Post on 01-Apr-2018
Effect of continuous renal replacement therapy on outcome in paediatric acute liver failure
Dr Akash DEEP (corresponding author)MD, FRCPCH akash.deep@nhs.netKing’s College Hospital, Denmark Hill, London SE5 9RS
Dr Claire E STEWARTMBBS, BScclairematthews@doctors.org.ukKing’s College Hospital, Denmark Hill, London SE5 9RS
Prof Anil DHAWANMD, FRCPCHanil.dhawan@nhs.netKing’s College Hospital, Denmark Hill, London SE5 9RS
Dr Abdel DOUIRIBSc, MSc, PhD, FHEAabdel.douiri@kcl.ac.ukDepartment of Primary Care and Public Health Sciences & NIHR Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust. King's College London, UK
Institution address:King’s College HospitalDenmark Hill London SE5 9RSUK
Address for reprints: PICU, King’s College Hospital, Denmark Hill, London, SE5 9RS, UK
Financial support:No funding was received for this project and as such the authors have nothing to declare
Acknowledgements:
We wish to thank Dr Palaniswamy Karthikeyan who helped us in the final version of the manuscript. Dr. Abdel Douiri acknowledges financial support from the National Institute for Health Research (NIHR) Biomedical Research and from the NIHR
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Collaboration for Leadership in Applied Health Research and Care South London at King's College Hospital NHS Foundation Trust though not for this project. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health
Key words: Acute liver failure ; children; renal replacement therapy, outcomes
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ABSTRACT
Objective: To establish the effect of continuous renal replacement therapy (CRRT)
on outcome in paediatric acute liver failure (PALF).
Design: Retrospective cohort study.
Setting: 16 bed paediatric intensive care unit (PICU) in a university affiliated tertiary
care hospital and specialist liver centre.
Patients: All children (0-18years) admitted to PICU with PALF between Jan 2003-
Dec 2013.
Interventions: Children with PALF were managed according to a set protocol. The
guidelines for CRRT in PALF were changed in 2011 following preliminary results to
indicate the earlier use of CRRT for both renal dysfunction and detoxification.
Measurements and Main Results: Of 165 children admitted with PALF, 136 met
the inclusion criteria and 45 of these received CRRT prior to transplantation or
recovery. Of the children managed with CRRT 26 (58%) survived; 19 were
successfully bridged to liver transplantation and 7 spontaneously recovered. Cox
proportional hazards regression model clearly showed reducing hyperammonaemia
by 48hrs after initiating CRRT 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
CRRT from PICU admission was lower in survivors compared to non-survivors (HR,
3
0.96; 95% CI, 0.916-1.007; p= 0.095). Change in practice to initiate early and high
dose CRRT 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). Amongst children with PALF who did not
receive a liver transplant, use of CRRT significantly improved survival (HR, 4; 95%
CI, 1.5-11.6; p=0.006).
Conclusion: CRRT can be used successfully in critically ill children with PALF to
provide stability and bridge to transplantation. Inability to reduce ammonia by 48
hours confers poor prognosis. CRRT should be considered at an early stage to help
prevent further deterioration and buy time for potential spontaneous recovery or
bridge to liver transplantation.
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INTRODUCTION
Paediatric 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 oedema 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 stabilise 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 paediatric intensive care units and has significantly reduced mortality [7-9].
AKI is a common multi-factorial complication of PALF that occurs in approximately
55% of all cases [10-12]. Renal dysfunction pre-transplant determines the degree of
renal dysfunction post- transplant. Therefore tackling AKI pre-transplant should
improve the condition of the patient post-transplant. In these patients CRRT has also
been shown to successfully reduce ammonia [13], lactate [14,15] and optimise 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
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ammonia [17,18], high lactate [19] and fluid overload [20] are associated with
increased mortality. In addition to the risk of AKI in PALF, hyperammonaemia
contributes to the development of cerebral oedema, and there is a strong risk of fluid
overload especially after fluid resuscitation due to the systemic inflammatory
response syndrome (SIRS).This raises the question whether the use of CRRT
should be extended to non-renal 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 currently 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 METHOD
Study population
King’s College Hospital is a supra-regional centre for liver referrals in the
United Kingdom and operates one of the largest liver transplantation programmes 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 Paediatric Acute
Liver Failure Study Group [22]: “1) No evidence of pre-existing chronic liver disease
2) Biochemical evidence of acute liver injury (elevation in AST/ALT) within 8 weeks
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of the onset of symptoms 3) Hepatic-based coagulopathy (PT>15 or INR>1.5 in the
presence of 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 post
transplant care were excluded. Children who were commenced on CRRT prior to
transplantation or recovery were included in the CRRT treatment group (Figure 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 2 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 characteristics including age, gender, height,
weight, details and duration of presenting symptoms and signs, time to first medical
contact, time to PICU transfer and pre-referral care were also recorded. Aetiology of
PALF was classified into 7 categories: indeterminate, toxic, infectious, metabolic,
ischaemic, infiltrative 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
(CIS). Paediatric logistic organ dysfunction score (PELOD) and Pedatric Index of
Mortality (PIM2) were calculated for each patient [23]. Timing of listing for liver
transplantation and indication along with transplant date, type and details of any
post-operative complications and the date that the child was removed from the list
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due to spontaneous recovery or clinical deterioration were included. Duration of
PICU stay, survival on hospital discharge and survival at 6 months post discharge
were also recorded.
For children commenced on CRRT, time from PICU admission 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
pressure, percentage fluid overload and creatinine were recorded. Indications for
CRRT were classified into the following eight categories: oligo-anuria, hyperkalaemia
>5.5mmol/L, fluid overload >10%, hyperammoneamia >200mol/L, hepatic
encephalopathy grade >2, hyponatraemia <130meq/L, lactate >2mol/L not
responding to fluid therapy or metabolic acidosis pH<7.1 resistant to fluid therapy.
Importantly not 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.
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Continuous renal replacement therapy
The duty consultant paediatric intensivist determined the requirement for
CRRT. CRRT was commenced according to a local protocol with pre-dilution to
achieve required ammonia and lactate clearances and electrolyte and fluid
homeostasis (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 pre-defined according to body weight - 6.5 Fr
(14%), 8 Fr (28%),10 Fr (15%), 11.5 Fr (32%) and 13.5 Fr (11%). Children <10 kg
were filtered using HF03, 10kg - 50kg using HF07 and >50 kg using HF1200
(membrane surface area HF03 = 0.3 m2, HF07 = 0.7 m2, HF 1200 = 1.2 m2). All the
filters were made of polyethersulfone fiber. Pre-dilution 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 mls/kg/hour less than the
prescribed dose.
The machine used for CRRT was “Aquarius” (Nikkiso Europe GmbH,
Hannover). 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 250mls/min depending on age (Table 1). Pre-dilution continuous
venous venous haemofiltration (CVVH) was the most commonly used modality.
Anticoagulation used was prostacyclin (2-6ng/kg/min) if the activated clotting time
(ACT) was 160-220 seconds and low dose heparin if ACT <160 seconds unless
contraindicated. If ACT >220 seconds no anticoagulation was used. To facilitate
toxin removal, CRRT dose was sequentially increased to a maximum of 100
mls/kg/hour.
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Statistical analysis
Statistical data was analyzed with STATA software version 14 (StataCorp,
College Station, Tex). Continuous data was expressed as the mean ± standard
deviation 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: a) death awaiting
transplantation b) death after transplantation c) alive with native liver d) alive with
transplanted organ. Secondary outcome measures included the trend in markers for
disease progression after initiating CRRT. The data was analysed to see what, if
any, variables on admission were associated with mortality and to identify prognostic
markers in children with PALF on CRRT. Univariate analysis was performed to
compare variables between survivors and non-survivors at hospital discharge using
the unpaired t-test for continuous data and Fisher’s exact test for categorical data.
For analysing trends in markers of disease progression, regression lines and box
plots were used and compared by primary outcome. Analysis of variance and
covariance (ANOVA) 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 was adjusted for
severity of illness using the PELOD scoring system. A p value of less than 0.05 was
considered statistically significant.
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Ethics
Since it was a retrospective analysis of already collected routine data, ethical
approval was not deemed necessary , however as per institutional practice, this
project was registered as service evaluation project - 2592
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.
45 of these children received CRRT as part of their management (Figure 1). A
comparison between patient demographics and selected physiological and
laboratory values on admission to PICU are shown in the supplementary table.
Amongst the patients who underwent CRRT, the commonest aetiology was
indeterminant (53%) followed by metabolic (20%), and toxic (13%).
Baseline characteristics between survivors and non-survivors treated with
CRRT were compared (Table 2). Non-survivors were significantly younger (p=0.017)
and weighed less (p=0.006). They also spent on average ten days more on the
ward prior to PICU transfer (p=0.051). Toxic (p=0.024) or metabolic (p=0.015)
aetiology was associated with higher mortality. Peak arterial ammonia in the first
twenty-four hours of admission were also significantly higher amongst non-survivors
(p=0.025). All children who died on CRRT were ventilated and on inotropes.
Anticoagulation and complications in CRRT
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A total of 198 filters were utilised between the 45 patients receiving CRRT
for PALF. Prostacyclin was used in 72% of these filters, unfractionated heparin in
18% filters and no anticoagulant 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 efficacy of prostacyclin as an anticoagulant was
acceptable with 1.9 bleeding episodes per 1000 hours of CRRT and hypotension
requiring fluids or vasopressors occurring in less than 10% of filter episodes. The site
of venous access (femoral versus internal jugular) did not contribute to circuit life
among this sub-group. There was 1 episode of haemo-pneumothorax with internal
jugular venous catheter insertion and 3 episodes of vascular access re-wiring due to
thrombus;overall the procedure was well tolerated.
Timing of initiation and indications for CRRT
The median time to initiate CRRT from PICU admission was 27± 6.9 hours
and one in three were started on CRRT within the first eight hours of admission to
the unit. Median time to initiate CRRT in survivors was lower as compared to non-
survivors (15.8 ±3.0 hours versus 32.4 ± 6.9 hours; p =0.023). Thirty patients
(66.7%) had multiple indications for starting CRRT. The most common indications
were oligo-anuria (n=14, 31%) hyperammonaemia (n=13, 29%), hepatic
encephalopathy (n=12, 27%), high lactate (n=10, 22%), fluid overload (n=6, 13%),
resistant metabolic acidosis (n=3, 7%), resistant hyperkalaemia (n=1, 2%) and
hyponatraemia (n=1, 2%). The mean duration of CRRT was 54 hours.
Effect on outcome
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Overall survival of patients with ALF on CRRT at discharge was 58% (Figure
2). A significant increase in mortality was seen in children who were less than one
year old (HR, 6; 95% CI, 2.0-18.2; p=0.001) (Figure 3). Severity was adjusted for by
the PELOD score as opposed to the PIM2 score as it does not accurately reflect
outcomes in PALF [25].
Twenty-six of the forty-five patients were bridged successfully to either native
organ recovery (n=7) or successful liver transplantation (n=19). In total 24 patients
requiring CRRT underwent a liver transplant and 79% of these survived. Of the 21
who did not, only one third spontaneously recovered. As liver transplantation
interferes with the natural progression of disease, we looked at the effect of CRRT
only in those children with PALF who did not undergo transplantation i.e., either had
spontaneous regeneration of native liver or died without a transplant – those who
received CRRT had a significantly increased chance of survival (HR, 4; 95% CI, 1.5-
11.6; p=0.006) (Figure 4).
Cox proportional hazards regression model adjusting for severity of illness
(PELOD), ammonia at presentation, ability of CRRT to decrease ammonia by 48
hours and time to initiate CRRT from PICU admission clearly shows that in spite of
high ammonia levels in both survivors and non-survivors at initiation of CRRT, a
decrease in ammonia by 48 hours of starting CRRT 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 CRRT from PICU admission was also found to be lower in survivors
compared to non-survivors , although statistical significance is borderline (HR,0.96;
95% CI 0.916-1.007; p= 0.095). For very 1 hour delay in initiating CRRT, likelihood of
mortality increased by 4%.
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Efficacy of CRRT
To review the efficacy of CRRT in PALF, daily markers of disease progression
including arterial ammonia, lactate, percentage fluid overload, creatinine and mean
arterial pressure were reviewed using ANOVA at 0, 24, 48 hours after initiation of
CRRT (Table 3). There was a significant reduction in ammonia (p=0.001) and
lactate (p=0.043) within 48 hours of initiating CRRT amongst survivors. Although the
mean level of creatinine and percentage fluid overload also decreased, the
difference was not statistically significant.
Figure 5 is a box plot analysis of the trend in ammonia over time by mortality.
This clearly demonstrates that although ammonia is high at initiation of CRRT in both
survivors and non-survivors, in survivors the ammonia is significantly lower after 48
hours of CRRT while in non-survivors levels remained high (p=<0.001). As
demonstrated by multivariate analysis, inability of ammonia to be removed even after
48 hours of CRRT is a poor prognostic sign (p=0.004).
Although not a controlled variable change, survival in PALF increased by
9% from 65% before the change in guidelines in 2011. Figure 6 shows the trend in
survival pre and post guideline change. The most significant difference was seen in
the first 14 days (HR, 3; 95% CI, 1.0-10.3; p=0.063).
DISCUSSION
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Despite the increasing use of CRRT in children with acute liver failure, there is
a paucity of data surrounding its effect on outcome and applicability as a
detoxification mechanism. The present study examined an11 year institutional
experience from the PICU at a specialist liver unit to evaluate whether the use of
CRRT in these critically ill children is of justifiable benefit.
Of note, when the prospective paediatric CRRT registry (ppCRRT) was split
into survival rates according to the diagnoses that led to the use of CRRT, children
with liver disease had the lowest survival at 31% compared to the 58% average for
all other diagnoses [26]. In this study almost all children who required CRRT also
required inotropes (91%) and ventilation (100%). This suggests 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
misrepresentative to compare outcomes of the treatment and non-treatment group.
Likewise, it would be unethical to withhold CRRT from a critically ill child due to its
proven success in AKI, a common complication of PALF, and anecdotal and
theoretical evidence for detoxification in PALF for the purpose of a randomised
controlled trial. As such evidence will need to be sought through observational
studies to establish the effect on outcome.
This study found that children frequently had more than one indication for
CRRT prior to commencing therapy. Traditionally CRRT has been used to manage
renal dysfunction which is a common complication of PALF. It is important not to
forget that AKI is often multi-factorial in PALF with hypovolaemia being the most
common precipitating factor setting the stage for acute tubular necrosis [27].
Although renal impairment was the indication for CRRT in a significant number of
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patients included in this study (oligo-anuria 31%, fluid overload 13% and resistant
hyperkalaemia 2%), more frequently CRRT is being used regardless of the presence
or absence of renal dysfunction as a detoxification mechanism. The potential for
recovery of native organ function coupled with the insufficient donor organ supply
and risk of death or deterioration awaiting a compatible transplant, has focussed
attention on using detoxification mechanisms as liver support devices until recovery
from PALF or bridging to transplantation. As such initiating CRRT in PALF now
serves a dual purpose 1) for managing the AKI and fluid imbalances which frequently
complicate cases, and 2) as a detoxification mechanism for the high ammonia,
lactate and metabolic disturbances which set in.
In this study two of the indications for initiating CRRT were hyperammonemia
>200 micromoles/litre or hepatic encephalopathy greater than grade 2, which was
present in a quarter of children (29% and 27% respectively). It is well established
that when ammonia is not metabolised by the failing liver, it is detoxified to glutamine
in the brain which is osmotically active and this is now thought to be responsible for
astrocyte swelling and cytotoxic oedema seen in PALF [28-31]. Amongst survivors,
CRRT was successful in reducing arterial ammonia (p=<0.001). Interestingly there
was a much greater mortality amongst children whose level of arterial ammonia rose
between the value at admission to PICU to the value at initiation of CRRT. This
suggests that the intensivist should not wait, but intervene early at the first sign of
rising hyperammonemia. Ability to reduce ammonia after 48 hours of starting CRRT
was the most significant factor for survival on multivariate analysis (p=0.004). This is
important as in rapidly progressive PALF, the first 24-48 hours are vital to create a
good milieu to facilitate spontaneous regeneration or prevent deterioration whilst
16
awaiting for a suitable donor organ to become available. It remains to be seen
whether this could be used as a marker of prognosis to help guide decisions
regarding transplantation or prioritisation of scarce donor organs.
Other significant risk factors for mortality in children with PALF treated with
CRRT on admission included age (p=0.017), weight (p=0.006), time on ward prior to
PICU transfer (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 PALF with toxic and metabolic
aetiology. Age less than 1 year lends a significantly worse prognosis to this group of
patients (Figure 3) due to their smaller size, rapidly progressive aetiologies and
increased waiting time for liver transplantation. This implies in the case of rapidly
progressive PALF, early transfer to specialist liver transplant centres is critical
especially in younger children with raised ammonia or INR >4 of toxic or metabolic
aetiology as mortality is significantly higher.
In order to see whether CRRT can alter the natural progression of PALF,
those patients with PALF who did not undergo transplantation and only received
medical interventions were analysed. The survival without transplant was much
higher amongst the children who received CRRT versus those who did not (Figure
4). CRRT in these patients optimises overall milieu including fluid balance and
removal of toxic products to facilitate spontaneous recovery.
Due to reports of increased survival in using CRRT as a detoxification
mechanism and earlier initiation in adult patients with acute liver failure (ALF), and
preliminary findings at our PICU, the PICU guidelines on the indications for CRRT in
PALF were changed in January 2011. In addition to signs of renal dysfunction,
17
CRRT was initiated for hepatic encephalopathy (grade >2) hyperammonaemia (NH3
>150µmol/L & not getting controlled, or an absolute value >200µmol/L) along with
metabolic abnormalities including hyponatremia. Higher doses of CRRT were also
introduced, starting at 60mls/kg/hour and increasing to 100mls/kg/hour if toxin
removal was inadequate, and bigger sized vascaths appropriate to all age groups
were introduced to ensure adequate circuit life and CRRT dose delivery. The effect
of these changes (Figure 7) is seen predominantly in the first 14 days, which is the
time critical period to ensure that the child is in a stable condition either for
spontaneous regeneration or liver transplantation.
Despite its increasing uptake, clear-cut consensus is lacking surrounding
optimal CRRT delivery including time of initiation and dose. There is a growing body
of evidence from adults with AKI that earlier initiation of CRRT has a significant
beneficial impact on survival [32,33]. This study likewise found that delays in
initiation of treatment are associated with higher mortality and suggests the
intensivist should intervene at an early stage to have the best chance of survival.
Regarding optimal doses, Davenport et al. showed improved cardiovascular stability
in ALF using high filtration rates in particular where severe lactic acidosis was
present or vasopressors were required, which applied to 93% of the children with
PALF on CRRT in our group. [34]. In paediatrics recent reports from France and
Tokyo have demonstrated improved beneficial effects in children with PALF
undergoing high volume haemofiltration [35, 36]. As such at King’s College
Hospital, CRRT is started early in the course of PALF patients who are intubated and
ventilated for grade >2 encephalopathy with high arterial ammonia levels, using
hemofiltration as the preferred modality. The dose is then increased as required to
18
achieve effective ammonia clearance due to the increased risk of mortality without a
delta fall as highlighted in this study.
Another area of controversy is the use of anticoagulation. Despite the
prolongation of routine coagulation tests in acute liver failure, Habib et al highlighted
the need for anticoagulation due to the procoagulant state [37]. Anticoagulation is
therefore used in nearly all children with PALF undergoing CRRT in this study, with
prostacyclin being the most frequently used anticoagulant. No complications related
to anticoagulant use were observed. In addition to beneficial effects of prostacyclin
as an anticoagulant, it can help to optimise oxygen delivery and uptake in critically 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 centres have started using citrate despite initial fears of citrate
accumulation as it is now shown that this can be predicted by the Ca total/Ca ionic
ratio. Though this ratio can rise, equalisation of initial metabolic acidosis is possible
without major disturbances of acid-base and electrolyte status with acceptable filter
lives [39].
This study has its limitations. Firstly, 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 for the severity of illness especially
when the aetiology is diverse, Ideally a propensity score should be used which
controls for the characteristics leading to the decision to use CRRT, however it was
not feasible due to the sample size and variability in characteristics of patients
treated with CRRT versus those without. Therefore it is difficult to make conclusions
19
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 prioritisation of donor organs
are critical, such as in rapidly progressing PALF, the importance of stabilising 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 window of opportunity for successful liver transplantation. Moreover, if
patients are to undergo transplantation, they are presented in a more stable
condition especially with regards to fluid homeostasis which can significantly reduce
mortality in this frequently fatal condition.
20
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FIGURE LEGENDS
- Figure 1 Study profile. PALF, paediatric acute liver failure; PICU, paediatric intensive
care unit; CRRT, continuous renal replacement therapy
- Figure 2 Outcome of all children with PALF requiring CRRT. PALF, paediatric acute
liver failure; CRRT, continuous renal replacement therapy; PICU, paediatric intensive care
unit
- Figure 3 Kaplan Meir curve for 60-day survival of children PALF on CRRT. PALF,
paediatric acute liver failure; CRRT, continuous renal replacement therapy
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- Figure 4 Kaplan Meir curve for 60-day survival of children PALF on CRRT versus
those not on CRRT in non-transplanted group. PALF, paediatric acute liver failure;
CRRT, continuous renal replacement therapy
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- Figure 5 Box plot of the trend in ammonia level (umol/L) by survival. CRRT,
continuous renal replacement therapy
- Figure 6 Kaplan Meir curve for 60-day survival of children PALF on CRRT. PALF,
paediatric acute liver failure; CRRT, continuous renal replacement therapy
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TABLES
- Table 1 CRRT set up using CVVH, CRRT, continuous renal replacement therapy;
CVVH, continuous venous venous haemofiltration
Weight (kg) <3.5 3.5-4.9 5-14.9 15-29.9 30-49.9 >50Filter Size HF03 HF03 HF03 HF07+ HF07+ HF07+
Aqualine Size S S S S S Adult
Blood Flow Rate (ml/min) 50 50-80 100 150 200 250
Ultrafiltration Rate (ml/kg/hr) 60 60 60 60 60 3000
max.Priming Volume (ml) 96 96 96 118 159 159
- Table 2 Baseline characteristics of patients treated with CRRT on admission to
PICU PICU, paediatric intensive care unit; PALF, paediatric acute liver failure; MAP,
mean arterial pressure; AST, asparate aminotransferase; INR, international normalised
ratio; CRRT, continuous renal replacement therapy; PIM2, paediatric index of mortality;
LIU, liver injury unit; PELOD, pediatric logistic organ dysfunction score; FO, fluid overload
All CRRT (n=45)
Survivors (n=26)
Non-survivors(n=19)
P-value (survivors vs
non)
Age, months 68±9.8 88±13.4 41±12.1 0.017*Female, n (%) 18 (40) 10 (38) 8 (42) 0.811Male, n (%) 27 (60) 16 (62) 11 (58) 0.811Weight (kg) 23.5±3.9 32.8±5.8 11.9±3.2 0.006*Time on the ward prior to PICU transfer, days 10.7±2.8 6.5±1.2 16.3±6.1 0.051*
Aetiology of PALF: Indeterminate, n (%) 24 (53) 16 (62) 8 (42) 0.206 Toxic, n (%) 6 (13) 6 (23) 0 (0) 0.024* Infectious, n (%) 3 (7) 2 (8) 1 (5) 0.754 Metabolic, n (%) 9 (20) 2 (8) 7 (37) 0.015* Ischaemic, n (%) 1 (2) 0 (0) 1 (5) 0.247 Infiltrative, n (%) 2 (4) 0 (0) 2 (11) 0.086Encephalopathy grade ≥2, n (%) 12 (27) 5 (19) 7 (37) 0.078MAP, mmHg 66±2.4 65±3.3 67±3.8 0.717Urine output, mls/kg/hr 2.6±0.5 2.3±0.6 3.0±1.0 0.552Lactate, mmol/L 5.1±0.7 4.6±0.9 5.8±1.1 0.366Ammonia, umol/L (0hrs) 173±14.9 153±13.7 212±33.1 0.061Ammonia, umol/L (24hrs) 159±17.8 110±11.5 198±24.7 0.009*Ammonia, umol/L (48hrs) 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
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Creatinine 68±9.6 72±10.1 62±18.0 0.593AST, umol/L 2486±547 3075±892 1741±488 0.229INR 4.5±0.2 4.8±0.4 4.1±0.3 0.162Platelets, 109/L 194±20.2 212±28.0 170±28.5 0.403PELOD score 9.6±1.1 8.4±1.3 11.1±1.9 0.228Inotropes, n (%) 41 (91) 23 (88) 19 (100) 0.131Intubated and ventilated, n (%) 45 (100) 26 (100) 19 (100) N/ATime to initiation of CRRT (hrs) 27.0±6.9 15.8±3.0 32.4±6.9 0.023*
- Table 3 Trend in mean ammonia, lactate and percentage fluid overload between
survivors and non-survivors before and after starting CRRT. CRRT, continuous renal
replacement therapy MAP, mean arterial pressure
Survivors (n=26)
Non-survivors (n=19) P-value
Arterial ammonia, umol/L On admission 173±17 201±31 0.402 CRRT (0hrs) 155±14 205±31 0.115 CRRT (24hrs) 110±11 198±25 0.001* CRRT (48hrs) 90±11 253±50 0.001* P value (0 vs 48hrs) 0.001* 0.420Lactate, meq/L On admission 4.6±0.9 5.8±1.0 0.382 CRRT (0hrs) 4.0±0.9 6.8±2.0 0.169 CRRT (24hrs) 3.0±0.6 3.5±0.7 0.590 CRRT (48hrs) 1.6±0.2 3.1±0.8 0.043* P value (0 vs 48hrs) 0.012* 0.042*Fluid overload, % CRRT (0hrs) 5.6±1.7 5.3±1.3 0.896 CRRT (24hrs) 4.9±1.3 3.1±2.1 0.448 CRRT (48hrs) 3.9±1.4 3.1±3.1 0.798 P value (0 vs 48hrs) 0.444 0.517Creatinine, mmol/L CRRT (0hrs) 70±8.8 66±19.0 0.836 CRRT (24hrs) 64±7.7 54±10.7 0.440 CRRT (48hrs) 57±7.5 50±9.1 0.554 P value (0 vs 48hrs) 0.266 0.453MAP, mmHg CRRT (0hrs) 72±3.2 68±5.4 0.504 CRRT (24hrs) 68±4.1 68±3.8 1.000 CRRT (48hrs) 76±4.9 62±8.2 0.129 P value (0 vs 48hrs) 0.498 0.541
- Supplementary table Baseline characteristics of all patients on admission to PICU
PICU, paediatric intensive care unit; PALF, paediatric acute liver failure; MAP, mean
arterial pressure; AST, asparate aminotransferase; INR, international normalised ratio;
CRRT, continuous renal replacement therapy; PIM2, paediatric index of mortality;
PELOD, pediatric logistic organ dysfunction score
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30
All (n=136)
CRRT (n=45)
Survivors (n=101)
Non-survivors
(n=35)
P-value (survivors vs
non)
Age, months 54±5.7 68±9.8 63±7.0 28±7.4 0.006*Age, months MEDIAN 20 50 27 4Female, n (%) 61 (45) 18 (40) 48 (48) 13 (37) 0.033Male, n (%) 75 (55) 27 (60) 53 (52) 22 (63) 0.033Weight (kg) 20.4±3.0 23.5±3.9 25.9±4.3 9.3±2.0 0.027*Duration of illness prior to admission to hospital, days 7.0±0.9 9.2±1.6 6.4±0.9 8.4±2.2 0.319
Time on the ward prior to PICU transfer, days 7.9±1.2 10.7±2.8 5.6±0.6 13.2±3.7 0.001*
Aetiology of PALF: Indeterminant, n (%) 67 (48) 24 (53) 56 (55) 11 (31) 0.018* Toxic, n (%) 19 (14) 6 (13) 18 (18) 1 (3) 0.026* Infectious, n (%) 20 (15) 3 (7) 10 (10) 10 (29) 0.012* Metabolic, n (%) 21 (16) 9 (20) 11 (11) 10 (29) 0.027* Ischaemic, n (%) 1 (1) 1 (2) 0 (0) 1 (3) 0.229 Infiltrative, n (%) 6 (4) 2 (4) 4 (4) 2 (6) 0.647 Autoimmune, n (%) 2 (2) 0 (0) 2 (2) 0 (0) 1.000Grade of encephalopathy Grade <2, n (%) 89 (65) 23 (51) 69 (68) 20 (57) 0.302 Grade ≥2, n (%) 47 (35) 22 (49) 32 (32) 15 (43) 0.302Heart rate, beats/minute 124±3.5 119±5.2 121±4.3 133±5.4 0.134Respiratory rate, breaths/minute 28±1.4 26±2.1 27±1.4 32±2.9 0.090MAP, mmHg 64±1.9 66±2.5 65±2.4 62±3.1 0.503Urine output, mls/kg/hr 2.5±0.3 2.6±0.5 2.5±3.1 2.4±0.5 0.985Arterial: pH 7.37±0.01 7.38±0.27 7.38±0.02 7.36±0.03 0.603 HCO3-, mmol/L 24.1±0.7 24.2±1.1 23.9±0.7 24.5±1.5 0.686 Lactate, mmol/L 4.7±0.4 5.1±0.7 3.9±0.4 6.3±0.7 0.003* Ammonia, umol/L (admission) 141±10.9 152±20.0 136±13.3 158±19.5 0.387 Ammonia, umol/L (24hr peak) 155±8.9 186±17.1 132±9.6 179±21.8 0.025*Venous: Urea, mmol/L 5.4±0.5 5.1±1.0 5.1±0.4 6.3±1.2 0.222 Creatinine, mmol/L 65±4.5 68±9.6 69±4.6 57±10.5 0.230 AST, umol/L 2877±368 2486±547 2994±488 2612±509 0.666 Bilirubin, umol/L 217±16.8 283±25.8 222±21.2 205±26.2 0.665 INR 4.1±0.3 4.5±0.2 3.7±0.2 5.2±0.7 0.006* Platelets, 109/L 173±11.5 194±20.2 187±13.8 137±19.5 0.057Ionotropes, n (%) 67 (49) 42 (93) 32 (32) 35 (100) <0.001*Intubated and ventilated, n (%) 89 (65%) 45 (100) 54 (53) 35 (100) <0.001*CRRT, n (%) 45 (100) 26 (26) 19 (54) 0.003*Mortality risk score PIM2 53±2.8 54±4.1 39±2.9 54±6.3 0.016* PELOD 7±5.9 10±6.2 5±4.8 12±6.1 0.006*
DECLARATIONS
Conflicts of Interest
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
Financial Disclosure
Dr. Abdel Douiri acknowledges financial support from the National Institute for Health Research (NIHR) Biomedical Research and from the NIHR Collaboration for Leadership in Applied Health Research and Care South London at King's College Hospital NHS Foundation Trust though not for this project. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health
Ethical Statement:
This study has been registered as a service improvement project at King’s College Hospital and all guideline changes were reviewed by the clinical guideline committee prior to implementation
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