St. George’s Hospital, Blackshaw Road, Tooting , London SW17 0QT, UKUnited Kingdom
Intensive Care Unit, Royal Adelaide Hospital, Adelaide, SA 5000, AustraliaAustralia
Intensive Care Unit, Royal Adelaide Hospital, Adelaide, SA 5000, Australia; Discipline of Acute Care Medicine, University of Adelaide, Adelaide, SA 5000, AustraliaAustralia
Also available as PDF (figures and tables appear in the PDF).
Background : Continuous Renal Replacement Therapy (CRRT) is the preferred means of renal replacement therapy (RRT) in many intensive care units. Most units use only one type of RRT fluid or identify a standard ‘default’ fluid. Little data is available comparing the effects of using different RRT fluids. We aimed to identify the biochemical consequences of receiving CRRT with potassium and phosphate free fluid, Hemosol-B0, or potassium and phosphate containing fluid, Phoxilium, as a default RRT fluid. Methods : Retrospective observational study in a mixed Level III Intensive Care Unit (ICU). A period of two-six months study were compared during which either Hemosol-B0 or Phoxilium were used as the unit’s default fluid. Daily biochemistry results and K+ and PO4 3- supplementation were recorded in all patients over eighteen years requiring CRRT during the study period; data was collected on 35 patients in the Hemosol-B0 group and 31 patients in the Phoxilium group. Our primary outcome was the proportion of CRRT treatment during which [PO4 3-], [Ca2+]pl and [HCO3 - ] pl were in the normal range, and secondary outcome the need for non-RRT fluid K+ and PO4 3- supplementation. Results : Phoxilium was associated with a greater proportion of the CRRT delivery time spent with [PO4 3-] above the normal range. Furthermore, Phoxilium was associated with more time spent with ionised [Ca2+]pl and [HCO3 - ]pl below the normal range. Phoxilium significantly decreased the requirement for phosphate but not potassium supplementation. Conclusions : Patients receiving Phoxilium should be monitored to avoid hyperphosphataemia, hypocalcaemia and metabolic acidosis. Phoxilium use does not abrogate the need to handle concentrated potassium solutions.
Keywords: Acute kidney injury; Dialysis; Hyperkalemia; Intensive care; Phosphataemia; Acute kidney injury; Dialysis; Hyperkalemia; Intensive care; Phosphataemia
Acute kidney injury (AKI) is increasingly common in critically
ill patients and associated with significant morbidity and mor-
tality.1 One large multicenter study showed that over 16% of
critically ill patients are diagnosed with AKI within forty-eight
hours of ICU admission with a 22% overall incidence of AKI
during ICU admission, as defined by the (risk, injury, failure,
loss of kidney function, and end-stage kidney disease) RIFLE
2 3 classification.2 AKI is an independent risk factor for death.3 In-
hospital mortality for patients with AKI exceeds 25%4 and mor-
tality amongst ICU patients requiring renal replacement therapy
approaches 70%.5
Continuous renal replacement therapy (CRRT) is the
favored treatment modality for AKI in critically ill patients in
Australasia. Many units, including ours, use Hemosol-B0 as
5 3their standard CRRT fluid.5 Hemosol-B0 does not contain PO43-
+ or K+, leaving patients susceptible to hypophosphataemia and
hypokalaemia unless plasma levels ([PO4 ]pl and [K ]pl) are as-
siduously monitored and maintained.6 Depending on CRRT in-
tensity and duration the incidence of hypophosphataemia with
CRRT can exceed 65%.
Phosphate is required to form the high-energy bond
that provides the major energy currency required for metabo-
lism. Complications of hypophosphatemia include respiratory
muscle dysfunction and prolonged respiratory failure,7 cardiac
dysrhythmia (particularly ventricular tachycardia), reduced
myocardial contractility and neuromuscular depression. Longer
term, hypophosphataemia is associated with delayed recovery
from AKI and higher incidence of chronic renal failure one year
after dialysis commencement.8 Hypophosphataemia is indepen-
dently associated with worse ICU survival; the duration of hypo-
phosphataemia predicts mortality.9
Phoxilium is a phosphate and potassium containing
CRRT fluid, introduced to mitigate the risk of hypophosphatae-
mia and need for potassium supplementation.10 The composition
of Hemosol-B0 and Phoxilium are compared in Table 1. Con- Previous work identified that after administering Phoxili-
- 2+ um for 42 hours to selected patients median [HCO3-]pl and i[Ca2+]
3pl were reduced but [PO43-]pl maintained relative to a matched
cohort who continued to receive Hemosol-B0.10 It is common
practice in most intensive care units to identify a default fluid to
be used for CRRT. The biochemical consequences of replacing
Hemosol-B0 with Phoxilium as the default CRRT fluid to an un-
selected patient cohort, and the potential benefit of minimizing
+ handling of concentrated K+ solutions (identified as a high risk
intervention by organizations in Australia, Canada, the US and
11, 12 UK ), remain unknown.
We undertook a retrospective observational cohort
study to investigate the hypothesis that using Phoxilium, rather
than Hemosol-B0, as a standard CRRT fluid would be associated
with more normal and consistent phosphate levels and lower re-
quirements for non-RRT electrolyte supplementation. The pri-
mary study end-point was the proportion of RRT duration spent
3- + 3with plasma [PO4 ] within the normal range. Secondary analy-
sis were performed to identify (i) differences in the proportion
- 2+ of the RRT period spent with [HCO3-]pl and i[Ca2+]pl in the normal
range and (ii) differences in the requirement for non-RRT fluid
+ 3- K+ and PO43- supplementation.
Critically ill patients over 18 years old admitted to the Royal
Adelaide Hospital Intensive Care Unit between October 2011
and October 2012 who required renal replacement therapy were
recruited into the study.
Patients underwent CRRT with continuous veno-venous hae-
modiafiltration (CVVHDF) with 40 ml/kg/hr effluent rate. This
relatively high RRT dose was used to ensure minimum achieved
doses of 25 mls/kg/hr (previous local audit data identified that
Phosphate 0 1.2
Potassium 0 4
Bicarbonate 32 30
Lactate 3 0
Calcium 1.75 1.25
Magnesium 0.5 0.6
Sodium 140 140
Chloride 109.5 115.9
patients prescribed CRRT receive CRRT for an average 16
hours/day). Two six-month treatment periods were compared:
during the first period, from October 2011 to March 2012, the
standard renal replacement fluid was Hemosol-B0, (Hemosol-
+ B0 standard period) with K+ added to RRT fluid bags at the cli-
nicians discretion. During the second period, from May 2012 to
October 2012, Phoxilium was the default CVVHDF fluid (Phox-
ilium standard period). Both fluids were manufactured by Gam-
bro, Lundia AB, Lund, Sweden. Patients receiving RRT fluid
other than the designated default for that period were excluded
from data analysis. The study was performed with local ethics
committee approval.
Demographic, clinical and outcome data were recorded and
mean delivered dialysis dose calculated. Daily plasma [PO43-]pl,
2+ - + 2+ i[Ca ]pl, [HCO3 ]pl, [K ]pl and [Mg ]pl results were documented
throughout the duration of RRT. Supplementation with K+ and
3- PO43- was recorded. Normal ranges refer to those used by the
SA Pathology laboratory (SA Pathology, Rundle Mall, Adelaide,
SA 5000, Australia) who were responsible for blood chemistry
analysis during the study period.
Categorical variables are expressed as number (percentage) and
compared using Chi-squared or Fisher’s exact test as indicated.
Continuous variables are expressed as mean and standard devia-
tion (SD) or when non-normally distributed as median (inter-
quartile range), with between group comparisons performed by
t-test or Wilcoxon rank-sum test. A two-tailed p value <0.05 was
considered statistically significant. All analysis were undertaken
using Stata/MP 14.0, Stata Corp LP software.
There were 86 patients admitted to the Royal Adelaide Hospital
Intensive Care Unit between October 2011 and 2012 requiring
RRT. Of these 7 patients were excluded from the Hemosol-B0
Table 2. Patient clinical and outcome data: median (IQR) unless otherwise stated.
group and 4 from the Phoxilium due to unavailability of dialysis
records or absent biochemical data. A further 9 patients were
excluded as they received Hemosol-B0 during the Phoxilium
standard period; no patients received Phoxilium during the He-
mosol-B0 period as Phoxilium was not available. Data was col-
lected on 35 patients in the Hemosol-B0 group and 31 patients
in the Phoxilium group.
There was no significant difference in patient demo-
graphics, presence of chronic kidney disease, illness severity,
length of stay, time ventilated or hospital mortality between the
study groups (Table 2). Initial electrolytes prior to CRRT were
not statistically different. There were no significant differences
in the aetiology of AKI between the groups, in both groups sep-
sis was the most common precipitant (51% in the Hemosol-B0
group vs. 57% in the Phoxilium group) followed by cardiogenic
3shock, hypovolaemia and drug toxicity. There was no between-
group difference in the cumulative insulin dose administered
+ whilst receiving CRRT (p=0.591).
Plasma biochemistry values during CRRT administration
are illustrated in Figure 1. For clarity only the first 5 days are
included in the figure since only eight patients in each group un-
derwent more than 5 days of CRRT. Data for the entire duration
of CRRT is included in the data analysis.
Compared to patients receiving CRRT with Hemosol-B0, Phox-
ilium recipients spent a greater proportion of CRRT duration
3with [PO43-]pl outside the normal range (Hemosol-B0 45.3% vs.
Phoxilium 66.9% of patient days; p<0.001). In the Phoxilium
3group the median [PO43-]pl exceeded the upper limit of the nor-
mal range on days 2-5 (Normal range: 0.65-1.45 mmol/l).
2+ Patients in the Phoxilium group spent more time with i[Ca2+]pl be-
low the normal range than patients receiving Hemosol-B0 (He-
mosol–B0 45% vs. Phoxilium 77.7% of patient days; p<0.001).
59.2 (54-67) 59.5 (46-70) 0.81
21 (54) 18 (58) 0.72
27.5 (23-33.75) 26.5 (20.25-31) 0.50
13 (33.3) 12 (38.7) 0.64
50 (23-89) 45 (34-105) 0.69
37.8 (37.8-39.63) 38.7 (38.7-39.95) 0.87
205 (74-684) 155 (70-235) 0.47
4 (1-12) 3 (0-5) 0.19
24 (61.5) 21 (67.7) 0.59
(Normal range: 1.1-1.3 mmol/l).
- In the Phoxilium group [HCO3-]pl was abnormally low for a
greater proportion of time than in the Hemosol-B0 group (He-
mosol-B0 26% vs. Phoxilium 68.5% of patient days; p<0.001).
Starting from similar initial values, median [HCO3-]pl remained
low on day 1 in both groups; however, median [HCO3-]pl normal-
ized on days 2-5 in the Hemosol-B0 group whilst remaining low
in the Phoxilium group. (Normal range: 22-32 mmol/l).
There was no difference between the groups in the proportion of
+ 2+ RRT duration spent with [K+]pl or [Mg2+]pl in the normal range
(Hemosol-B0 85.8% and 61.8% vs. Phoxilium 89.4% and 73.1%
of patient days; p=0.30 and 0.27 respectively); in both groups
+ 2+ median [K ] and [Mg ] were normal on each day of CRRT.
+ 2+ (Normal ranges: K+ 3.5-4.9 mmol, Mg2+ 0.7-0.95 mmol/l).
Phoxilium use abrogated the need for phosphate supplementa-
tion – no patients in the Phoxilium group required phosphate supdays of renal replacement therapy with either
plementation whilst 26% of patients in the Haemosol-B0 group
3required PO43- supplementation. KCl was added to Hemosol-B0
in all but four of the Hemosol-B0 group. In the Phoxilium group,
45% of patients required non-RRT fluid potassium supplementa-
tion vs. 41% of patients receiving Hemosol-B0 (p>0.05).
-
- When used as a standard CRRT fluid in a tertiary metropolitan
intensive care unit, treating AKI with CRRT using Phoxilium,
compared to Hemosol-B0, was associated with a greater propor-
3tion of treatment time spent with abnormally high [PO43-]pl, low
2+ ionized [Ca2+]pl and low [HCO3-]pl. Phoxilium use reduced the
need for phosphate but not non-RRT fluid potassium supplemen-
tation.
Phoxilium use was associated with a significant period
3of time spent with [PO43-]pl above the normal range. The median
3- [PO4 ]pl was minimally elevated and mild hyperphosphataemia
is generally well-tolerated in the short-term, although likely to
2+ contribute to i[Ca2+]pl suppression and promotion of metabolic
acidaemia, both deleterious to the critically ill. Chronic hyper-
phosphataemia is associated with cardiovascular risk and mor-
13,14 tality in end-stage renal failure ; further study is needed to
identify whether analogous processes occur during short-term
hyperphosphataemia.
2+ 3- Low [Ca2+] and increased [PO43-] in Phoxilium contrib-
2+ ute to lowering i[Ca2+]pl. Potential consequences include vaso-
pressor resistance, decreased myocardial performance, arrhyth-
mia, neuromuscular dysfunction and impaired coagulation.
Patients in our study were critically ill, as indicated by their
Acute Physiology and Chronic Health Evaluation II (APACHE
II) scores, and even mild manifestations of these complications
would be deleterious.
Potential mechanisms by which Phoxilium might sup-
- press [HCO3-]pl include: (i) lower [HCO3-] and absent lactate
(the metabolism of which consumes hydrogen ions) relative to
Hemosol-B0 (ii) relatively high [HPO42-]pl in patients receiving
17 18 Phoxilium.17 Consequences of acidaemia in vivo are complex18;
acidaemia is associated with impaired myocardial performance,
arrhythmia and vasopressor insensitivity as well as altered drug
pharmacology and immune and metabolic dysregulation.19
Again, given the severity of illness of our patient population,
these complications are poorly tolerated.
Although Phoxilium contains K+, its use in preference
to Hemosol-B0 did not reduce the need for non-RRT fluid K+
supplementation. This suggests that a policy of adding K+ to
RRT fluid at clinicians discretion is at least as effective at main-
+ taining [K+]pl as using RRT fluid containing KCl as standard.
Indeed two potential advantages of an RRT fluid not contain-
ing KCl as standard are (i) use in hyperkalaemic patients (the
probable reason for 9 patients in the Phoxilium period receiving
Hemosol-B0) and (ii) the option to use a potassium salt with a
weak anion such as acetate instead of chloride. Nevertheless,
Hemosol-B0 requires more handling of KCl concentrate when
supplementation to the RRT fluid is considered. Hospital surveil-
lance systems identify KCl administration as the most frequent
source of fatal drug errors11; guidelines recommend limiting KCl
availability in clinical areas, and storage in a locked cupboard
with meticulous (and time consuming) safety check procedures
in place prior to its use.20
Using Phoxillium removed the need for phosphate sup-
plementation. Our data are consistent with the important data
published by Chua et al10 that identified metabolic acidosis and
hypocalcaemia amongst selected patients receiving CRRT in
whom Phoxilium had been introduced to at clinicians discretion.
However, in contrast to their finding that plasma [PO43-] was bet-
ter maintained in patients receiving Phoxilium, we found that
that the use of Phoxilium was associated with a greater propor-
tion of time spent outside the normal plasma range of [PO43-].
The difference can be explained by the different way in which
the RRT fluids were used. In our study, the RRT fluids were used
as unit defaults rather than at the discretion of the treating con-
sultant (although clinicians could actively choose to use either
fluid). This reflects common practice in many intensive care
units, whereby a default CRRT fluid is identified, with the option
to select an alternative at clinician’s discretion. Notably, the de-
fault fluid was used in 89% of cases underlining the importance
of ‘default’ clinical pathways and suggesting limited selection
bias.
The use of potassium and phosphate containing renal
15,16 replacement fluids in patients with AKI with hyperkalaemia and
hyperphosphataemia is potentially harmful. In our study 9 of the
+ Phoxilium group with the highest [K+] received Hemosol-B0
+ and the plasma [K+] following initiation of RRT was the same
in both groups, suggesting that clinicians, appropriately, avoided
+ Phoxilium in patients with high baseline [K+]. However, several
2patients with high baseline [HPO42-]pl were initiated on RRT with
Phoxilium, reflecting the common observation that establishing
a ‘default’ clinical pathway can inadvertently impede the appli-
2cation of clinical judgement. These data reinforce the view that
a patient centred RRT strategy is preferable to a ‘one size fits all’
approach.
Our study further builds on previous work by standard-
izing the dialysis modality and dose, extending the study period
to encompass the duration of RRT and measuring the important
+ safety outcome of K+ supplementation.
+
+
+
As a retrospective study the possibility of selection bias is ac-
knowledged, in particular 9 patients received Hemosol-B0 dur-
ing the ‘Phoxilium standard’ period. Clinicians may have fa-
+ 3voured Hemosol-B0 in patients with high [K+] or [PO43-]. In a
+ randomized study K+ containing CRRT fluid might be expected
to promote hyperkalaemia precluding the safe undertaking of a
randomized, blinded comparison.
Although obtained retrospectively, biochemical datas-
ets resist ascertainment bias. This was a single-centre study al-
beit in a large metropolitan hospital with broad casemix.
Our outcomes are primarily biochemical, clinical outcomes as-
sociated with Hemosol-B0 vs. Phoxilium, or indeed RRT flu-
ids in general, remain to be evaluated. We reviewed all RRT for
AKI, the majority being short term. Studying a subgroup of pa-
tients requiring longer-term intensive care RRT might identify
particular benefits of Phoxilium as hypophosphataemia becomes
3more problematic and other drivers of acidosis defervesce. Al-
though units frequently designate a ‘standard’ RRT fluid, and in-
deed in the well-regarded RENAL study all participating centres
3- 5 agreed to use Hemosol-B0 for CVVHDF,5 with the availability
of alternative RRT fluids such as Phoxilium trials evaluating pa-
tient centred RRT prescription are warranted.
In critically ill patients treated for AKI with continuous veno-
venous haemodiafiltration, Phoxilium was associated with hy-
perphosphataemia, hypocalcaemia and metabolic acidosis com-
pared to Hemosol-B0. Phoxilium use reduced supplementary
phosphate requirements; the presence of KCl in Phoxilium offers
both advantages and disadvantages. These results inform clini-
cians of anticipated biochemical consequences of using these
RRT fluids, and highlight the importance of patient-centred RRT
fluid selection.
The authors declare that they have no conflicts of interest.