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* From the Division of Pulmonary and Critical Care, Bridgeport Hospital and Yale University School of Medicine, Bridgeport, CT.
Correspondence to: Constantine A. Manthous, MD, FCCP, Bridgeport Hospital, West Tower 6, 267 Grant St, Bridgeport, CT 06610; e-mail: pcmant{at}bpthosp.org
Abstract
Objective: We hypothesized that patients with septic
shock who achieve negative fluid balance (
-500 mL) on any day in
the first 3 days of management are more likely to survive than those
who do not.
Design: Retrospective chart review.
Patients: Thirty-six patients admitted with the diagnosis of septic shock.
Setting: Twelve-bed medical ICU of a 300-bed community teaching hospital.
Methods: Medical
records of 36 patients admitted to our medical ICU over a 21-month
period were examined. Patients with septic shock who required dialysis
prior to hospitalization were not included. A number of demographic and
physiologic variables were extracted from the medical records.
Admission APACHE (acute physiology and chronic health evaluation) II
and daily sequential organ failure assessment (SOFA) scores were
computed from the extracted data. Variables were compared between
survivors and nonsurvivors and in patients who did vs those who did not
achieve negative ( 500 mL) fluid balance in 
1 day of the first 3
days of management. Survival risk ratios (RRs) were used as the measure
of association between negative fluid balance and survival. RRs were
adjusted for age, APACHE II scores, SOFA scores on the first and third
days, and the need for mechanical ventilation, by stratified
analyses.
Results: Patients ranged in age from 16 to
85 years with a mean (± SE) age of 67.4 ± 3.3 years. The mean
admission APACHE II score was 25.4 ± 1.4, and the day 1 SOFA score
was 9.0 ± 0.8. Twenty patients did not survive; nonsurvivors had
higher mean APACHE II scores than survivors (29.8 vs 20.4,
respectively) and higher first day SOFA scores than survivors (10.8 vs
6.9, respectively), and they were more likely to require
vasopressors and mechanical ventilation compared to patients who
survived. Whereas all 11 patients who achieved a negative balance of
> 500 mL on 1 of the first 3 days of treatment survived, only 5
of 25 patient who failed to achieve a negative fluid balance of > 500
mL by the third day of treatment survived (RR, 5.0; 95% CI, 2.3 to
10.9; p = 0.00001). At least 1 day of net negative fluid balance in
the first 3 days of treatment strongly predicted survival across the
strata of age, APACHE II scores, first- and third-day SOFA scores, the
need for mechanical ventilation, and creatinine levels measured at
admission.
Conclusion: These results suggest that at
least 1 day of negative fluid balance ( -500 mL) achieved by the
third day of treatment may be a good independent predictor of survival
in patients with septic shock. These findings suggest the hypothesis
"that negative fluid balance achieved in any of the first 3 days of
septic shock portends a good prognosis," for a larger
prospective cohort study.
Key Words: diuresis • ICU • kidney • multiple organ failure • renal • septic shock • urine
The cardiovascular derangemnts of septic shock in humans include arteriolar and venular dilation and capillary leak.1 2 3 Intravascular volume replace- ment during resuscitation most frequently converts the circulation to a high-output hypotensive state.4 During recovery from septic shock, as vascular tone returns and edema is retrieved to the intravascular
space, increased venous return should result in adiuretic phase if the heart and kidneys have notfailed as a result of the septic insult. In this retrospective pilot study, we hypothesized that patients with septic shock who achieve negative fluid balance on any of the first 3 days of therapy are more likely to survive than those who do not.
Materials and Methods
Our hospital investigational review board waived formal review of this study. Our ICU maintains a logbook of all patients and their primary admission diagnoses. We submitted a list of all patients admitted to our medical ICU between July 1997 and March 1999 with the ICU admitting diagnosis of septic shock to our Medical Records Department. A uniform data abstraction tool was used to gather data from charts. Records were examined first to determine whether patients met the published criteria for septic shock,5 including the following criteria: (1) a systolic BP < 90 mm Hg or a > 30 mm Hg decrease from baseline that is unresponsive to fluids and/or to the requirement of inotropic medications; (2) hypothermia or hyperthermia (temperature, < 36°C or > 38°C, respectively); and (3) tachypnea (> 20 breaths/min). Only patients meeting consensus criteria5 for septic shock and who were not receiving dialysis prior to admission were included in this study. Variables extracted from the medical records of patients who met the criteria for septic shock included the following: age; gender; APACHE (acute physiology and chronic health evaluation) II score (on the first day of septic shock); daily fluid inputs and outputs; lowest recorded mean arterial pressure each day; daily arterial blood gas levels and laboratory test results; daily Glasgow coma scale scores; highest doses of vasoactive medications each day; administered diuretics; and culture results. Daily sequential organ failure assessment (SOFA) scores6 were computed for each patient when complete data were available.
The physiologic and demographic characteristics of patients who
survived were compared to those who did not survive by nonpaired
Student’s t tests. A p value < 0.05 signified statistical
significance. Using stratified analyses, the risk ratios (RRs) of
survival for patients with net negative fluid balance ( -500 mL) on
any of the first 3 days of therapy compared to those of patients who
failed to achieve net negative balance on any of the first 3 days were
computed across the strata of selected risk factors for adverse
outcomes in septic shock. Where appropriate, threshold levels were
defined using standard norms or medians where no such norms exist.
These thresholds were an APACHE II score of < 20, a SOFA score of
< 10, age < 65 years, and a serum creatinine level < 2.0
mg/dL. The choice of day 3 in classifying patients with respect
to fluid balance was empiric and was defined a priori; it
was thought that 3 days marks a reasonable juncture for assessment of
progress in a trial of therapy and with regard to the use of ongoing
therapies. Summary estimates using both the Mantel-Haenszel
test7
and precision-based8
approaches were
computed. Ninety-five percent confidence intervals (CIs) were
calculated using the method of Greenland and Robbins9
for
sparse data. Only the Mantel-Haenszel test estimates are reported
because of the similarity with the precision-based estimates. Given the
small sample size and the absence of mortality in the group that
achieved net negative fluid balance, the meaningful simultaneous
adjustment of multiple risk factors could not be performed.
Results
Of 44 cases listed in our ICU logbook, 36 patients with a mean (± SE) age of 67.4 ± 3.3 years (median, 72 years; range, 16 to 91 years) met strict inclusion criteria for septic shock and had no history of dialysis. Twenty-five patients were admitted through the emergency department, and 11 patients were transferred into the ICU from the hospital. The mean APACHE II score of patients on the first day that they satisfied the criteria for septic shock was 25.4 ± 1.4 (median, 25.5; range, 11 to 46). The first day SOFA scores ranged from 3 to 17, with a mean of 9.0 ± 0.8. Fifteen patients had documented Gram-negative rod infections, 9 patients had Gram-positive coccal infections, 2 patients had fungal infections, 3 patients had positive cultures for both Gram-negative rods and Gram-positive cocci, and 7 patients had culture-negative septic shock.
Mortality
Twenty of 36 patients (56%) did not survive hospitalization. Nine
patients died within 3 days of hospital admission, and care was limited
(no code) or withdrawn for all but one patient. Table 1
lists the characteristics of patients based on outcome. As expected,
the first day APACHE II score, first day SOFA score, frequencies of
encephalopathy, the need for vasopressors, and the need for mechanical
ventilation were greater in the patients who died in the hospital.
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All patients who achieved net negative fluid balances on any of the
first 3 days of therapy (n = 11) lived. By comparison, only 5 of 25
patients who failed to achieve 1 day of net negative fluid balance by
day 3 lived (RR, 5.0; 95% CI, 2.3 to 10.9; p = 0.00001). Figure 1
demonstrates fluid balance among patients who survived (top,
A), those who died (middle, B), and the aggregate daily
mean values for these two groups (bottom, C). The mean fluid
balance was persistently net positive for those patients who died. Of
20 patients who died, 17 never achieved even 1 day of net negative
fluid balance. One of the remaining three patients achieved a negative
fluid balance of < 500 mL. Table 2 shows a comparison of characteristics for patients who were alive by
day 3 in terms of those patients who did achieve a negative fluid
balance vs those who did not ( -500 mL) on 1 day.
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-500 mL)
across all strata of selected prognostic indicators of septic shock
(Table 3
). These indicators included the APACHE II score at admission, age, the
need for mechanical ventilation, SOFA scores on days 1 and 3, and
creatinine level measured at admission. For example, adjusting for day
1 or day 3 SOFA scores, patients who achieved negative fluid balance on
1 day were more than three times as likely to survive as those who
did not achieve negative fluid balance (RR adjusted for day 1 SOFA
score, 3.2; 95% CI, 1.5 to 6.6; RR adjusted for day 3 SOFA score, 3.5;
95% CI, 1.5 to 8.2). Although based on small numbers of
patients, the highest estimates of survival RRs for those
patients who achieved negative fluid balance on 1 of the first 3 days
of therapy were obtained in categories that traditionally portend the
worst prognosis. For example, among patients with admission APACHE II
scores 20, those who achieved negative fluid balance ( -500 mL)
on 1 of the first 3 days of therapy were six times as likely to survive
as those who did not. Similarly, among patients with first day SOFA
scores 10, those who achieved net negative fluid balance on 1
of the first 3 days of therapy were six times as likely to survive.
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The available data from this small retrospective study suggest that for patients presenting with septic shock, negative fluid balance on any of the first 3 days after admission is associated with better survival rates than for patients who do not achieve negative fluid balance (100% vs 31%, respectively; RR, 5.0; 95% CI, 2.3 to 10.9). This observed association was consistent across all levels of prognostic indicators of septic shock.
The study is limited by its small sample size and by the resulting instability of the stratum-specific survival RR estimates. Although the association held at each stratum of the known prognostic indicators, it cannot be said with a high degree of certainty that the association would remain this strong in a simultaneous adjustment of all known prognostic indicators of septic shock. Furthermore, the choice of day 3 as the critical day to assess whether or not a patient had achieved negative fluid balance (on any day) was empiric, although it was defined a priori. That one fourth of all patients were already dead by day 3 (some of whom had care withdrawn) would suggest, perhaps, that an earlier assessment would be more meaningful to families and caretakers alike. It can, however, be argued that 3 days is a reasonable duration for a trial of therapy.
The theoretical underpinnings of this simple observation are appealing and integrate hemodynamic and renal physiology. Since septic shock is characterized by vasodilation and capillary leak (an ebb phase), which often leads to systemic hypoperfusion, successful resuscitation includes refilling the underfilled system. Attenuation of the septic cascade (of mediators) during successful treatment is expected to cause a return of normal vascular tone and the retrieval of fluid from the peripheral circulation and third space back to the central circulation. Excess fluid then should be eliminated via increased urine output, assuming that the heart and kidneys continue to function well (a flood phase). Renal failure, by itself, is associated with worse clinical outcomes in patients with sepsis.10 11 Negative fluid balance may signal both the resolution of the hemodynamic derangements of sepsis and that the kidneys and heart have not failed as a result of the septic insult. Thus, it is not surprising that the combination of these two signals portends a good prognosis.
One might question whether the administration of diuretics could
account for the observations of this study. However, there was no
significant difference in the use of diuretics between patients in the
group that achieved a negative fluid balance of -500 mL on 1 day
and those who did not. If this observation is confirmed in a
larger study, negative fluid balance is not likely to be the cause of
improved outcome but rather a marker for or an effect of the successful
management of septic shock. Clinicians should not seek to achieve
negative fluid balance as an end in itself.
The shortcomings of this investigation limit the extrapolation of these results to all patients with septic shock. This hypothesis should be reexamined and verified in a much larger cohort before it is used to prognosticate and manage patients. Nonetheless, if confirmed in prospective studies, fluid balance in any of the first 3 days of septic shock could provide a simple and inexpensive method of augmenting current prognostic indicators. This would be of obvious benefit to anxious family members and caretakers alike.
Footnotes
Abbreviations: APACHE = acute physiology and chronic health evaluation; CI = confidence interval; RR = risk ratio; SOFA = sequential organ failure assessment
Received for publication October 4, 1999. Accepted for publication January 13, 2000.
References
This article has been cited by other articles:
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  L. Durairaj and G. A. Schmidt Fluid Therapy in Resuscitated Sepsis: Less Is More Chest, January 1, 2008; 133(1): 252 - 263. [Abstract] [Full Text] [PDF]
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W. E. Johnston PRO: Fluid Restriction in Cardiac Patients for Noncardiac Surgery is Beneficial Anesth. Analg., February 1, 2006; 102(2): 340 - 343. [Full Text] [PDF]
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G. S. Martin, E. W. Ely, F. E. Carroll, and G. R. Bernard Findings on the Portable Chest Radiograph Correlate With Fluid Balance in Critically Ill Patients Chest, December 1, 2002; 122(6): 2087 - 2095. [Abstract] [Full Text] [PDF]
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T. Quasim, D. C. McMillan, J. Kinsella, C. A. Manthous, and Y. Amoateng-Adjepong Negative Fluid Balance as Predictor of Mortality Chest, October 1, 2001; 120(4): 1424 - 1425. [Full Text] [PDF]
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