How much excess fluid impairs outcome of sepsis?
How much excess fluid impairs outcome of?sepsis?
Kelly R. Genga 2
James A. Russell 0 1 2
Dear Editor
0 Division of Critical Care Medicine, St. Paul's Hospital, University of British Columbia , 1081 Burrard Street, Vancouver, BC V6Z 1Y6 , Canada Full author information is available at the end of the article
1 Division of Critical Care Medicine, St. Paul's Hospital, University of British Columbia , 1081 Burrard Street, Vancouver, BC V6Z 1Y6 , Canada
2 Centre for Heart Lung Innovation (HLI), St. Paul's Hospital, University of British Columbia , 1081 Burrard Street, Vancouver, BC V6Z 1Y6 , Canada
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Fluid administration is fundamental in the treatment
of sepsis and septic shock, but it is more difficult than a
simple chemistry titration. Trials [1] and guidelines [2]
recommend early and adequate fluid resuscitation in
patients with sepsis and septic shock, as too little fluid
may extend the duration of shock and organ ischemia,
both important predictors of outcome. However, we [3]
and others [4] have found associations between excess
fluid administration and increased mortality due to
septic shock, leading us to recommend a cautious approach
to fluid resuscitation [5]. The definition of just how much
fluid is adequate (or not) for good management of septic
patients has been debated for years, and it is not yet clear
precisely how much fluid is ?excessive?, thereby
increasing the risk of mortality.
In a recent article in Intensive Care Medicine, Marik
and colleagues [6] reported the results of their carefully
designed cohort study of a large U.S. database (2013
Premier Hospital Discharge database; n? =? 23,513 patients)
in which they examined the relationships of fluid
administration with outcomes (hospital mortality) of severe
sepsis and septic shock. They also ?assessed trends in the
difference between actual and expected mortality in the
low fluid range (1?5?L day one fluids) and the high fluid
range (5?9+ L day one fluids)?. The 5-L cut-off is
interesting as it was defined by previously reported results [7]
and confirmed very nicely by these authors. Day 1 fluid
input averaged 4.4?L and was higher in patients who were
ventilated and in shock than in patients without these
diagnoses. Lower fluid volume (1?4.99?L) was associated
with slightly lower mortality. Increasing fluid volume
to >5? L was associated with increased risk of death?an
additional 2.3% for each extra liter exceeding 5?L. In
addition, the actual mortality exceeded the expected
mortality for patients who received >5? L of fluids on day 1,
particularly in those receiving ?7? L. This difference
(actual vs. expected mortality) was found in patients who
were (1) ventilated but not in shock, (2) in shock but not
ventilated, and (3) ventilated and in shock (as
demonstrated in Fig.?3 in the original paper).
The strengths of this cohort study are mainly the
large sample size, across a wide range of U.S.
hospitals, a priori defined fluid threshold, and the analytic
approaches, (propensity matching of cases and controls,
actual vs. expected mortality). Also (although this is a
pragmatic cohort study), the authors evaluated the
similarities between their study and important randomized
controlled trials (RCTs) of early goal-directed therapy
(EGDT) in the USA (PROCESS [8]), UK (PROMISE [9]),
and Australia (ARISE [10]).
The greatest limitation of the study is that it is an
association study, i.e., we can only speculate on causality. It
is not surprising that patients in shock and/or on
ventilation were sicker, needed more fluids, and had higher
mortality. Thus, we are depending on the adequacy of
the actual versus predicted mortality comparisons to
suggest that fluid administration of >5? L was associated
with increased mortality in patients in shock and/or on
ventilation. Another limitation is that day 1 was defined
and calculated as a calendar day, not 24? h. This would
have impacted day 1 results, as the fluid-administered
patients who had a 1-h day 1 are included in the same day
1 as patients who had a 23-h day 1. Although the authors
adjusted for this variation in the duration of day 1 by
excluding patients who received less than 1? L, this may
not be an adequate adjustment.
This study is reminiscent of the one conducted by
Kumar et? al. which showed associations of delays in
antibiotics and increased mortality of septic shock [11],
leading to strong recommendations for early (within 1?h)
antibiotic treatment of patients in septic shock [2].
However, while there will likely not be RCTs of early versus
delayed antibiotics for ethical reasons, there are now at
least four trials of EGDT [1, 8?10] versus usual care. The
?post-Rivers? RCTs show no difference between EGDT
and usual care has led to interpretations that usual care
(that limited fluids compared to EGDT) is supported by
meta-analyses [12] and is now preferred [13].
Although the results reported by Marik and colleagues
[6] seem to align with those of these RCTs and
metaanalyses, it must be (...truncated)