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.


http://jama.jamanetwork.com/article.aspx?articleid=2454911#ArticleInformation

http://jama.jamanetwork.com/article.aspx?articleid=2454911#ArticleInformation

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). vitrag24 - www.medicalgeek.com

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. vitrag24 - www.medicalgeek.com

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. vitrag24 - www.medicalgeek.com

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 vitrag24 - www.medicalgeek.com

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. vitrag24 - www.medicalgeek.com

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


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)?


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).


http://emcrit.org/plasmalyte/three-myths-about-plasmalyte-normosol-and-lr/

http://emcrit.org/plasmalyte/three-myths-about-plasmalyte-normosol-and-lr/

http://emcrit.org/epinephrine/understanding-lactate-in-sepsis-using-it-to-our-advantage/

http://emcrit.org/epinephrine/understanding-lactate-in-sepsis-using-it-to-our-advantage/

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. vitrag24 - www.medicalgeek.com

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


http://www.esicm.org/blog/?p=267

http://stemlynsblog.org/split-trial-published-saline-or-plasmalyte-on-the-icu-st-emlyns/

http://stemlynsblog.org/split-trial-published-saline-or-plasmalyte-on-the-icu-st-emlyns/

http://foamcast.org/2015/10/08/foamcastini-core-content-journal-club/

http://foamcast.org/2015/10/08/foamcastini-core-content-journal-club/

http://www.wessexics.com/The_Bottom_Line/Review/index.php?id=1851026200264600090







http://www.pulmcrit.org/2015/10/the-split-trial-internal-vs-external.html





http://www.emlitofnote.com/2015/10/not-much-to-say-about-split.html

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.


Questions…….?


Thank you

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