Intensive Care Med (1999) 25: 686696
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
Received: 16 September 1998
Accepted: 16 April 1999
)
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
The use of maximum SOFA score to
quantify organ dysfunction/failure in
intensive care. Results of a prospective,
multicentre study
Abstract Objective: To evaluate the
performance of total maximum se-
quential organ failure assessment
(SOFA) score and a derived mea-
sure, delta SOFA (total maximum
SOFA score minus admission total
SOFA) as a descriptor of multiple
organ dysfunction/failure in inten-
sive care.
Design: Prospective, multicentre
and multinational study.
Setting: Forty intensive care units
(ICUs) from Australia, Europe,
North and South America.
Patients: Data on 1,449 patients,
evaluated at admission and then
consecutively every 24 h until ICU
discharge (11,417 records) during
May 1995. Excluded from data col-
lection were all patients with a
length of stay in the ICU less than
2 days following uncomplicated
scheduled surgery.
Main outcome measure: Survival
status at ICU discharge.
Interventions: The collection of raw
data necessary for the computation
of a SOFA score on admission and
then every 24 h, and basic demo-
graphic and clinical statistics.
Measurements and main results:
Mean total maximum SOFA score
presented a very good correlation to
ICU outcome, with mortality rates
ranging from 3.2 % in patients with-
out organ failure to 91.3 % in pa-
tients with failure of all the six or-
gans analysed. A maximum score
was reached 1.1  0.2 days after ad-
mission for all the organ systems
analysed. The total maximum SOFA
score presented an area under the
ROC curve of 0.847 (SE 0.012),
which was significantly higher than
any of its individual components.
The cardiovascular score (odds ratio
1.68) was associated with the highest
relative contribution to outcome.
No independent contribution could
be demonstrated for the hepatic
score. No significant interactions
were found.
Principal components analysis dem-
onstrated the existence of a two-fac-
tor structure that became clearer
when analysis was limited to the
presence or absence of organ failure
(SOFA score 3 points) during the
ICU stay. The first factor comprises
respiratory, cardiovascular and neu-
rological systems and the second co-
agulation, hepatic and renal sys-
tems.
Delta SOFA also presented a good
correlation to outcome. The area
under the receiver operating char-
acteristic (ROC) curve was 0.742
(SE 0.017) for delta SOFA, lower
than the total maximum SOFA
score or admission total SOFA
score. The impact of delta SOFA on
prognosis remained significant after
correction for admission total
SOFA.
Conclusions: The results show that
total maximum SOFA score and
delta SOFA can be used to quantify
the degree of dysfunction/failure al-
 687

ready present on ICU admission, the
degree of dysfunction/failure that
appears during the ICU stay and the
cumulative insult suffered by the
patient. These properties make it a
good instrument to be used in the
evaluation of organ dysfunction/
failure.
Key words Severity of illness index
Sepsis Multiple organ failure
Multiple organ dysfunction
syndrome Intensive care Critical
care

when applied to more homogeneous groups of patients

Introduction
In recent years, a series of negative results in clinical tri-
als 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 underestimat-
ed 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 be-
tween an event and its consequences is known. In the
case of sepsis (and multiple organ failure) our knowl-
edge is very limited and only an indirect and partial rela-
tionship 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 sep-
sis 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, re-
sulting in a large dispersion of mortality risks [17, 18].
Additionally, the presence and impact of other con-
founding 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 pro-
posed 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, effec-
tive in their specific scope, fail to reduce all cause hos-
pital mortality. A recent example is selective decon-
tamination of the digestive tract (SDD); it has been
demonstrated to diminish the prevalence of nosocomi-
al pneumonia [22], but does not consistently decrease
hospital mortality [23, 24]. In other cases, therapeutic
interventions have failed to demonstrate beneficial ef-
fects in multicentre trials [1] and have been found to
be associated with a significant reduction in mortality
[25].
The awareness of these factors led the Working
Group on Sepsis-related Problems of the European So-
ciety of Intensive Care Medicine (ESICM) to organise
a consensus meeting in Paris (December 1994) to create
the so-called sepsis-related organ failure assessment
(SOFA) score [26], later called sequential organ failure
score since it is not restricted to sepsis. The rationale be-
hind this decision was the necessity to find an objective
and simple way to describe individual organ dysfunc-
tion/failure in a continuous form, from mild dysfunction
to severe failure, that can be used over time to measure
the evolution of individual (or aggregated) organ dys-
function in clinical trials on sepsis or for the clinician at
the bedside.
A retrospective evaluation of the application of this
score to the first 24 h in the ICU on 1,643 patients with
early sepsis on an international database [26] demon-
strated a good correlation to mortality and an accept-
able distribution of the patients among the several
groups. To confirm these retrospective findings, a pro-
spective, multinational study was initiated, the main re-
sults of which are presented elsewhere [27].
The aim of this work was to evaluate the perfor-
mance of total maximum SOFA score and a derived
measure, delta SOFA (total maximum SOFA minus ad-
mission total SOFA, that is, the magnitude of organ dys-
function appearing during the ICU stay) as a descriptor
of multiple organ dysfunction/failure in intensive care.
Materials and methods
Patients
Two months before the start of data collection, all participants in
the working group on sepsis-related problems of the ESICM were
invited to collaborate. Data collection took place from May 1,
1995, to May 31, 1995. Forty ICUs from 16 countries in Australia
(1), Europe (35), North (1) and South America (3) participated in
the study. Patients with a length of stay (LOS) in the ICU less
than 2 days following uncomplicated scheduled surgery were ex-
cluded from data collection.
For each patient a simple set of variables was collected that in-
cluded basic demographic characteristics and all the variables of
the SOFA score [26] (see Appendix). Data were registered on ad-
mission and every 24 h thereafter using the worst values until ICU
discharge. All data were collected as raw data. In the co-ordinating
centre (Erasme Hospital, Free University of Brussels, Belgium),
data were entered into a computer format using a continuous pro-
688
Fig. 1 Frequency distribution of maximum SOFA in survivors
(open bars, n = 1131) and non-survivors (black bars, n = 313). As-
terisks present the relationship between maximum SOFA score
and ICU mortality, with the logistic regression curve superimposed
cess of monitoring of its completeness and correction. For a single
missing value a replacement was calculated using the mean value
of the result preceding and that following the missing one. When
more than one consecutive value was missing it was considered as
a missing value in the analysis. More details about data collection
are given elsewhere [27].
Methods
Maximum organ failure scores were calculated for all the six com-
ponents 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 dys-
function/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 sig-
nificance 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 charac-
teristic (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 associ-
ated with each component of the system, we fitted a logistic regres-
sion 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 depen-
dent variable and delta SOFA and admission SOFA as the inde-
pendent variables. Logistic regression analysis was used to evalu-
ate 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 in-
terrelations 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 de-
pendent and which variables are independent (opposite to regres-
sion where this specification must be done). This technique allows
for the identification of association patterns of the different vari-
ables under consideration, without first having to specify a cause-
and-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:
e4:0473 + 0:2790(TMS)
Pr =
1 + e4:0473 + 0:2790(TMS)
where Pr is the probability of death in the ICU and TMS
is the total maximum SOFA score during the ICU stay.
In all the organ systems analysed, the maximum
SOFA score during the ICU stay for that specific organ
presented an acceptable frequency distribution among
the various groups (Fig. 2). The differences between sur-
 689

Table 1 Maximum SOFA scores for the six organ systems in the
global population, in survivors and in non-survivors. The differen-
ces between survivors and non-survivors were always significant
(p < 0.001). Results are presented as mean standard deviation
Component Global population Survivors Non-survivors
(n = 1,444) (n = 1,131) (n = 313)
Respiratory 2.2 1.3 2.0 1.3 3.0 1.1
Cardiovascular 1.5 1.5 1.2 1.3 2.9 1.4
Renal 1.0 1.2 0.8 1.0 1.9 1.4
Coagulation 1.0 1.1 0.8 1.0 1.7 1.3
Hepatic 0.7 1.0 0.6 0.9 1.3 1.3
Neurological 1.7 1.7 1.4 1.5 2.9 1.6
Total Maximum
SOFA score 8.2 5.4 6.7 4.5 13.6 4.8

Table 2 Number of organ failures (maximum SOFA score L

3 points) and ICU outcome
Number Number % of Death in Mortality Maximum
of organ of patients patients the ICU rate SOFA
failures (n) (%) scorea
0 507 35.1 16 3.2 3.1 2.2
1 360 24.9 38 10.6 7.0 2.2
2 243 16.8 62 25.5 10.1 2.0
3 175 12.1 90 51.4 13.7 1.9
4 93 6.5 57 61.3 16.4 1.5
5 43 3.0 29 67.4 19.4 1.3
6 23 1.6 21 91.3 21.3 1.5
a
mean standard deviation
Fig. 2 Mortality rate (bars) and number of patients in each organ
system (*), according to maximum SOFA score
for the neurological score to 4.9 for liver failure) than
the time needed to reach a maximum SOFA score, and
vivors and non-survivors were always significant (Ta- significant differences were noted between the different
ble 1). The mortality rate increased as the score in- organ systems analysed (p < 0.001). The neurological
creased in all organ systems (Fig. 2). For respiratory system was the first to fail, the respiratory, cardiovascu-
and neurological scores the patterns were less clear, es- lar, renal and coagulation systems occupied an interme-
pecially when the scores were lower than 3 points. diate position and the hepatic was the last (Fig. 3).
The number of organ failures (maximum SOFA In the evaluation of the discriminative power of the
score 3) also showed a significant correlation to ICU scores, the area under the ROC curve was used. The
outcome, with mortality rates ranging from 3.2 % in pa- best discriminative power was shown for the cardiovas-
tients without any organ failure to 91.3 % in patients cular score (0.802, standard error (SE) 0.015), the renal
with failure of all the six organs analysed (Table 2). score (0.739, SE 0.016) and the respiratory score (0.736,
The mean maximum SOFA score also showed a corre- SE 0.016). For the neurological score the value was in-
sponding increase, with values ranging from termediate (0.727, SE 0.016). Coagulation (0.684, SE
3.1  2.2 points in patients without organ failures to 0.018) and hepatic scores (0.655, SE 0.019) had a lower
21.3  1.5 points in patients with six organ failures. The discriminative power. The aggregated score (total maxi-
maximum SOFA score occurred shortly after admission mum SOFA score) presented an area under the ROC
for all organ systems analysed (1.1  0.2 days) with curve of 0.847 (SE 0.012) which was significantly higher
mean values ranging from 0.8 days (95 % confidence in- (cardiovascular score p = 0.005, all others p < 0.001)
terval 0.60.9 days) for the neurological score to than any of its individual components (Fig. 4).
1.4 days (95 % confidence interval 1.21.5 days) for the In order to evaluate the relative contribution to out-
respiratory score. come of each of the six individual organ system dysfunc-
If we limit the analysis to organ failures (SOFA 3 tions, a non-stepwise logistic regression equation was
points), the time required to reach maximum values developed, relating the score for each organ to the out-
was longer (mean 2.9 + 1.1 days, ranging from 1.6 days come in the ICU. In this way, the exponent of the esti-
690

Fig. 3 Mean time to reach maximum SOFA score in patients with

organ failure (SOFA 3). Values are presented as mean  95 %
confidence intervals for the mean. The numbers of patients in
each of the systems were: respiratory 644, cardiovascular 392, renal
198, coagulation 190, hepatic 119 and neurological 561
mated coefficient (b) for each organ score represents
the factor by which the odds ratio of ICU death changes
when the score for that particular organ increases
1 point. The results (Table 3) demonstrated that the car-
diovascular score was associated with the highest rela-
tive contribution to outcome (odds ratio 1.68, 95 % con-
fidence interval 1.491.91), followed by the renal (odds
ratio 1.46, 95 % confidence interval 1.291.64), the neu-
rological (odds ratio 1.40, 95 % confidence interval
1.281.55), the coagulation (odds ratio 1.22, 95 % confi-
dence interval 1.061.40) and the respiratory (odds ratio
1.18, 95 % confidence interval 1.011.38) scores. No
such contribution could be demonstrated for the hepatic
score (odds ratio 0.82, 95 % confidence interval
0.601.11).
The same technique was used to evaluate significant
interactions among the six components of the SOFA
score. However, no conclusive results could be demon-
Fig. 4 Discriminative power of total maximum SOFA score, delta
SOFA and admission total SOFA score. The receiver operating
characteristics (ROC) curve summarises the relationship between
sensitivity (number of true positives) and 1 minus specificity (num-
ber of false positives) for all the possible values of the score. The
reference line represents the discriminative power of a score no
better than chance (area under ROC curve 0.5). The values within
brackets are standard errors. The outcome used was vital status at
ICU discharge
strated. A trend (non-significant) was found for interac-
tions between respiratory and coagulation scores (odds
ratio 1.14, 95 % confidence interval 0.971.33), respira-
tory 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), re-
nal 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 identi-
fy 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 b SE Wald p R Odds-ratio
(95 % confidence intervals)
Respiratory 0.164 0.080 4.176 0.041 0.038 1.176 (1.0071.378)
Cardiovascular 0.521 0.063 68.242 < 0.001 0.210 1.683 (1.4881.905)
Renal 0.377 0.061 37.951 < 0.001 0.154 1.458 (1.2941.643)
Coagulation 0.198 0.072 7.482 0.006 0.060 1.219 (1.0591.404)
Hepatic 0.202 0.155 1.702 0.192 0.000 0.817 (0.6031.107)
Neurological 0.339 0.049 48.703 < 0.001 0.176 1.404 (1.2751.545)
Constant 3.750 0.351 113.930
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

Table 4 Principal components analysis of the six components of

the SOFA system. Results are presented for maximum values dur-
ing ICU stay (top) and for the presence of organ failure (SO-
FA L 3 points) during ICU stay (bottom), after varimax rotation
Component Factor 1 Factor 2
Maximum values during ICU stay
Respiratory 0.3578 0.7221
Cardiovascular 0.5844 0.5168
Renal 0.6796 0.1154
Coagulation 0.7662 0.1711
Hepatic 0.7605 0.1269
Neurological 0.0057 0.8737
Organ failures (SOFA L 3 points) during ICU stay
Respiratory 0.1252 0.7812
Cardiovascular 0.3212 0.6960
Renal 0.6248 0.1409
Coagulation 0.7500 0.1580
Hepatic 0.7398 0.0928 Fig. 5 Delta SOFA score and ICU mortality. A linear relation ex-
Neurological 0.0505 0.7636 ists between delta SOFA and ICU mortality

Table 5 Delta SOFA (total maximum SOFA score minus admis- ing the ICU stay. The first factor comprises the re-
sion total SOFA score) and ICU outcome spiratory, cardiovascular and neurological scores and
Delta Number of % of Death in Mortality the second the coagulation, hepatic and renal compo-
SOFA patients patients the ICU (n) rate (%) nents.
0 390 27.0 38 9.7 Delta SOFA presented a mean value of 3.0  3.3
1 234 16.2 20 8.5 points, median 2.0 points, range 019 points. Delta
2 191 13.2 29 15.2 SOFA was significantly higher (p < 0.001) in non-survi-
3 140 9.7 26 18.6 vors than in survivors (5.5  4.1 points versus
4 118 8.2 29 24.6 2.3  2.7 points). As presented in Table 5, ICU mortality
5 90 6.2 24 26.7
6 72 5.0 29 40.3 increased as the delta SOFA score increased. The asso-
7 53 3.7 24 45.3 ciation between mean delta SOFA and ICU mortality
8 39 2.7 21 53.8 followed a linear pattern (Fig. 5, Table 5). Delta SOFA
9 33 2.3 17 51.5 presented an area under the ROC curve of 0.742 (SE
10 22 1.5 16 72.7 0.017) (Fig. 4), which was significantly lower (p < 0.001)
11 20 1.4 12 60.0 than that of the total maximum SOFA score and slightly
12 16 1.1 9 56.3
13 9 0.6 7 77.8 lower (non-significant) than that of the admission total
14 5 0.3 4 80.0 SOFA score (0.772, SE 0.015).
L 15 12 0.8 8 66.7 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 non-
of the SOFA score. The results (Table 4) demonstrated stepwise logistic regression equation was developed.
the existence of a two-factor structure, each compris- Results demonstrate that both were important for out-
ing three components of the system, that became come, and with a similar weight (Table 6). The associat-
more clear when the analysis was limited to the pres- ed odds ratios, for a 1 point change in the score were
ence or absence of organ failure (SOFA score 3) dur- 1.36 (95 % confidence interval 1.301.42) for the admis-

Table 6 Relative contribution for outcome in the ICU of the admission SOFA score and delta SOFA
Variable b SE Wald p R Odds-ratio (95 % confidence intervals)
Admission total SOFA 0.308 0.022 192.784 < 0.001 0.356 1.361 (1.3031.421)
score
Delta SOFA 0.312 0.024 170.274 < 0.001 0.334 1.367 (1.3031.432)
Constant 4.765 0.247 372.404
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 inter-
val 1.301.43) for the delta SOFA score.
Discussion
Multiple organ dysfunction syndrome (MODS) has be-
come the leading cause of morbidity and mortality in in-
tensive 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 trau-
ma [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 syn-
drome, in which specific variables could be tested
against outcome. Various efforts to this end have ap-
peared 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 in-
stead 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 multicen-
tre representative database of critically ill patients. The
system proposed by Le Gall et al., logistic organ dys-
function (LOD) score, was developed with very sophis-
ticated 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 Prob-
lems of the ESICM to perform a prospective, multina-
tional validation study. The main data have been pre-
sented elsewhere [27]. Based on these data, we studied
the validity of two complementary measures as descrip-
tors 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 corre-
lation 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 neu-
rological and respiration scores, where the patterns
were not clear. The same relation was present when we
limited the analysis to organ failure (SOFA score 3
points). The discriminative power was very good (area
under ROC curve 0.847, SE 0.012). For individual organ
scores, the best discriminative power was seen for car-
diovascular score. In multivariate analysis the impact
on outcome of organ dysfunction/failure was higher for
cardiovascular (odds ratio 1.68) and renal (odds ratio
1.46) scores. The hepatic dysfunction/failure did not
show a significant impact on prognosis (odds ratio
0.82). No significant interactions were seen between in-
dividual organ failures. Using principal components
analysis, a clear pattern was seen when we analysed or-
gan failures (SOFA score 3 points), with a two-factor
structure: respiratory, cardiovascular and neurological,
and coagulation, hepatic and renal. In the overall analy-
sis the same pattern was present although less clear, with
the cardiovascular score having an intermediate posi-
tion.
The amount of organ dysfunction/failure occurring
after ICU admission (delta SOFA) also showed a good
correlation to outcome. On multivariate analysis this ef-
fect was still significant after controlling for admission
score. It should be noted that the delta SOFA ability to
distinguish between patients who died and patients
who survived was lower than that of the total maximum
SOFA score or even than of the admission SOFA score.
This stresses the importance of the degree of physiolog-
ical derangement on admission to the ICU [4648] and
of cumulative organ dysfunction [31, 43] to the progno-
sis.
Why use a total maximum SOFA score instead of a
simpler measure? Our rationale was that a daily evalua-
tion would not be able to capture the overall amount of
organ dysfunction/failure sustained by the patient dur-
ing the course of the disease. Different organs are af-
fected in this complex physiopathological process at dif-
ferent points in time [32] and a daily evaluation, al-
though appealing, can miss the total amount of organ
dysfunction sustained by the patient, leading to an un-
derestimation of the cumulative insult suffered. It has
been shown that mortality due to MODS depends on
the number of failing organs [31, 43, 49], on the severity
of the dysfunction/failure [43, 44], on the particular
combination of failing organs [4951] and on the dura-
tion [31, 49]. Our system, following the path of previous
work by Marshall et al. [43], allows the quantification of
all these conditions. Alternative approaches, based on
the daily application of severity scores have been pro-
posed [48, 5257] but are usually limited to the first
days in the ICU [48, 54] or have later failed to confirm
their initial performances [58].
Additionally, the proposed system allows the distinc-
tion between the dysfunction/failure already present at
ICU admission (which depends mainly on admission
policies), the dysfunction/failure that appears during

the ICU stay and the evaluation of the total insult suf-
fered by the patient. All are very important by them-
selves, as shown in Table 6, but also address comple-
mentary 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 ac-
cording 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 limita-
tion 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 quantifi-
cation of the total insult suffered by the patient during
the ICU stay (total maximum SOFA) was a very impor-
tant 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 rele-
vant 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 neu-
rological dysfunction in critically ill patients have re-
cently 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 phe-
nomenon.
Our study presents some limitations that must be ac-
knowledged. First, we only evaluated the relationship
of SOFA with ICU outcome and not with hospital or
693
30-day mortality. This fact could have introduced some
bias in the analyses and more research should be under-
taken to examine whether there exists a link between
organ dysfunction/failure during the ICU stay, short-
term (ICU) mortality and long-term mortality. For that
purpose, patients must be followed after ICU discharge
and monitored for the development of further complica-
tions. Second, SOFA, similar to all the published organ
failure scores, uses the Glasgow coma score for neuro-
logical evaluation [65] and this computation can be
very difficult or impossible in sedated patients and very
prone to errors in data collection. Certainly we need to
develop better ways to assess neurological dysfunction
in the critically ill, non-trauma patient.
The best treatment for MODS is certainly preven-
tion. Unfortunately, this is not possible in many cases.
New diagnostic tools and new therapeutic options are
needed to deal with this complex syndrome that is re-
sponsible for so many deaths. In the meantime, instru-
ments like the SOFA score and their derived measures
should be used for the evaluation and quantification of
organ dysfunction/failure.
Acknowledgements The authors want to acknowledge the efforts
in data collection by all the participants in the study. A complete
list of participating centres can be found in J.-L. Vincent et al. [27].
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 val-
ues is shown below:
A patient was admitted to the ICU subsequent to sur-
gery 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 neuro-
logical 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 im-
proved with the patient being weaned from the ventila-
tor on day 2 and presenting a PaO2/FiO2 ratio of 420 on
the day of discharge. Cardiovascular support with do-
butamine was needed on days 1 and 2. A mild renal dys-
function (creatinine 1.6) was present on days 1 and 2.
Thrombocytopenia (minimal value 40 103platelets/
mm3) and hyperbilirubinaemia (maximum serum biliru-
bin 7.8 mg/dl) appeared during the ICU stay. Neurologi-
cal function worsened during days 2 and 3 (Glasgow
694

SOFA score 1 2 3 4
Respiration < 400 < 300 < 200 < 100
PaO2/FiO2 mm Hg with respiratory support with respiratory support
Coagulation < 150 < 100 < 50 < 20
Platelets x 103/mm3
Liver 1.21.9 2.05.9 6.011.9 > 12.0
Bilirubin, mg/dL (2032) (33101) (102204) (> 204)
(mmol/L)
Cardiovascular MAP < 70 mm Hg Dopamine K 5 or Dopamine < 5 or Dopamine > 1.5 or epine-
Hypotensiona Dobutamine (any dose) epinephrine K 0.1 or phrine > 0.1 or norepine-
norepinephrine K 0.1 phrine > 0.1
Central Nervous System 1314 1012 69 <6
Glasgow coma score
Renal 1.21.9 2.03.4 3.54.9 > 5.0
Creatinine, mg/dL (110170) (171299) (300440) or (> 440) or
(mmol/L) or urine output < 500 mL/day < 200 mL/day
a
adrenergic agents administered for at least one hour (doses given are in mg/kg min)

coma score 12) and then improved, with a Glasgow The summary of the evolution of the patient in terms of SOFA
Coma Score of 15 at discharge. score is given bellow
The patient was discharged to the ward on day 5, still Day 0 Day 1 Day 2 Day 3 Day 4 Day 5
with thrombocytopenia and hyperbilirubinaemia. Respiratory 3 3 2 2 1 0
The summary of the evolution of the patient in terms Cardiovascular 1 2 2 0 0 0
of SOFA score is given below. Renal 0 1 1 0 0 0
Total maximum SOFA score was 14 points, and delta Coagulation 0 1 1 3 3 3
SOFA score 9 points Hepatic 0 1 2 2 3 3
Neurological 1 1 2 2 1 0
Total maximum SOFA score was 14 points, and delta SOFA score
9 points.

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