Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis Raghunathan K, Shaw A, Nathanson B, et al. Critical Care Medicine, July 2014 INTRODUCTION Background • Fluid therapy is used to restore effective circulating blood volume and to promote tissue/organ perfusion. • Guidelines recommend early resuscitation with IV crystalloids as the preferred fluid therapy and against using hydroxyethyl starches due to increased risk of AKI. • Resuscitation with isotonic saline can induce hyperchloremia and metabolic acidosis and have been associated with alterations in renal blood flood and effects on immune function. • Balanced fluids avoid biochemical effects and have been associated with reduced perioperative mortality and ICU morbidity. Current Thoughts • Crystalloids differ in chloride content and strong ion difference (SID = sodium - chloride conc): - Lactated Ringer’s solution (LR): contains electrolytes, a high SID and physiologic chloride content - Isotonic saline (IS): does not contain electrolytes, has an SID = 0 and supraphysiologic chloride content STUDY OVERVIEW Study Type • Retrospective cohort study Objective • To examine the association between receipt of balanced fluids vs. nonbalanced fluids during initial resuscitation and in-hospital mortality, renal morbidity, ICU and hospital lengths of stay in a large cohort of adults admitted with vasopressor-dependent sepsis Enrollment • 53,448 critically ill adult patients who were admitted to one of at least 360 geographically and structurally diverse hospitals in the US between November 2005 and December 2010 • 6,730 patients studied (3,365 patients in each group) Inclusion Criteria • Critically ill patients ≥18 years old • Primary or secondary diagnosis of sepsis • Receiving vasopressors and received at least 2L of crystalloids for resuscitation by day 2 • Blood cultures and 3 consecutive days of antibiotic treatment Exclusion Criteria • Early adverse outcomes (e.g. ARF) that could dictate fluid choice • ESRD on dialysis PTA • Surgery • Transferred out of the ICU Outcomes • Primary outcome: in-hospital mortality after hospital day 2 • Secondary outcomes: ARF ± dialysis, hospital and ICU lengths of stay STUDY DESIGN & METHODS Study Design • Dose-response relationships were analyzed according to the proportion of balanced fluids received • Controlled for differences severity of illness and patient management (e.g. monitoring procedures, utilization of diagnostic tests, administration of supportive therapies and pharmacologic treatments) • Adjusted for confounding influence of hospital-specific factors (practice variation) • Conducted secondary sensitivity analyses Statistical Analysis • All analyses were performed using Stat/SE 11.2 • Cohorts assembled by application of inclusion/exclusion criteria and evaluated for balance on all measured covariate ...

1. Association between the choice of IV crystalloid and in-hospital
mortality
among critically ill adults with sepsis
Raghunathan K, Shaw A, Nathanson B, et al.
Critical Care Medicine, July 2014
INTRODUCTION
Background
• Fluid therapy is used to restore effective circulating blood
volume and to promote tissue/organ perfusion.
• Guidelines recommend early resuscitation with IV crystalloids
as the preferred fluid therapy and against
using hydroxyethyl starches due to increased risk of AKI.
• Resuscitation with isotonic saline can induce hyperchloremia
and metabolic acidosis and have been
associated with alterations in renal blood flood and effects on
immune function.
• Balanced fluids avoid biochemical effects and have been
associated with reduced perioperative mortality
and ICU morbidity.
Current
Thoughts

2. • Crystalloids differ in chloride content and strong ion
difference (SID = sodium - chloride conc):
- Lactated Ringer’s solution (LR): contains electrolytes, a high
SID and physiologic chloride content
- Isotonic saline (IS): does not contain electrolytes, has an SID
= 0 and supraphysiologic chloride content
STUDY OVERVIEW
Study Type • Retrospective cohort study
Objective • To examine the association between receipt of
balanced fluids vs. nonbalanced fluids during initial
resuscitation and in-hospital mortality, renal morbidity, ICU
and hospital lengths of stay in a large cohort of
adults admitted with vasopressor-dependent sepsis
Enrollment • 53,448 critically ill adult patients who were
admitted to one of at least 360 geographically and structurally
diverse hospitals in the US between November 2005 and
December 2010
• 6,730 patients studied (3,365 patients in each group)
Inclusion
Criteria
• Critically ill patients ≥18 years old
• Primary or secondary diagnosis of sepsis
• Receiving vasopressors and received at least 2L of crystalloids
for resuscitation by day 2
• Blood cultures and 3 consecutive days of antibiotic treatment
Exclusion
Criteria
• Early adverse outcomes (e.g. ARF) that could dictate fluid

3. choice
• ESRD on dialysis PTA
• Surgery
• Transferred out of the ICU
Outcomes • Primary outcome: in-hospital mortality after
hospital day 2
• Secondary outcomes: ARF ± dialysis, hospital and ICU lengths
of stay
STUDY DESIGN & METHODS
Study
Design
• Dose-response relationships were analyzed according to the
proportion of balanced fluids received
• Controlled for differences severity of illness and patient
management (e.g. monitoring procedures,
utilization of diagnostic tests, administration of supportive
therapies and pharmacologic treatments)
• Adjusted for confounding influence of hospital-specific
factors (practice variation)
• Conducted secondary sensitivity analyses
Statistical
Analysis
• All analyses were performed using Stat/SE 11.2
• Cohorts assembled by application of inclusion/exclusion
criteria and evaluated for balance on all measured
covariates
• 1:1 Propensity score matching to adjust for baseline
differences between the groups
• Multilevel mixed logistic regression model to predict the

4. propensity for receipt of balanced fluids by day 2
• Sensitivity analyses using Generalized Estimating Equation
models to analyze the incremental effects of
balanced fluids on all outcomes within propensity-matched
quintiles of total crystalloid volume and
predicted mortality risk
• Univariate comparisons using chi-square or t-tests
• Categorical data: frequencies and proportions; Continuous
variables: medians and interquartile ranges
• P-value <0.05 was significant
RESULTS
Population • At baseline prior to propensity matching:
- Patients who received balanced fluids were: younger, received
larger crystalloid volumes and were
MORE likely to receive colloids, steroids, invasive monitoring
and mechanical ventilation; LESS
likely to have a diagnosis of heart or chronic renal failure and
hypertension or diabetes with
complications
- Similar ARF rates, dialysis, ICU and hospital length of stay
Outcomes • Primary outcome: Absolute in-hospital mortality
beyond day 2: balanced fluids group 19.6% vs. no-
balanced fluids 22.8% (relative risk ratio 0.86; 95%CI, 0.78-
0.94) (table 1)
• Secondary outcomes: no significant differences between the
groups and no significant differences in

5. dose-response heterogeneity for ARF ± dialysis, hospital and
ICU lengths of stay (supplemental data)
Additional
Analyses
• Median total crystalloid volume during resuscitation: 2.5L to
10.5L
• Predominant fluid type:
- No-balanced group: IS
- Balanced fluid group: LR (the majority received <40% of
all fluids as balanced solutions)
• NNT = 31
• Relative risk of in-hospital mortality was incrementally
LOWER by 3.4% on average per 10% increase in the 0
proportion of balance fluids (figure 2)
• Risk of mortality was lowest among those receiving the
greatest
proportion of balanced fluids regardless of the total crystalloid
volume (figure 3)
• Those receiving larger proportions of balanced fluids were
less
likely to die within any given volume quintile (supplemental
data)
• Mortality odds DECREASED by 7.5% on average per 10%
increase in the proportion of balanced fluids received among
those at the lowest risk of death (supplemental data)
CONCLUSION
Author’s

6. Conclusion
• In-hospital mortality was lower following initial resuscitation
with balanced versus non-balanced crystalloids
among nonoperative patients admitted with early vasopressor -
dependent sepsis
• Mortality was progressively lower among patients receiving
greater proportions of balanced crystalloids
• IF this association represents a causal relationship, they
estimate one less in-hospital death for every 31
patients treated with balanced fluids rather than saline during
initial resuscitation in sepsis
DISCUSSION
Strengths • Large patient population
• Decent external validity
• Controlled for confounders and differences at baseline
Limitations • Retrospective, observational study
• Based on insurance claims and ICD-9 codes
• No laboratory values (e.g. chem 7, ABG, etc.)
• Very few patients exclusively receive balanced fluids
• Carrier solutions and IV fluids < 500 mL were excluded from
totals
CLINICAL APPLICATION
Currently, crystalloid fluids are used as the standard
resuscitation fluid in sepsis. Many studies have compared the
usage of
crystalloid fluids versus colloid fluids in sepsis, but there is
little data comparing the usage of different types of crystalloid
fluids, except in postoperative studies. This study showed a
significant difference in mortality between the usage of
balanced

7. fluids, such as Lactated Ringer’s, versus non-balanced fluids,
like isotonic saline, in patients with sepsis. There are many
variables that can occur during the management of sepsis and it
is difficult to determine if fluid choice solely has a significant
effect on mortality. Furthermore, since this is a retrospective
cohort study, there are many limitations. Though the findings
of
this study are statistically significant, it is not necessarily that
clinically significant. This study supports the need for
prospective, clinical trials to investigate the effects of
“balanced” versus “nonbalanced” fluids.
Lower risk of
mortality
↑ proportion of balanced fluids
↓ risk of in-hospital mortality
Fig. 2
Fig. 3