Effect of Continuous Renal Replacement Therapy
on Outcome in Pediatric Acute Liver Failure*
Akash Deep, MD, FRCPCH1; Claire E. Stewart, MBBS, BSc1; Anil Dhawan, MD, FRCPCH2;
Abdel Douiri, BSc, MSc, PhD, FHEA3
Objectives: To establish the effect of continuous renal replace-
ment therapy on outcome in pediatric acute liver failure.
Design: Retrospective cohort study.
Setting: Sixteen-bed PICU in a university-affiliated tertiary care
hospital and specialist liver centre.
Patients: All children (0–18 yr) admitted to PICU with pedi-
atric acute liver failure between January 2003 and December
2013.
Interventions: Children with pediatric acute liver failure were man-
aged according to a set protocol. The guidelines for continuous
renal replacement therapy in pediatric acute liver failure were
changed in 2011 following preliminary results to indicate the
*See also p. 1949.
1
Pediatric Intensive Care Unit, King’s College Hospital, London, United
Kingdom.
2
Pediatric Hepatology, Gastroenterology and Nutrition Center, King’s
College Hospital, London, United Kingdom.
3
Department of Primary Care and Public Health Sciences, NIHR Biomedi-
cal Research Centre at Guy’s and St Thomas’ NHS Foundation Trust,
King’s College, London, United Kingdom.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions
of this article on the journal’s website (http://journals.lww.com/ccmjournal).
All authors declare that the answer to the questions on your competing
interest form, www.icmje.org/coi_disclosure.pdf, are all no and therefore
have nothing to declare.
Dr. Deep is the supervisor who conceptualized the project and supervised
data collection, interpretation and has reviewed and edited the article. He
is the corresponding author. Dr. Stewart collected the data, analyzed the
initial data and wrote the article. Dr. Dhawan is the hepatology consultant
who has helped in the discussion of the results and interpretation of data
and article revision. Dr. Douiri is the statistician who performed the data
analysis and statistical inferences.
Dr. Abdel Douiri acknowledges financial support from the National Institute for
Health Research (NIHR) Biomedical Research and from the NIHR Collabora-
tion for Leadership in Applied Health Research and Care, South London, at
King’s College Hospital, National Health Service Foundation Trust though not
for this project. The views expressed are those of the authors and not neces-
sarily those of the NHS, the NIHR, or the Department of Health. The remaining
authors have disclosed that they do not have any potential conflicts of interest.
Address requests for reprints to: Akash Deep, MD, FRCPCH, PICU,
King’s College Hospital, Denmark Hill, London, United Kingdom. E-mail:
akash.deep@nhs.net
Copyright © 2016 by the Society of Critical Care Medicine and Wolters
Kluwer Health, Inc. All Rights Reserved.
DOI: 10.1097/CCM.0000000000001826
1910 www.ccmjournal.org October 2016 • Volume 44 • Number 10
Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
earlier use of continuous renal replacement therapy for both renal
dysfunction and detoxification.
Measurements and Main Results: Of 165 children admitted with
pediatric acute liver failure, 136 met the inclusion criteria and 45 of
these received continuous renal replacement therapy prior to trans-
plantation or recovery. Of the children managed with continuous
renal replacement therapy, 26 (58%) survived: 19 were success-
fully bridged to liver transplantation and 7 spontaneously recovered.
Cox proportional hazards regression model clearly showed reduc-
ing hyperammonemia by 48 hours after initiating continuous renal
replacement therapy significantly improved survival (HR, 1.04; 95%
CI, 1.013–1.073; p = 0.004). On average, for every 10% decrease
in ammonia from baseline at 48 hours, the likelihood of survival
increased by 50%. Time to initiate continuous renal replacement
therapy from PICU admission was lower in survivors compared to
nonsurvivors (HR, 0.96; 95% CI, 0.916–1.007; p = 0.095). Change
in practice to initiate early and high-dose continuous renal replace-
ment therapy led to increased survival with maximum effect being
visible in the first 14 days (HR, 3; 95% CI, 1.0–10.3; p = 0.063).
Among children with pediatric acute liver failure who did not receive
a liver transplant, use of continuous renal replacement therapy sig-
nificantly improved survival (HR, 4; 95% CI, 1.5–11.6; p = 0.006).
Conclusion: Continuous renal replacement therapy can be used suc-
cessfully in critically ill children with pediatric acute liver failure to pro-
vide stability and bridge to transplantation. Inability to reduce ammonia
by 48 hours confers poor prognosis. Continuous renal replacement
therapy should be considered at an early stage to help prevent fur-
ther deterioration and buy time for potential spontaneous recovery or
bridge to liver transplantation. (Crit Care Med 2016; 44:1910–1919)
Key Words: acute liver failure; children; outcomes; renal
replacement therapy
P
ediatric acute liver failure (PALF) is a rare but often
fatal disorder. Although some children spontaneously
recover, mortality remains high due to the high risk of
sepsis, cerebral edema, and multi-organ failure that follows
the abrupt loss of hepatic function. Mortality rates of up to
70% have been reported without a liver transplant, which is the
only known curative treatment (1). However, knowing which

children will recover and in how much time, and which ones
will rapidly deteriorate, remains an enigma for intensivists
(2). In the wake of organ scarcity on one hand and subjecting
children to unnecessary transplantation with risks of surgery
and life-long immunosuppression on the other, the role of
supportive therapies to stabilize a child to help facilitate these
decisions is an area of growing importance (3–5).
One of the most significant achievements in intensive
care medicine in the last 40 years has been the development
of continuous renal replacement therapy (CRRT) (6). CRRT
is now the mainstay treatment for managing acute kidney
injury (AKI) in PICUs and has significantly reduced mortality
(7–9). AKI is a common multifactorial complication of PALF
that occurs in approximately 55% of all cases (10–12). Renal
dysfunction pretransplant determines the degree of renal dys-
function posttransplant. Therefore, tackling AKI pretransplant
should improve the condition of the patient posttransplant.
In these patients, CRRT has also been shown to successfully
reduce ammonia (13), reduce lactate (14, 15), and optimize
fluid balance (16). However, all of these observations have
been reported in adult patients. Recent research on critically
ill children with PALF has demonstrated that high ammonia
(17, 18), high lactate (19), and fluid overload (20) are associ-
ated with increased mortality. In addition to the risk of AKI
in PALF, hyperammonemia contributes to the development
of cerebral edema, and there is a strong risk of fluid overload
especially after fluid resuscitation due to the systemic inflam-
matory response syndrome. This raises the question whether
the use of CRRT should be extended to nonrenal indications in
patients with PALF, as a detoxification mechanism.
Despite its rapidly increasing uptake, evidence to evaluate
whether CRRT is of justifiable benefit in these situations is cur-
rently lacking (21), and there are no agreed guidelines on when
or what dose it should be initiated in PALF. This study aimed
to describe our experience on the use of CRRT in PALF from
over a decade of data.
MATERIALS AND METHODS
Study Population
King’s College Hospital is a supra-regional centre for liver refer-
rals in the United Kingdom and operates one of the largest liver
transplantation programs in Europe. All children admitted to the
PICU at King’s College Hospital that met the criteria for PALF
from January 2003 to December 2013 were entered into the PALF
registry. PALF was defined according to the criteria used by the
PALF Study Group (22): “1) No evidence of preexisting chronic
liver disease; 2) Biochemical evidence of acute liver injury (eleva-
tion in aspartate aminotransferase/alanine aminotransferase)
within 8 weeks of the onset of symptoms; 3) Hepatic-based coag-
ulopathy (prothrombin time [PT] > 15 or international normal-
ized ratio [INR] > 1.5 in the presence of hepatic encephalopathy
[HE] or PT > 20 or INR > 2 in the absence of HE) within 8 weeks
of the onset of symptoms.” Children with PALF admitted to the
PICU for only posttransplant care were excluded. Children who
were commenced on CRRT prior to transplantation or recovery
Critical Care Medicine www.ccmjournal.org 1911
Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Pediatric Critical Care
Figure 1. Study profile. CRRT = continuous renal replacement therapy,
PALF = pediatric acute liver failure.
were included in the CRRT treatment group (Fig. 1). Factors
affecting survival in children with PALF treated with CRRT were
studied. Due to preliminary findings, the guideline for CRRT in
PALF was changed in 2011; therefore the clinical outcomes in
these two eras, pre- and post-2011, have been compared.
Data Collection
Medical records, laboratory data, and observation charts were
reviewed for all patients in the PALF registry. Patient charac-
teristics including age, gender, height, weight, details and dura-
tion of presenting symptoms and signs, time to first medical
contact, time to PICU transfer, and prereferral care were also
recorded. Etiology of PALF was classified into seven categories:
indeterminate, toxic, infectious, metabolic, ischemic, infiltra-
tive, and autoimmune.
For clinical observations and laboratory data, admission and
peak values within the first 24 hours were recorded from the
unit’s Clinical Information System. Pediatric Logistic Organ
Dysfunction (PELOD) score and Pediatric Index of Mortality
(PIM) 2 were calculated for each patient (23). Timing of list-
ing for liver transplantation and indication along with trans-
plant date, type, and details of any postoperative complications
and the date that the child was removed from the list due to
spontaneous recovery or clinical deterioration were included.
Duration of PICU stay, survival on hospital discharge, and sur-
vival at 6 months postdischarge were also recorded.
For children commenced on CRRT, time from PICU admis-
sion to initiation of CRRT, indication, duration, and markers of
disease progression at 0, 24, and 48 hours after starting CRRT
including arterial ammonia, lactate, mean arterial blood pres-
sure, percentage fluid overload, and creatinine were recorded.
Indications for CRRT were classified into the following
eight categories: oligo-anuria, hyperkalemia greater than 5.5
mmol/L, fluid overload greater than 10%, hyperammonemia
greater than 200 μmol/L, hepatic encephalopathy grade greater
than 2, hyponatremia less than 130 mEq/L, lactate greater than
2 μmol/L not responding to fluid therapy, or metabolic acido-
sis pH less than 7.1 resistant to fluid therapy. Importantly, not
Deep et al
one single indication was considered a sole reason to initiate
CRRT; it was a clinical decision and all contributory factors
were recorded. The daily percentage fluid overload prior to and
post initiation of CRRT was calculated using the formula by
Goldstein et al (24).
Any complications secondary to CRRT including catheter
malfunction, anticoagulation problems, bleeding, thrombosis,
infection, or shock were also recorded.
CRRT
The duty consultant pediatric intensivist determined the
requirement for CRRT. CRRT was commenced according to
a local protocol with predilution to achieve required ammo-
nia and lactate clearances and electrolyte and fluid homeo-
stasis (Table 1). All children had ultrasound-guided venous
access via a high flow double lumen catheter (“Vascath”;
Gambro, Stockholm, Sweden) placed either in the internal
jugular, subclavian, or the femoral vein. The sizes of the double
lumen venous access catheters used were predefined accord-
ing to body weight—6.5F (14%), 8F (28%), 10F (15%), 11.5F
(32%), and 13.5F (11%). Children with less than 10 kg were
filtered using HF03, 10–50 kg using HF07, and greater than
50 kg using HF1200 (membrane surface area: HF03 = 0.3 m2,
HF07 = 0.7 m2, and HF1200 = 1.2 m2). All the filters were made
of polyethersulfone fiber. Predilution was incorporated in all
filtration episodes using “Accusol 35,” a lactate-free electrolyte
solution. The net delivered dose varied and on an average was
8.2 ± 1.1 mL/kg/hr less than the prescribed dose.
The machine used for CRRT was “Aquarius” (Nikkiso Europe
GmbH, Hannover, Germany). Details of CRRT recorded
included vascath size and location, anticoagulation dose, filter
life, dose of CRRT, and complications. Blood flow rates ranged
from 50 to 250 mL/min depending on age (Table 1). Predilution
continuous venovenous hemofiltration was the most commonly
used modality. Anticoagulation used was prostacyclin (2–6 ng/
kg/min) if the activated clotting time (ACT) was 160–220 sec-
onds and low-dose heparin if the ACT was less than 160 sec-
onds unless contraindicated. If ACT is more than 220 seconds,
no anticoagulation was used. To facilitate toxin removal, CRRT
dose was sequentially increased to a maximum of 100 mL/kg/hr.
Statistical Analysis
Statistical data were analyzed with STATA software version
14 (StataCorp, College Station, TX). Continuous data were
Table 1. Continuous Renal Replacement Therapy Set Up Using Continuous Venovenous
hemofiltration
Weight (kg) < 3.5 3.5–4.9
Filter size HF03 HF03
Aqualine size S S
Blood flow rate (mL/min) 50 50–80
Effluent flow rate (mL/kg/hr) 60 60
Priming volume (mL) 96 96
1912 www.ccmjournal.org October 2016 • Volume 44 • Number 10
Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
expressed as the mean ± sd and categorical data as the actual
count with percentages unless stated otherwise. The primary
outcome of this study was survival up to 60 days after the PICU
admission with or without liver transplantation: 1) death await-
ing transplantation, 2) death after transplantation, 3) alive with
native liver, and 4) alive with transplanted organ. Secondary
outcome measures included the trend in markers for disease
progression after initiating CRRT. The data were analyzed to see
what, if any, variables at admission were associated with mortal-
ity and to identify prognostic markers in children with PALF
on CRRT. Univariate analysis was performed to compare vari-
ables between survivors and nonsurvivors at hospital discharge
using the unpaired t test for continuous data and Fisher exact
test for categorical data. For analyzing trends in markers of dis-
ease progression, regression lines and box plots were used and
compared by primary outcome. Analysis of variance (ANOVA)
and covariance was used to compare disease severity markers
at 0, 24, and 48 hours after initiation of CRRT. Kaplan-Meier
curves and Cox model were used to look at survival of children
up to 60 days after admission. Data were adjusted for severity of
illness using the PELOD scoring system. A p value of less than
0.05 was considered statistically significant.
Ethics
Since it was a retrospective analysis of already collected routine
data, ethical approval was not deemed necessary.
RESULTS
Baseline Characteristics
From January 2003 to December 2013, 136 patients with PALF
met the inclusion criteria of being managed on the unit prior
to transplantation or recovery. Forty-five of these children
received CRRT as part of their management (Fig. 1). A com-
parison between patient demographics and selected physi-
ologic and laboratory values on admission to PICU are shown
in Supplementary Table 1 (Supplemental Digital Content 1,
http://links.lww.com/CCM/B878). Among the patients who
underwent CRRT, the common etiology was indeterminant
(53%) followed by metabolic (20%) and toxic (13%).
Baseline characteristics between survivors and nonsurvivors
treated with CRRT were compared (Table 2). Nonsurvivors were
significantly younger (p = 0.017) and weighed less (p = 0.006).
They also spent on average 10 days more on the ward prior
5–14.9 15–29.9 30–49.9 > 50
HF03 HF07+ HF07+ HF07+
S S S Adult
100 150 200 250
60 60 60 3,000 maximum
96 118 159 159
 Pediatric Critical Care

Table 2. Baseline Characteristics on Admission to PICU for Children Started on

Continuous Renal Replacement Therapy for Pediatric Acute Liver Failure
All CRRT Survivors Nonsurvivors p (Survivors vs
Parameter (n = 45) (n = 26) (n = 19) Nonsurvivors)

Age, mo 68 ± 9.8 88 ± 13.4 41 ± 12.1 0.017

Female, n (%) 18 (40) 10 (38) 8 (42) 0.811
Male, n (%) 27 (60) 16 (62) 11 (58) 0.811
Weight (kg) 23.5 ± 3.9 32.8 ± 5.8 11.9 ± 3.2 0.006
Time on the ward prior to PICU transfer, d 10.7 ± 2.8 6.5 ± 1.2 16.3 ± 6.1 0.051
Etiology of pediatric acute liver failure, n (%)
 Indeterminate 24 (53) 16 (62) 8 (42) 0.206
 Toxic 6 (13) 6 (23) 0 (0) 0.024
 Infectious 3 (7) 2 (8) 1 (5) 0.754
 Metabolic 9 (20) 2 (8) 7 (37) 0.015
 Ischemic 1 (2) 0 (0) 1 (5) 0.247
 Infiltrative 2 (4) 0 (0) 2 (11) 0.086
Encephalopathy grade ≥ 2, n (%) 12 (27) 5 (19) 7 (37) 0.078
Mean arterial pressure, mm Hg 66 ± 2.4 65 ± 3.3 67 ± 3.8 0.717
Urine output, mL/kg/hr 2.6 ± 0.5 2.3 ± 0.6 3.0 ± 1.0 0.552
Lactate, mmol/L 5.1 ± 0.7 4.6 ± 0.9 5.8 ± 1.1 0.366
Ammonia, μmol/L (0 hr) 173 ± 14.9 153 ± 13.7 212 ± 33.1 0.061
Ammonia, μmol/L (24 hr) 159 ± 17.8 110 ± 11.5 198 ± 24.7 0.009
Ammonia, μmol/L (48 hr) 165 ± 34.1 90 ± 11.1 253 ± 54.9 0.009
Bilirubin 283.09 ± 25.8 314 ± 37.3 246.2 ± 31.6 0.200
Creatinine 68 ± 9.6 72 ± 10.1 62 ± 18.0 0.593
Aspartate aminotransferase, μmol/L 2,486 ± 547 3,075 ± 892 1,741 ± 488 0.229
International normalized ratio 4.8 ± 0.2 4.0 ± 0.4 5.5 ± 0.3 0.062
Platelets, 10 /L9
194 ± 20.2 212 ± 28.0 170 ± 28.5 0.403
Pediatric Logistic Organ Dysfunction score 9.6 ± 1.1 8.4 ± 1.3 11.1 ± 1.9 0.228
Inotropes, n (%) 42 (93) 23 (88) 19 (100) 0.131
Intubated and ventilated, n (%) 45 (100) 26 (100) 19 (100) Not applicable
Time to initiation of CRRT (hr) a
27.0 ± 6.9 15.8 ± 3.0 32.4 ± 6.9 0.023
CRRT = continuous renal replacement therapy.

to PICU transfer (p = 0.051). Toxic (p = 0.024) or metabolic
(p = 0.015) etiology was associated with higher mortality. Peak
arterial ammonia in the first 24 hours of admission were also
significantly higher among nonsurvivors (p = 0.025). All chil-
dren who died on CRRT were ventilated and on inotropes.
Anticoagulation and Complications in CRRT
A total of 198 filters were utilized between the 45 patients
receiving CRRT for PALF. Prostacyclin was used in 72% of
these filters, unfractionated heparin in 18% filters, and no anti-
coagulant in 10%. Median filter life was 59 hours (44.7–60.2)
using prostacyclin, 27 hours (21.1–33.7) using heparin, and
20 hours (14.6–25.3) using no anticoagulation. Safety and effi-
cacy of prostacyclin as an anticoagulant was acceptable with
1.9 bleeding episodes per 1,000 hours of CRRT and hypoten-
sion requiring fluids or vasopressors occurring in less than
10% of filter episodes. The site of venous access (femoral vs
internal jugular) did not contribute to circuit life among this
subgroup. There was one episode of hemopneumothorax with
internal jugular venous catheter insertion and three episodes
of vascular access rewiring due to thrombus; overall the proce-
dure was well tolerated.

Critical Care Medicine www.ccmjournal.org 1913

Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Deep et al

Effect on Outcome
Overall survival of patients
with ALF on CRRT at dis-
charge was 58% (Fig. 2). A
significant increase in mor-
tality was seen in children
who were less than 1-year old
(heart rate [HR], 6; 95% CI,
2.0–18.2; p = 0.001; Fig. 3).
Severity was adjusted for by
the PELOD score as opposed
to the PIM2 score as it does
not accurately reflect out-
comes in PALF (25).
Twenty-six of the 45
patients were bridged success-
Figure 2. Outcome of all children with pediatric acute liver failure (PALF) requiring continuous renal fully to either native organ
replacement therapy (CRRT). recovery (n = 7) or successful
liver transplantation (n = 19).
In total, 24 patients requiring
CRRT underwent a liver trans-
plant and 79% of these sur-
vived. Of the 21 who did not,
only one third spontaneously
recovered. As liver transplanta-
tion interferes with the natu-
ral progression of disease, we
looked at the effect of CRRT
only in those children with
PALF who did not undergo
transplantation, that is, either
had spontaneous regeneration
of native liver or died with-
out a transplant—those who
received CRRT had a signifi-
cantly increased chance of sur-
vival (HR, 4; 95% CI, 1.5–11.6;
p = 0.006; Fig. 4).
Cox proportional hazards
regression model adjust-
Figure 3. Kaplan-Meir curve for 60-d survival of children with pediatric acute liver failure on continuous renal ing for severity of illness
replacement therapy. (PELOD), ammonia at pre-
sentation, ability of CRRT to
Timing of Initiation and Indications for CRRT decrease ammonia by 48 hours, and time to initiate CRRT
The median time to initiate CRRT from PICU admission was from PICU admission clearly shows that in spite of high
27 ± 6.9 hours and one in three were started on CRRT within ammonia levels in both survivors and nonsurvivors at ini-
the first 8 hours of admission to the unit. Median time to initi- tiation of CRRT, a decrease in ammonia by 48 hours of
ate CRRT in survivors was lower compared to nonsurvivors starting CRRT significantly improved survival (HR, 1.04;
(15.8 ± 3.0 vs 32.4 ± 6.9 hr; p = 0.023). Thirty patients (66.7%) 95% CI, 1.013–1.073; p = 0.004). On average, for every
had multiple indications for starting CRRT. The most common 10% decrease in ammonia from baseline at 48 hours, the
indications were oligo-anuria (n = 14; 31%), hyperammone- likelihood of survival increased by 50%. Time to initiate
mia (n = 13; 29%), hepatic encephalopathy (n = 12; 27%), high CRRT from PICU admission was also found to be lower
lactate (n = 10; 22%), fluid overload (n = 6,;13%), resistant in survivors compared to nonsurvivors, although statistical
metabolic acidosis (n = 3; 7%), resistant hyperkalemia (n = 1; significance is borderline (HR, 0.96; 95% CI, 0.916–1.007;
2%), and hyponatremia (n = 1; 2%). The mean duration of p = 0.095). For every 1 hour delay in initiating CRRT, likeli-
CRRT was 54 hours. hood of mortality increased by 4%.

1914 www.ccmjournal.org October 2016 • Volume 44 • Number 10

Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
 Pediatric Critical Care

Of note, when the prospec-

tive pediatric CRRT registry
was split into survival rates
according to the diagnoses that
led to the use of CRRT, chil-
dren with liver disease had the
lowest survival at 31% com-
pared to the 58% average for
all other diagnoses (26). In this
study, almost all children who
required CRRT also required
inotropes (91%) and ventila-
tion (100%). This suggests
that the children who went on
to require CRRT in PALF were
much more unstable during
their admission and highlights
just how sick these children
are. As such, it would be mis-
representative to compare out-
Figure 4. Kaplan-Meir curve for 60-d survival of children with pediatric acute liver failure on continuous renal comes of the treatment and
replacement therapy (CRRT) versus those not on CRRT in nontransplanted group. nontreatment group. Likewise,
it would be unethical to with-
Efficacy of CRRT hold CRRT from a critically ill child due to its proven success
To review the efficacy of CRRT in PALF, daily markers of dis- in AKI, a common complication of PALF, and anecdotal and
ease progression including arterial ammonia, lactate, percent- theoretical evidence for detoxification in PALF for the purpose
age fluid overload, creatinine, and mean arterial pressure were of a randomized controlled trial. As such evidence will need to
reviewed using ANOVA at 0, 24, and 48 hours after initiation of be sought through observational studies to establish the effect
CRRT (Table 3). There was a significant reduction in ammonia on outcome.
(p = 0.001) and lactate (p = 0.043) within 48 hours of initiating This study found that children frequently had more than
CRRT among survivors. Although the mean level of creatinine one indication for CRRT prior to commencing therapy.
and percentage fluid overload also decreased, the difference Traditionally, CRRT has been used to manage renal dysfunc-
was not statistically significant. tion, which is a common complication of PALF. It is impor-
Figure 5 is a box plot analysis of the trend in ammo- tant not to forget that AKI is often multifactorial in PALF
nia over time by mortality. This clearly demonstrates that with hypovolemia being the most common precipitating fac-
although ammonia is high at initiation of CRRT in both tor setting the stage for acute tubular necrosis (27). Although
survivors and nonsurvivors, in survivors the ammonia renal impairment was the indication for CRRT in a significant
is significantly lower after 48 hours of CRRT, whereas in number of patients included in this study (oligo-anuria, 31%;
nonsurvivors levels remained high (p ≤ 0.001). As demon- fluid overload, 13%; and resistant hyperkalemia, 2%), more
strated by multivariate analysis, inability of ammonia to be frequently CRRT is being used regardless of the presence or
removed even after 48 hours of CRRT is a poor prognostic absence of renal dysfunction as a detoxification mechanism.
sign (p = 0.004). The potential for recovery of native organ function coupled
Although not a controlled variable change, survival in PALF with the insufficient donor organ supply and risk of death or
increased by 9% from 65% before the change in guidelines in deterioration awaiting a compatible transplant, has focused
2011. Figure 6 shows the trend in survival pre and post guide- attention on using detoxification mechanisms as liver sup-
line change. The most significant difference was seen in the port devices until recovery from PALF or bridging to trans-
first 14 days (HR, 3; 95% CI, 1.0–10.3; p = 0.063). plantation. As such, initiating CRRT in PALF now serves a
dual purpose: 1) for managing the AKI and fluid imbalances,
DISCUSSION which frequently complicate cases and 2) as a detoxification
Despite the increasing use of CRRT in children with acute mechanism for the high ammonia, lactate, and metabolic dis-
liver failure (ALF), there is a paucity of data surrounding its turbances which set in.
effect on outcome and applicability as a detoxification mecha- In this study, two of the indications for initiating CRRT were
nism. The present study examined an 11-year institutional hyperammonemia greater than 200 µmol/L or hepatic enceph-
experience from the PICU at a specialist liver unit to evaluate alopathy greater than grade 2, which was present in a quarter
whether the use of CRRT in these critically ill children is of of children (29% and 27%, respectively). It is well established
justifiable benefit. that when ammonia is not metabolized by the failing liver, it

Critical Care Medicine www.ccmjournal.org 1915

Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Deep et al

Table 3. Analysis of Variance and among children whose level of arterial ammonia rose between
Covariance Between 0, 24, and 48 Hours of the value at admission to PICU to the value at initiation of
CRRT. This suggests that the intensivist should not wait, but
Initiating Continuous Renal Replacement
intervene early at the first sign of rising hyperammonemia.
Therapy; Trend in Mean Ammonia, Lactate, Ability to reduce ammonia after 48 hours of starting CRRT
and Percentage Fluid Overload Between was the most significant factor for survival on multivariate
Survivors and Nonsurvivors Before analysis (p = 0.004). This is important as in rapidly progressive
and After Starting Continuous Renal PALF, the first 24–48 hours are vital to create a good milieu
Replacement Therapy to facilitate spontaneous regeneration or prevent deterioration
while awaiting for a suitable donor organ to become available.
Survivors Nonsurvivors It remains to be seen whether this could be used as a marker of
Parameter (n = 26) (n = 19) p
prognosis to help guide decisions regarding transplantation or
Arterial ammonia, μmol/L prioritization of scarce donor organs.
Other significant risk factors for mortality in children with
  On admission 173 ± 17 201 ± 31 0.402
PALF treated with CRRT at admission included age (p = 0.017),
  CRRT (0 hr) 155 ± 14 205 ± 31 0.115 weight (p = 0.006), time on ward prior to PICU transfer
  CRRT (24 hr) 110 ± 11 198 ± 25 0.001 (p = 0.051), serum lactate (p = 0.003), INR (p = 0.062), peak
levels of arterial ammonia in the first 24 hours (p = 0.009), and
  CRRT (48 hr) 90 ± 11 253 ± 50 0.001
PALF with toxic and metabolic etiology. Age less than 1 year
p (ANOVA) < 0.001 0.1945 lends a significantly worse prognosis to this group of patients
Lactate, mEq/L (Fig. 3) due to their smaller size, rapidly progressive etiolo-
gies, and increased waiting time for liver transplantation. This
  On admission 4.6 ± 0.9 5.8 ± 1.0 0.382
implies in the case of rapidly progressive PALF, early transfer to
  CRRT (0 hr) 4.0 ± 0.9 6.8 ± 2.0 0.169 specialist liver transplant centers is critical especially in younger
  CRRT (24 hr) 3.0 ± 0.6 3.5 ± 0.7 0.590 children with raised ammonia or INR greater than 4 of toxic or
metabolic etiology as mortality is significantly higher.
  CRRT (48 hr) 1.6 ± 0.2 3.1 ± 0.8 0.043
In order to see whether CRRT can alter the natural progres-
p (ANOVA) 0.0535 0.1990 sion of PALF, those patients with PALF who did not undergo
Fluid overload, % transplantation and only received medical interventions were
analyzed. The survival without transplant was much higher
  CRRT (0 hr) 5.6 ± 1.7 5.3 ± 1.3 0.896
among the children who received CRRT versus those who did
  CRRT (24 hr) 4.9 ± 1.3 3.1 ± 2.1 0.448 not (Fig. 4). CRRT in these patients optimizes overall milieu
  CRRT (48 hr) 3.9 ± 1.4 3.1 ± 3.1 0.798 including fluid balance and removal of toxic products to facili-
tate spontaneous recovery.
p (ANOVA) 0.4273 0.7645
Due to reports of increased survival in using CRRT as
Creatinine, mmol/L a detoxification mechanism and earlier initiation in adult
  CRRT (0 hr) 70 ± 8.8 66 ± 19.0 0.836 patients with ALF, and preliminary findings at our PICU, the
PICU guidelines on the indications for CRRT in PALF were
  CRRT (24 hr) 64 ± 7.7 54 ± 10.7 0.440 changed in 2011. In addition to signs of renal dysfunction,
  CRRT (48 hr) 57 ± 7.5 50 ± 9.1 0.554 CRRT was initiated for hepatic encephalopathy (grade > 2) or
p (ANOVA) 0.5910 0.7177 hyperammonemia (NH3 > 150 µmol/L and not getting con-
trolled, or an absolute value > 200 µmol/L) along with meta-
Mean arterial pressure, mm Hg bolic abnormalities including hyponatremia. Higher doses
  CRRT (0 hr) 72 ± 3.2 68 ± 5.4 0.504 of CRRT were also introduced, starting at 60 mL/kg/hr and
  CRRT (24 hr) 68 ± 4.1 68 ± 3.8 1.000
increasing to 100 mL/kg/hr if toxin removal was inadequate,
and bigger-sized vascaths appropriate to all age groups were
  CRRT (48 hr) 76 ± 4.9 62 ± 8.2 0.129 introduced to ensure adequate circuit life and CRRT dose
p (ANOVA) 0.4503 0.7021 delivery. The effect of these changes is seen predominantly in
ANOVA = analysis of variance, CRRT = continuous renal replacement the first 14 days, which is the time critical period to ensure that
therapy. the child is in a stable condition either for spontaneous regen-
eration or liver transplantation.
is detoxified to glutamine in the brain, which is osmotically Despite its increasing uptake, clear-cut consensus is lacking
active and this is now thought to be responsible for astrocyte surrounding optimal CRRT delivery including time of initia-
swelling and cytotoxic edema seen in PALF (28–31). Among tion and dose. There is a growing body of evidence from adults
survivors, CRRT was successful in reducing arterial ammonia with AKI that earlier initiation of CRRT has a significant ben-
(p ≤ 0.001). Interestingly, there was a much greater mortality eficial impact on survival (32, 33). This study likewise found

1916 www.ccmjournal.org October 2016 • Volume 44 • Number 10

Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
 Pediatric Critical Care

CRRT in our group. In pediat-

rics, recent reports from France
and Tokyo have demonstrated
improved beneficial effects in
children with PALF undergo-
ing high volume hemofiltra-
tion (35, 36). As such at King’s
College Hospital, CRRT is
started early in the course of
PALF patients who are intu-
bated and ventilated for grade
greater than 2 encephalopathy
with high arterial ammonia
levels, using hemofiltration
as the preferred modality.
The dose is then increased as
required to achieve effective
ammonia clearance due to
the increased risk of mortal-
ity without a delta fall as high-
lighted in this study.
Another area of controversy
is the use of anticoagulation.
Despite the prolongation of
routine coagulation tests in
Figure 5. Box plot of the trend in ammonia level (μmol/L) by survival. CRRT = continuous renal replacement therapy. ALF, Habib et al (37) high-
lighted the need for anticoagu-
lation due to the procoagulant
that delays in initiation of treatment are associated with higher state. Anticoagulation is therefore used in nearly all children
mortality and suggests that the intensivist should intervene at with PALF undergoing CRRT in this study, with prostacyclin
an early stage to have the best chance of survival. Regarding being the most frequently used anticoagulant. No complica-
optimal doses, Davenport et al (34) showed improved cardio- tions related to anticoagulant use were observed. In addition
vascular stability in ALF using high filtration rates in particular to beneficial effects of prostacyclin as an anticoagulant, it
where severe lactic acidosis was present or vasopressors were can help to optimize oxygen delivery and uptake in critically
required, which applied to 93% of the children with PALF on ill patients, which can help improve ultimate prognosis (38).
This study validates the acceptable
safety and efficacy of prostacyclin as
an anticoagulant in CRRT for PALF.
Some centers have started using
citrate despite initial fears of citrate
accumulation as it is now shown
that this can be predicted by the Ca
total-to-Ca ionic ratio. Though this
ratio can rise, equalization of initial
metabolic acidosis is possible with-
out major disturbances of acid–base
and electrolyte status with acceptable
filter lives (39).
This study has its limitations.
First, this is a single centre experience
with a relatively small sample size.
It is extremely difficult to compare
outcomes between CRRT and non-
CRRT groups despite controlling
Figure 6. Kaplan-Meir curve for 60-d survival of children with pediatric acute liver failure on continuous for the severity of illness especially
renal replacement therapy. when the etiology is diverse. Ideally

Critical Care Medicine www.ccmjournal.org 1917

Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Deep et al
a propensity score should be used, which controls for the char-
acteristics leading to the decision to use CRRT; however, it was
not feasible due to the sample size and variability in charac-
teristics of patients treated with CRRT versus those without.
Therefore, it is difficult to make conclusions that outcomes are
related to the treatment effect of CRRT only, although there are
significant associations, these must be further tested. However,
due to the rarity and severity of PALF, we feel the results are of
value for guiding best practice.
CONCLUSIONS
When decisions regarding risks of surgery and prioritization of
donor organs are critical, such as in rapidly progressing PALF,
the importance of stabilizing a child to help facilitate these
decisions is fundamental to survival. This study demonstrates
that early, intensive CRRT can be used successfully in PALF
for managing both AKI and toxin accumulation to provide an
environment conducive to regeneration or to prolong the win-
dow of opportunity for successful liver transplantation. Fur-
thermore, if patients are to undergo transplantation, they are
presented in a more stable condition especially with regards to
fluid homeostasis that can significantly reduce mortality in this
frequently fatal condition.
ACKNOWLEDGMENT
We thank Dr. Palaniswamy Karthikeyan who helped us in the
final version of the article.
REFERENCES
1. Bansal S, Dhawan A: Acute liver failure. Indian J Pediatr 2006;
73:931–934
2. Shanmugam NP, Dhawan A: Selection criteria for liver transplantation
in paediatric acute liver failure: The saga continues. Pediatr Transplant
2011; 15:5–6
3. Stadlbauer V, Jalan R: Acute liver failure: Liver support therapies. Curr
Opin Crit Care 2007; 13:215–221
4. Phua J, Lee KH: Liver support devices. Curr Opin Crit Care 2008;
14:208–215
5. Hoste EA, Dhondt A: Clinical review: Use of renal replacement thera-
pies in special groups of ICU patients. Crit Care 2012; 16:201
6. Kramer P, Wigger W, Rieger J, et al: [Arteriovenous haemofiltration: A
new and simple method for treatment of over-hydrated patients resis-
tant to diuretics]. Klin Wochenschr 1977; 55:1121–1122
7. Boschee ED, Cave DA, Garros D, et al: Indications and outcomes
in children receiving renal replacement therapy in pediatric intensive
care. J Crit Care 2014; 29:37–42
8. Xue JL, Daniels F, Star RA, et al: Incidence and mortality of acute renal
failure in Medicare beneficiaries, 1992 to 2001. J Am Soc Nephrol
2006; 17:1135–1142
9. Waikar SS, Curhan GC, Wald R, et al: Declining mortality in patients
with acute renal failure, 1988 to 2002. J Am Soc Nephrol 2006;
17:1143–1150
10. Mohan N, Raghunathan V, Dhaliwal M, et al: Prevalence of acute kid-
ney injury network (AKIN) in paediatric non acetaminophen acute liver
failure (pNA-ALF) & addition of akin staging to king’s college criteria
(Kcc) in pNA-ALF improves prognostic value. J Clin Exp Hep 2013;
3:S17
11. Ellis D, Avner ED, Starzl TE: Renal failure in children with hepatic fail-
ure undergoing liver transplantation. J Pediatr 1986; 108:393–398
12. Moore K: Renal failure in acute liver failure. Eur J Gastroenterol Hepa-
tol 1999; 11:967–975
1918 www.ccmjournal.org October 2016 • Volume 44 • Number 10
Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
13. Slack AJ, Auzinger G, Willars C, et al: Ammonia clearance with
haemofiltration in adults with liver disease. Liver Int 2014; 34:
42–48
14. Barton IK, Streather CP, Hilton PJ, et al: Successful treatment of
severe lactic acidosis by haemofiltration using a bicarbonate-based
replacement fluid. Nephrol Dial Transplant 1991; 6:368–370
15. Kirschbaum B, Galishoff M, Reines HD: Lactic acidosis treated with
continuous hemodiafiltration and regional citrate anticoagulation. Crit
Care Med 1992; 20:349–353
16. Bouchard J, Mehta RL: Volume management in continuous renal
replacement therapy. Semin Dial 2009; 22:146–150
17. Drolz A, Jäger B, Wewalka M, et al: Clinical impact of arterial ammo-
nia levels in ICU patients with different liver diseases. Intensive Care
Med 2013; 39:1227–1237
18. Bhatia V, Singh R, Acharya SK: Predictive value of arterial ammo-
nia for complications and outcome in acute liver failure. Gut 2006;
55:98–104
19. Bernal W, Donaldson N, Wyncoll D, et al: Blood lactate as an early
predictor of outcome in paracetamol-induced acute liver failure: A
cohort study. Lancet 2002; 359:558–563
20. Sutherland SM, Zappitelli M, Alexander SR, et al: Fluid overload and
mortality in children receiving continuous renal replacement therapy:
The prospective pediatric continuous renal replacement therapy reg-
istry. Am J Kidney Dis 2010; 55:316–325
21. Chevret L, Durand P, Lambert J, et al: High-volume hemofiltration
in children with acute liver failure. Pediatr Crit Care Med 2014;
15:e300–e305
22. Squires RH Jr, Shneider BL, Bucuvalas J, et al: Acute liver failure in
children: The first 348 patients in the pediatric acute liver failure study
group. J Pediatr 2006; 148:652–658
23. Leteurtre S, Duhamel A, Grandbastien B, et al: Paediatric Logistic
Organ Dysfunction (PELOD) score. Lancet 2006; 367:897; author
reply 900–902
24. Goldstein SL, Currier H, Graf Cd, et al: Outcome in children receiv-
ing continuous venovenous hemofiltration. Pediatrics 2001; 107:
1309–1312
25. Matthews CE, Goonasekera C, Dhawan A, et al: Validity of pediatric
index of mortality 2 (PIM2) score in pediatric acute liver failure. Crit
Care 2014; 18:665
26. Symons JM, Chua AN, Somers MJ, et al: Demographic characteristics
of pediatric continuous renal replacement therapy: A report of the
prospective pediatric continuous renal replacement therapy registry.
Clin J Am Soc Nephrol 2007; 2:732–738
27. Albrecht J, Norenberg MD: Glutamine: A Trojan horse in ammonia
neurotoxicity. Hepatology 2006; 44:788–794
28. Rao KVR, Reddy PVB, Tong X, et al: Brain edema in acute liver failure:
Inhibition by L-histidine. Am J Pathol 2010; 176:1400–1408
29. Desjardins P, Du T, Jiang W, et al: Pathogenesis of hepatic encepha-
lopathy and brain edema in acute liver failure: Role of glutamine rede-
fined. Neurochem Int 2012; 60:690–696
30. Scott TR, Kronsten VT, Hughes RD, et al: Pathophysiology of cere-
bral oedema in acute liver failure. World J Gastroenterol 2013; 19:
9240–9255
31. Tsai MH, Chen YC, Lien JM, et al: Hemodynamics and metabolic
studies on septic shock in patients with acute liver failure. J Crit Care
2008; 23:468–472
32. Karvellas CJ, Farhat MR, Sajjad I, et al: A comparison of early versus
late initiation of renal replacement therapy in critically ill patients with
acute kidney injury: A systematic review and meta-analysis. Crit Care
2011; 15:R72
33. Wang X, Jie Yuan W: Timing of initiation of renal replacement therapy
in acute kidney injury: A systematic review and meta-analysis. Ren Fail
2012; 34:396–402
34. Davenport A, Will EJ, Davidson AM: Improved cardiovascular stability
during continuous modes of renal replacement therapy in critically ill
patients with acute hepatic and renal failure. Crit Care Med 1993;
21:328–338
35. Chevret L, Durand P, Lambert J, et al: High-volume hemofiltration
in children with acute liver failure. Pediatr Crit Care Med. 2014;
15:e300–e305
 Pediatric Critical Care

36. Ide K, Muguruma T, Shinohara M, et al: Continuous veno-venous
hemodiafiltration and plasma exchange in infantile acute liver failure.
Pediatr Crit Care Med 2015; 16:e268–e274
37. Habib M, Roberts LN, Patel RK, et al: Evidence of rebalanced coagu-
lation in acute liver injury and acute liver failure as measured by throm-
bin generation. Liver Int 2014; 34:672–678
38. Bihari D, Smithies M, Gimson A, et al: The effects of vasodilation with
prostacyclin on oxygen delivery and uptake in critically ill patients.
N Engl J Med 1987; 317:397–403
39. Schultheiß C, Saugel B, Phillip V, et al: Continuous venovenous
hemodialysis with regional citrate anticoagulation in patients with liver
failure: A prospective observational study. Crit Care 2012; 16:R162

Critical Care Medicine www.ccmjournal.org 1919

Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.