if the TMP is maintained, the fluid removal is much the same. A dialysate fluid lacking in uraemic metabolites maintains the necessary concentration gradient if it is pumped past the membrane in a direction counter-current to blood flow. The concentration gradient necessary for efficient diffusion is dependent upon the speed of dialysate flow. This is the principle mode of action of the conventional haemodialysis machine which supplies flesh dialysate to the membrane at 500 ml/min, thus achieving highly efficient diffusive solute removal. With the advent of viable haemofiltration systems much work has been done on the relative values of convective as opposed to diffusive solute removal. In the critically ill ITU patient it would appear that dialysate flow rates can be kept as low as 500ml/h if a continuous renal replacement therapy is used. Evidently the determinants of these two physiological processes (ultrafiltration with convection and diffusion) are the determinants of the efficiency of each individual renal support technique. To manipulate the factors affecting each process will affect the efficacy and type of the renal support employed. As far as diffusion is concerned, the number of collisions that a particular molecule achieves, under Brownian Motion, with the semi-permeable membrane affects the probability of its passing through a membrane pore. Thus it is not only the concentration gradient which affects molecular diffusion (molecules in high concentrations colliding more frequently), but the speed of molecular travel as well. The fast moving molecule will collide with the membrane more often, increasing the probability of molecular passage. As the kinetic energy of the plasma solutes should be constant at a constant blood temperature, the velocity of the individual molecule is dependent upon its size. Large molecules, travelling more slowly, will
152
C U R R E N T A N A E S T H E S I A A N D CRITICAL C A R E
Blood flow in
neable membrane
ate & Filtrate flow
Dialysate flow .____----" r
m ~ , Filtration
~--~
Diffusion
Blood flow out
Fig.2 - -
Schematic diagram of dialysis with filtration.
collide less often, and diffuse through the membrane at a slower rate than small, high-velocity ions. For example, the removal of potassium ions by diffusion is more efficient than the removal of the larger, more sluggish urea or creatinine molecule. Correction of hyperkalaemia alone by extracorporeal renal support is thus more swift than the correction of uraemia. Also affecting ultrafiltration rate is the permeability of the membrane to water, a function of individual dialyser and membrane design. This permeability, which is unique to each type of dialyser, is known as the ultrafiltration coefficient (KUf), and is defined as the number of millilitres of fluid per hour that cross the membrane per mmHg transmembrane pressure. The higher the ultrafiltration coefficient, the more efficient the fluid removal (and therefore convective solute removal). Manufacturers of dialysers and haemofilters quote the ultrafiltration coefficients of their products in the accompanying literature and whilst a quantitative assessment of individual products is difficult (this being limited by in vitro measurements often being quoted) a rough comparison can be made. Membranes designed for
use in haemodialysis units (where ultrafiltration is of secondary importance to solute removal by diffusion) have relatively low ultrafiltration coefficients, typically 2.0-10.0ml/h/mmHg. Those membranes designed specifically for haemofiltration, where the convective removal of solutes is the chief aim, have higher ultrafiltration coefficients, around 30-60 ml/h/ mmHg. It should be appreciated that while these values give some guidelines to the overall permeability of individual membranes, a layer of plasma protein adsorbs almost instantaneously on to all membrane surfaces in vivo, forming a second, complex membrane which will affect ultrafiltration rates. Moreover, this second membrane may have unpredictable sieving properties as its composition and pore size may continue to change over several hours. There are other determinants of solute and fluid removal across a semipermeable membrane but whilst important in the overall efficacy of renal support systems, a detailed discussion of sieving coefficients, compartmentalisation effects and hydrophilicity is not within the scope of this paper. Those interested are referred to the supplied bibliography. Membranes Many different polymeric materials have been considered as the basis for semipermeable membrane manufacture. Those currently available commercially can be divided into three groups: cellulose, cellulose esters, and synthetic. 1. Cellulose, a naturally occuring polymer derived from processed cotton, is relatively cheap and easy to produce. The use of cellulose membranes is still widespread in haemodialysis units where it is most often found as cuprammonium cellulose (Cuprophan). Recent work has shown that negatively charged hydroxyl groups in cellulose membranes can cause complement activation which in turn leads to leucopenia caused by pulmonary leucostasis. 6'7 The sequestration of leucocytes in the pulmonary vasculature causes V/Q mismatching and consequent arterial blood gas disturbance. 2. Cellulose esters utilise an acetate (or sometimes amino) layer bound to the hydroxyl groups. The resulting barrier is claimed to be more biocompatible than the hydroxyl groups of unsubstituted Cuprophan, resulting in less complement activation. These membranes, although more expensive to produce than simple Cuprophan remain relatively cheap. The same principle is employed when dialysers are reused (after sterilization with formaldehyde or glutaraldehyde) where the protein adsorption mentioned above forms a protective layer. Despite the increased biocompatibility of these membranes the ultrafiltration coefficients of cellulose membranes are usually too low to allow their use as haemofilters. The theoretical risk of complement activation in either type also precludes their use with acutely oxygen-
ACUTE RENAL SUPPORT IN THE ITU dependent patients. In other words, the membrane of choice for the critically ill patient is synthetic. 3. Synthetic membranes are formed either by linear polycondensation or by linear addition. These polymers, although expensive if compared to standard cellulose membranes, have inherent properties that suit them to ITU use. Polyacrylonitrile (PAN), manufactured as 'AN69' by Hospal Ltd., is highly biocompatible causing minimal complement or leucocyte activation. This membrane is also highly 'wettable' resulting in high ultrafiltration rates (a KUf of between 20 and 60ml/h/mmHg, depending upon membrane surface area), with large pore size which allows for efficient diffusion. These membranes are therefore eminently suitable for the combined renal replacement therapy of haemodiafiltration (see below). Other synthetics include polysulphone and polymethyl methacrylate. With the membrane of a dialysis or haemofiltration circuit contributing 90% of foreign body contact with patient blood, high biocompatability should be a primary consideration when choosing this circuit component. The optimal surface area of a dialyser or haemofilter membrane is 0.5-1.5 m 2, depending upon patient size, metabolic rate, and mode of therapy employed. Obviously, if continuous renal support is offered on the ITU, as opposed to intermitted dialysis, a smaller, less efficient membrane can be used as renal support is not limited to a few hours a day. To provide a suitable surface area in a container of manageable size the membrane is either supplied as several thousand straw-like hollow fibres packed and glued into a cylindrical casing, or as a sandwich of parallel fiat plates screwed into a box casing. This latter was thought to have some biocompatability advantages as the polyurethane glue, or potting compound, used in hollow fibre devices has a tendency to trap the ethylene oxide gas used to sterilize the equipment after manufacture. The absence of potting compound in fiat-plate designs may have reduced the incidence of anaphylactoid reactions to this sterilising agent, but careful priming of the extracorporeal circuit prior to use with at least 1.51 of normal saline should remove all toxic gas. The priming volume of hollow fibre designs is usually slightly (10%) lower than that of a flat plate filter of comparable surface area, but with most priming volumes in the region of 60-100 ml the difference will be neglible for most patients. The blood compartment volume of the more rigid hollow fibre filters is also more predictable than that of the compliant flat plates which can expand slightly under high transmembrane pressure, but again, for all but the smallest or most unstable patient the difference will be neglible. In the final analysis the authors prefer the use of hollow fibre filters because they provide comparable results and are cheaper than fiat plates. When a membrane of suitable size and type has been chosen the circuit set-up should be considered. At its most basic, extracorporeal renal support can be
153
provided by a circuit linking an artery to a vein (femoral and brachial sites most usually) and interposing a haemofilter of a type described above. The hydrostatic pressure necessary for ultrafiltration of plasma is provided by the patient's blood pressure. Therefore, this technique is well suited for the fluid overloaded patient with a stable, normal-to-high blood pressure. The filtration of plasma can, to some extent, be regarded as 'self-limiting' as a significant drop in intravascular volume should cause the drop in blood pressure (transmembrane pressure) necessary to reduce the filtration rate. The fluid balance is maintained by the simultaneous reinfusion of a pre-prepared replacement fluid. The uraemic metabolites are removed stochiometrically, so in the severely uraemic or catabolic patient it may be difficult to correct blood chemistry without adding a counter-current flow of dialysate as previously discussed. The same solution as the replacement fluid can be used, and a dialysate flow rate of 1000ml/h is usually sufficient for all but the most catabolic patient. This technique is evidently unsuitable for the haemodynamically unstable patient or one with a mean arterial pressure of less than 60-70 mmHg. The consequent drop in blood flow through the circuit in such patients not only reduces the volume of filtrate obtained, but predisposes the circuit to clotting, despite anticoagulation with heparin and/or epoprostanol. In such patients, the majority of those with acute renal failure in the ITU, a system of pumped haemofiltration is required.
Circuits If a pump is introduced into the circuit the cannulation of large arteries becomes unnecessary; a large vein such as the femoral or internal jugular can be cannulated with a single double-lumen catheter of the Quinton type. The maintenance of transmembrane pressure depends upon the speed of the blood pump and the filtration rate can therefore be controlled by the nurse caring for the patient. An increase in blood pump speed increases the pressure exerted by the blood within the filter, and so increases the ultrafiltration rate. Fluid balance is still maintained by the reinfusion of a replacement fluid, but the much larger volumes of filtrate obtainable from such a system mean that control of the uraemic patient's symptoms is faster and more predictable than the variable volumes filtered in an unpumped circuit. The system is no longer dependent on the patient's blood pressure, and provided that the fluid balance is closely monitored, even haemodynamically unstable patients can be successfully treated in this way. The relatively high speed of the blood passage through the PVC circuit also decreases (but does not remove) the risk of extracorporeal clotting. If the speed can be
154
CURRENT ANAESTHESIA AND CRITICAL CARE
Table - - Electrolyte content of haemofiltration replacement fluid (typical)
Sodium Potassium Calcium Magnesium Chloride Lactate Glucose Osmolarity
140-142 mmol/l 0 - 4 mmol/l (often increased in use) 1.75 mmol/1 0.75 mmol/1 100-119 mmol/1 40-45 mmol/1 1.0-8.0 g/l 285-335 mosmol/l
kept high, typically 100-300ml/min, and anticoagulation is adequate, circuits can be made to last for several days, optimising the efficiencyof a continuous process of blood chemistry correction. The usual type of pump employed is a peristaltic roller pump propelling around 10ml blood per revolution. These pumps are reasonably accurate, simple to maintain, and easy to run. Disadvantages of such a design include haemolysis of blood components by the roller, spallation of microscopic elements from the pump insert, and the risk of cracks to the tubing after long-term use. As with the unpumped circuit, the inclusion of a counter current dialysate flow will increase the diffusive efficiency of the system - this is haemodiafiltration. Again, the speed of dialysate flow determines the efficiency of solute removal; in practice dialysate flows of 1000 ml/min coupled with blood flows of 150-200ml/min will produce adequate clearance of solutes. The substitution fluid used in haemofiltration and haemodiafiltration is a sterile crystalloid containing most of the plasma electrolytes present in their normal values (see Table). Trace elements are not added (and so will be removed by diffusion during renal support) and patient levels should be monitored and adjusted regularly. The fact that large amounts of the fluid are required, 2-31/h in haemodiafiltration, adds significantly to the cost of haemofiltration techniques as a whole. The reinfusion fluid obviously needs to be sterile, but the dialysate fluid need only be pyrogen-free. In dialysis a clean, concentrated dialysate is diluted with treated water which has had various toxic salts containing, for example, aluminium, calcium and copper removed by deionisation and reverse osmosis. The equipment required for this water treatment is very expensive and bulky, and is usually impractical for the ITU. In fact, despite the increased cost of using a sterile fluid as a dialysate, the ability of haemofiltration techniques to do without this specialised plant can be a positive advantage. At its simplest, a single roller pump can be used to control blood flow, and two infusion pumps to administer the replacement fluid and anticoagulant. Although cheap and effective this set-up does not include the safety features necessary when dealing with extracorporeal circuitry such as transducers monitoring the blood pressure in access and return lines and an air detection facility. Several purpose-
built machines are available which include these devices, and usefully incorporate all the components into one box. The relatively inexpensive and versatile Hospal BSM22 is commonly used in ITUs. This machine was not designed with haemofiltration in mind, but is a module of Hospal's successful Monitral dialysis machine and as such incorporates some dialysis features inappropriate to intensive care. It is however a simple, easily run device which works relatively well. Its major disadvantage is the manual control of fluid balance. The filtrate needs to be drained into a measuring device, the fluid balance calculated and the reinfusion pump adjusted. As the filtrate obtained is not always constant and other variables (urine output, drug volumes, fluid challenges) can frequently affect the calculations, the system is labour intensive, with consequent effects on nursing manpower and costs. Gambro have produced a fully automated haemofiltration machine, the HFM10, which weighs the filtrate on a set of scales fixed under the pump. This device automatically supplies the appropriate amount of reinfusion fluid and the need for time-consuming measuring and recalculation is obviated. The HFM10 is, however, considerably more expensive than the BSM22 and has less overall versatility. Other similar machines are available such as that manufactured by the German company Sartorius, and several are currently under development.
Anticoagulation All extracorporeal circuits require anticoagulation and the most commonly used method remains heparinisation. Dosage schedules for heparinisation depend on many factors, including patient size and previous coagulation state. Typically a loading dose of 3000iu is given if coagulation times are not prolonged, followed by an infusion of 10iu/kg/h. This may be reduced to 3iu/kg/h if coagulation times are prolonged or omitted in extreme cases. It is important to assess coagulation times regularly, either by laboratory tests such as the activated partial thromboplastin time or in the ITU by the activated clotting time, in order to avoid over-anticoagulation of the patient. In problematic cases, e.g. where heparin is ineffective due to low antithrombin III levels or there is a heparin induced thrombycytopenia syndrome there are alternatives such as prostacyclin or low molecular weight heparin. Prostacyclin in particular provides circuit anticoagulation without contribution to the risk of bleeding. In addition to anticoagulant therapy circuit patency may be maintained by reducing the viscosity of the blood, e.g. by pre-dilution of blood with the haemofltration replacement fluid or increasing blood flow rate. Both of these latter techniques may also increase ultrafiltration rate.
ACUTE RENAL SUPPORT IN THE ITU
155
The Future
References
The major component of the profits made by the companies that supply dialysis and haemofiltration equipment come from the sale of disposables; that is the membrane and accompanying circuit. A chronic dialysis unit that dialyses 30 people a day will therefore be far more profitable than an ITU which may only use 3 - 4 circuits a week. This encourages the companies to devote most funding for research and development to chronic dialysis rather than acute haemofiltration technology, a fact that has left the design of hardware used for renal support in ITUs lagging someway behind that used in dialysis units. The technology is already available for automated fluid balance, more accurate blood pumps, and the warming of the extracorporeal circuit, but those machines that have either been designed or, more usually, adapted for use with the critically ill (where accuracy of fluid balance and maintenance of physiological norms are surely paramount) often lack some or all of these features that enable swift and easy set-up, accurate control, and comfort for the patient. There is a need for a haemodiafiltration machine which is dedicated for use in the ITU and incorporates some of the functions currently available in dialysis machines.
1. Kolff WJ. First clinical experience with the artificial kidney. Ann Int Med 1965; 62:608 2. Cameron JS. Acute renal failure in the intensive care unit today. Intensive Care Med 1986; 12:64-70 3. Abel J J, Rowntree LG, Turner PB. On the removal of diffusable substances from the circulating blood of living animals by dialysis. J Pharmacol Exp Therapeutics 1914; 5: 275 4. Alwall N. Therapeutic and diagnostic problems in severe renal failure. Copenhagen, Scandinavian University Books, 1963 5. Wendon J, Smithies M, Sheppard M, BuUen K, Tinker J, Bihari D. Continuous high volume venous-venous haemofiltration in acute renal failure. Intensive Care Med 1989; 15:1-6 6. Cazenave J-P, Mulvihill J. Interactions of blood with surfaces: hemocompatibility and thromboresistance of biomaterials. Contr Nephrol 1988; 62:118-127 7. Haeffner-Cavaillon N, Fischer E, Bacle F, Carreno MP, Maillet F, Cavaillon JM, Kazatcbkine MD. Complement activation and induction of interleukin-1 production during haemodialysis. Contr Nephrol 1988, 62:86-98
Further reading Henderson LW, Quellhorst EA, Baldamus CA, Lysaght MJ. Hemofiltration. Berlin, Springer-Verlag, 1986 Cogan MG, Garavoy MR. Introduction to Dialysis. New York, Churchill Livingstone, 1985 Daugirdas JT, Ing TS. Handbook of Dialysis. Boston, Little Brown & Co., 1988
D. W. Jacobson and A. R. W e b b
With mortality in excess of 90%, acute renal failure was largely untreatable until 1944 when Willem Kolff successfully dialysed a patient with sulphonamide induced acute renal failure. 1 Since that initial treatment a plethora of renal replacement devices and procedures have reduced the current mortality of uncomplicatedacute renal failure to around 8%. 2 The mortality of acute renal failure in the ITU patient, however, remains high, increasing with the number of other failed organs; often assumed to be 100% with two other major organ system failures, z
The poor membrane technology and lack of suitable anticoagulant (heparin was not clinically available until 1933) limited the application of their discovery. After the Second World War much work was done on dialysis machine design, anticoagulation, dialysate composition, vascular access, and crucially, membrane technology. Manipulation of the physiological principles was also explored. In the 1950s Alwall described experiments in Sweden using semipermeable membranes as isolated ultrafilters. 4 This process, which became known as haemofiltration, was initially envisaged as a method of fluid removal, but after much refnement it now forms the basis of the majority of the support offered to critically ill patients with acute renal failure.
History Although of various designs and with confusing nomenclature, all the extracorporeal renal replacement therapies currently available rely on the same two physiological principles that Kolff's early machine employed; ultrafiltration and diffusion. Kolff's original device was a 40m length of cellulose sausage skin wrapped in a spiral around a drum which was half submerged in a bath of dialysate, x Blood was propelled along the tube by the Archimedes' Screw principle when the drum was rotated. Solute removal was by diffusion across the primitive membrane and fluid was removed by what little ultrafiltration the system provided. This cellulose membrane was considerably more successful, however, than the collodion membrane used 30 years earlier by Abel et al. 3 who had passed rabbit blood through collodion tubes and obtained a filtrate in which salicylate, previously fed to the animals, was detectable. This process, which Abel termed 'vividiffusion' was the first successful treatment of a living animal by dialysis.
Haemofiltration (Fig. 1) The limiting factor in the early haemofiltration designs was the poor solute removal. Haemofiltration is ultrafiltration of blood, ultrafiltration being the passage of fluid, under pressure, across a semipermeable membrane. Solutes are carried along with the fluid by solvent drag, that is convection. In practice this driving pressure is the hydrostatic pressure difference on either side of the membrane, the
Mr D. W. Jacobson, RGN Charge Nurse (ITU), Dr A. R. Webb, MB MRCP Consultant Physician (ITU), Bloomsbury Department of Intensive Care, The Middlesex Hospital, Mortimer Street, London W1N 8AA, UK Current Anaesthesia and Critical Care
© 1992LongmanGroupUK Ltd
(1992)3, 150-155 150
ACUTE RENAL SUPPORT IN THE ITU Blood flow in
7
Filtrate flow
ation
151
correct such patients' pH was associated with a high mortality.5 The efficiency of the process is limited by the volume of plasma filtrate removed and replacement fluid reinfused. The bulk movement of fluid and solutes by ultrafiltration is affected by the pressure difference across the membrane, the transmembrane pressure. The positive pressure on the blood side of the membrane can be maximised by increasing the blood flow speed with a mechanical pump, or by optimising the patient's blood pressure in an arterio-venous circuit. Limiting pressure drop across the arterial line in an AV circuit can be achieved by keeping this line as short as possible, reducing the resistance it exerts on blood flow. Conversely, a longer venous line will provide more resistance post-filter, increasing hydrostatic pressure, and thus ultrafiltration, inside the filter itself.
Dialysis and haemodiafiltration (Fig. 2) e membmne
~
Blood flow out
Fig. 1 - - Schematic diagram of haemofiltration.
transmembrane pressure (TMP). To increase the TMP (and thus the amount of filtrate) the pressure difference must also be maximised, either by increasing the pressure on the blood side of the membrane, or be decreasing it on the filtrate side. Thus, to maximise TMP the speed of blood flow can be increased (assuming no change in circuit dimensions), or the filtrate pressure can be reduced by using a pump to apply a negative pressure to the plasma filtrate. Alwall described lowering the filtrate collection vessel of his haemofilter out of a window to maximise the pressure difference between the membrane and the vessel. 4 He commented that this system did not work in the Swedish winter, as the filtrate froze! As the plasma solutes are removed stoichiometrically, large volumes of ultrafiltrate need to be produced to significantly affect the uraemic patient's blood chemistry, in practice 400- 600 ml/h. In the catabolic, often septic ITU patient, it may be difficult to remove enough of the ever-increasing amounts of uraemic metabolites, or to correct the ensuing acidaemia. Wendon et al. showed that this inability to
Adding a diffusive element to this process of ultrafiltration increases the efficiency of solute removal while, if the TMP is maintained, the fluid removal is much the same. A dialysate fluid lacking in uraemic metabolites maintains the necessary concentration gradient if it is pumped past the membrane in a direction counter-current to blood flow. The concentration gradient necessary for efficient diffusion is dependent upon the speed of dialysate flow. This is the principle mode of action of the conventional haemodialysis machine which supplies flesh dialysate to the membrane at 500 ml/min, thus achieving highly efficient diffusive solute removal. With the advent of viable haemofiltration systems much work has been done on the relative values of convective as opposed to diffusive solute removal. In the critically ill ITU patient it would appear that dialysate flow rates can be kept as low as 500ml/h if a continuous renal replacement therapy is used. Evidently the determinants of these two physiological processes (ultrafiltration with convection and diffusion) are the determinants of the efficiency of each individual renal support technique. To manipulate the factors affecting each process will affect the efficacy and type of the renal support employed. As far as diffusion is concerned, the number of collisions that a particular molecule achieves, under Brownian Motion, with the semi-permeable membrane affects the probability of its passing through a membrane pore. Thus it is not only the concentration gradient which affects molecular diffusion (molecules in high concentrations colliding more frequently), but the speed of molecular travel as well. The fast moving molecule will collide with the membrane more often, increasing the probability of molecular passage. As the kinetic energy of the plasma solutes should be constant at a constant blood temperature, the velocity of the individual molecule is dependent upon its size. Large molecules, travelling more slowly, will
152
C U R R E N T A N A E S T H E S I A A N D CRITICAL C A R E
Blood flow in
neable membrane
ate & Filtrate flow
Dialysate flow .____----" r
m ~ , Filtration
~--~
Diffusion
Blood flow out
Fig.2 - -
Schematic diagram of dialysis with filtration.
collide less often, and diffuse through the membrane at a slower rate than small, high-velocity ions. For example, the removal of potassium ions by diffusion is more efficient than the removal of the larger, more sluggish urea or creatinine molecule. Correction of hyperkalaemia alone by extracorporeal renal support is thus more swift than the correction of uraemia. Also affecting ultrafiltration rate is the permeability of the membrane to water, a function of individual dialyser and membrane design. This permeability, which is unique to each type of dialyser, is known as the ultrafiltration coefficient (KUf), and is defined as the number of millilitres of fluid per hour that cross the membrane per mmHg transmembrane pressure. The higher the ultrafiltration coefficient, the more efficient the fluid removal (and therefore convective solute removal). Manufacturers of dialysers and haemofilters quote the ultrafiltration coefficients of their products in the accompanying literature and whilst a quantitative assessment of individual products is difficult (this being limited by in vitro measurements often being quoted) a rough comparison can be made. Membranes designed for
use in haemodialysis units (where ultrafiltration is of secondary importance to solute removal by diffusion) have relatively low ultrafiltration coefficients, typically 2.0-10.0ml/h/mmHg. Those membranes designed specifically for haemofiltration, where the convective removal of solutes is the chief aim, have higher ultrafiltration coefficients, around 30-60 ml/h/ mmHg. It should be appreciated that while these values give some guidelines to the overall permeability of individual membranes, a layer of plasma protein adsorbs almost instantaneously on to all membrane surfaces in vivo, forming a second, complex membrane which will affect ultrafiltration rates. Moreover, this second membrane may have unpredictable sieving properties as its composition and pore size may continue to change over several hours. There are other determinants of solute and fluid removal across a semipermeable membrane but whilst important in the overall efficacy of renal support systems, a detailed discussion of sieving coefficients, compartmentalisation effects and hydrophilicity is not within the scope of this paper. Those interested are referred to the supplied bibliography. Membranes Many different polymeric materials have been considered as the basis for semipermeable membrane manufacture. Those currently available commercially can be divided into three groups: cellulose, cellulose esters, and synthetic. 1. Cellulose, a naturally occuring polymer derived from processed cotton, is relatively cheap and easy to produce. The use of cellulose membranes is still widespread in haemodialysis units where it is most often found as cuprammonium cellulose (Cuprophan). Recent work has shown that negatively charged hydroxyl groups in cellulose membranes can cause complement activation which in turn leads to leucopenia caused by pulmonary leucostasis. 6'7 The sequestration of leucocytes in the pulmonary vasculature causes V/Q mismatching and consequent arterial blood gas disturbance. 2. Cellulose esters utilise an acetate (or sometimes amino) layer bound to the hydroxyl groups. The resulting barrier is claimed to be more biocompatible than the hydroxyl groups of unsubstituted Cuprophan, resulting in less complement activation. These membranes, although more expensive to produce than simple Cuprophan remain relatively cheap. The same principle is employed when dialysers are reused (after sterilization with formaldehyde or glutaraldehyde) where the protein adsorption mentioned above forms a protective layer. Despite the increased biocompatibility of these membranes the ultrafiltration coefficients of cellulose membranes are usually too low to allow their use as haemofilters. The theoretical risk of complement activation in either type also precludes their use with acutely oxygen-
ACUTE RENAL SUPPORT IN THE ITU dependent patients. In other words, the membrane of choice for the critically ill patient is synthetic. 3. Synthetic membranes are formed either by linear polycondensation or by linear addition. These polymers, although expensive if compared to standard cellulose membranes, have inherent properties that suit them to ITU use. Polyacrylonitrile (PAN), manufactured as 'AN69' by Hospal Ltd., is highly biocompatible causing minimal complement or leucocyte activation. This membrane is also highly 'wettable' resulting in high ultrafiltration rates (a KUf of between 20 and 60ml/h/mmHg, depending upon membrane surface area), with large pore size which allows for efficient diffusion. These membranes are therefore eminently suitable for the combined renal replacement therapy of haemodiafiltration (see below). Other synthetics include polysulphone and polymethyl methacrylate. With the membrane of a dialysis or haemofiltration circuit contributing 90% of foreign body contact with patient blood, high biocompatability should be a primary consideration when choosing this circuit component. The optimal surface area of a dialyser or haemofilter membrane is 0.5-1.5 m 2, depending upon patient size, metabolic rate, and mode of therapy employed. Obviously, if continuous renal support is offered on the ITU, as opposed to intermitted dialysis, a smaller, less efficient membrane can be used as renal support is not limited to a few hours a day. To provide a suitable surface area in a container of manageable size the membrane is either supplied as several thousand straw-like hollow fibres packed and glued into a cylindrical casing, or as a sandwich of parallel fiat plates screwed into a box casing. This latter was thought to have some biocompatability advantages as the polyurethane glue, or potting compound, used in hollow fibre devices has a tendency to trap the ethylene oxide gas used to sterilize the equipment after manufacture. The absence of potting compound in fiat-plate designs may have reduced the incidence of anaphylactoid reactions to this sterilising agent, but careful priming of the extracorporeal circuit prior to use with at least 1.51 of normal saline should remove all toxic gas. The priming volume of hollow fibre designs is usually slightly (10%) lower than that of a flat plate filter of comparable surface area, but with most priming volumes in the region of 60-100 ml the difference will be neglible for most patients. The blood compartment volume of the more rigid hollow fibre filters is also more predictable than that of the compliant flat plates which can expand slightly under high transmembrane pressure, but again, for all but the smallest or most unstable patient the difference will be neglible. In the final analysis the authors prefer the use of hollow fibre filters because they provide comparable results and are cheaper than fiat plates. When a membrane of suitable size and type has been chosen the circuit set-up should be considered. At its most basic, extracorporeal renal support can be
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provided by a circuit linking an artery to a vein (femoral and brachial sites most usually) and interposing a haemofilter of a type described above. The hydrostatic pressure necessary for ultrafiltration of plasma is provided by the patient's blood pressure. Therefore, this technique is well suited for the fluid overloaded patient with a stable, normal-to-high blood pressure. The filtration of plasma can, to some extent, be regarded as 'self-limiting' as a significant drop in intravascular volume should cause the drop in blood pressure (transmembrane pressure) necessary to reduce the filtration rate. The fluid balance is maintained by the simultaneous reinfusion of a pre-prepared replacement fluid. The uraemic metabolites are removed stochiometrically, so in the severely uraemic or catabolic patient it may be difficult to correct blood chemistry without adding a counter-current flow of dialysate as previously discussed. The same solution as the replacement fluid can be used, and a dialysate flow rate of 1000ml/h is usually sufficient for all but the most catabolic patient. This technique is evidently unsuitable for the haemodynamically unstable patient or one with a mean arterial pressure of less than 60-70 mmHg. The consequent drop in blood flow through the circuit in such patients not only reduces the volume of filtrate obtained, but predisposes the circuit to clotting, despite anticoagulation with heparin and/or epoprostanol. In such patients, the majority of those with acute renal failure in the ITU, a system of pumped haemofiltration is required.
Circuits If a pump is introduced into the circuit the cannulation of large arteries becomes unnecessary; a large vein such as the femoral or internal jugular can be cannulated with a single double-lumen catheter of the Quinton type. The maintenance of transmembrane pressure depends upon the speed of the blood pump and the filtration rate can therefore be controlled by the nurse caring for the patient. An increase in blood pump speed increases the pressure exerted by the blood within the filter, and so increases the ultrafiltration rate. Fluid balance is still maintained by the reinfusion of a replacement fluid, but the much larger volumes of filtrate obtainable from such a system mean that control of the uraemic patient's symptoms is faster and more predictable than the variable volumes filtered in an unpumped circuit. The system is no longer dependent on the patient's blood pressure, and provided that the fluid balance is closely monitored, even haemodynamically unstable patients can be successfully treated in this way. The relatively high speed of the blood passage through the PVC circuit also decreases (but does not remove) the risk of extracorporeal clotting. If the speed can be
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CURRENT ANAESTHESIA AND CRITICAL CARE
Table - - Electrolyte content of haemofiltration replacement fluid (typical)
Sodium Potassium Calcium Magnesium Chloride Lactate Glucose Osmolarity
140-142 mmol/l 0 - 4 mmol/l (often increased in use) 1.75 mmol/1 0.75 mmol/1 100-119 mmol/1 40-45 mmol/1 1.0-8.0 g/l 285-335 mosmol/l
kept high, typically 100-300ml/min, and anticoagulation is adequate, circuits can be made to last for several days, optimising the efficiencyof a continuous process of blood chemistry correction. The usual type of pump employed is a peristaltic roller pump propelling around 10ml blood per revolution. These pumps are reasonably accurate, simple to maintain, and easy to run. Disadvantages of such a design include haemolysis of blood components by the roller, spallation of microscopic elements from the pump insert, and the risk of cracks to the tubing after long-term use. As with the unpumped circuit, the inclusion of a counter current dialysate flow will increase the diffusive efficiency of the system - this is haemodiafiltration. Again, the speed of dialysate flow determines the efficiency of solute removal; in practice dialysate flows of 1000 ml/min coupled with blood flows of 150-200ml/min will produce adequate clearance of solutes. The substitution fluid used in haemofiltration and haemodiafiltration is a sterile crystalloid containing most of the plasma electrolytes present in their normal values (see Table). Trace elements are not added (and so will be removed by diffusion during renal support) and patient levels should be monitored and adjusted regularly. The fact that large amounts of the fluid are required, 2-31/h in haemodiafiltration, adds significantly to the cost of haemofiltration techniques as a whole. The reinfusion fluid obviously needs to be sterile, but the dialysate fluid need only be pyrogen-free. In dialysis a clean, concentrated dialysate is diluted with treated water which has had various toxic salts containing, for example, aluminium, calcium and copper removed by deionisation and reverse osmosis. The equipment required for this water treatment is very expensive and bulky, and is usually impractical for the ITU. In fact, despite the increased cost of using a sterile fluid as a dialysate, the ability of haemofiltration techniques to do without this specialised plant can be a positive advantage. At its simplest, a single roller pump can be used to control blood flow, and two infusion pumps to administer the replacement fluid and anticoagulant. Although cheap and effective this set-up does not include the safety features necessary when dealing with extracorporeal circuitry such as transducers monitoring the blood pressure in access and return lines and an air detection facility. Several purpose-
built machines are available which include these devices, and usefully incorporate all the components into one box. The relatively inexpensive and versatile Hospal BSM22 is commonly used in ITUs. This machine was not designed with haemofiltration in mind, but is a module of Hospal's successful Monitral dialysis machine and as such incorporates some dialysis features inappropriate to intensive care. It is however a simple, easily run device which works relatively well. Its major disadvantage is the manual control of fluid balance. The filtrate needs to be drained into a measuring device, the fluid balance calculated and the reinfusion pump adjusted. As the filtrate obtained is not always constant and other variables (urine output, drug volumes, fluid challenges) can frequently affect the calculations, the system is labour intensive, with consequent effects on nursing manpower and costs. Gambro have produced a fully automated haemofiltration machine, the HFM10, which weighs the filtrate on a set of scales fixed under the pump. This device automatically supplies the appropriate amount of reinfusion fluid and the need for time-consuming measuring and recalculation is obviated. The HFM10 is, however, considerably more expensive than the BSM22 and has less overall versatility. Other similar machines are available such as that manufactured by the German company Sartorius, and several are currently under development.
Anticoagulation All extracorporeal circuits require anticoagulation and the most commonly used method remains heparinisation. Dosage schedules for heparinisation depend on many factors, including patient size and previous coagulation state. Typically a loading dose of 3000iu is given if coagulation times are not prolonged, followed by an infusion of 10iu/kg/h. This may be reduced to 3iu/kg/h if coagulation times are prolonged or omitted in extreme cases. It is important to assess coagulation times regularly, either by laboratory tests such as the activated partial thromboplastin time or in the ITU by the activated clotting time, in order to avoid over-anticoagulation of the patient. In problematic cases, e.g. where heparin is ineffective due to low antithrombin III levels or there is a heparin induced thrombycytopenia syndrome there are alternatives such as prostacyclin or low molecular weight heparin. Prostacyclin in particular provides circuit anticoagulation without contribution to the risk of bleeding. In addition to anticoagulant therapy circuit patency may be maintained by reducing the viscosity of the blood, e.g. by pre-dilution of blood with the haemofltration replacement fluid or increasing blood flow rate. Both of these latter techniques may also increase ultrafiltration rate.
ACUTE RENAL SUPPORT IN THE ITU
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The Future
References
The major component of the profits made by the companies that supply dialysis and haemofiltration equipment come from the sale of disposables; that is the membrane and accompanying circuit. A chronic dialysis unit that dialyses 30 people a day will therefore be far more profitable than an ITU which may only use 3 - 4 circuits a week. This encourages the companies to devote most funding for research and development to chronic dialysis rather than acute haemofiltration technology, a fact that has left the design of hardware used for renal support in ITUs lagging someway behind that used in dialysis units. The technology is already available for automated fluid balance, more accurate blood pumps, and the warming of the extracorporeal circuit, but those machines that have either been designed or, more usually, adapted for use with the critically ill (where accuracy of fluid balance and maintenance of physiological norms are surely paramount) often lack some or all of these features that enable swift and easy set-up, accurate control, and comfort for the patient. There is a need for a haemodiafiltration machine which is dedicated for use in the ITU and incorporates some of the functions currently available in dialysis machines.
1. Kolff WJ. First clinical experience with the artificial kidney. Ann Int Med 1965; 62:608 2. Cameron JS. Acute renal failure in the intensive care unit today. Intensive Care Med 1986; 12:64-70 3. Abel J J, Rowntree LG, Turner PB. On the removal of diffusable substances from the circulating blood of living animals by dialysis. J Pharmacol Exp Therapeutics 1914; 5: 275 4. Alwall N. Therapeutic and diagnostic problems in severe renal failure. Copenhagen, Scandinavian University Books, 1963 5. Wendon J, Smithies M, Sheppard M, BuUen K, Tinker J, Bihari D. Continuous high volume venous-venous haemofiltration in acute renal failure. Intensive Care Med 1989; 15:1-6 6. Cazenave J-P, Mulvihill J. Interactions of blood with surfaces: hemocompatibility and thromboresistance of biomaterials. Contr Nephrol 1988; 62:118-127 7. Haeffner-Cavaillon N, Fischer E, Bacle F, Carreno MP, Maillet F, Cavaillon JM, Kazatcbkine MD. Complement activation and induction of interleukin-1 production during haemodialysis. Contr Nephrol 1988, 62:86-98
Further reading Henderson LW, Quellhorst EA, Baldamus CA, Lysaght MJ. Hemofiltration. Berlin, Springer-Verlag, 1986 Cogan MG, Garavoy MR. Introduction to Dialysis. New York, Churchill Livingstone, 1985 Daugirdas JT, Ing TS. Handbook of Dialysis. Boston, Little Brown & Co., 1988