Normal Saline is not Normal? Evidence Based Medicine Chloride liberal vs. Chloride restrictive IV Fluid Wisit Cheungpasitporn, MD

1. Evidence Based Medicine:
Wisit Cheungpasitporn, MD.
PGY-3, Internal Medicine

2. “Normal Saline is Bad”

3. Normal Saline is not Normal?
• May induce or exacerbate:
– hyperchloremia and metabolic acidosis
– renal vasoconstriction and decreased glomerular
filtration rate (GFR)
– prolong time to first micturition
– decrease urine output in major surgery.
JAMA. 1970;214(9):1710
Crit Care Resusc. 2011;13(4):262-270

4. • 2 L of saline decreased cortical perfusion in
human study participants compared with
Plasma-Lyte

5. Do patients in ICU Chloride- Chloride-Liberal -Acute Kidney
Restrictive IV IV fluids Injury
fluids -ICU and hospital
survival

9. Method
• A prospective, open-label, before-and-after
pilot study in the 22-bed ICU.
• The Austin Hospital, a tertiary care hospital
affiliated with the University of Melbourne.
• Control period: February 18 to August
17, 2008
• Intervention period: February 18 to August
17, 2009.

10. Method
• Control period: IV fluids were given according
to clinician preferences with free use of
Chloride-rich fluids.
– 0.9% saline (chloride concentration: 150 mmol/L)
(Baxter Pty Ltd)
– 4% succinylated gelatin solution (chloride
concentration: 120 mmol/L) (Gelofusine, BBraun)
– 4% albumin in sodium chloride (chloride
concentration: 128 mmol/L) (4% Albumex, CSL
Bioplasma).

11. Method
• Following a 6-month phase-out period that
included education and preparation of all ICU
staff and logistic arrangements for fluid
accountability and delivery.
• No additional training was provided to nursing
or medical staff.

12. Method
• The intervention period: Chloride-Restrictive
IV fluids
– lactated crystalloid solution (chloride
concentration: 109 mmol/L) (Hartmann
solution, Baxter Pty Ltd)
– A balanced buffered solution (chloride
concentration: 98 mmol/L) (Plasma-Lyte
148, Baxter Pty)
– A 20% albumin solution (chloride concentration:
19 mmol/L) (20% Albumex, CSL Bioplasma).

15. Method
• The intervention period:
– Chloride-rich fluids available only after
prescription by the attending for specific
conditions (eg, hyponatremia, traumatic brain
injury, and cerebral edema).
– Similar fluid changes were instituted in the ED but
not in the OR or general wards.

16. Method
• Collected data on
– Age, sex, APACHE II and III scores, SAPS II, and multiple
clinical characteristics.
– pre-ICU admission serum Cr levels and daily Cr during
ICU admission.
– RRT, excluding pts with preexisting ESRD on long-term
dialysis and RRT for drug toxicity.
– In RRT-treated survivors of ICU stay, data on dialysis
status at 3 mths after discharge were obtained.
– RRT was initiated according to the criteria of the
Randomised Evaluation of Normal vs Augmented
Level (RENAL) Replacement Therapy in ICU Trial.

18. Method
• Primary outcomes:
– increase in Cr from baseline to peak ICU level and
incidence of AKI according to the
risk, injury, failure, loss, end-stage (RIFLE) system
definitions.
• Secondary post hoc analysis outcomes:
– the need for RRT
– length of stay in ICU and hospital
– survival.

19. RIFLE criteria
• The RIFLE criteria was put forward by the Acute Dialysis
Quality Initiative (ADQI) in 2005.

20. The AKIN "Acute Kidney Injury Network" criteria were published in 2007
after a meeting in the Netherlands comprised of multiple experts on AKI.

21. Method
• Baseline Cr: the lowest Cr available in the 1-
month period prior to ICU admission.
• If not available, Cr was estimated using the
MDRD equation (assuming a lower limit of
normal baseline GFR of 75 mL/min).

23. Statistical Analysis
• All statistical analysis was performed using Stata
version 11 (StataCorp) and SAS version 9.2 (SAS
Institute).
• Baseline comparisons were performed using χ2 tests
for equal proportion.
• Continuously normally distributed variables were
compared using t tests.
• Non–normally distributed data were compared using
Wilcoxon rank sum tests.
• The increase in Cr from ICU admission to peak level
was analyzed using generalized linear modeling.

24. Statistical Analysis
• AKI and the need for RRT were analyzed using
logistic regression.
• Time-to-event analysis was performed using
Cox proportional hazard modeling with
results reported as HRs with 95% CIs and
presented as Kaplan-Meier curves.
• Comparisons between survival curves were
performed using log-rank tests.

25. Statistical Analysis
• Multivariable sensitivity analysis was
performed on all outcomes, adjusting for
covariates of sex, APACHE III
score, diagnosis, operative status, admission
type (elective or emergency) and baseline Cr.

26. Statistical Analysis
• Subgroup analyses according to time in
ICU, APACHE score, risk of death, presence of
sepsis, and cardiac surgery.
• Assessed all outcome variables after excluding
pts in whom baseline Cr was not known.
• To reduce the chance of a type I error due to
reporting multiple outcomes, a 2-sided P
value of .01 was used to indicate statistical
significance.

27. Results

29. Results
• Patients received less chloride: 694–>496
mmol/patient.
• Average Cr rose by 0.25 mg/dL per pt in
control period — but only by 0.17 mg/dL in
the intervention period during ICU stay before
adjustment (22.6 vs. 14.8 μmol/l; P=0.03;
adjusted P=0.07).

31. Results
• 10% of pts needed RRT during control v.s.
6.3% during intervention period (p = .005).
• After adjustment for covariates, this
association remained for incidence of injury
and failure class of RIFLE-defined AKI (OR, 0.52
[95% CI, 0.35-0.75]; p<.001) and use of RRT
(OR, 0.52 [95% CI, 0.33-0.81]; p = .004).

34. Results
• No differences in mortality, hospital or ICU
length of stay or need for long-term dialysis
requirements .

35. Conclusion
• The implementation of a chloride-restrictive
strategy in a tertiary ICU was associated with a
significant decrease in the incidence of AKI
and use of RRT.

36. Strengths and Limitations
• This study raises very important questions on
the safety of chloride-rich solutions and might
lead to important changes in our fluid
resuscitation strategies.
• One Center
• Not randomized/Not Blind
• The intervention was of bundle-of-care kind
(Hawthorne effect)
• Heterogeneity of IV fluids

37. Strengths and Limitations
• Is IV fluid with bicarb(?cost) better than
Saline?
• Cost?
• Future prospective trials have to confirm the
findings.

39. Special Thanks to:
• Dr. Knight ; my EBM preceptor and fly fishing
master