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Blood Purification in Sepsis and Acute Kidney
Injury in Critically Ill Patients
P.M. Honoré, N. Dobbeleire, and O. Joannes-Boyau
J.-L. Vincent (ed.), Annual Update in Intensive Care and Emergency Medicine 2011
DOI 10.1007/978-3-642-18081-1, ˇ Springer Science+Business Media LLC 2011
Introduction
Despite major advances in blood purification therapies, numerous questions
remain. As a result, clinicians may still have some hesitation regarding the real
efficacy of these techniques in sepsis as well as the best mode of hemofiltration
therapy when treating patients with septic shock plus acute kidney injury (AKI)
[1]. However, despite major recent therapeutic improvements, septic shock
remains a leading cause of mortality in intensive care patients [2]. In addition,
according to the latest available literature, it is of paramount importance to real-
ize that the mortality rate of patients with septic AKI is much higher compared
to that of patients with non-septic AKI [3, 4]. In the last decade, several milestone
studies [5, 6] have shown that dose of therapy is important in terms of mortality,
although recent so-called negative trials have challenged this concept. Neverthe-
less, a critical dose is still desirable and beyond that dose, mortality will be
affected [7, 8]. We should not forget, however, that these studies carry some very
important limitations [9, 10]. Regarding specifically rationale, it seems at least
theoretically reasonable that effectively removing mediators from the tissue,
where they are harmful, and transporting them to the central circulation must be
effective. Effectiveness through only a passive transportation mechanism remains
elusive. Indeed, the surface of the central blood compartment is about 30 m2,
which is much smaller than the surface of the capillary blood compartment,
which is about 300 m2 [11], so that passive transport between these two asym-
metric compartments will not yield the same elimination rate on both sides. As
a consequence, when a given technique is able to remove 40 % of the mediators
from the central blood compartment, it will only represent 4 % of the removal
into the capillary blood compartment if the removal is only a passive mechanism
(Fig. 1). It is, therefore, easy to understand, that another, active transportation
mechanism has to take place [11]. This chapter will review the most recent
insights regarding rationale and especially the ‘new active transportation between
two asymmetric compartments’ hypothesis [11] and will also review the strengths
and the weaknesses of the so-called recent negative studies regarding dose of con-
tinuous renal replacement therapy (CRRT) in critically ill patients.
273
VII
30 Sq
Meter
40 %
300 Sq
Meter
4 %
Active Transportation
80 Fold
Exchange Volume 
of 3-4 Liters/H
Fig. 1. The ‘active transportation’ hypothesis. From [15] with permission
‘New Active Transportation between two Asymmetric Compartments’
Hypothesis and New Insights into Rationale and Potential
Mechanisms
Pro-mediators as well as mediators are removed at interstitial and tissue levels
following removal from the blood compartment, until a so-called threshold point
is reached at which some pathways and cascades are stopped [12]. At this level,
the cascades are interrupted and no further harm can be done to the tissues.
Until recently, this mechanism was believed to be a passive transportation path-
way. As mentioned in the introduction, effectiveness through only a passive
transportation mechanism remains elusive. Indeed, as discussed, passive trans-
port between the asymmetric central and capillary blood compartments will not
yield the same elimination rate on both sides [11]. The potential beneficial use of
high volume hemofiltration (HVHF) and especially of high replacement volumes
(3 to 5 liters/hour) has been emphasized in recent years [13, 14], but mainly for
increasing immunomodulation of septic shock, most probably – although not
proven – by increasing removal of middle and large molecules [13, 14]. It is only
very recently that it has been shown that high replacement volumes (3 to 5 liters/
hour) used during hemofiltration cannot only remove but can also displace medi-
ators throughout the body [15, 16]. Indeed, this technique can induce a 20- to 80-
fold increase in lymphatic flow [15–18]. This finding can result in a concomitant
274 P.M. Honoré, N. Dobbeleire, and O. Joannes-Boyau
VII
substantial drag and displacement of mediators and cytokines to the blood com-
partment where they become available for removal. Thus, the use of high volumes
of replacement fluid might be of great importance, not only for extraction but
also to stimulate lymphatic transport between the interstitium and tissue com-
partments and the blood compartment although these are very asymmetric com-
partments. Once these mediators are in the lymphatic system, they will be avail-
able in the central blood compartment but inside the lymphatic compartment,
they will also be available for removal by the liver and the reticulo-endothelial
system which have an extremely large capacity of storage and may work as buffer
storage. Indeed, these systems will be able to absorb huge quantity of mediators
during a storm and releasing them during the aftermath in order to make them
available somewhat later for further removal by hemofiltration [19]. Obviously,
confirmation of this new working hypothesis requires several experiments (which
are underway) and these should incorporate the latest technology, including
nuclear imaging techniques, in order to effectively trace the mediators from the
tissue, through the lymphatic circulation and inside the central blood compart-
ment [20]. Another more invasive procedure would be to catheterize the thoracic
duct in order to collect the lymph and to make direct measurements of mediators
from time to time as was performed in the past when treating severe acute pan-
creatitis [21]. Another possibility would be to measure indirect markers of media-
tor activity at the tissue level. Indeed, markers of apoptosis and oxidative stress
occurring in the tissue, especially inside the inflammatory cells, may be a good
alternative in place of direct measurements [22]. In recent years, Kellum et al.
have provided additional evidence [23]. These investigators induced sepsis in a
rat model and randomly assigned the animals to hemofiltration or sham in order
to assess the effect on liver production of mediators through nuclear factor-kappa
B (NF-κB) production. Application of hemofiltration improved not only hemody-
namics but also survival. These experiments also demonstrated for the first time
that hemofiltration was able not only to reduce mediator blood levels but also
mediator production in the liver. The exact mechanism of this upstream down-
regulated effect remains to be elucidated. Nevertheless, measurement of NF-κB
production might also be seen as an indirect tool to measure a reduction in pro-
mediator production induced by the immunomodulation related to hemofiltra-
tion. Nonetheless, this technique would need the systematic realization of a liver
biopsy which is still quite an invasive procedure in critically ill patients.
New Therapeutic Targets Defined by the Latest Findings
Timing of hemofiltration remains a crucial aspect, but recent investigations have
clarified the issue somewhat. Indeed, a recently published study by Kellum and
co-workers [23] shed new light on this controversial issue. These authors con-
ducted a study (the so-called GenIMS Study for genetic and Inflammatory Mark-
ers of Sepsis) in nearly 2,000 patients hospitalized for community acquired pneu-
monia (CAP) [24]. They evaluated the pro- and anti-inflammatory balance in
these patients by measuring the ratio of interleukin (IL)-6 (pro-inflammatory) to
IL-10 (anti-inflammatory), and subsequently investigated whether a defined pro-
file of this ratio could be a good predictor of the evolution of CAP into sepsis,
septic shock and eventually death.In this study, 31 % of patients developed severe
sepsis and 26 % exhibited high circulating levels of cytokines. The highest risk of
Blood Purification in Sepsis and Acute Kidney Injury in Critically Ill Patients 275
VII
death was correlated with a high ratio of pro- and anti-inflammatory cytokine
levels (p value < 0.001). As a consequence, a hemofiltration technique, which
could lower the pro- and anti-inflammatory cytokine levels, would improve sur-
vival whenever the intervention was given (during the hyper-inflammatory phase
or during the immuno-paralysis period) by reducing both levels in order to
recover a better immune homeostasis [24]. Hence, the technique can be per-
formed irrespective of the status of inflammation in patients during their stay in
an intensive care unit (ICU) [11, 19].
Recent Positive Studies regarding Blood-Purification for Acute
Kidney Injury in the ICU
The pioneer study on dosing blood purification in the ICU was set up by Ronco
and co-workers in a study publish in the Lancet in the early 2000s [5]. This pro-
spective randomized controlled study of 425 patients compared three doses of
therapy: 20, 35 and 45 ml/kg/h in ICU patients with AKI. Survival in the 35 ml/
kg/h and 45 ml/kg/h groups was significantly higher than in the 20 ml/kg/h group
with a difference of nearly 20 % and p values of 0.0007 and 0.0013, respectively.
In addition to this finding, the study also showed that in the 35 and 45 ml/kg/h
groups, survivors had a significantly lower urea at start when compared to non-
survivors, suggesting that timing was also important in that study [5, 11]. More-
over, with this study, the foundations for the high volume technique were also
laid by Ronco who showed that in their subgroup of sepsis patients, increasing
the volume of treatment from 35 to 45 ml/kg/h could improve outcome, thus sug-
gesting that septic AKI should be handled differently [5, 25]. That study effec-
tively demonstrated that hemofiltration could be considered as a viable medica-
tion in the ICU. The volume of treatment not only has to be adapted to body
weight but also to the severity and type of illness of the ICU patient (septic or
non-septic AKI). Finally, the authors also looked at renal recovery; the percent-
ages of complete renal recovery were 95, 92 and 90 %, for the three doses respec-
tively, suggesting also that dosing might affect renal recovery. The pivotal study
was further confirmed by the trial by Saudan et al. [6]. In this prospective ran-
domized study in ICU patients with AKI, the authors compared two doses of
CRRT. The first group started with continuous veno-venous hemofiltration
(CVVH) alone at a dose of 25 ml/kg/h and the second group started with CVVH
at a dose of 25 ml/kg/h plus continuous veno-venous hemodiafiltration
(CVVHDF) at 18 ml/kg/h, giving a total dose of 42 ml/kg/h, very comparable to
the 35 ml/kg/h dose in the Ronco study. It was, therefore, not surprising to see
that the survival rates at 28 days were 39 % (25 ml/kg/h group) and 59 % (42 ml/
kg/h group) (p value < 0.03). Renal recovery was also assessed and was 71 and
78 %, respectively, suggesting again that a higher dose was correlated with a bet-
ter renal recovery rate. In the same line, a study performed by Schiffl and col-
leagues [26] but this time evaluating the use of hemodialysis in a prospective ran-
domized fashion in ICU patients with AKI and comparing extended daily dialysis
versus every other day dialysis during four hours. The mortality rates at the end
of dialysis treatment were 28 % for the daily dialysis group and 46 % for the every
other day dialysis group. Renal recovery was also much quicker in the daily dialy-
sis group suggesting that dosing, whatever the technique used, was of paramount
importance for renal recovery [27]. As mentioned above, a number of observa-
276 P.M. Honoré, N. Dobbeleire, and O. Joannes-Boyau
VII
tional studies [28–30], with higher fluid replacement in CVVH seem to demon-
strate an additional beneficial effect of this strategy on survival, although meth-
odological restrictions must be taken into consideration.
Recently, a South American team headed by Cornejo performed a similar
observational study with a protocol of pulse HVHF (85 ml/kg/h for 6–8 hours) in
20 septic patients with multiple organ dysfunction syndrome and obtained com-
parable results [31]. They created an algorithm based on the international recom-
mendations for sepsis treatment and incorporated intermittent HVHF (100 ml/
kg/h for a single 12 hour period) as a salvage therapy for patients in refractory
septic shock [31]. All these studies were only single center, non-randomized and
uncontrolled, but they all showed the same results and proved at least that HVHF
can be delivered safely.
Update on Very Recent Negative Trials in Critically ill Patients
with AKI
Although all these studies were promising, larger studies and randomized con-
trolled clinical trials were needed, especially regarding dosing and timing of RRT.
The results from one such study, the so-called VA/NIH study were published in
2008 [7]. This was a very large and well conducted randomized study comparing
two different doses of CRRT (20 versus 35 ml/kg/h) and two different intensities
of intermittent RRT depending on the hemodynamic status of the patient. This
study was not able to show that intensive renal support in critically ill patients
with AKI resulted in decreased mortality, improved recovery of kidney function,
or reduced rate of non-renal organ failure as compared with less-intensive ther-
apy. Several criticisms have been formulated against this study [9, 10], notably
related to the supposed 35 ml/kg/h dose of CVVH in the intensive treatment
group. This group was split into an 18 ml/kg/h dose of dialysis (1500 ml/h) and a
17 ml/kg/h of convection rate, giving an actual dose of roughly 15 ml/kg/h (when
taking into account the pre-dilution modality instead of full post-dilution). Addi-
tionally, the patients were enrolled in the study and treated relatively late in the
course of the illness, as compared to other studies (after a mean of 7 days in the
ICU and 10 days in hospital). Of note also, is the fact that more than 65 % of the
patients received either intermittent hemodialysis or sustained low efficiency
dialysis (SLED) treatment within 24 hours prior to the randomization.
More related to the timing of RRT, a Swedish study published a number of
years ago, demonstrated the importance of the initial therapy on the renal recov-
ery rate after AKI in ICU patients [32]. In the same vein, a recent review high-
lighted that in the recently published VA/NIH (ATN) trial [7], the delay in timing
was most probably responsible for the high rate of dialysis dependency [33].
Recently, a multicenter French study evaluated the impact of early hemofiltration
in 12 French ICUs [34]. The design was to evaluate the impact of hemofiltration
on organ dysfunction, plasmatic cytokines and mortality. The study design was
set up in the late 1990s before the Ronco study was published. Therefore, the dose
of hemofiltration was fixed (2 liters per hour) regardless of the body weight of the
patient. Of the 80 patients enrolled in the study, 76 were included in the study
protocol. Patients with severe sepsis or septic shock were included within the first
24 hours following the initial organ failure. The included septic patients did not
have any form of AKI when the hemofiltration was started. Randomization was
Blood Purification in Sepsis and Acute Kidney Injury in Critically Ill Patients 277
VII
performed between hemofiltration on top of classical treatment of sepsis or clas-
sical treatment of sepsis alone. As the body weight was close to 80 kg, the final
dose given was 25 ml/kg/hour and so still far from the 35 ml/kg/hour given in the
Ronco study. The primary objective was to evaluate the number, the severity and
the duration of organ failure at Day 14 using the SOFA (Sequential Organ Failure
Assessment) score. The studyhad to be prematurely stopped because of an insuf-
ficient number of inclusions but also because of the fact that, in the hemofiltra-
tion group, the number and severity of organ failures was significantly higher
compared to the control group. Nevertheless, no significant differences in mortal-
ity were seen at any time between the two groups although there was a trend in
favor of the control group. The take home message of this study was that hemofil-
tration should not be started in classical hyperdynamic septic shock without any
kidney injury unless the patient is in refractory septic shock, and the dose of
25 ml/kg/h was not able to improve mortality. Whether a dose of 35 ml/kg/h may
improve survival remains to be investigated. Another very recent negative trial is
the RENAL (Randomized Evaluation of Normal versus Augmented Level) study
conducted by the Anzics investigators in Australia and New-Zealand [8]. In this
study, 1508 critically ill patients with AKI were randomized to a dose of CVVHDF
of 25 ml/kg/h or a dose of 40 ml/kg/h. The primary objective was to evaluate mor-
tality at 90 days. No difference was observed between the two groups in terms of
mortality. Although this trial was very well conducted, two criticisms can be
made: First, as 50 % of the dose was given in diffusion, the dose in convection
was only 20 ml in the higher intensity group and so a bit far from the 35 ml of the
Ronco study. The second comment that can be made is that the study design was
for global AKI including septic and non-septic AKI. The study was not really
designed to evaluate the dose in septic AKI and even less in septic shock patients
with AKI [35]. A take home message of this study was that for non-septic AKI, a
dose of 25 ml/kg/h may be sufficient. Another interesting finding of this study
when compared to the NIH trial [7] is the fact that because of quasi exclusive use
of CRRT instead of intermittent therapies in the RENAL trial and certainly, also
due to the early timing of this study, the rate of dialysis dependency was reduced
by 50 % in the RENAL study compared to the NIH study [36].
Potential Impact of High Cut-off Membranes in Future Sepsis Trials
Already some years ago, a pilot trial looked at the performance of high cut-off
membranes in septic patients with AKI [37]. Thirty patients were randomized
into two groups, one with a high cut-off membrane (about 60 kDa) and another
with a classical cut-off (about 35 kDa). This study showed that in the high cut-off
group, norepinephrine dose was significantly less than in the classical cut-off
group (p < 0.0002) and the clearance of IL-6 and IL-1 receptor antagonist (IL-1ra)
was increased by more that ten fold (p < 0.0001).
The first results from a very recently completed randomized study, the so
called HICOSS (High Cut-Off Sepsis) study were presented at the 10th WFSCICCM
in Florence in 2009 [38]. The design forecast inclusion of 120 patients in septic
shock plus AKI randomized to either a conventional membrane or a high cut-off
membrane (60 kDa). These patients were treated for five consecutive days using
a continuous veno-venous hemodialysis (CVVHD) mode. The primary objective
was mortality at 28 days. The study was stopped prematurely because of a lack of
278 P.M. Honoré, N. Dobbeleire, and O. Joannes-Boyau
VII
difference between groups after 81 patients had been included. Mortality at day
28 was similar (31 % for the high cut-off group versus 33 %) and there were no
differences in terms of vasopressor use, duration of mechanical ventilation, or
duration of ICU stay. The only positive finding of the study was a safety issue as
there was no difference in albumin levels between groups and this high cut-off
membrane is safe. It should be emphasized that the study was realized in
CVVHD, a mode in which no synergy can be observed between HVHF and high
permeability hemofiltration (HPHF). Indeed, CVVH would be much more effi-
cient at removing mediators and cytokines as shown by another recent study
[39]. In this ex-vivo study, blood from healthy volunteers was spiked with endo-
toxin and than randomized to a high cut-off filter of 100 kDa at a dose of 16.6 ml/
kg/h or the same filter plus a dose of 80 ml/kg/h. Clearance of cytokines was
nearly 10 fold higher in the mixed high cut-off and HVHF group demonstrating
a synergy between HVHF and HPHF [39].
What Is the Future for Blood Purification?
Most of the large randomized trials investigating hemofiltration doses in AKI
patients are now completed, but the results of one, comparing HVHF with stan-
dard CVVH in septic AKI, are still being collected and analyzed. The IVOIRE
study (hIgh VOlume in Intensive caRE) compared treatment with CVVH for a
period of 96 h at 35 versus 70 ml/kg/h in septic AKI [40, 41]. As reviews showed
indirect evidence that early initiation of therapy could be associated with further
improvement in mortality, it was decided to start therapy in septic shock at the
injury level of the RIFLE classification [42]. The first patient was randomized at
the end November 2005 but most centers joined only in mid-2006. The overall
primary objective of this study was to assess the effects of early high-volume
CVVH (70 ml/kg/h) on 28-day mortality in patients with septic shock compli-
cated by acute renal insufficiency. The secondary objectives were to assess the
consequences of hemofiltration on hemodynamic parameters, doses and duration
of use of catecholamines, organ failure, duration of artificial ventilation and
extravascular lung water, morbidity rate, duration of ICU stay and early mortality
(96 h), and mortality after 60 and 90 days. IVOIRE was a randomized multicenter
clinical trial. In all cases, patients were treated in accordance with current recom-
mendations in the literature. This study was a superiority trial, aiming to detect
a reduction of at least 15 % in mortality rate. An estimated sample size with 240
patients in each arm was calculated to give > 80 % power to detect such a differ-
ence at an α of 0.5. The team at the center coordinating the IVOIRE trial con-
ducted two pilot studies to prepare for this trial [43, 44]. The choice of hemofil-
tration volume in the control group (35 ml/kg/h) was motivated by the latest rec-
ommendations in the literature applied to intensive care. The choice for the high-
volume group (70 ml/kg/h) was made by consensus, taking into account intensive
care practices using this latest technique and the opinion of investigators who
were consulted at various congresses, and taking into account that, at present,
there is no reference in the literature that allows a specific treatment volume to be
selected. The duration of treatment (96 hours) was motivated by the experience of
the team and the pilot studies, which were based on the same periods. This dura-
tion corresponds to the critical period of septic shock during which treatment
has the greatest impact on survival. It is also the duration stipulated for other
Blood Purification in Sepsis and Acute Kidney Injury in Critically Ill Patients 279
VII
sepsis treatments in large studies at present. Block randomization was used by
means of a dedicated website. Data regarding losses of trace elements, vitamins,
amino acids and other nutrients, apoptosis, oxidative stress, renal repair capacity
index, cytokines and mediators and antibiotic pharmacokinetics are being col-
lected as part of this study. By the end of December 2009, more than 140 patients
had been randomized with more than 45 patients in the last year. The first
interim analysis took place in January 2010. The expected mortality of the first
100 patients according to three severity scores (SOFA, SAPS II and logistic organ
dysfunction [LOD]) was 68 % whereas the observed mortality at 28 days was
39 % and at day 90 only 48 %. Hence, the observed global mortality was much
less than expected. This low mortality informs the medical community that
HVHF is a very safe technique and that the early start (at injury level) may
improvemortality. Ongoing analyses will tell us in the near future whether a
higher dose of 70 ml is desirable in septic shock plus AKI plus three organ fail-
ures. Other details regarding the study can be found at the NCT website [40].
Two other recent studies need to be highlighted. The so-called EUPHAS (Early
Use of Polymyxin B Hemoperfusion in Abdominal Sepsis) study tested the impact
of polymyxin (PMX) B hemoperfusion on hemodynamics, SOFA score and mor-
tality in 64 patients with abdominal sepsis requiring urgent laparotomy [45]. The
patients were randomized into two groups: PMX and control. The PMX group
showed a significant improvement in hemodynamics as well an improved mortal-
ity at 28 days after adjusting for the initial SOFA score. This very selected group
of patients did not exhibit any signs of renal injury. The DO-RE-MI study (Dose
Response Multicenter International Collaborative Initiative) was conducted in 30
ICUs in 8 countries [46]. The primary objective was to see the effect of dose of
CRRT. Of 15,200 ICU patients, 553 had AKI and were treated with CRRT or inter-
mittent renal replacement therapy (IRRT). There were no differences in mortality
between the group treated with less than 35 ml/kg/h versus the group with more
than 35 ml/kg/h. The only significant differences between the two groups were in
ICU length of stay and duration of mechanical ventilation which were shorter in
the group with a dose larger than 35 ml/kg/h. Nevertheless, the major finding of
this study is that the delivered dose was significantly less than the prescribed
dose. The difference was about 8 ml/kg/h suggesting that we should prescribe
about 5 to 10 ml more than our target dose. The exact determination of timing
regarding AKI [47] and a better delineation of the type of AKI [48] will represent
major challenges in the future of blood purification. Moreover, a better under-
standing of the immunomodulatory effects of AKI has to be achieved in order to
better define the best timing of CRRT [49].
Conclusions and Recommendations for the Clinician at the Bedside
Regarding the use of CRRT in ICU in 2011, it is safe to say that optimalization of
delivered dose has a role to play: Therefore an ultrafiltration rate of around
35 ml/kg/h, with adjustment for predilution, can still be recommended for the
septic patient with AKI. Recent studies, like the VA/NIH trial, did not have
enough power to change this recommendation in view of its shortcomings. The
RENAL study, which was conducted perfectly, was not designed to specifically
assess the septic AKI population but rather the global critical care AKI popula-
tion. Finally, the recommendation in septic AKI (and surely in septic shock
280 P.M. Honoré, N. Dobbeleire, and O. Joannes-Boyau
VII
patients with AKI) is to keep going with a continuous technique, a pure CVVH
mode and at a dose of 35 ml/kg/h while awaiting for the results of other studies,
like IVOIRE, to be published. In non-septic AKI, 25 ml/kg/h should be a target
dose as demonstrated in the RENAL study. Nonetheless, we have to consider the
impact of the DO-RE-MI study suggesting that we should prescribe 5 to 10 ml
higher and so perhaps a dose of 30–35 ml/kg/h to have a delivered dose of 25 ml/
kg/h. In the meantime, we can say that the global results of IVOIRE show that
HVHF is safe regarding mortality and that early intervention at the injury level
may be warranted in terms of global survival. Further ongoing analyses will
inform us in the near future whether a higher dose is better than 35 ml/kg/h in
patients with septic shock plus AKI plus three organ failures. Better understand-
ing of the immunomodulatory effects of AKI has to be achieved in order to better
define the best timing of CRRT.
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Blood Purification in Sepsis and Acute Kidney Injury in Critically Ill Patients 283
VII
	Blood Purification in Sepsis and Acute Kidney Injury in Critically Ill Patients
	Introduction
	‘New Active Transportation between two Asymmetric Compartments’ Hypothesis and New Insights into Rationale and Potential Mechanisms
	New Therapeutic Targets Defined by the Latest Findings
	Recent Positive Studies regarding Blood-Purification for Acute Kidney Injury in the ICU
	Update on Very Recent Negative Trials in Critically ill Patients with AKI
	Potential Impact of High Cut-off Membranes in Future Sepsis Trials
	What Is the Future for Blood Purification?
	Conclusions and Recommendations for the Clinician at the Bedside
	References