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Patients with chronic kidney disease established on regular dialysis are susceptible to brain injury. These patients are at increased risk of subdural hemorrhage due to the prescription of coumarin anticoagulants, intracerebral hemorrhage secondary to hypertension, and cerebral abscesses secondary to central venous dialysis access catheter-associated infections. These patients have chronically high levels of urea and other azotemic toxins, and as such, delaying dialysis treatments will lead to even higher chemistries, and thereby increase the risk of RRT-induced cerebral edema. So for this group of patients, RRT should be considered once the patient has been stabilized.13
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Choice of Renal Replacement Therapy
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The key strategy of any RRT is to remove small water-soluble solutes. Urea clearance from the plasma water is faster during hemodialysis treatments than urea movement from cells into the plasma water. As such, this sets up a urea gradient. In addition, water transport across cell membranes through aquaporin channels is some 20 times faster than the corresponding transcellular passage of urea through urea transporters.14 This can result in an osmotic gradient developing between the plasma and the brain (Figure 42-1). Renal replacement therapy, particularly intermittent hemodialysis (HD), can lead to cerebral edema not only in acute experimental animal models of HD15 but also in the outpatient setting of dialyzing healthy patients with end-stage kidney failure.16 This swelling of the brain associated with HD is termed the dialysis disequilibrium syndrome.
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Although RRT is primarily designed to remove small water-soluble toxins that accumulate in kidney failure, it is also used to correct the metabolic acidosis associated with kidney failure, and therefore dialysates either contain bicarbonate or lactate in supraphysiologic concentrations. The rapid correction or increase in plasma bicarbonate, rather than correcting intracellular acidosis, may paradoxically worsen intracellular acidosis,17 as bicarbonate being charged does not readily cross lipid-rich cell membranes, unlike carbon dioxide (Figure 42-2). Intracellular acidosis increases cell swelling and will exacerbate any underlying cerebral edema. These changes in plasma bicarbonate compared to cerebrospinal fluid bicarbonate typically lead to changes in the respiratory center in the medulla, with alteration in breathing patterns in healthy outpatient dialysis subjects.18 Thus, too rapid a correction of plasma bicarbonate in nonventilated brain-injured patients may potentially adversely affect cerebral oxygenation.
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In addition, the connection of a patient to an extracorporeal circuit can lead to hypotension, which can potentially compromise cerebral perfusion. The passage of blood across the dialyzer, particularly those with a very negative surface charge (zeta potential), can lead to the generation of potent vasodilators, bradykinin, nitric oxide, and the anaphylotoxins C3a and C5a,19 and it is now recognized that both cardiac and cerebral perfusion can fall within the first few minutes of initiating standard outpatient hemodialysis.20, 21 This effect on cardiac perfusion may be exacerbated in cases of subarachnoid hemorrhage or severe cerebral edema, owing to the associated neurogenic cardiac stunning. Bradykinin and complement activation by the extracorporeal circuit can be reduced by rinsing the circuit with isotonic bicarbonate rather than saline, and some centers advocate priming the dialyzer with albumin to coat the membrane to reduce membrane reactions. However, priming the circuit with blood, particularly aged blood, may exacerbate any reactions owing to the acidic nature of stored blood.22 Similarly, angiotensin-converting enzyme inhibitors prevent bradykinin degradation, and as such should be avoided.
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Several different modes of RRT are potentially available.
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Peritoneal dialysis (PD) is a form of continuous renal replacement therapy (CRRT), and as such the fall in serum urea and osmolality during treatment are slower than that compared to intermittent HD,23 but even so the dialysis disequilibrium syndrome has still been reported during PD.24 Peritoneal dialysate fluids are hyponatremic relative to blood, with a sodium concentration of 132 mEq/L, but are hypertonic owing to a high glucose content, varying from 13.6 to 38.6 g/dL, and so may cause patients to become hyponatremic. Large intraperitoneal volume exchanges of hypertonic glucose solutions can adversely impact cerebral perfusion and cerebral perfusion pressure by reducing right atrial filling and cardiac output.25 To minimize these potential changes, peritoneal dialysis prescriptions should use the lowest glucose concentrations possible and avoid major swings in intraperitoneal volumes. This can best be achieved by using peritoneal dialysis cycler machines with a tidal exchange.
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Intermittent hemodialysis/hybrid therapies
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Brain edema occurs during routine outpatient thrice-weekly HD.16 Thus, intermittent HD increases brain swelling in the patient with acute neurologic injury.26 ICP increases not only because of changes in osmotic gradients and a rapid increase in arterial pH but also because of abrupt falls in mean arterial pressure, and thus cerebral perfusion pressure.27 Intermittent RRT should therefore only be considered as a treatment option in cardiovascularly stable patients without changes of increased ICP or a midline shift on cerebral imaging (See Figure 42-1). Small solute removal is more efficient by diffusion down a concentration gradient rather than convection, where there is removal of plasma water and the solutes contained within it. Thus, urea removal is faster with hemodialysis than hemofiltration (Figure 42-3). Hence, hemofiltration or hemodiafiltration are preferable treatments, and the rate of urea and other small solute clearances can be further slowed by infusing the replacement fluids prefilter/-dialyzer rather than postfilter/-dialyzer (Figure 42-4).
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If intermittent hemodialysis is the only renal replacement modality available, then the prescription should be modified to minimize cardiovascular instability, using a high sodium and calcium dialysate concentration, cooling the dialysate to 35°C, and minimizing changes in effective blood volume.28 In addition, the rate of change in serum osmolality should be minimized by utilizing slower blood pump and dialysate flows, with smaller surface area dialyzer membranes, and lower dialysate bicarbonate concentrations,29 thus moving from a standard intermittent hemodialysis prescription to one of slow extended dialysis, or a hybrid therapy. Whereas the standard practice for outpatient hemodialysis is thrice weekly, patients with acute brain injury should be treated daily, to minimize the peaks and troughs in blood urea, thus reducing the time-averaged urea concentration. Hypotension during intermittent hemodialysis is typically due to a high ultrafiltration rate leading to plasma volume depletion by being faster than compensatory refilling from extracellular fluid.
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There are no randomized prospective trials that have investigated the optimum predialysis urea to minimize changes in ICP during dialysis; however, clinical practice suggests that a predialysis blood urea nitrogen less than 30 to 35 mg/dL reduces the risk of ICP increasing during treatment.29
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Continuous dialysis/hemofiltration therapies
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In patients with increased ICP, continuous forms of arteriovenous hemofiltration and/or dialysis have been shown to cause fewer changes in ICP and central perfusion pressure (CPP) than intermittent therapies30, 31 because of a combination of slower changes in plasma osmolality and greater cardiovascular stability (See Figure 42-2).12 However, with the introduction of pumped venous hemofiltration, dialysis and hemodiafiltration, and in particular high-volume exchange, greater changes in osmolality have become possible (Figure 42-5). Thus, when performing CRRT in critically ill patients with AKI, hemofiltration is preferable to dialysis, as this leads to a slower rate of change in serum urea and other small solutes and also greater cardiovascular stability owing to additional cooling, particularly with predilutional fluid replacement32 (See Figure 42-4). Sodium balance during hemofiltration tends to be positive, as the amount of sodium in the ultrafiltrate is typically less than that in the plasma. The ratio of ultrafiltrate to plasma is termed the sieving coefficient, and for sodium the sieving coefficient is less than 1.0. Even so, a replacement fluid with a sodium concentration > 140 mmol/L should initially be used to prevent hyponatremia.33 At the start of treatment, in critically ill patients with increased ICP, small volume exchanges should initially be used, and only when the patient has been shown to be stable should the exchange volume be increased.
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Renal replacement therapy can be used to clear several drugs and/or toxins in cases of coma due to drug self-poisoning, toxicity, and some metabolic encephalopathies (eg, methylmalonic acidemia), particularly if the toxin is water-soluble and has a limited volume of distribution. Intermittent hemodialysis will more quickly remove such drugs and/or toxins compared to CRRT, provided the patient has adequate cardiovascular stability, but then may be followed by a rebound in plasma concentrations, especially if the toxin has a large volume of distribution. In such cases CRRT following a hemodialysis session may be helpful in preventing rebound. Slow extended hemodialysis or hybrid therapy would also be a therapeutic option.
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Recently isovolemic CRRT has been advocated for treating patients without AKI who have been resuscitated after cardiac arrest and not regained consciousness.34 There have been initial encouraging reports of increased survival for those patients treated for 8 hours with high-volume hemofiltration.35