Reviews

The Current State of Nonuremic Applications for

Blackwell Publishing, Ltd.

Extracorporeal Blood Purification

Andrew E. Briglia
Department of Medicine, Division of Nephrology, University of Maryland, Baltimore, Maryland

ABSTRACT

Despite the commonly accepted indications for hemodialysis describes the application of extracorporeal blood purification
and extracorporeal depuritive techniques, some clinicians have in clinical states including sepsis, rhabdomyolysis, congestive
come to rely on blood purification for clinical states where the heart failure, hepatic failure, tumor lysis syndrome, adult respi-
targeted substance for removal differs from uremic waste prod- ratory distress syndrome, intravenous contrast exposure, and
ucts. Over the last decade, a number of studies have emerged to lactic acidosis. Additional comments are provided to review
help define the application of extracorporeal blood purifica- existing literature on thermoregulation and osmoregulation,
tion (ECBP) to these “nonuremic” indications. This review including acute brain injury.

There are a number of commonly accepted indications improve outcome are being sought. Sepsis is a condition
Address correspondence to: Andrew E. Briglia, DO, Division of Nephrology, University of Maryland, 22 South Greene St., N3W143, Baltimore, MD 21201, or e-mail: abriglia@medicine.umaryland.edu.

for extracorporeal blood purification (ECBP), including in which an imbalance between inflammatory and anti-
uremia and correction of acid-base and electrolyte abnor- inflammatory mediators develops, and patients may fluc-
malities in the presence of acute renal failure (ARF) and tuate between these two phases (14). In addition, patients
extracellular fluid volume overload. However, some cli- with sepsis have been described as having a state of
nicians and researchers have come to rely increasingly immunoparalysis due to their inability to respond to
on ECBP modalities for removal of potentially toxic endotoxin. Cases of ARF requiring dialysis have been
molecules in cases where ARF is absent or where renal found to be associated with a greater frequency of infec-
replacement therapy is not absolutely indicated. Some of tions and sepsis (15). Therefore ARF may play a role in
these are listed in Table 1. Several nonuremic applica- perpetuating sepsis (16).
tions for ECBP, such as schizophrenia (1–8), pancreatitis Extracorporeal cytokine modulation in sepsis and
(3–5), and psoriasis (2,6,9) will not be discussed because septic shock has received considerable attention. Recent
they have been nicely reviewed elsewhere (2,5). The pur- evidence suggests a relationship between cytokine gene
pose of this review is to cite recent literature as it applies promoter polymorphisms and mortality in patients with
to the application of blood purification to disease states ARF (17). Many inflammatory cytokines, such as tumor
such as sepsis, rhabdomyolysis, and congestive heart fail- necrosis factor (TNF)-α, interleukin (IL)-1, 6, and 8, and
ure. Reviews on nonuremic applications for ECBP have platelet-activating factor (PAF) are water soluble middle
been published (5,10) and complications of extracorpo- molecules (Table 2) (18,19), making them candidates for
real therapy have been thoroughly described (11,12). removal by hemofiltration and hemodiafiltration. How-
ever, serum cytokine levels may not always correspond
with inflammation at the tissue level (13,20–22) and
Sepsis removal of proinflammatory cytokines such as TNF-α
and IL-1 may be accompanied by potentially undesirable
Renal replacement modalities have been extensively removal of anti-inflammatory cytokines such as IL-6 and
applied to sepsis and multiple organ dysfunction (MOD), IL-10 (23).
and are currently part of multiple organ support therapy Continuous renal replacement therapy (CRRT) has been
(MOST) (13). Because of the high morbidity and mortal- advocated as a means of reducing peak plasma levels of
ity rates associated with sepsis and MOD, strategies to cytokines as they appear sequentially over time (“peak
concentration hypothesis”) (24). Much of the cytokine
clearance associated with convective techniques may be
Address correspondence to : Andrew E. Briglia, DO, Division attributed to membrane adsorption, particularly during
of Nephrology, University of Maryland, 22 South Greene St.,
N3W143, Baltimore, MD 21201, or e-mail: abriglia@medicine. the first hour of continuous venovenous hemofiltration
umaryland.edu. (CVVH) and following a change of the membrane filter.
Seminars in Dialysis —Vol 18, No 5 (September–October) Convective elimination of these mediators may also be
2005 pp. 380–390 augmented by increasing blood flow from 100 to 200 ml /
380
 NONUREMIC APPLICATIONS FOR EXTRACORPOREAL BLOOD PURIFICATION 381
TABLE 1. Nonuremic applications for extracorporeal blood filters with high-flux or high-permeability characteristics
purification (30,31). Short-term high-volume hemofiltration (STH-
Sepsis
VHF) consisting of isovolemic hemofiltration with 35 L
Rhabdomyolysis of replacement solution administered over 4 hours
Thermoregulation followed by CVVH with a fluid exchange rate of 24 L/day
Refractory congestive heart failure and cardiopulmonary bypass has also been described (32,33).
Hepatic failure Several favorable hemodynamic and immunologic
Tumor lysis syndrome
Adult respiratory distress syndrome effects have been observed with hemofiltration, includ-
Radiocontrast-induced nephropathy ing improvement of postsurgical blood loss and alveolar
Osmoregulation arterial oxygen gradients in pediatric cardiac surgery
Lactic acidosis patients (34), reduced vasopressor (dopamine) dose (35),
Schizophrenia
Acute pancreatitis
and attenuation of immunoparalysis in mononuclear
Psoriasis cells, defined as a restored ability to produce TNF-α
in response to endotoxin. The latter effect was dimin-
ished after 24 hours, possibly due to saturated membrane
adsorption. It should be noted that the effects on whole
min with an AN69 membrane (25). In addition, higher blood mononuclear cells were more sustained in patients
rates of convection appear to be associated with greater given high-flux hemodialysis with polysulfone filters
survival, as patients with MOD and renal dysfunction (36).
experienced a reduction in mortality from 59% to 42% Although animal data (37,38) support the use of ECBP
( p = 0.0013) when convective rates were increased from in sepsis, particularly hemofiltration, studies evaluating
20 ml/kg/hr to 35 ml/kg/hr (or from approximately the survival in human subjects are not as favorable. A
1500 ml/hr to 2500 ml/hr in a 70 kg adult). Increasing recent prospective randomized controlled trial evaluated
convective rates further to 45 ml/kg/hr (approximately 24 patients on CVVH using a fluid exchange rate of 2 L/
3000 ml/hr in a 70 kg adult) did not confer additional hr (12 hemofiltration, 12 control; 10 with septic shock in
benefit (26). each group). Survival was identical (8 of 12 patients) in
These findings have led some researchers to question each group, and mean Acute Physiology and Chronic
whether it is time to move from a “renal” dose of hemo- Health Evaluation II (APACHE II) scores (hemofiltra-
filtration (or CVVH) to a “septic” dose. For this reason, some tion, 21.8 ± 4.0; control, 22.2 ± 6.4; p = 0.91) were not
investigators have studied the effects of high-volume different. Serum concentrations of C3, C5a, IL-6, IL-8,
hemofiltration (HVHF) (with more than 50–100 L of IL-10, and TNF-α were measured at baseline and at 2,
fluid replacement daily) in septic patients and have 24, 26, 48, and 72 hours; however, CVVH was not asso-
demonstrated significantly greater reductions in serum ciated with an overall reduction in these mediators nor an
concentrations of C3a, an anaphylatoxin, and vasopressor improvement in pressor requirements, oxygenation, or
requirements compared with those in patients placed on MOD score. The authors concluded that CVVH was
CVVH at conventional ultrafiltration rates (24,27,28). insufficient to modulate soluble mediators of sepsis and
Other authors favor HVHF using a fluid exchange rate of cannot be advocated for application in sepsis without
85 ml/kg/hr for 6–8 hours followed or preceded by concurrent ARF (39). Moreover, another study found no
CVVH at a fluid exchange rate of 35 ml/kg/hr (29), and effect of increasing ultrafiltrate volumes (72–96 L/day)
still others have described cytokine removal using hemo- or initiating early hemofiltration (within 7 hours of study
inclusion) on 28-day survival in 106 oliguric intensive
care unit (ICU) patients (40).
Other data suggest that hemofiltration does not decrease
TABLE 2. Convective removal of mediators
plasma concentrations of cytokines in systemic inflam-
Mediator Molecular weight (Da) Sieving coefficient matory response syndrome (SIRS) (41) or in trauma
patients with MOD and the absence of ARF (42). More-
AA mediators 600 0.5 – 0.91 over, additional markers of endothelial injury, such as
Bradykinin 1100
Endothelin 2500 0.19
soluble tissue factor, thrombomodulin, E-selectin, and
C3a/C5a 11,000 0.11– 0.77 endothelin-1, do not appear to be affected by CVVH
Factor D 24,000 (43). A recent meta-analysis demonstrated the absence of
MDS 600–30,000 a significant reduction in mortality by hemofiltration in
LPS 67,000 controlled human studies; however, the same analysis
LPS fragments < 1000–20,000
TNF-α (trimer) 17,000 (54,000) 0.0 – 0.2 suggests that plasma filtration may provide a benefit
STNFr 30,000–50,000 < 0.1 (see below) (23). Finally, although CVVH may provide
IL-1 17,500 0.07– 0.42 better clearance for TNF-α than continuous venovenous
IL-1ra 24,000 0.28 – 0.45 hemodialysis (CVVHD) (44), the transport mechanism
IL-6 22,000
IL-8 8000 0.0 – 0.48
(conventional versus diffusion) does not seem to affect
IL-10 18,000 0.0 the plasma concentration of other cytokines, and studies
INF-α 20,000 comparing continuous hemofiltration with intermittent
With permission from: Schetz M. Non-renal indications for hemodialysis have not demonstrated a clear advantage
continuous renal replacement therapy. Kidney Int 56(suppl 72):S88– of one modality over the other (45,46). Therefore the
S94, 1999. application of convective techniques in sepsis as
382 Briglia
immunomodulating therapy is not clearly established,
and more randomized controlled trials are required to
define the role of these modalities in cases of sepsis
where renal failure is absent.
Hybrid extracorporeal circuits combining plasma
filtration, adsorptive columns, and hemofilters have
recently emerged. Coupled plasma filtration adsorption
(CPFA) (14,47) incorporates a plasma filter in sequence
with a hemofilter. In addition, a sorbent cartridge pro-
cesses the filtered effluent from the plasma filter and
then returns it to the circuit. One study (47) reported
improved mean arterial pressure, decreased norepineph-
rine requirement, and restored leukocyte responsiveness
to lipopolysaccharide in a prospective crossover trial
of 10 patients treated with CPFA with hemodialysis (10
hours per treatment) or continuous venovenous hemo-
diafiltration (CVVHDF) in random order. Another uncon-
trolled trial of 12 consecutive patients with septic shock
also suggested salutary hemodynamic effects with this
technique (48). Apheresis (plasma exchange or plasma
filtration) with or without hemodialysis has been used
in patients with ARF and MOD (49). Several authors
have reported adsorption of cytokines, amelioration of
the immunoparalysis state accompanying sepsis, and
improved cardiovascular parameters; however, a survival
benefit with this technique has yet to be conclusively
demonstrated (50,51). Hemolipodialysis is yet another
sorbent-based technology that utilizes a dialysis solution
that is saturated with liposomes, which are spherical
phospholipid bilayers embedded with molecules of
vitamin E. The solution bathing the liposomes contains
vitamin C as well as other electrolytes (52). This meth-
odology is undergoing evaluation for removal of free
radicals and other lipid-soluble, hydrophobic, and protein-
bound toxins that are found in sepsis (52).
Rhabdomyolysis
Rhabdomyolysis occurs as a complication of myocyte
necrosis due to either traumatic (crush injury, strenuous
exercise) or nontraumatic causes (ethanol, inherited
defects in cellular metabolism) (53–56) and is diagnosed
by the finding of myoglobinuria, positive blood or uri-
nalysis, and concurrent absence of red blood cells on
urine sediment. Hemoglobin (molecular weight [MW]
64,000 Da) is structurally related to myoglobin (MW
17,000 Da) and can also induce ARF (55). Once it
occurs, rhabdomyolysis can cause ARF by the following
mechanisms: tubular obstruction by myoglobin casts,
tubular cell damage by lipid oxidant injury mediated by
the heme group of myoglobin, and vasoconstriction (57).
ARF caused by rhabdomyolysis was originally described
during World War II (54) and is found in more than 50%
of patients admitted with creatine kinase levels greater
than 5000 IU/L (57). Renal dysfunction has been esti-
mated to occur in 16.5–33% of cases, and the incidence
of dialysis has been estimated to be 31–61% (58).
The definitive approach to extracorporeal therapy for
rhabdomyolysis has not been established. Renal replace-
ment therapy may be indicated for hyperkalemia, a
common electrolyte complication of tissue necrosis.
Both plasma exchange and charcoal hemoperfusion have
been utilized; the former was associated with only 10%
clearance of serum myoglobin in a porcine model (59).
While myoglobin may be more amenable to removal by
convection than diffusion, due to its molecular weight,
the timing and application of either hemofiltration or
hemodialysis in this situation remain investigational.
Both CVVH and continuous arteriovenous hemofiltra-
tion (CAVH) have been successfully applied to patients
with rhabdomyolysis and ARF for the removal of serum
myoglobin (60–64). One study found that the mean
clearance of myoglobin was 22 ml/min (mean ultrafiltra-
tion rate of 2153 ± 148 ml/hr), but later decreased to
14 ml/min. The sieving coefficient (the percentage of the
concentration of a plasma solute that appears in the ultra-
filtrate) for myoglobin was reduced from 0.6 during the
first 9 hours of therapy with an acrylonitrile membrane
(AN69 0.9 m2 surface area) to 0.4 during the subsequent
7 hours. Sieving coefficients for urea, creatinine, and
phosphorus, on the other hand, remained stable at 1.0
during the first 16 hours of CVVH treatment. Similarly,
other authors have found that CVVH provides a constant
fraction of free myoglobin removal and that steady state
is reached after 14 days of therapy, possibly due to bind-
ing of myoglobin to plasma proteins (64). Others (65)
have reported removal of serum myoglobin in CVVH
using a high-flux F80 polysulfone membrane and an
ultrafiltration rate of 1 L/hr. Other investigators have
either employed continuous hemodiafiltration (66,67) or
detected rapid decreases in serum myoglobin levels
independent of changes in renal function or ECBP
method (18,68,69). Because myoglobin has a minimal
nephrotoxic capability in the absence of aggravating
factors such as volume depletion, acidosis, and aciduria
(56,58,70), prophylactic renal replacement therapy
based on the presence of an elevated creatine phospho-
kinase (CPK) level alone cannot be recommended.
Moreover, not all rhabdomyolysis leads to ARF, and the
prognosis of rhabdomyolysis-induced ARF is benign
(71), as recovery of renal function is usually expected
within 3 months of the initial insult, if the patient sur-
vives (72).
Thermoregulation
Both hemodialysis and peritoneal dialysis have been
described in patients with hypo- and hyperthermia. The
extra- and intracorporeal management of hypothermia
has been summarized (5). With specific regard to hypo-
thermia, recommendations have been made to warm
dialysate fluid to 104°F, to avoid ultrafiltration to mitigate
volume depletion and anticoagulants due to coagulo-
pathy, and to utilize femoral vein central access, given
the risk of cardiac irritability imposed by internal jugular
and subclavian catheters. The cooling effects of CRRT
have been advocated as a means of treating hyperthermia
that occurs as part of the neuroleptic malignant syndrome
(62,64). A recent trial observed improved hemodynamics
with CVVH, but no change in hepatosplanchnic oxygen-
ation (73). Others have commented on the heat transfer
abilities of CVVHD (74).
 NONUREMIC APPLICATIONS FOR EXTRACORPOREAL BLOOD PURIFICATION
Refractory Congestive Heart Failure and
Cardiopulmonary Bypass
Refractory congestive heart failure is a state of
impaired cardiorenal dynamics leading inevitably to up-
regulation of the renin-angiotensin-aldosterone axis and
progressive renal sodium and water retention. The in-
exorable progression of interstitial and pulmonary extra-
vascular fluid overload may ultimately become resistant
to conventional measures such as inotropic and diuretic
agents. Therefore patients may ultimately require extra-
corporeal therapy for purposes of ultrafiltration and to
control ensuing azotemia and electrolyte abnormalities.
There is growing support for convective therapies in this
setting. Twenty-four patients with New York Heart Asso-
ciation functional class IV heart failure (17 subjects with
ischemic heart disease and 7 with idiopathic dilated cardio-
myopathy) in the cardiac ICU who were receiving differ-
ent doses of inotropic, diuretic, and afterload-reducing
agents were provided ultrafiltration (75). The mean treat-
ment time was 9 ± 3 hours, and the range of ultrafiltra-
tion was 4300–7000 ml. Relief of pulmonary edema,
ascites, and peripheral edema were documented, and
patients were found to have improved response to subse-
quent diuretic therapy (mean dose of furosemide reduced
from 380 ± 157 mg/day to 112 ± 70 mg/day after ultrafil-
tration). Moreover, hemodynamic data obtained from pul-
monary artery catheterization revealed decreased mean
right atrial pressure, pulmonary capillary wedge pressure
(PCWP), and pulmonary artery pressure. Other parameters
such as heart rate, systemic arterial pressure, cardiac out-
put, and systemic vascular resistance were not affected.
Down-regulation of the neurohormonal axis (76–78)
and possibly removal of myocardial depressant factors
(79) have been postulated as mechanisms responsible for
improvement. Isolated ultrafiltration removes fluid that
is nearly isosmotic and isonatric with plasma, creating
more efficient solute and volume removal than diuretics
(urine sodium approximately 100 mEq/L with furo-
semide administration) (80–82). The induction of tran-
sient hypovolemia by ultrafiltration may also improve
the response to angiotensin-converting enzyme (ACE)
inhibitors, making ACE inhibitors more effective in sus-
taining body weight reduction than in individuals who
are provided ultrafiltration but are not concurrently
treated with this class of medication. Generally, high-
flux membranes (KUF > 20 ml/hr × mmHg × m2) made of
polysulfone, polyamide, polymethyl methacrylate, or
polyacrylonitrile are used (82). The progression to cardio-
genic shock with multiorgan failure may ensue (83),
making intermittent CVVH and slow continuous ultra-
filtration (SCUF) favored modalities to remove excess
sodium and water, restore left ventricular dynamics by
reducing preload, and improve renal perfusion (84–90).
In addition, isolated ultrafiltration (77,91–93) and perito-
neal dialysis (94) have been applied in this setting.
Therefore convective modalities may hold promise as a
bridge to cardiac transplantation or insertion of ventricu-
lar assist devices in patients with severely decompen-
sated congestive heart failure.
Neurohormonal modulation has also been docu-
mented in this setting. One study (95) demonstrated
383
decreases in plasma renin, aldosterone, and norepineph-
rine and an increase in urine output in cases of hemofil-
tration prescribed to ultrafilter 500 ml/hr until right atrial
pressure had declined to 50% of baseline. Hemofiltration
has also been used to attenuate fluid overload incurred as
a consequence of cardiopulmonary bypass, both intra-
and postoperatively (96,97). Some authors invoke the
role of hemofiltration in modulating the inflammatory
response associated with cardiopulmonary bypass by
removing TNF-α and IL-1α, which may decrease
intramyocardial nitric oxide and cyclic guanosine mono-
phosphate (cGMP) and act as negative inotropes (98,99).
Other investigators have reported improved laboratory
parameters (significantly less postoperative anemia, hypo-
albuminemia, and thrombocytopenia) (99), a reduced
incidence of pleural effusions, and negligible removal of
vasoactive agents with hemofiltration (100).
Convection may soon be accomplished via a long-
term indwelling catheter that is capable of direct plasma
extraction (82). The intracorporeal plasma separation
system (IPSS) is a device consisting of 130 hollow fibers
(each 1.5 cm in length) whose filtration topography allows
for higher shear flow rate and lower viscosity from blood
in the vena cava (3–6 L/min). Subsequently transmem-
brane pressure is reduced (20 mmHg versus 50–100
mmHg in conventional hemofiltration) and plasma water
removal is increased (60% versus 15–20% with whole
blood in a conventional extracorporeal circuit) (101).
This modality allows for slow plasma water removal
(approximately 2 L/day) and has potential applications
in patients with congestive heart failure or other chronic
volume overload states (101).
Hepatic Failure
The etiologies of combined hepatic and renal failure
have been described in several reviews (102–104). ECBP
has been applied in this setting; however, no single
modality is effective for eliminating all toxins that are
associated with hepatic failure (Table 3) due to large dis-
parities in their molecular weight (105). In addition,
ECBP methodologies are not capable of replacing the
synthetic and metabolic functions of the liver and may
remove regenerative substances (105). Some forms of
hepatic failure, such as hepatorenal syndrome, are only
cured by orthotopic liver transplantation (OLT); there-
fore, dialysis in this situation has traditionally been con-
sidered to be ineffective and to be used solely as a bridge
to OLT for a limited time (104,106–108). Isolated ultra-
filtration and hemofiltration have been prescribed to
remove sodium and water from patients who have refrac-
tory edema and nephrotic syndrome (109). CVVH has
been used in patients with combined hepatic and renal
failure to remove middle molecular weight molecules
that are believed to be responsible for hepatic encephal-
opathy. A reduction in molecules in the 45–60 Da range
has been demonstrated with CVVH, which was corre-
lated with improvement in the coma scale (110).
The Molecular Adsorbents Recirculating System
(MARS) is currently used in Europe and Asia for the
removal of albumin-bound toxins from patients with
384 Briglia
TABLE 3. Toxins associated with hepatic failure: relation to blood
purification
Small molecular weight toxins removable by hemodialysis
Ammonia
False neurotransmitters
γ-aminobutyric acid (GABA)
Octopamine (false neurotransmitter)
Middle molecular weight substances removable by hemofiltration
Cytokines (IL-6, IL-1, TNF)
Middle moleculesa
Albumin-bound or large molecular weight toxins removable by plasma
exchange
Aromatic amino acidsb
Bile acids
Bilirubin
Endotoxin
Endotoxin-induced substances such as nitrous oxide, cytokines (IL-
6, IL-1, TNF-α)
Indolsb
Mercaptansa,b
Phenolsa,b
Short chain fatty acidsa
Substances removable by hemoperfusion
Bile acidsb
Bilirubin (conjugated and unconjugated) b
Cytokines (IL-6, IL-1, TNF)
Mercaptansa,b
Phenolsa,b
a
Phenolic acids, fatty acids, and mercaptans have all been shown to
inhibit sodium-potassium ATPase activity and may contribute to the
cerebral edema associated with severe hepatic encephalopathy.
b
Albumin bound.
With permission from Kaplan AA, Epstein M. Extracorporeal blood
purification in the management of patients with hepatic failure. Semin
Nephrol 17:576–582, 1997.
both fulminant hepatic failure (FHF) and acute-on-
chronic (A-on-C) hepatic failure. The patient’s blood is
dialyzed against an albumin-based solution, which is
regenerated by further dialysis against a bicarbonate-
based solution and adsorption using charcoal and ion
exchange columns. Albumin-bound toxins are subse-
quently exchanged across a high-flux membrane (111).
Improved hepatic encephalopathy grade, increased syn-
thetic ability with increased serum clotting factor con-
centrations, improved urine volume, and decreased plasma
renin levels have all been demonstrated (112–120).
CVVHDF has recently been modified to incorporate an
albumin-based dialysate used in a single-pass approach
and has been found to effectively remove bilirubin. This
technique is currently undergoing investigation (121).
Hemodiadsorption, or “liver dialysis,” consists of a
hybrid circuit of diffusive and sorbent-based therapies.
Hemodialysis is provided with a dialysate suspension
containing sorbents, which provide a large surface area
for adsorption, as well as 40 g of powdered charcoal
added to 80 g of polystyrene sulfonate and physiologic
amounts of sodium, chloride, bicarbonate, and calcium.
Future sorbent suspensions may contain branched chain
amino acids such as isoleucine and more selective cation
exchangers such as zirconium silicates (122).
Trials evaluating liver dialysis in patients with FHF
and A-on-C (119,123–129) prescribed treatments for 6
hours daily for 1–5 days at blood flow rates of 180–225
ml/min. A return to a previous level of chronic hepatic
insufficiency or improvement in physical condition suffi-
cient to allow transplantation in A-on-C patients was
reported (71.5% versus 35.7% for controls, p = 0.036).
However, there was no significant improvement in out-
come for FHF (defined as a trend toward normal hepatic
function), perhaps due to a higher frequency of sepsis
and SIRS in the FHF cohort (122).
Potential complications associated with liver dialysis
include coagulopathy and increased risk of bleeding in
patients with disseminated intravascular coagulation,
possibly due to platelet loss during therapy. Because of
the limited ability of a charcoal-based sorbent to remove
albumin-bound toxins, “push-pull pheresis” has been
developed to incorporate a plasma filter module (122).
Hemoperfusion operates on the sorbent principle by
exposing blood to a column that is filled with sorbents
such as activated charcoal (removes water soluble sub-
stances such γ-amino butyric acid [GABA], mercaptans,
and inhibitors of Na+/K+-ATPase) or ion exchange resins
(remove protein-bound [bile acids and aromatic amino
acids] and lipid soluble substances). Unfortunately, the
largest study of hemoperfusion evaluated patients with
FHF and found no survival advantage (130). The effi-
ciency of hemoperfusion is reduced by rapid saturation
of the sorbent column and the need for column changes
at intervals of 3–5 hours (122). Hemoperfusion has also
been associated with the loss of platelets, fibrinogen, and
other clotting factors (122,123).
Apheresis, namely plasma exchange, is capable of
removing albumin-bound macromolecular substances
(endotoxin, aromatic amino acids, and bile constituents)
and was successful in a small population of patients with
cholestatic liver disease (131); however, it has little impact
on survival when used alone as an ECBP modality in
FHF (132,133). Plasma exchange has also improved
hepatic encephalopathy and neurologic status when
combined with hemodiafiltration as a bridge to OLT
(134–136).
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) generally occurs fol-
lowing cytoreductive therapy and is associated with
renal tubular deposition of uric acid, xanthine, and
phosphate (137). ARF requiring hemodialysis was not
uncommon in patients with acute lymphoblastic leuke-
mia (ALL) and Burkitt’s lymphoma following chemo-
therapy (138), and indices to predict the occurrence of
ARF have been reported (139). Fortunately, in our insti-
tution as in others, the advent of the recombinant urate
oxidase analog rasburicase has reduced the incidence of
TLS and the need for renal replacement therapy in this
setting.
Early initiation of renal replacement therapy has been
advocated to remove purine by-products and to amelio-
rate the hyperphosphatemia, hyperkalemia, and hypo-
calcemia associated with this disorder (140). While
molecules such as uric acid and phosphate are effectively
removed by diffusive therapy (18), CVVH has been used
to prevent phosphate rebound following conventional
 NONUREMIC APPLICATIONS FOR EXTRACORPOREAL BLOOD PURIFICATION
hemodialysis as prophylaxis against ARF in pediatric
patients (141).
Adult Respiratory Distress Syndrome
Adult respiratory distress syndrome (ARDS) has been
defined as low arterial oxygen (PaO2 < 75 mmHg) in the
setting of high inspired oxygen requirement (FiO2 > 0.5),
diffuse pulmonary infiltrates, and PCWP less than 18
mmHg (142). The application of ECBP, primarily con-
vection, remains controversial in this area. Retrospective
studies have shown an improvement in patients treated
with CRRT (143,144); however, other trials have yielded
less favorable results. For example, nine ARDS patients
treated with hemofiltration showed trends in reduced
PCWP and increased PaO2/FiO2 ratio at the expense of a
decrease in cardiac output and a trend toward reduced
oxygen delivery (145). Other investigators identified a
trend toward increased survival in patients who received
CAVH (56% versus 17% in the control group, p = 0.29)
despite a lack of improvement in hemodynamic and gas
exchange parameters (146).
The rationale for convection-based extracorporeal
therapy lies in its ability to reduce hydrostatic pressure
within the pulmonary circulation and thus decrease extra-
vascular lung water (18,147). Several mechanisms are
thought to be responsible for extravascular lung water
accumulation in ARDS: ischemia-reperfusion injury in
other organ systems, resulting in down-regulation of pul-
monary epithelial sodium channels and aquaporin-5 (148);
release of macrophage-derived inflammatory mediators,
such as cytokines, complement components, and arachi-
donic acid derivatives (149); increased alveolar capillary
pressure, resulting in fracture of small capillaries and
fluid extravasation (150); and high levels of positive end-
expiratory pressure (PEEP), producing antinatriuresis
through reduced glomerular filtration rate (GFR), renal
blood flow, and free water clearance (151).
Induction of hypothermia has been reported with
CAVH (152), and this cooling effect was associated with
decreased minute ventilation and reduced oxygen con-
sumption by 70% independent of changes in fluid bal-
ance. The development of permissive hypercapnia with
administration of bicarbonate-containing replacement
solution may also have contributed to the improvement
in lung function (152).
Radiocontrast-Induced Nephropathy
Radiocontrast-induced nephropathy (RCIN) remains
a prevalent cause of nosocomial ARF. A recent trial
demonstrated that 37% of patients with baseline serum
creatinine greater than 1.8 mg/dl experienced an increase
in this parameter by 25% or more, and approximately
7% required hemodialysis after coronary intervention.
These patients also experienced greater in-hospital and
1-year mortality rates (153).
The syndrome occurs as a consequence of several intra-
renal aberrations, including a brief episode of vasodila-
tion followed by vasoconstriction, tubular cell epithelial
385
toxicity and luminal obstruction, and renal medullary
ischemia (153–155). In addition, predisposing factors such
as advanced age, abnormal baseline serum creatinine,
presence of diabetes mellitus, and volume of contrast
injected (> 100 cc) have been associated with greater
decrements in GFR (156). Despite their lower osmolal-
ity, newer intravenous contrast agents are still capable of
inducing renal medullary ischemia (155,157). Moreover,
there is evidence that low-osmolality agents may only
confer benefit in patients with existing abnormal renal
function (serum creatinine > 1.6 mg/dl) (155,158).
Conservative measures, including saline with or with-
out furosemide and mannitol, calcium channel antago-
nists, dopamine, fenoldopam, atrial natriuretic peptide,
acetylcysteine, sodium bicarbonate, and theophylline
have been proposed to reduce the incidence of RCIN
(153,159–162). Both hemodialysis and peritoneal dialy-
sis are capable of removing contrast media (163–166);
however, hemodiafiltration is more effective than either
hemodialysis or hemofiltration.
Determining the efficacy of ECBP in this circum-
stance is complicated by a lack of randomized controlled
trials, by differences in the time interval from time of
contrast exposure to extracorporeal therapy, and by dif-
ferences in the dialyzer membranes used (164,167–170).
A recent randomized prospective trial compared intrave-
nous saline infusion alone (1 ml/kg/hr 12 hours before
and after intravenous contrast administration) with saline
before and hemodialysis after contrast administration
(171) in patients with moderately to severely impaired
renal function (serum creatinine concentration > 2.3 mg/
dl). High-flux hemodialysis was initiated between 30
minutes and 280 minutes (median 120 minutes) after the
first bolus of radiocontrast was given to those in the
hemodialysis group. While patients in the nonhemodia-
lysis group received significantly less contrast than those
in the treatment arm (143 ± 115 ml versus 210 ± 143 ml,
respectively, p = 0.007), prophylactic hemodialysis
offered no benefit in cases where more than 150 ml of
contrast media was administered. The reasons for this
observation are unclear; however, delay of institution of
therapy (more than 20 minutes), reduced renal perfusion
due to contrast-induced osmotic shifts, and a twofold
greater incidence in coronary angiography in the hemo-
dialysis group may be responsible. Furthermore, there
were no differences in the prevalence of cardiovascular
endpoints between the two groups (171).
Another trial randomized patients with serum creati-
nine greater than 2 mg/dl to receive either hemofiltration
or isotonic saline started 4–8 hours prior to and 18–
24 hours following percutaneous coronary intervention
using nonionic, low-osmolality contrast media. CVVH
was prescribed to provide a blood flow of 100 ml /min
and replacement fluid rate of 1000 ml/hr with no net
ultrafiltration. Patients in the control group received iso-
tonic saline at an infusion rate of 1 ml/kg body weight/
hr (provided that the cardiac ejection fraction was greater
than 40%). In-hospital mortality was significantly lower
in the hemofiltration group (2% hemofiltration versus
14% control, p = 0.02), as was 1-year mortality (10%
hemofiltration versus 30% control, p = 0.01) (172).
While these findings may be accounted for by the
386
bicarbonate flux that CVVH provides, the cost of materi-
als and ICU stay required for this modality raises ques-
tions regarding the feasibility of this approach.
Osmoregulation
Several authors have described the use of extracorpo-
real therapy for the correction of dysnatremia with or
without renal failure. Because the rate of serum sodium
correction is not firmly established, several approaches
have been taken. Reduced dialysate sodium concentra-
tion (138 mEq/L) was utilized in a patient with hyper-
natremia and ARF. Serum sodium concentration decreased
from 193 mEq/L to 168 mEq/L after one treatment and
then to 148 mEq/L following two additional treatments.
The patient regained sensorium and developed no neuro-
logic sequelae (173). Others report the successful use of
heparin-free hemodialysis in burn patients with hyper-
natremia (174). Additional data exist to support the use
of hypotonic dialysate sodium concentrations (110 mEq/
L) in patients with hypernatremia and concurrent extra-
cellular fluid overload in the setting of hepatic insuffi-
ciency, trauma, and diabetic ketoacidosis (175).
Continuous venovenous hemodiafiltration was initiated
in a pediatric patient with anuric ARF, hyperosmolar
coma, and cardiac arrest (176). Dialysate sodium
concentration (NaCl + NaHCO3) was reduced at 6-hour
intervals to maintain the sum of dialysate sodium chlo-
ride and sodium bicarbonate at 3 mEq/L less than the
serum sodium concentration (corrected for serum glu-
cose concentration). The patient later fully recovered
without lasting neurologic complications, demonstrating
that modulation of serum osmolality with extracorporeal
blood purification can be safely performed.
Cerebral edema, which can develop in patients who
sustain brain injuries as a result of trauma or systemic ill-
ness, represents a unique situation in which caution must
be used with the hemodialysis prescription (177). Con-
ventional hemodialysis has the potential to increase
brain water content by several mechanisms (178,179),
including urea removal and bicarbonate supplementation
(177,180–182). Hemodialysis removes urea more rapidly
from plasma than from cerebrospinal fluid (CSF). As
a result, water is transferred from plasma to brain tissue
(177) and intracellular idiogenic osmoles are formed
(177,181,182). In addition, bicarbonate, a charged mole-
cule that must be converted to carbon dioxide to cross the
blood–brain barrier, creates an environment of paradoxical
acidosis in the CSF and promotes further formation of
idiogenic osmoles (177,183,184). Intracerebral hypoxia
can worsen the situation by stimulating production of
lactate and vasodilatory substances that increase intrace-
rebral pressure (177,185,186).
In order to maintain cerebral perfusion pressure and
cerebral blood flow without increasing intracerebral pres-
sure, some recommend initiation of conventional hemo-
dialysis at low blood flow rates (50–200 ml/min) utilizing
dialysate that contains high sodium (e.g., 140–150 mEq/
L) and low bicarbonate (e.g., 30 mEq/L) concentrations,
thereby limiting osmotic gradients and increases in
plasma pH, and that has been cooled to 35.5°C to
Briglia
improve cardiovascular stability (177,187). Treatments
of 2 hours with 100 ml of 20% mannitol infused during
the second hour are advocated, but may be cautiously
increased in time or provided daily. Hemodialysis should
be performed with a synthetic low-flux filter that has
been primed with human albumin to coat the membrane
and maintain effective circulating plasma volume. Sys-
temic anticoagulation should be avoided, given the obvious
risk of intracerebral hemorrhage; however, regional anti-
coagulation with agents such as trisodium citrate or pros-
tacyclin may be considered (177,188–190). It should be
noted that prostacyclin may reduce cerebral perfusion
pressure and increase intracerebral pressure due to its
vasodilatory properties (74,177,187,191). CRRT may be
particularly useful in cases of cerebral edema, since
CVVHD and CVVHDF may impart greater intracranial
stability than intermittent modalities due to less pro-
found changes in serum osmolality, urea, and bicarbon-
ate concentrations. CRRT also has the advantage of
providing improved cardiovascular stability based on
thermal losses of the CRRT circuit (74).
Lactic Acidosis
Lactic acidosis is associated with poor outcome in
critically ill patients (177,192–195), therefore lactate has
been targeted for removal by ECBP. While the kidneys pro-
cess approximately one-third of exogenous lactate through
metabolism in the renal cortex and by means of urinary
excretion (177,192,193), CRRT has been found to con-
tribute very little (< 3%) to overall lactate clearance. This
occurs despite a preserved sieving coefficient of approxi-
mately 1.0 (lactate concentration in ultrafiltrate equal to
that of plasma) (177,192,193,196). These studies suggest
that CRRT is not a reliable method for treating lactic
acidosis and does not disguise hyperlactatemia or tissue
hypoxia. Although some researchers (18,177,197–199)
have reported a benefit of extracorporeal lactate clear-
ance by hemofiltration or hemodiafiltration, others (196)
support the notion that increased lactate clearance is a
reflection of the improved endogenous acid-base and
metabolic status achieved during extracorporeal therapy.
Conclusion
The application of ECBP to nonuremic indications
remains an area of ongoing research and controversy.
Because of conflicting data between animal and human
subjects, and as a result of shortcomings in study design,
including lack of randomized trials and the limited
number of study subjects, it is difficult to justify the use
of extracorporeal methodologies for these situations.
Therefore insufficient data exist to make ECBP the stan-
dard of care for these conditions.
Acknowledgments
The author would like to thank Geetha Stachowiak for
her assistance in the preparation of this manuscript.
 NONUREMIC APPLICATIONS FOR EXTRACORPOREAL BLOOD PURIFICATION
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