The SPLIT Randomized Clinical Trial - Journal Club

Effect of a Buffered Crystalloid
Solution vs Saline on Acute
Kidney Injury Among Patients in
the Intensive Care Unit
The SPLIT Randomized
Clinical Trial
DR. VITRAG SHAH
FIRST YEAR FNB RESIDENT,
DEPARTMENT OF CCEM,
SGRH, DELHI
MODERATOR
DR.Saurabh Taneja
vitrag24 - www.medicalgeek.com

Effect of a Buffered Crystalloid Solution vs Saline on Acute
Kidney Injury Among Patients in the Intensive Care Unit
The SPLIT Randomized Clinical Trial
 Paul Young, FCICM; Michael Bailey, PhD; Richard Beasley, DSc;
Seton Henderson, FCICM; Diane Mackle, MN;
Colin McArthur, FCICM; Shay McGuinness, FANZCA;
Jan Mehrtens, RN; John Myburgh, PhD; Alex Psirides, FCICM;
Sumeet Reddy, MBChB; Rinaldo Bellomo, FCICM ; for the SPLIT
Investigators and the ANZICS CTG
 JAMA. 2015;314(16):1701-1710. doi:10.1001/jama.2015.12334.
 Published on October 7, 2015.

Background
 NS is the most common intravenous fluid used in
fluid resuscitation, but it is associated with increased
risks of AKI and mortality.
 The theoretical risk of acute kidney injury (AKI)
associated with an increased chloride load among
critically ill patients has been supported by a large
prospective, sequential period pilot study of ICU
patients (1). Similarly, a propensity-matched analysis
has revealed that an increased chloride load is
associated with an increased morbidity and mortality
among patients with a systemic inflammatory
response (2).

Background
 One alternative to saline is a buffered crystalloid
solution with an electrolyte composition that more
closely resembles that of plasma, such as the prototype
compound sodium lactate solutions or proprietary
“buffered” or “balanced” crystalloid solutions
 Although it is biologically plausible that saline worsens
renal function compared with buffered crystalloids, the
effects of buffered crystalloids have not been evaluated
in randomized trials in the broad range of patients in the
ICU to whom they might be administered if used in
preference to saline.

Objective
 The stated objective of this study was to determine the
effect of a buffered crystalloid compared with saline on
renal complications in patients admitted to the intensive
care unit.
 Young et al have conducted the first large multicentre
prospective randomised controlled trial to investigate
the risks associated with normal saline vs. a balanced
solution (plasmalyte 148) administration in the ‘SPLIT
study’ (3). The results of this study were first
presented at the recent ESICM annual congress, LIVES
2015 in Berlin.

Study Design
 Prospective, investigator initiated, multicenter, blinded,
cluster-randomized, double crossover study
 N=2278 - Buffered crystalloid group (n=1162) , Saline (n=1116)
 Setting: 4 tertiary ICUs in NewZealand
 Enrollment: April 2014 to Oct 2014
 Upto Discharge/Death/90 days cencoring point
 Alternating 7-week treatment blocks, total 28 weeks
 Analysis: Intention-to-treat
 Primary outcome: Proportion of patients with AKI
 Secondary outcome: Proportion of patients requiring RRT
& in-hospital mortality

Study Design
 Three ICUs were general medical and
surgical ICUs; 1 ICU had a predominance of
cardiothoracic and vascular surgical patients.
 No established statistical methodologies for
prospectively determining sample sizes for
this type of study and hence no sample size
calculations were performed

Inclusion Criteria
 All ICU patients receiving crystalloid fluid
therapy as clinically indicated

Exclusion Criteria
 Patients who were on renal replacement
therapy (RRT) for end-stage renal failure,
were currently receiving RRT, or expected to
require RRT within 6 hours
 Patients who were admitted to the ICU solely
for consideration of organ donation or for
palliative care were excluded, as were those
who were previously enrolled in the study.

Participants
 All 2278 eligible patients were enrolled
 Of the enrolled patients, 1152 of 1162 patients
(99.1%) in the buffered crystalloid group and
1110 of 1116 patients (99.5%) in the saline
group were analyzed.

Baseline Characteristics
 Baseline characteristics were similar in both groups,
Including: age; co-morbidities; time from ICU admission
to first fluid; volume of fluid administered prior to
enrolment and APACHE II score
 Mean age : Around 60 years ,Apprx.two-thirds were men
 Most patients were admitted to the ICU following elective
surgery,most commonly cardiovascular surgery, and
relatively few had comorbidities.
 The mean (SD) APACHE II scores : 14.1 (6.9) for the
buffered crystalloid group and 14.1 (6.7) for the saline
group vitrag24 - www.medicalgeek.com

INTERVENTIONS
 Participating ICUs were assigned a masked
study fluid, either saline or a buffered crystalloid,
for alternating 7-week treatment blocks.
 Two ICUs commenced using 1 fluid and the
other 2 commenced using the alternative fluid.
Two crossovers occurred so that each ICU used
each fluid twice over the 28 weeks of the study.
 The treating clinician determined the rate and
frequency of fluid administration.

INTERVENTIONS
 Crystalloid treatment during intervention and
procedures performed outside the ICU was the
assigned study fluid as far as possible
 No restrictions placed on other fluids or
therapies
 Buffered crystalloid group and saline group
received similar volumes of study fluid (median
[IQR]), 2000ml [1000-3500ml] vs 2000ml [1000-
3250ml], P=0.63
 Most of this fluid was provided on the first day.vitrag24 - www.medicalgeek.com

MAIN OUTCOMES AND MEASURES
 The primary outcome was proportion of
patients with AKI based on RIFLE criteria
('injury' or greater and based solely on
creatinine component) within 90 days of
enrollment (defined as a rise in serum
creatinine level of at least 2-fold or a serum
creatinine level of ≥3.96mg/dL with an
increase of 0.5mg/dL)
 Main secondary outcomes were incidence
of RRT use and in-hospital mortality.vitrag24 - www.medicalgeek.com

Subgroup Analysis
 Both the primary outcome and the risk of in-hospital mortality
were examined in 5 predefined subgroup pairs. These
subgroups were based on Acute Physiology and Chronic
Health Evaluation (APACHE) III-j admission diagnoses and the
calculated APACHE II illness severity score (ranging from 0-71)
in the 24 hours prior to first fluid administration.
 The subgroups were the presence or absence of each of the
following:
 An admission diagnosis of sepsis,
 An admission diagnosis of trauma with or without a diagnosis of
traumatic brain injury,
 A cardiac surgical admission diagnosis,
 Preenrollment APACHE II score of 25 or higher.vitrag24 - www.medicalgeek.com

Results
 2278 patients eligible
o 1152/1162 (99.1%) received buffered
crystalloid
o 1110/1116 (99.5%) received saline

Primary Outcome
 Proportion of Patients with AKI within 90
Days
o Buffered Crystalloid Group 102/1067 (9.6%)
o Saline Group 94/1025 (9.2%)
o Absolute Difference 0.4% (95% CI -2.1% –
2.9%)
o RR 1.04 (95% CI, 0.80 – 1.36; p = 0.77)

Secondary Outcome
 Incidence of RRT
o Saline Group 38/1110 (3.4%)
o Absolute Difference -0.1% (95% CI -1.6% –
1.4%)
o RR 0.96 (95% CI, 0.62 – 1.50; p = 0.91)

Secondary Outcome
 In-Hospital Morality
o Saline group 95/1110 (8.6%)
o Absolute Difference -1.0% (95% CI -3.3% –
1.2%)
o RR 0.88 (95% CI, 0.67 – 1.17; p = 0.40)

Critical appraisal - Strengths
 Addresses a highly relevant question in practice and
builds upon the knowledge from previous fluid trials
 This study has outstanding internal validity: it is a
well-powered randomized trial with excellent
enrollment and minimal bias
 Physicians were blinded to type of fluid used (NS vs
PL). Intervention and control fluids were packaged in
macroscopically indistinguishable 1000mls bag
labeled "Fluid A" or "Fluid B“
 Trial recruited and conducted on time and within 6
months vitrag24 - www.medicalgeek.com

Critical appraisal – Strengths
 Pragmatic design in that treating clinicians determined the
rate and frequency of fluid administration. The two groups
had similar amounts of fluid administered (median=2
liters).
 Statistical analysis plan was published before completing
recruitment which helped eliminate analysis bias
 Primary end point was based on a serum creatinine
measurement which helped removed observer bias
 99.3% of patients eligible for study were analyzed which
removed selection bias

Limitations
 Even though clinicians were blinded 2/3 were able to guess the
assigned treatment. Maybe the development of
hypercholoremia and metabolic acidosis in patients receiving
saline may have unblinded some physicians
 No sample size calculations performed. There are no study
specifications for cluster-randomized trials; so all patients were
enrolled during the specified time period for the study.
 >90% of patients had received fluids, mostly PL (60%), prior to
study enrollment. This fluid was not considered in the analysis.
 This was a heterogenous population with a low incidence of
AKI, which makes it difficult to extrapolate findings to higher-risk
groups
 Primary outcome data not available for 7.5%vitrag24 - www.medicalgeek.com

Limitations
 The volume of fluid administered following randomisation was
modest, with a median of 2L administered. It remains unknown if
such a modest amount of fluid would result in any
hyperchloraemia. However, data on serum chloride levels was not
collected.
 The mean APACHE II score was 14 in both arms and the hospital
mortality did not exceed 9%. therefore a clinically important
increase or decrease in risk of in-hospital mortality could be
missed. It is unclear if the toxic effect of a high chloride load
(assuming there was a significantly elevated chloride in the N
Saline arm) would result in a clinically significant difference among
patients at low risk.

Unanswered questions
 Over 60% of these patients arrived to the ICU from
the operating room, most of which was after elective
surgery, most of which was cardiovascular. Only
15% arrived from the Emergency Department, and
only 4% carried a diagnosis of sepsis & majority did
not have many comorbid conditions
 Unanswered Questions - Limited external validity:
– What is the effect on all patients, namely those
admitted from the emergency department?
– Is there a difference in patients requiring more
than 2 liters of fluid (e.g. sepsis)?vitrag24 - www.medicalgeek.com

CONCLUSIONS AND RELEVANCE
 Among patients receiving crystalloid fluid
therapy in the ICU, use of a buffered
crystalloid compared with saline did not
reduce the risk of AKI. Further large
randomized clinical trials are needed to
assess efficacy in higher-risk populations
and to measure clinical outcomes such as
mortality.

Bottom Line Pearls:
 It appears we may be SPLITting hairs over fluid
choices. Giving a couple of liters? Fluid choice
may not matter. The study does provide
reassurance that in elective or moderately sick
intensive care patients, giving up to 2L 0.9%
sodium chloride results in no increased risk of
kidney injury compared with PlasmaLyte.
 SPLIT does not provide literature for larger
volume resuscitations & patients with high risk
of mortality. vitrag24 - www.medicalgeek.com

Discussion
 Studies often focus on the divide between NS and balanced
crystalloids (e.g. plasmalyte and LR). However, there are also
substantial differences between plasmalyte and LR:
o Plasmalyte contains 23 mM of sodium gluconate, which is mostly
excreted unchanged in the urine and might even act as an osmotic
diuretic.
o Plasmalyte contains 27 mM of sodium acetate, which the body
converts into bicarbonate. Concerns have been raised about potential
vasodilatory and pro-inflammatory effects of acetate .
o LR contains 28 mM of sodium lactate, which the body converts into
bicarbonate. Although lactate has a bad reputation due to its
association with shock, lactate production is often an adaptive
physiologic response to stress (e.g. sodium lactate may be used as a
fuel by the heart and brain).

Discussion
 Normal saline is occasionally referred to as “abnormal saline” due
to its physiologic abnormality, but plasmalyte is also quite
abnormal. There is nothing physiologic about infusing sodium
gluconate and sodium acetate.
 Among all of these solutions, LR is arguably the most physiologic
because it is a balanced crystalloid constructed from anions
normally present in the blood (chloride and lactate).
 Comparison of NS vs. plasmalyte is complicated because the renal
effects of gluconate and acetate are poorly understood. Therefore,
a trial of NS vs. plasmalyte is simultaneously testing three
unknowns: the effect of gluconate, the effect of acetate, and the
effect of non-anion gap metabolic acidosis. This makes it difficult to
understand the results.

Take Home Message
 Although no definitive answer is given to the
question of which fluid to give for fluid
resuscitation in the critically ill, at the moment
it seems you are safe if you still want to use
0.9% saline or low-chloride crystalloid
solutions at a volume of 2L or less.
 Remember the Goldilocks principle: not too
much, not too little, but just the right amount.
Fluids are a drug and we must monitor the
effect they have on patients. vitrag24 - www.medicalgeek.com

Summary
 The SPLIT trial reveals that low volumes of NS (e.g. two
liters per entire ICU stay) produce the same renal outcomes
as plasmalyte, but it does not reveal whether larger volumes
of normal saline are equivalent to plasmalyte.
 The SPLIT study does not clarify whether hyperchloremic
metabolic acidosis is safe.
 Differences between plasmalyte and LR make it incorrect to
assume that results obtained with plasmalyte will apply to
LR.
 Although this study is well designed with excellent internal
validity, it adds little to our understanding of large-volume
resuscitation.

For More Thoughts on This Topic
Checkout:
 Stephen Shepard at ESICM Lives 2015: SPLIT Trial
 Simon Carley at St. Emlyn’s: SPLIT trial published. Saline or
Plasmalyte on the ICU?
 Lauren Westafer and Jeremy Faust at FOAMCast: Core
Content Journal Club
 Adrian Wong at The Bottom Line: Effect of a Buffered
Crystalloid Solution vs Saline on Acute Kidney Injury Among
Patients in the Intensive Care Unit – The SPLIT Randomized
Clinical Trial
 Josh Farkas at PulmCrit: The SPLIT Trial – Internal vs External
Validity
 Ryan Radecki at EMLit of Note: Not Much to Say About SPLIT

1. Yunos NM, Bellomo R, Hegarty C, et al.: Association between a chloride-
liberal vs chloride-restrictive intravenous fluid administration strategy and kidney
injury in critically ill adults: JAMA 2012; 308:1566-72
2. Shaw AD, Schermer CR, Lobo DN, et al.: Impact of intravenous fluid
composition on outcomes in patients with systemic inflammatory response
syndrome: Crit Care 2015; 19:334
3. Young P, Bailey M, Beasley R, et al.: Effect of a Buffered Crystalloid Solution
vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The
SPLIT Randomised Clinical Trial: JAMA 2015; 314(16):1701-1710.
4. Bellomo et al : Association Between a Chloride-Liberal vs Chloride-Restrictive
Intravenous Fluid Administration Strategy and Kidney Injury in Critically Ill Adults
: JAMA. 2012;308(15):1566-1572. vitrag24 - www.medicalgeek.com

Questions…….?

Thank you
THANK YOU

The SPLIT Randomized Clinical Trial - Journal Club

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The SPLIT Randomized Clinical Trial - Journal Club