Combination of extracorporeal membrane oxygenation and continuous renal replacement therapy in critically ill patients: a systematic review
Combination of extracorporeal membrane oxygenation and continuous renal replacement therapy in critically ill patients: a systematic review
Han Chen 0
Rong-Guo Yu 1
Ning-Ning Yin 0
Jian-Xin Zhou 0
0 Department of Critical Care Medicine, Beijing Tiantan Hospital, Capital Medical University , Beijing 100050 , China
1 Surgical Intensive Care Unit, Fujian Provincial Clinical College of Fujian Medical University , Fuzhou 350001, Fujian , China
Introduction: Extracorporeal membrane oxygenation (ECMO) is used in critically ill patients presenting acute cardiac and/or pulmonary dysfunctions, who are at high risk of developing acute kidney injury and fluid overload. Continuous renal replacement therapy (CRRT) is commonly used in intensive care units (ICU) to provide renal replacement and fluid management. We conducted a review to assess the feasibility, efficacy and safety of the combination of ECMO and CRRT and to illustrate the indications and methodology of providing renal replacement therapy during the ECMO procedure. Method: We searched for all published reports of a randomized controlled trial (RCT), quasi-RCT, or other comparative study design, conducted in patients undergoing ECMO plus CRRT. Two reviewers independently selected potential studies and extracted data. We used the modified Jadad scale and the Newcastle-Ottawa for quality assessment of RCTs and non-RCTs, respectively. Statistical analyses were performed using RevMan 5.2. Results: We identified 19 studies meeting the eligibility criteria (seven cohort, six case control, one historically controlled trial and five studies of technical aspects). There are three major methods for performing CRRT during ECMO: ? independent CRRT access? , ? introduction of a hemofiltration filter into the ECMO circuit (in-line hemofilter)? and ? introduction of a CRRT device into the ECMO circuit? . We conducted a review with limited data synthesis rather than a formal meta-analysis because there could be greater heterogeneity in a systematic review of non-randomized studies than that of randomized trials. For ECMO survivors receiving CRRT, overall fluid balance was less than that in non-CRRT survivors. There was a higher mortality and a longer ECMO duration when CRRT was added, which may reflect a relatively higher severity of illness in patients who received ECMO plus CRRT. Conclusions: The combination of ECMO and CRRT in a variety of methods appears to be a safe and effective technique that improves fluid balance and electrolyte disturbances. Prospective studies would be beneficial in determining the potential of this technique to improve the outcome in critically ill patients.
Extracorporeal membrane oxygenation (ECMO) is a
lifesaving technique used in critically ill patients presenting
acute cardiac and/or pulmonary dysfunctions, who are
at high risk of developing acute kidney injury (AKI) and
fluid overload (FO). The AKI severity can be stratified
using the RIFLE [1,2] (risk, injury, failure, loss, and
endstage) classification definitions, which include changes in
urine output and serum creatinine. Previous studies using
the RIFLE definition in ECMO patients demonstrated that
the incidence of AKI exceeded 70% [3-6], and these
studies also suggest an association between poor outcomes
Renal replacement therapy (RRT) consists of a broad
range of techniques. A distinction can be made based on
membrane permeability, method of molecular clearance
(diffusion or convection or a combination of both) and
the duration of treatment and equipment used . The
nomenclature of an entire continuous renal replacement
therapy (CRRT) mode is based on the type of vascular
access and the primary method of molecular clearance.
For example, CAVH represents continuous
arteriovenous hemofiltration. Although CRRT was initially
developed using arterial and venous access, the pump-driven
venovenous access is widely used and has now replaced
the use of arteriovenous access. Peritoneal dialysis (PD)
is another method that can be included in CRRT, but it
is very seldom used for the treatment of AKI in patients
admitted to intensive care units (ICU) .
CRRT is commonly used in ICUs to provide an easily
initiated and efficient method of renal replacement and
fluid management. The combination of ECMO and CRRT
seems to be a good method for treating ECMO patients
who have developed AKI. However, previous studies show
wide variations in practice regarding RRT during ECMO
. The combination of ECMO and CRRT has been
reviewed , but to date, no review has been conducted.
Therefore, we presented this review to illustrate the
methodology of providing RRT during the ECMO procedure,
and to assess the feasibility, efficacy and safety of the
combination of these two types of therapy.
We conducted a systematic review of published reports
of a randomized controlled trial (RCT), quasi-RCT, or
other comparative study design, conducted in patients
undergoing ECMO plus CRRT (including continuous
venovenous hemofiltration (CVVH), continuous
venovenous hemodialysis (CVVHD), continuous venovenous
hemodiafiltration (CVVHDF), continuous arteriovenous
hemofiltration (CAVH), continuous arteriovenous
hemodialysis (CAVHD), continuous arteriovenous
hemodiafiltration (CAVHDF) and slow continuous ultrafiltration
(SCUF). Studies that introduced the technical aspects of
the combination of ECMO and CRRT were also included.
The exclusion criteria were: 1) studies reported the
application of CRRT prior to ECMO; 2) studies reported the
application of ECMO plus intermittent RRT; 3) animal
experiments; and 4) case report or case series.
We searched the major international medical
bibliographical databases: Medline (via PubMed), Web
of Science, Cumulative Index of Nursing and Allied
Health Literature (CINAHL), ProQuest Health & Medical
Complete and the OvidSP database which includes
the ACP Journal Club, Cochrane Central Register of
Controlled Trials, Cochrane Database of Systematic
Reviews, Cochrane Methodology Register, Abstracts of
Reviews of Effects, Health Technology Assessment, NHS
Economic Evaluation Database and BIOSIS Previews. We
also searched trial registries for ongoing trials. We used
text words or Medical Subject Headings (MeSH) headings
containing ? continuous renal replacement therapy? , ?
continuous venovenous hemodialysis? , ? continuous venovenous
hemodiafiltration? , ? continuous venovenous hemofiltration? ,
? continuous arteriovenous hemodialysis? , ? continuous
arteriovenous hemodiafiltration? , ? continuous arteriovenous
hemofiltration? , ? continuous hemofiltration? , ? slow
continuous ultrafiltration? and ? extracorporeal membrane
oxygenation? in the search. The PubMed search strategy is
presented as an example in Figure 1. We also searched
personal files and reference lists. The search was performed
independently by two investigators (HC, RGY) and was
completed on 20 December 2013, with no restriction of
publication status, date or language.
Study selection and quality assessment
Two reviewers (HC, RGY) independently screened
retrieved database files and the full text of potentially
eligible studies for relevance. Foreign language papers were
translated if necessary. Disagreements were resolved by
consensus or by discussion with another investigator
(JXZ). We used the modified Jadad scale  for quality
assessment of RCTs, and the Newcastle - Ottawa quality
assessment scale (NOS)  for quality assessment of
non-RCTs. The NOS was developed for cohort and case
control studies. The NOS is categorized into three
dimensions: selection, comparability and outcome (cohort
studies) or exposure (case control studies). A rating
between zero and nine stars is used for a semi-quantitative
assessment of studies, where five or more indicates a
The following data were extracted for each trial: author
and year of publication, study type, study population and
number, technical parameters, indicators of ECMO,
indicators of CRRT, main outcome and complications.
Technical parameters included the method of combining
ECMO and CRRT, anticoagulation strategy, ECMO canal
position, ECMO pump type and blood flow rate, ECMO
Figure 1 PubMed search strategy.
modality selection (venovenous ECMO (VV-ECMO) or
venoarterial ECMO (VA-ECMO)) and CRRT mode
selection. The outcomes assessed included mortality, ECMO
duration, fluid balance, complications and renal function
Statistical analyses were performed using RevMan 5.2.
Odds risks ((OR) with 95% confidence intervals (CI))
were calculated for dichotomous data. Outcome
measures were quantitatively summarized, if possible, using
a random effects model. Heterogeneity among combined
study results was assessed by the degree of inconsistency
(I2) . A value of 0% indicates no observed
heterogeneity, and increasing values of I2 reflect increasing
heterogeneity; a value of >25% shows at least low-to-moderate
heterogeneity. When the degree of statistical
heterogeneity was greater than this threshold, we investigated
possible explanations by using sensitivity analysis.
Figure 2 shows the results of the search and selection
processes. There were 173 citations after de-duplication
with EndNote X5, of which we excluded 142 citations
Figure 2 Process for identification of the included studies.
after examining the title and abstract. Thirty-one
citations were obtained in full text and 12 of these were
excluded: four investigated patients who underwent
ECMO plus CRRT, but without comparison, one with
ECMO plus intermittent RRT, two with duplicate
publication, one with commentary, one cross-sectional
survey, one with CRRT only, one with ECMO only and one
review. In total, 19 studies were included, consisting of
seven cohort studies [13-19], six case control studies
[20-25], one historically controlled trial  and five
studies of technical aspects [27-31]. Seventeen studies
were published in English [13-23,26] and two in Chinese
with English abstracts [24,25]. Since no RCTs were
found, quality assessment was performed using the NOS,
while studies of technical aspects were not assessed. Five
studies were assigned five stars [20-22,24,25], one study
was assigned six stars , six studies were assigned seven
stars [13-15,17-19] and two studies were assigned nine
stars [16,26]. These studies are summarized in Table 1.
Additional file 1 shows the technical parameters of ECMO
and CRRT in these studies.
Technical aspects of combining ECMO and CRRT
There are a number of methods for performing CRRT
during ECMO, which can be classified in three major
ways: performing RRT through venous access independent
of the ECMO circuit, introduction of a hemofiltration filter
into the ECMO circuit using intravenous infusion pumps
to control the ultrafiltrate volume and inclusion of a CRRT
device in the ECMO circuit (Figure 3).
Independent CRRT access The simplest way to perform
CRRT is through venous access independent of the
ECMO circuit. However, if the patient has not
undergone previous cannulation of a central venous line, the
situation is complicated because anticoagulation
increases the risks of bleeding. Poor catheter drainage may
also occur during the CRRT period.
Introduction of a hemofiltration filter into the ECMO
circuit (in-line hemofilter) The introduction of a
hemofiltration filter into the ECMO circuit is the most widely
used method of CRRT and has the advantage of being
relatively simple and inexpensive. The hemofilter is
placed after the pump to provide forward blood flow.
The filter inlet is connected after the pump and the
outlet is reconnected to the ECMO circuit to allow
return of the blood flow to the proximal limb of the
ECMO circuit. Because of the existence of a shunt,
there could be a gap between the measured flow and
the flow being delivered to the patient (which indicates
the hemofilter blood flow rate). An ultrasonic flow
probe should be placed on the arterial line of the ECMO
circuit to determine the actual flow delivered to the
The amount of replacement fluid, dialysis and effluent
fluid is controlled by the intravenous infusion pumps
included in the circuit. All methods of molecular clearance
are not meant to exist at the same time. Different
combinations of the molecular clearance methods are used to
achieve different CRRT modes, such as CVVH, CVVHD,
CVVHDF and SCUF. There are several methods to
determine the amount of fluid being removed. One possible
method is to assume that the fluid delivered/removed is
equal to the rate of the infusion pumps. This assumption
may be inaccurate as the infusion pumps are actually flow
restrictors. Sucosky et al. reported a standard error in net
ultrafiltrate volume removed from the patient of up to
848.5 ? 156 ml over a period of 24 hours in laboratory
Measuring the actual volume of the ultrafiltrate
removed by weight or using a volumetric measuring device
could be the most precise method. However, this
requires strict control by the nursing staff and an
inevitable increase in the nursing workload. Another defect is
the absence of pressure monitoring in the hemofiltration
circuit, which may lead to delayed detection of clotting
or rupture of the filter.
Introduction of a CRRT device into the ECMO circuit
The ECMO circuit can serve as a platform for additional
organ support therapies. It is possible to connect a CRRT
device to the venous limb of the ECMO circuit before the
pump, which drives the blood from the ECMO circuit into
the CRRT device. After blood purification the blood is
returned to the ECMO circuit before the ECMO pump. If
a centrifugal ECMO pump is used, it is necessary to place
the CRRT machine after the pump because of the risk of
air entrapment. Reconnection to return blood from the
CRRT device is required before the oxygenator to trap air
or clots before return to the patients, and to avoid venous
admixture due to the shunt. Santiago et al. reported that
ECMO and CRRT devices functioned correctly in all cases
after connection of the CRRT device to the ECMO circuit.
No pressure changes were observed before or after the
inclusion of the CRRT device in the ECMO circuit. Longer
filter life was achieved with this method than when CRRT
was performed through an independent venous access
. Symons et al. reported that introduction of a CRRT
device into the ECMO circuit provides more accurate fluid
management during ECMO .
Indications for ECMO and ECMO mode selection
Six studies used VA-ECMO alone [13,15,18,22,24,25],
predominantly in patients with heart disease. The main
indications for ECMO were heart failure and cardiac
arrest. Another six studies used both VV-ECMO and
Table 1 Study features and quality assessment
Goto, 2011  Case control study No restriction Apr 2002 to Feb 2011 Heart disease
Hamrick, 2003  Case control study Children, one year 1990 to 2001 Congenital heart disease
Kolovos, 2003  Case control study Children Jul 1995 to Jun 2001 Congenital heart disease
Luo, 2009  Case control study Adult Feb 2005 to Jun 2008 Heart disease after surgery, 45
chronic heart failure
Luo, 2010  Case control study Adult Jul 2005 to Jul 2009 CPR patients 11
Yap, 2003  Case control study Adult Dec 1998 to Jun 2001 Heart disease 10
Betrus, 2007  Retrospective cohort study Children 1993 to 2001 Congenital heart disease 42
Cavagnaro, 2007  Retrospective cohort study Children, one year May 2003 to May 2005 No restriction
Gbadegesin, 2009  Retrospective cohort study Children, ≤3 years Jan 2000 to Apr 2005 Congenital heart disease
Hoover, 2008  Retrospective cohort study Children ≥1 month 1990 to 2006 Respiratory failure
Retrospective cohort study Children, ˂18 years
Number of S1 S2 S3 S4 C1 C2 E1/O1 E2/O2 E3/O3 Total
14 1 0 1 1 0 0 1 1 0 5
53 1 0 1 1 0 0 1 1 0 5
74 1 1 1 1 0 0 1 1 0 6
Figure 3 Two typical methods of combining ECMO and the CRRT circuit. A = ECMO pump; B = Oxygenator; C = Hemofilter; D = Dialysis fluid;
E = Effluent fluid; F = Replacement fluid; G = Intravenous pump; H = CRRT device; I = Ultrasonic flow probe. CRRT, continuous renal replacement
therapy; ECMO, extracorporeal membrane oxygenation.
VA-ECMO [14,16,19,20,23,26], of which, the main
indications were heart failure in three studies [19,20,23],
respiratory failure in one study  and both heart and
respiratory failure in two studies [14,26]. The femoral
artery and the femoral vein were the preferred sites for
ECMO access in adults, while in pediatric patients, neck
vascular access was more likely to be chosen.
Indications for CRRT and CRRT mode selection
Nine studies reported the indications for CRRT treatment,
including acute renal failure or AKI [16,17,22,24,27], FO
[14-17,19,27,29] and metabolic disturbance such as
hyperkalemia, electrolyte disturbances or azotemia [14-16,29].
CVVH was employed in five studies [16-19,26], while
two studies employed CVVHD and two studies used
CVVHDF [13,23]. Multiple modes, including CVVH,
CVVHD, CVVHDF and SCUF, were selected in three
studies [14,27,28]. Eleven studies used the in-line
hemofilter method to provide CRRT [13-20,22,23,26], two of
which reported using CRRT devices in cases where
ultrafiltration exceeded two liters per hour [17,19]. Three
studies employed a CRRT device connected to the ECMO
Thirteen studies reported in-hospital mortality [14-26],
with a statistically significant increase in the risk of
mortality in ECMO + CRRT patients compared with patients
receiving ECMO only (OR 5.89, 95%CI 4.38 to 7.92,
P <0.00001, Figure 4). There was evidence of mild
heterogeneity across the studies (I2 = 29%) although additional
sensitivity analysis showed no heterogeneity (I2 = 0) after
two studies were excluded [16,26]. In one study, patients
were matched for age, weight, diagnosis and ECMO mode
; in the other study, patients were matched for similar
age (1? year) and similar PRISM III scores at the time of
ECMO cannulation (3?) . The OR was 6.82 (95%CI
4.97 to 9.36, P <0.00001), after the two studies were
excluded (data not shown). We intended to analyze the
relationship between different ECMO modes (VA or VV) and
mortality, but unfortunately, we were unable to acquire
the required data despite our attempts to contact the
authors. Figure 5 shows the mortality rate in children with
congenital heart disease, with increased risk of mortality
observed in ECMO + CRRT patients (OR 6.19, 95%CI
3.89 to 9.87, P <0.00001).
Four studies compared fluid balance between ECMO
and ECMO + CRRT groups [14,16,22,26]. These showed
that for ECMO survivors receiving CRRT, overall fluid
balance was less than that in non-CRRT survivors.
Gbadegesin et al. reported less fluid balance in survivors
than in non-survivors who received ECMO therapy .
Symons et al. found that the in-line CRRT device allowed
more accurate fluid management during extracorporeal
life support, which may contribute to the shorter duration
of extracorporeal life support .
Renal function recovery
Four studies reported the recovery of renal function before
hospital discharge [14,16,17,19]. Three studies showed a
full-recovery or no requirement for additional RRT in all
survivors before hospital discharge [14,16,19]. Paden et al.
reported the recovery of renal function and
discontinuation of renal replacement in 96% (65/68) of patients
before hospital discharge. The follow-up showed that one
neonatal patient had normal creatinine one month later.
Two pediatric patients developed end-stage renal disease;
one received PD and subsequent renal transplant, while
the other had diminished function without a requirement
for RRT .
Figure 4 Forest plot of in-hospital mortality.
Eight studies compared the ECMO duration between
ECMO and ECMO + CRRT groups [13-19,26]. Blijdorp
et al. reported that the ECMO duration was shorter in
the ECMO + CRRT group , whereas another seven
studies showed a longer ECMO duration when CRRT
Bleeding was reported in three studies [20,23,24],
including intracranial hemorrhage and gastrointestinal
bleeding. Plasma free hemoglobin (FHb) was measured in two
studies [13,15]. The ECMO + CRRT group had a higher
peak FHb level compared with the ECMO alone group,
which indicated that there is enhanced hemolysis during
combined ECMO and CRRT compared with ECMO alone.
Infection was reported in three studies [23-25]. Cavagnaro
et al. reported acute pre-renal insufficiency associated with
excessive ultrafiltration, which was corrected quickly by
decreasing the ultrafiltration rate and stopping the diuretics.
There is an important cardiorenal interaction in patients
with either acute or chronic severe heart failure, with renal
Figure 5 Forest plot of in-hospital mortality in children with congenital heart disease.
function commonly decreased in such patients. There is
also evidence that both acute and chronic renal
dysfunction might contribute to myocardial damage . ECMO
is a lifesaving technique used in critical care patients
presenting acute cardiac and/or pulmonary dysfunctions. It
has been reported that FO during ECMO support is
associated with increased risk of mortality . CRRT is an
important and efficient therapy that can be combined with
ECMO to treat AKI and FO.
There is wide variation in the application of CRRT
during ECMO. Besides the three methods we have
described previously, CRRT can also be performed under
gravity. A ? Y? tube system is used to deliver dialysis fluid,
with two plastic locks used to control the dialysis flow
speed. Effluent fluid is collected in two five-liter bags
located below the patient. Ponte et al. reported the
application of this method in a 22-year-old man, and
achieved a zero net balance throughout the procedure
; in fact, this method could be considered as a
variant of the in-line hemofilter method. Yap et al. reported
a different direction of blood flow through the
hemofilter in their study, in which the inlet catheter of the
hemofilter was connected to the proximal limb (before
the pump) of the ECMO circuit and the outlet, to the
distal limb (after the pump) . The results of an
international cross-sectional survey show that 21.5% (14/65)
of centers used an in-line hemodiafilter exclusively and
50.8% (33/65) of centers exclusively introduced a CRRT
device into the ECMO circuit . The most frequently
reported indications were FO (43%), prevention of
FO (16%), AKI (35%), electrolyte disturbances (4%) and
? other? (2%).
A higher mortality rate was observed after data
synthesis, which indicates that the requirement for renal
placement therapy could be the risk factor for mortality.
However, although mild heterogeneity was observed in
our study, additional sensitivity analysis showed no
heterogeneity after the exclusion of two studies that had
matched the baseline data of patients. No difference in
survival was observed in these two studies, which
suggests that adding CRRT to ECMO in a non-randomized
fashion reflects a relatively higher severity of illness in
patients. Data from an entirely heterogeneous group of
patients in terms of age and diagnosis may lead to
confounding effects; therefore, a subgroup of children with
congenital heart disease was analyzed and similar results
were obtained. Thus, it can be speculated that, as a
component of multiple organ dysfunction syndrome (MODS),
the presence of AKI itself rather than the requirement for
CRRT, is the independent risk factor for mortality in
critically ill patients undergoing ECMO. The difference in
ECMO duration can also be explained in this way.
A recently published paper by Luo et al.  showed
that AKI is associated with in hospital mortality in critically
ill patients, no matter if it was defined by RIFLE, AKIN
or KDIGO criteria. Worse outcome was associated with
increased severity of AKI. In populations needing ECMO,
a similar situation was observed [36,37]. In a cohort
study by Zwiers et al.  using RIFLE criteria, two
thirds of neonates receiving ECMO had AKI, and the
mortality risk in the Failure category was significantly
increased. We attempted to assess differences in AKI
between ECMO and ECMO plus CRRT groups; however,
few data were available and, thus, we were unable to
finish the assessment.
In both adults and children, a number of studies have
shown that a lower FO index at CRRT initiation
improves survival [33,38-40]. It has been reported that
cumulative FO is independently associated with mortality,
worse oxygenation, prolonged ICU stay and duration of
mechanical ventilation in critically ill patients receiving
CRRT . CRRT provides an easily initiated and efficient
method of fluid management. The potential benefit of
CRRT and improved fluid balance is indicated by some
theoretical advantages, such as enhancing the removal of
inflammatory mediators; allowing for more aggressive
intervention with nutritional support and achieving more
rapid optimal caloric intake .
Hemolysis could be a specific complication of
combining ECMO and CRRT, with erythrocyte
fragmentation caused by the combination of shear stress, positive
pressure, wall impact forces and properties of
nonendothelialized surfaces . The ECMO + CRRT group
had a higher peak FHb level compared with the ECMO
alone group in the two studies in which hemolysis was
investigated. A higher peak FHb level could be a negative
predictor of the change in renal function, possibly due to
adverse effects of excess FHb on multi-organ system
function. The tetrameric hemoglobin dissociates into dimers
after release from cells, which are easily filtered by the
glomeruli . FHb precipitates and causes intra-tubular
obstruction under acidic conditions, especially with
volume depletion, resulting in acute tubular necrosis and
acute renal failure. Furthermore, Gbadegesin et al.
reported that the circulating FHb adversely affects cardiac
recovery and the removal from ECMO . A
retrospective study of children receiving ECMO showed that, after
controlling for baseline data, a higher mortality rate and
longer ECMO duration was observed in children
presenting hemolysis .
Despite the presence of hemolysis, the recovery of
renal function seems to be satisfactory. In the absence of
primary renal disease presentation, chronic renal failure
did not occur in ECMO patients treated
concomitantly with CRRT. In the four studies that reported the
recovery of renal function, only one reported a case of a
15-year-old male who developed pulmonary hemorrhage,
AKI and respiratory failure. The renal biopsy demonstrated
microscopic polyangiitis and the patient received a renal
transplant due to irreversible renal injury . This
finding is also suggested by Meyer et al. . In their
study, most of the survivors (93%) showed recovery
of renal function without a continuing need for RRT.
The only exception was a patient with primary renal
disease, in whom poor renal function was probably
unrelated to either ECMO or CRRT. This finding could
encourage less reticence in the utilization of CRRT
This study has important limitations. There could be
greater heterogeneity in a systematic review of
nonrandomized studies than that of randomized trials .
Furthermore, it is recommended that the results from
different study designs should be expected to differ
systematically; hence, we conducted a review with limited
data synthesis rather than a formal meta-analysis, and
divided enrolled studies into subgroups according to the
study designs or according to the age and diagnosis.
Nevertheless, the trend in the mortality rate was similar
in the different subgroups. It should be emphasized that,
due to the heterogeneity, the pooled data should be
considered as a clinical reference/hint rather than a
validated conclusion. Further prospective studies are needed
to determine whether this technique can improve the
outcome of critically ill patients. It has been
demonstrated that combining ECMO and CRRT may enhance
hemolysis [13,15]; however, there were no studies
comparing the difference in the occurrence of hemolysis
between the methods using an in-line hemofilter and those
that combined a CRRT device.
The combination of ECMO and CRRT might be a safe
and effective technique that improves fluid balance and
ameliorates electrolyte disturbances. A variety of methods
for combining ECMO and CRRT can be chosen. A
prospective multicenter study would be beneficial in
determining the potential of this technique to improve the outcome
of critically ill patients.
Nineteen studies were included in this systematic
review to assess the feasibility, efficacy and safety of
the combination of ECMO and CRRT and to
illustrate the indications and methodology of
providing renal replacement therapy during the
There are three major methods for performing
CRRT during ECMO: ? independent CRRT access? ,
? introduction of a hemofiltration filter into the
ECMO circuit (in-line hemofilter)? and ? introduction
of a CRRT device into the ECMO circuit? .
The combination of ECMO and CRRT might be a
safe and effective technique that improves fluid
balance and ameliorates electrolyte disturbances.
Prospective studies are warranted to determine the
potential of this technique to improve the outcome
in critically ill patients.
Additional file 1: Technical parameters of included studies.
AKI: acute kidney injury; CAVH: continuous arteriovenous hemofiltration;
CAVHD: continuous arteriovenous hemodialysis; CAVHDF: continuous
arteriovenous hemodiafiltration; CI: confidence interval; CINAHL: Cumulative
Index of Nursing and Allied Health Literature; CRRT: continuous renal
replacement therapy; CVVH: continuous venovenous hemofiltration;
CVVHD: continuous venovenous hemodialysis; CVVHDF: continuous venovenous
hemodiafiltration; ECMO: extracorporeal membrane oxygenation; FHb: free
hemoglobin; FO: fluid overload; ICU: intensive care unit; MODS: multiple organ
dysfunction syndrome; NOS: Newcastle - Ottawa quality assessment scale;
OR: odds risk; PD: peritoneal dialysis; RCT: randomized controlled trial; RRT: renal
replacement therapy; SCUF: slow continuous ultrafiltration; VA-ECMO: venoarterial
extracorporeal membrane oxygenation; VV-ECMO: venovenous extracorporeal
HC and RGY participated in the database search, study selection and quality
assessment, data extraction, performing the statistical analysis, and drafted
the manuscript. The two authors contribute equally in this study. NNY
participated in the design of the study and performed the statistical analysis.
JXZ conceived of the study, and participated in its design and coordination
and helped to draft the manuscript. All authors edited the manuscript. All
authors read and approved the final manuscript.
We thank Tengfei Yu for drawing the schematic of the two typical methods
of combining ECMO and the CRRT circuit. This study was supported by
grants from the National Clinical Key Specialty (2011170).The funders had no
role in study design, data collection and analysis, decision to publish or
preparation of the manuscript.
1. Akcan-Arikan A , Zappitelli M , Loftis L , Washburn K , Jefferson L , Goldstein S : Modified RIFLE criteria in critically ill children with acute kidney injury . Kidney Int 2007 , 71 : 1028 ? 1035 .
2. Bellomo R , Ronco C , Kellum JA , Mehta RL , Palevsky P , Acute Dialysis Quality Initiative workgroup: Acute renal failure-definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group . Crit Care 2004 , 8 : R204? R212.
3. Gadepalli SK , Selewski DT , Drongowski RA , Mychaliska GB : Acute kidney injury in congenital diaphragmatic hernia requiring extracorporeal life support: an insidious problem . J Pediatr Surg 2011 , 46 : 630 ? 635 .
4. Lin CY , Chen YC , Tsai FC , Tian YC , Jenq CC , Fang JT , Yang CW : RIFLE classification is predictive of short-term prognosis in critically ill patients with acute renal failure supported by extracorporeal membrane oxygenation . Nephrol Dial Transplant 2006 , 21 : 2867 ? 2873 .
5. Smith AH , Hardison DC , Worden CR , Fleming GM , Taylor MB : Acute renal failure during extracorporeal support in the pediatric cardiac patient . ASAIO J 2009 , 55 : 412 ? 416 .
6. Yan X , Jia S , Meng X , Dong P , Jia M , Wan J , Hou X : Acute kidney injury in adult postcardiotomy patients with extracorporeal membrane oxygenation: evaluation of the RIFLE classification and the Acute Kidney Injury Network criteria . Eur J Cardiothorac Surg 2010 , 37 : 334 ? 338 .
7. Hoste EA , Dhondt A : Clinical review: use of renal replacement therapies in special groups of ICU patients . Crit Care 2012 , 16 : 201 .
8. Fleming GM , Askenazi DJ , Bridges BC , Cooper DS , Paden ML , Selewski DT , Zappitelli M : A multicenter international survey of renal supportive therapy during ECMO: the Kidney Intervention During Extracorporeal Membrane Oxygenation (KIDMO) group . ASAIO J 2012 , 58 : 407 ? 414 .
9. Askenazi DJ , Selewski DT , Paden ML , Cooper DS , Bridges BC , Zappitelli M , Fleming GM : Renal replacement therapy in critically ill patients receiving extracorporeal membrane oxygenation . Clin J Am Soc Nephrol 2012 , 7 : 1328 ? 1336 .
10. Oremus M , Wolfson C , Perrault A , Demers L , Momoli F , Moride Y : Interrater reliability of the modified Jadad quality scale for systematic reviews of Alzheimer? s disease drug trials . Dement Geriatr Cogn Disord 2001 , 12 : 232 ? 236 .
11. Wells G , Shea B , O? Connell D , Peterson J , Welch V , Losos M , Tugwell P : The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses . 2011 [http://www.ohri.ca/ programs/clinical_epidemiology/oxford.asp]
12. Higgins JP , Green S : Cochrane Handbook for Systematic Reviews of Interventions version 5.1. 0 [updated March 2011 ]. The Cochrane Collaboration; 2011 . Available from www.cochrane-handbook .org.
13. Betrus C , Remenapp R , Charpie J , Kudelka T , Brophy P , Smoyer WE , Lin JJ : Enhanced hemolysis in pediatric patients requiring extracorporeal membrane oxygenation and continuous renal replacement therapy . Ann Thorac Cardiovasc Surg 2007 , 13 : 378 ? 383 .
14. Cavagnaro F , Kattan J , Godoy L , Gonzales A , Vogel A , Rodriguez J , Faunes M , Fajardo C , Becker P : Continuous renal replacement therapy in neonates and young infants during extracorporeal membrane oxygenation . Int J Artif Organs 2007 , 30 : 220 ? 226 .
15. Gbadegesin R , Zhao S , Charpie J , Brophy PD , Smoyer WE , Lin JJ : Significance of hemolysis on extracorporeal life support after cardiac surgery in children . Pediatr Nephrol 2009 , 24 : 589 ? 595 .
16. Hoover NG , Heard M , Reid C , Wagoner S , Rogers K , Foland J , Paden ML , Fortenberry JD : Enhanced fluid management with continuous venovenous hemofiltration in pediatric respiratory failure patients receiving extracorporeal membrane oxygenation support . Intensive Care Med 2008 , 34 : 2241 ? 2247 .
17. Paden ML , Warshaw BL , Heard ML , Fortenberry JD : Recovery of renal function and survival after continuous renal replacement therapy during extracorporeal membrane oxygenation . Pediatr Crit Care Med 2011 , 12 : 153 ? 158 .
18. Ricci Z , Morelli S , Favia I , Garisto C , Brancaccio G , Picardo S : Neutrophil gelatinase-associated lipocalin levels during extracorporeal membrane oxygenation in critically ill children with congenital heart disease: preliminary experience . Pediatr Crit Care Med 2012 , 13 :e51? e54.
19. Wolf MJ , Chanani NK , Heard ML , Kanter KR , Mahle WT : Early renal replacement therapy during pediatric cardiac extracorporeal support increases mortality . Ann Thorac Surg 2013 , 96 : 917 ? 922 .
20. Goto T , Suzuki Y , Osanai A , Aoki K , Yamazaki A , Daitoku K , Fukuda I : The impact of extracorporeal membrane oxygenation on survival in pediatric patients with respiratory and heart failure: review of our experience . Artif Organs 2011 , 35 : 1002 ? 1009 .
21. Hamrick SE , Gremmels DB , Keet CA , Leonard CH , Connell JK , Hawgood S , Piecuch RE : Neurodevelopmental outcome of infants supported with extracorporeal membrane oxygenation after cardiac surgery . Pediatrics 2003 , 111 : E671? E675.
22. Yap HJ , Chen YC , Fang JT , Huang CC : Combination of continuous renal replacement therapies (CRRT) and extracorporeal membrane oxygenation (ECMO) for advanced cardiac patients . Ren Fail 2003 , 25 : 183 ? 193 .
23. Kolovos NS , Bratton SL , Moler FW , Bove EL , Ohye RG , Bartlett RH , Kulik TJ : Outcome of pediatric patients treated with extracorporeal life support after cardiac surgery . Ann Thorac Surg 2003 , 76 : 1435 ? 1441 .
24. Luo XJ , Wang W , Sun HS , Hu SS , Long C , Xu JP , Song YH , Hei FL : Extracorporeal membrane oxygenation for treatment of cardiorespiratory function failure in adult patients . Zhonghua Wai Ke Za Zhi 2009 , 47 : 1563 ? 1565 . In Chinese.
25. Luo XJ , Wang W , Sun HS , Xu JP , Hu SS , Long C , Song YH , Hei FL : Extracorporeal cardiopulmonary resuscitation in adult patients with cardiac arrest . Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2010 , 22 : 82 ? 84 . In Chinese.
26. Blijdorp K , Cransberg K , Wildschut ED , Gischler SJ , Jan Houmes R , Wolff ED , Tibboel D : Haemofiltration in newborns treated with extracorporeal membrane oxygenation: a case-comparison study . Crit Care 2009 , 13 : R48 .
27. Santiago MJ , S?nchez A, L? pez-Herce J , P? rez R , del Castillo J , Urbano J , Carrillo A : The use of continuous renal replacement therapy in series with extracorporeal membrane oxygenation . Kidney Int 2009 , 76 : 1289 ? 1292 .
28. Ricci Z , Morelli S , Vitale V , Di Chiara L , Cruz D , Picardo S : Management of fluid balance in continuous renal replacement therapy: technical evaluation in the pediatric setting . Int J Artif Organs 2007 , 30 : 896 ? 901 .
29. Rubin S , Poncet A , Wynckel A , Baehrel B : How to perform a haemodialysis using the arterial and venous lines of an extracorporeal life support . Eur J Cardiothorac Surg 2010 , 37 : 967 ? 968 .
30. Sucosky P , Dasi LP , Paden ML , Fortenberry JD , Yoganathan AP : Assessment of current continuous hemofiltration systems and development of a novel accurate fluid management system for use in extracorporeal membrane oxygenation . J Med Devices-Trans ASME 2008 , 2 : 035002 .
31. Symons JM , McMahon MW , Karamlou T , Parrish AR , McMullan DM : Continuous renal replacement therapy with an automated monitor is superior to a free-flow system during extracorporeal life support . Pediatr Crit Care Med 2013 , 14 : E404? E408.
32. Ronco C , Chionh CY , Haapio M , Anavekar NS , House A , Bellomo R : The cardiorenal syndrome . Blood Purif 2009 , 27 : 114 ? 126 .
33. Selewski DT , Cornell TT , Blatt NB , Han YY , Mottes T , Kommareddi M , Gaies MG , Annich GM , Kershaw DB , Shanley TP , Heung M : Fluid overload and fluid removal in pediatric patients on extracorporeal membrane oxygenation requiring continuous renal replacement therapy . Crit Care Med 2012 , 40 : 2694 ? 2699 .
34. Ponte B , Tenorio MT , Hiller R , Candela A , Liano F : Continuous dialysis by gravity through the filter of the extracorporeal membrane oxygenation . Nephrol Dial Transplant 2007 , 22 : 3676 ? 3677 .
35. Luo X , Jiang L , Du B , Wen Y , Wang M , Xi X : A comparison of different diagnostic criteria of acute kidney injury in critically ill patients . Crit Care 2014 , 18 : R144 .
36. Askenazi DJ , Ambalavanan N , Hamilton K , Cutter G , Laney D , Kaslow R , Georgeson K , Barnhart DC , Dimmitt RA : Acute kidney injury and renal replacement therapy independently predict mortality in neonatal and pediatric noncardiac patients on extracorporeal membrane oxygenation . Pediatr Crit Care Med 2011 , 12 :e1? e6.
37. Zwiers AJ , de Wildt SN , Hop WC , Dorresteijn EM , Gischler SJ , Tibboel D , Cransberg K : Acute kidney injury is a frequent complication in critically ill neonates receiving extracorporeal membrane oxygenation: a 14-year cohort study . Crit Care 2013 , 17 : R151 .
38. Foland JA , Fortenberry JD , Warshaw BL , Pettignano R , Merritt RK , Heard ML , Rogers K , Reid C , Tanner AJ , Easley KA : Fluid overload before continuous hemofiltration and survival in critically ill children: a retrospective analysis . Crit Care Med 2004 , 32 : 1771 ? 1776 .
39. Gillespie RS , Seidel K , Symons JM : Effect of fluid overload and dose of replacement fluid on survival in hemofiltration . Pediatr Nephrol 2004 , 19 : 1394 ? 1399 .
40. Goldstein SL , Somers MJ , Baum MA , Symons JM , Brophy PD , Blowey D , Bunchman TE , Baker C , Mottes T , McAfee N , Barnett J , Morrison G , Rogers K , Fortenberry JD : Pediatric patients with multi-organ dysfunction syndrome receiving continuous renal replacement therapy . Kidney Int 2005 , 67 : 653 ? 658 .
41. Mulholland JW , Massey W , Shelton JC : Investigation and quantification of the blood trauma caused by the combined dynamic forces experienced during cardiopulmonary bypass . Perfusion 2000 , 15 : 485 ? 494 .
42. Bunn HF , Esham WT , Bull RW : The renal handling of hemoglobin I. Glomerular filtration . J Exp Med 1969 , 129 : 909 ? 924 .
43. Lou S , MacLaren G , Best D , Delzoppo C , Butt W : Hemolysis in pediatric patients receiving centrifugal-pump extracorporeal membrane oxygenation: prevalence, risk factors, and outcomes . Crit Care Med 2014 , 42 : 1213 ? 1220 .
44. Meyer RJ , Brophy PD , Bunchman TE , Annich GM , Maxvold NJ , Mottes TA , Custer JR : Survival and renal function in pediatric patients following extracorporeal life support with hemofiltration . Pediatr Crit Care Med 2001 , 2 : 238 ? 242 .