Documente Academic
Documente Profesional
Documente Cultură
Springer-Verlag 1999
R. Moreno
J.-L. Vincent
R. Matos
A. Mendona
F. Cantraine
L. Thijs
J. Takala
C. Sprung
M. Antonelli
H. Bruining
S. Willatts
on behalf of the working group on
sepsisrelated problems of the ESICM
R. Moreno ( ) R. Matos
Unidade de Cuidados Intensivos
Polivalente, Hospital de St. Antnio dos
Capuchos, Alameda de St. Antnio dos
Capuchos, P-1150 Lisboa, Portugal
(e-mail: r.moreno@mail.telepac.pt,
Fax: + 3511-4 844635),
J.-L. Vincent A. Mendonca
Department of Intensive Care,
Erasme University Hospital, Brussels,
Belgium
F. Cantraine
Facult de Medicine,
Universit Libre de Bruxelles, Brussels,
Belgium
L. Thijs
Medical Intensive Care Unit,
Academisch Ziekenhuis Vrije Universiteit
Amsterdam, Amsterdam, The Netherlands
J. Takala
Department of Intensive Care,
Kuopio University Hospital, Kuopio,
Finland
C. Sprung
Department of Intensive Care,
Hadassah Hebrew University Medical
Center, Jerusalem, Israel
M. Antonelli
Istituto di Anestesiologia e Rianimazione,
Universit La Sapienza, Rome, Italy
H. Bruining
Intensive Care Unit,
Academisch Ziekenhuis Rotterdam,
Rotterdam, The Netherlands
S. Willatts
Directorate of Anaesthesia,
Bristol Royal Infirmary, Bristol, UK
O R I GI N A L
687
Introduction
In recent years, a series of negative results in clinical trials on sepsis [113] has challenged the classical adoption
of hospital mortality as the end point for the evaluation
of clinical trials in intensive care [14]. The use of this
measure has constituted the gold standard until now,
since it is easy to define and to measure and represents
a clinically very relevant end point. However, it has
been contested [15], since hospital policy can and does
change the location of deaths (e. g. discharging patients
to die) and mortality can be significantly underestimated in hospitals which discharge patients very early in
the course of their disease.
Recently authors have questioned the adequacy of
all cause mortality as an end point [16]. A meaningful
end point can only be chosen when a direct relation between an event and its consequences is known. In the
case of sepsis (and multiple organ failure) our knowledge is very limited and only an indirect and partial relationship can actually be established to most phenomena.
Moreover, all cause mortality implies the need for large
samples, with problems in reliability of data collection,
heterogeneity of enrolled patients and costs. Patients in
intensive care, even with strict inclusion criteria for sepsis or septic shock, do not constitute a homogeneous
sample. Patients have different diagnoses, time-courses,
ages, chronic illnesses (chronic health, co-morbidities),
different sites of infection and invading microorganisms
and different degrees of physiological dysfunction, resulting in a large dispersion of mortality risks [17, 18].
Additionally, the presence and impact of other confounding events such as inappropriate antimicrobial
therapy, inadequate medical-surgical management and
forgoing life-sustaining therapies must be analysed and
taken into account [19]. Several methods have been proposed to deal with this variation [18, 20, 21], but these
usually lead to complex, extensive (and expensive) data
collection and sophisticated analysis.
It has been shown that certain interventions, effective in their specific scope, fail to reduce all cause hospital mortality. A recent example is selective decontamination of the digestive tract (SDD); it has been
demonstrated to diminish the prevalence of nosocomial pneumonia [22], but does not consistently decrease
hospital mortality [23, 24]. In other cases, therapeutic
interventions have failed to demonstrate beneficial effects in multicentre trials [1] and have been found to
be associated with a significant reduction in mortality
688
Methods
Maximum organ failure scores were calculated for all the six components of the system during the entire ICU stay. The aggregate
score (total maximum SOFA score) was calculated summing the
worst scores for each of the components. The amount of organ dysfunction/failure appearing after ICU admission (delta SOFA) was
evaluated computing the total maximum SOFA score minus the
admission total SOFA score (Appendix). For purposes of analysis,
organ dysfunction was defined as a SOFA score of 1 or 2 points and
organ failure as a SOFA score 3. Chi-square statistics (with Yates
correction when applicable) were used to test for the statistical significance of categorical variables and one-way analysis of variance
was used to assess continuous variables. All statistical tests were
two-sided, and a significance level of 0.05 or less was used except
when stated otherwise.
The discriminative power of the scores, that is, the ability of the
scores to discriminate between patients who live and patients who
die, was defined by the area under the receiver operating characteristic (ROC) curve, computed by a modification of the Wilcoxon
statistics, as proposed by Hanley and McNeil [28]. The comparison
of the areas under ROC curves was made using the Z statistic with
correction for the correlation introduced by studying the same
sample [29].
For the computation of the odds ratios and interactions associated with each component of the system, we fitted a logistic regression model with outcome in the ICU as the dependent variable.
The maximum SOFA scores for each of the six systems were used
as independent variables. Later, pertinent interactions were added
to the model. The same method was applied in the evaluation of
the relative contributions of delta SOFA and admission total
SOFA score to prognosis, using outcome in the ICU as the dependent variable and delta SOFA and admission SOFA as the independent variables. Logistic regression analysis was used to evaluate the relationship between total maximum SOFA score and
ICU mortality. Linear regression analysis was used to evaluate the
correlation between mean delta SOFA and ICU mortality.
Exploratory factor analysis was applied to study meaningful interrelations among the six components of the SOFA score. This
type of analysis aims at analysing the interrelations between a set
of variables, without the need to consider which variables are dependent and which variables are independent (opposite to regression where this specification must be done). This technique allows
for the identification of association patterns of the different variables under consideration, without first having to specify a causeand-effect relationship [30]. An eigen value of 1 or more was
considered as significant.
The results are presented as means standard deviation except
when stated otherwise. The outcome measure used was survival
status at discharge from the ICU. Data analysis and statistics were
performed using the Statistical Package for Social Sciences
(SPSS) version 5.0 for MS DOS and 7.0 for Microsoft Windows at
the Intensive Care Unit, Hospital de Santo Antnio dos Capuchos,
Lisbon, Portugal.
Results
A total of 1,449 patients were studied for a total of
11,417 ICU days. Thirty-two percent of the patients
were admitted from the emergency room, 27 % from
the ward, 26 % from the operative theatre and 11 %
from other hospitals. Most patients were male (64 %),
with an overall mean age of 55 19 years ranging from
12 to 95 years. Non-operative patients comprised 44 %
of the sample. The median LOS in the ICU was
5.0 days (interquartile range 310 days). The overall
mortality in the ICU was 22 % with a corresponding
overall hospital mortality of 26 %. Five patients had
missing data in their ICU outcome and were excluded
from the analysis related to outcome. More details can
be found in the main description of the study [27].
Figure 1 shows the frequency distribution of total
maximum SOFA score in survivors and non-survivors.
The mean total maximum SOFA score was
8.2 + 5.4 points, median 7 points, range 024 points,
and was significantly higher in non- survivors than in
survivors (13.6 4.8 points versus 6.7 4.5 points,
p < 0.001). The relationship between total maximum
SOFA score and ICU outcome was established as:
Pr =
e4:0473 + 0:2790(TMS)
1 + e4:0473 + 0:2790(TMS)
689
Table 1 Maximum SOFA scores for the six organ systems in the
global population, in survivors and in non-survivors. The differences between survivors and non-survivors were always significant
(p < 0.001). Results are presented as mean standard deviation
Component
Respiratory
Cardiovascular
Renal
Coagulation
Hepatic
Neurological
Total Maximum
SOFA score
2.2 1.3
1.5 1.5
1.0 1.2
1.0 1.1
0.7 1.0
1.7 1.7
2.0 1.3
1.2 1.3
0.8 1.0
0.8 1.0
0.6 0.9
1.4 1.5
3.0 1.1
2.9 1.4
1.9 1.4
1.7 1.3
1.3 1.3
2.9 1.6
8.2 5.4
6.7 4.5
13.6 4.8
Number
of patients
% of
Death in Mortality Maximum
patients the ICU rate
SOFA
(n)
(%)
scorea
0
1
2
3
4
5
6
507
360
243
175
93
43
23
35.1
24.9
16.8
12.1
6.5
3.0
1.6
16
38
62
90
57
29
21
3.2
10.6
25.5
51.4
61.3
67.4
91.3
3.1 2.2
7.0 2.2
10.1 2.0
13.7 1.9
16.4 1.5
19.4 1.3
21.3 1.5
vivors and non-survivors were always significant (Table 1). The mortality rate increased as the score increased in all organ systems (Fig. 2). For respiratory
and neurological scores the patterns were less clear, especially when the scores were lower than 3 points.
The number of organ failures (maximum SOFA
score 3) also showed a significant correlation to ICU
outcome, with mortality rates ranging from 3.2 % in patients without any organ failure to 91.3 % in patients
with failure of all the six organs analysed (Table 2).
The mean maximum SOFA score also showed a corresponding increase, with values ranging from
3.1 2.2 points in patients without organ failures to
21.3 1.5 points in patients with six organ failures. The
maximum SOFA score occurred shortly after admission
for all organ systems analysed (1.1 0.2 days) with
mean values ranging from 0.8 days (95 % confidence interval 0.60.9 days) for the neurological score to
1.4 days (95 % confidence interval 1.21.5 days) for the
respiratory score.
If we limit the analysis to organ failures (SOFA 3
points), the time required to reach maximum values
was longer (mean 2.9 + 1.1 days, ranging from 1.6 days
690
strated. A trend (non-significant) was found for interactions between respiratory and coagulation scores (odds
ratio 1.14, 95 % confidence interval 0.971.33), respiratory and renal scores (odds ratio 1.09, 95 % confidence
interval 0.951.25), cardiovascular and renal scores
(odds ratio 1.07, 95 % confidence interval 0.961.07), renal and hepatic scores (odds ratio 1.11, 95 % confidence
interval 0.981.25), and hepatic and coagulation scores
(odds ratio 1.09, 95 % confidence interval 0.971.23).
Exploratory factor analysis was then used to identify meaningful interrelations among the six components
Table 3 Relative contributions to ICU outcome of the maximum value during ICU stay for each of the six components of the SOFA
score
Variable
SE
Wald
Odds-ratio
(95 % confidence intervals)
Respiratory
Cardiovascular
Renal
Coagulation
Hepatic
Neurological
Constant
0.164
0.521
0.377
0.198
0.202
0.339
3.750
0.080
0.063
0.061
0.072
0.155
0.049
0.351
4.176
68.242
37.951
7.482
1.702
48.703
113.930
0.041
< 0.001
< 0.001
0.006
0.192
< 0.001
0.038
0.210
0.154
0.060
0.000
0.176
1.176 (1.0071.378)
1.683 (1.4881.905)
1.458 (1.2941.643)
1.219 (1.0591.404)
0.817 (0.6031.107)
1.404 (1.2751.545)
b, coefficient; SE, standard error; Wald, Wald statistic, R, partial correlation. Odds-ratios are presented for a 1-point change in the scores
for each organ
691
Factor 1
Factor 2
0.7221
0.5168
0.1154
0.1711
0.1269
0.8737
0.7812
0.6960
0.1409
0.1580
0.0928
0.7636
Fig. 5 Delta SOFA score and ICU mortality. A linear relation exists between delta SOFA and ICU mortality
ing the ICU stay. The first factor comprises the respiratory, cardiovascular and neurological scores and
the second the coagulation, hepatic and renal components.
Delta SOFA presented a mean value of 3.0 3.3
points, median 2.0 points, range 019 points. Delta
SOFA was significantly higher (p < 0.001) in non-survivors than in survivors (5.5 4.1 points versus
2.3 2.7 points). As presented in Table 5, ICU mortality
increased as the delta SOFA score increased. The association between mean delta SOFA and ICU mortality
followed a linear pattern (Fig. 5, Table 5). Delta SOFA
presented an area under the ROC curve of 0.742 (SE
0.017) (Fig. 4), which was significantly lower (p < 0.001)
than that of the total maximum SOFA score and slightly
lower (non-significant) than that of the admission total
SOFA score (0.772, SE 0.015).
In order to evaluate the relative contribution to ICU
outcome of the amount of organ dysfunction present at
ICU admission (admission total SOFA score) and that
developing during ICU stay (delta SOFA score), a nonstepwise logistic regression equation was developed.
Results demonstrate that both were important for outcome, and with a similar weight (Table 6). The associated odds ratios, for a 1 point change in the score were
1.36 (95 % confidence interval 1.301.42) for the admis-
Table 5 Delta SOFA (total maximum SOFA score minus admission total SOFA score) and ICU outcome
Delta
SOFA
Number of
patients
% of
patients
Death in
the ICU (n)
Mortality
rate (%)
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
L 15
390
234
191
140
118
90
72
53
39
33
22
20
16
9
5
12
27.0
16.2
13.2
9.7
8.2
6.2
5.0
3.7
2.7
2.3
1.5
1.4
1.1
0.6
0.3
0.8
38
20
29
26
29
24
29
24
21
17
16
12
9
7
4
8
9.7
8.5
15.2
18.6
24.6
26.7
40.3
45.3
53.8
51.5
72.7
60.0
56.3
77.8
80.0
66.7
Table 6 Relative contribution for outcome in the ICU of the admission SOFA score and delta SOFA
Variable
Admission total SOFA
score
Delta SOFA
Constant
SE
Wald
0.308
0.022
192.784
< 0.001
0.356
1.361 (1.3031.421)
0.312
4.765
0.024
0.247
170.274
372.404
< 0.001
0.334
1.367 (1.3031.432)
b, coefficient; SE, standard error; Wald, Wald statistic, R, partial correlation. Odds-ratios are presented for a 1-point change in the score.
692
sion total SOFA score and 1.37 (95 % confidence interval 1.301.43) for the delta SOFA score.
Discussion
Multiple organ dysfunction syndrome (MODS) has become the leading cause of morbidity and mortality in intensive care [3133]. Described initially by Tilney et al.
in 1973 after massive acute blood loss and shock [34], it
was found later to be associated with infection [35, 36],
acute pancreatitis [37], burns [38], shock [39] and trauma [40].
As emphasised by a recent Consensus Conference
[41], there is a need for a comprehensive database to
test and validate optimal criteria for describing this syndrome, in which specific variables could be tested
against outcome. Various efforts to this end have appeared recently in the literature [26, 4244]. All were
built on the common assumptions: that one can describe
increasing dysfunction in individual organs and assess
MODS as a continuum of organ dysfunction/failure instead of an on/off phenomenon. However, limitations
exist for all. The systems proposed by Marshall et al.
(multiple organ dysfunction score) and by Bernard
et al.(Brussels score) have not been tested in a multicentre representative database of critically ill patients. The
system proposed by Le Gall et al., logistic organ dysfunction (LOD) score, was developed with very sophisticated statistical techniques to choose and weigh the
variables in a large international database. However, it
was developed and validated with data collected only
in the first 24 h in the ICU and no information exists
about its behaviour at later stages in the evolution of
MODS.
A panel of experts constructed the latest system,
SOFA score, based on a review of the literature. This
methodology, has been applied successfully in the past
[45] but needs extensive validation in order to evaluate
the adequacy of the variables chosen and their limits.
This was recognised in the original description [26] and
prompted the Working Group on Sepsis-related Problems of the ESICM to perform a prospective, multinational validation study. The main data have been presented elsewhere [27]. Based on these data, we studied
the validity of two complementary measures as descriptors of morbidity in intensive care: total maximum
SOFA score and delta SOFA.
The results show that, in this ICU patient database,
total maximum SOFA score showed a very good correlation to outcome and occurred early during the ICU
stay. All the individual organ scores were significantly
higher in non-survivors than in survivors, with a clear
correlation between increasing score and increasing
mortality except for low values (less than 3) of the neurological and respiration scores, where the patterns
693
the ICU stay and the evaluation of the total insult suffered by the patient. All are very important by themselves, as shown in Table 6, but also address complementary facets of a complex response. The admission
SOFA reflects the degree of failure already present
when the patient enters the ICU. This measurement,
that only the admission mortality prediction model [47]
is able to achieve, can be used to stratify patients according to severity of illness, for example, for inclusion
in clinical trials based on the admission SOFA score.
The delta SOFA measures the progress of the patient
during the ICU stay and is potentially influenced by
therapy. The fact that it was a good prognostic indicator
after controlling for admission SOFA score suggests
that strategies directed at the prevention and/or limitation of further organ dysfunction will have a significant
impact on prognosis, independent of the condition of
the patient on admission to the ICU. This certainly
needs further research. Last but not least, the quantification of the total insult suffered by the patient during
the ICU stay (total maximum SOFA) was a very important prognostic indicator. This suggests that it can be
used to quantify the impact of therapeutic interventions
on overall or organ-specific morbidity. Some but not all
of those interventions could also have an impact on
mortality, but to focus exclusively on mortality as an
end point could lead to an underestimation of the relevant effects of therapeutic interventions obscured by
the heterogeneity of causes of death.
What is the precise nature of the two-factor structure
observed? What are the precise relationships between
the respiratory, cardiovascular and neurological systems
or between the coagulation, hepatic and renal systems?
One tempting explanation could be the presence of
two targets in this complex syndrome. If this is the
case, the first association would represent the primary
insult (e. g. shock or severe respiratory failure) and the
second its late consequences, appearing as a result of
the host response to the primary insult. This two-target
explanation is consistent with previous descriptions
[41, 59] but must be tested in adequate models. The
presence of neurological dysfunction/failure in the first
factor could be explained by the presence of patients
with trauma in this database (181 patients, although
probably not all with head trauma) or by the early onset
of septic encephalopathy in MODS [60]. Moreover,
concerns about the reliability of the evaluation of neurological dysfunction in critically ill patients have recently been raised [61], although not shared by all the
researchers [62, 63]. Maybe when physiologists return
from the drawing board, as recently suggested [64], we
will gain more insight into the explanation of this phenomenon.
Our study presents some limitations that must be acknowledged. First, we only evaluated the relationship
of SOFA with ICU outcome and not with hospital or
Appendix
SOFA score was computed at admission and for every
24 h period from the most deranged values for each of
the organ systems considered [26].
An example of the computation of the associated values is shown below:
A patient was admitted to the ICU subsequent to surgery for a perforated duodenal ulcer, complicated by
peritonitis. At admission, he had respiratory failure
with a PaO2/FiO2 ratio of 180 on mechanical ventilation,
mild cardiovascular dysfunction (mean arterial pressure
60 mmHg without vasoactive drugs), and mild neurological dysfunction (Glasgow Coma score 14). There
were no renal, liver or coagulation disturbances (blood
creatinine 1.0 mg/dl, serum bilirubin 1.0 mg/dl and
250 103platelets/mm3). The SOFA score computed at
admission was 5 points.
During his ICU stay, the respiratory function improved with the patient being weaned from the ventilator on day 2 and presenting a PaO2/FiO2 ratio of 420 on
the day of discharge. Cardiovascular support with dobutamine was needed on days 1 and 2. A mild renal dysfunction (creatinine 1.6) was present on days 1 and 2.
Thrombocytopenia (minimal value 40 103platelets/
mm3) and hyperbilirubinaemia (maximum serum bilirubin 7.8 mg/dl) appeared during the ICU stay. Neurological function worsened during days 2 and 3 (Glasgow
694
SOFA score
Respiration
PaO2/FiO2 mm Hg
< 400
< 300
< 200
with respiratory support
< 100
with respiratory support
Coagulation
Platelets x 103/mm3
< 150
< 100
< 50
< 20
Liver
Bilirubin, mg/dL
(mmol/L)
Cardiovascular
Hypotensiona
1.21.9
(2032)
2.05.9
(33101)
6.011.9
(102204)
> 12.0
(> 204)
MAP < 70 mm Hg
Dopamine K 5 or
Dobutamine (any dose)
1314
1012
Dopamine < 5 or
epinephrine K 0.1 or
norepinephrine K 0.1
69
1.21.9
(110170)
2.03.4
(171299)
3.54.9
(300440) or
< 500 mL/day
> 5.0
(> 440) or
< 200 mL/day
adrenergic agents administered for at least one hour (doses given are in mg/kg min)
3
1
0
0
0
1
3
2
1
1
1
1
2
2
1
1
2
2
2
0
0
3
2
2
1
0
0
3
3
1
0
0
0
3
3
0
Total maximum SOFA score was 14 points, and delta SOFA score
9 points.
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