Journal of Antimicrobial Chemotherapy (1998) 41, Suppl.

A, 17

JAC

The systemic inflammatory response syndrome:

definitions and aetiology
Per-Olof Nystrm*
Department of Surgery, University Hospital, SE-581 85 Linkping, Sweden
Systemic inflammatory response syndrome (SIRS) is the clinical expression of the action of
complex intrinsic mediators of the acute phase reaction. SIRS can be precipitated by events
such as infection, trauma, pancreatitis, and surgery. At times, SIRS can compromise the
function of various organ systems resulting in Multiple Organ Dysfunction Syndrome
(MODS). SIRS and MODS are graded expressions of the inflammation associated with acute
illness. Mild forms are frequent in general wards for both medical and surgical patients but
those with severe forms require intensive care. Clinicians should learn to identify SIRS in
their patients at an early stage to determine the underlying cause and treatment before the
SIRS progresses to a more severe form.

sepsis are shown in Table I. Traditionally, sepsis was taken

to mean microbial infection even in the absence of infection proven by culture. The idea of a microbial cause of
all cases of sepsis is well established, so much so that
clinicians may speak of occult infection when the syndrome
occurs but bacteria cannot be cultured. Nearly all patients
with signs of sepsis are empirically treated with antimicrobial agents, since delaying treatment until definite
microbiological evidence of infection is available can result
in a higher rate of morbidity/mortality. When such treatment is unsuccessful it is common practice to discontinue
antibiotics for a period in the hope that further culture will
reveal any microorganisms present.
The clinical signs of sepsis, such as fever, tachycardia,
tachypnoea and leucocytosis, are common responses to
systemic infection. A triggerresponse concept of sepsis
emerged, in which bacteria were seen as the trigger, with
the pathophysiology being the response to that trigger. It
was now recognized that sepsis involved both microbial
and pathophysiological events, and this powerful concept
allowed clinicians to see the role of infection in the common inflammatory response. For example, uninfected
trauma patients and those with intra-abdominal infection
had similar clinical courses, both groups developing
multiple organ failure with identical microscopic pathologyautodestructive inflammation which seemed to be
independent of infection.5 Others found that the clinical
response persisted after eradication of the infection and
was itself associated with increased mortality.6 In animal

Introduction
The introduction of the term systemic inflammatory
response syndrome (SIRS) by the American College of
Chest Physicians and Society of Critical Care Medicine
(ACCP/SCCM) consensus conference1 recognized the
important role that endogenous mediators of systemic
inflammation play in sepsis, which was no longer regarded
as being caused by microbial pathogenicity factors alone.
This very different concept initiated a re-evaluation in
approach to clinical features of the acute severe illness
associated with infection.24 The similar definitions of
sepsis syndrome and SIRS indicate a change of perspective
rather than a new clinical entity.
In this review sepsis/SIRS will be viewed as a
triggermediatorresponse sequence, where SIRS is the
response to the action of intrinsic mediators. The identification of SIRS does not confirm a diagnosis of infection or
sepsis since the features of SIRS can be seen in many other
conditions such as trauma, pancreatitis, burns or infection,
or following major elective surgery (Figure 1). The pathophysiological responses can be quantified and, if appropriately scored, will provide a probability of mortality.

Previous definitions of sepsis

The varying contributions of local pathology, physiological
responses and microorganisms made the precise definition
of sepsis very difficult. Excerpts from various definitions of

*Tel: +46-13-223550 or -223541; Fax +46-13-223570; E-mail: per.olof.nystrom@mtk.us.lio.se

1
1998 The British Society for Antimicrobial Chemotherapy

P.-O. Nystrm
possibility of systemic response in the absence of invasive
infection. Such patients are common among both medical
and surgical patients.3 Do these patients have a genuine
infection that has failed to be cultured, or a focus of infection that is inaccessible for culture? Either is unlikely since
few sources of invasive infection escape detection with
modern imaging methods or remain undiagnosed by blood
culture. The same decision matrix also includes invasive
infection without accompanying systemic inflammation;
this clinical situation is sometimes encountered in immunocompromised patients. Thus the trigger may be present
without an adequate SIRS response, and a SIRS response
can occur in the absence of infection.

Figure 1. The ACCP/SCCM concept of systemic inflammation

(SIRS) as a common response to many initiating circumstances.
Depending on the severity of the insult patients may or may not
display SIRS. Modified from Bone et al.1

The consensus conference definitions of SIRS

and MODS

studies it was found that the severity of the physiological

response was a better predictor of outcome than the
microbial challenge.7,8 These and other studies showed the
value of breaking down sepsis into its components which
could then be studied separately.
The criteria defining sepsis are satisfied when proven
microbial infection and a systemic response are both
present (Table II). The decision matrix also shows the

The criteria proposed by the ACCP/SCCM are given in

Table III; they were derived from those previously used to
identify the sepsis syndrome (Table IV). At least two
criteria are needed for the identification of SIRS. The consensus conference also recognized a progression in the
disease state from simple SIRS/sepsis to severe SIRS/sepsis
in the presence of acute organ dysfunction, hypotension or
hypoperfusion. The next step in the progression is SIRS

Table I. Some previous definitions of sepsis which demonstrate the development of the concept of sepsis
as a combination of infection and pathophysiology
Definition of sepsis

Reference

Bacterial infection
The presence of at least one positive blood culture
concomitant with the presence of a septic
focus growing the same microorganism
Infection is a process, sepsis is the response
The systemic response to infection
Infection as a microbiological phenomenon was
differentiated from sepsis as a clincial syndrome
Sepsis can be defined as composed of two elements;
the abnormal presence of microbes, and the host
responses by endogenous mediators

Goris et al.5
(J. L. Meakins, personal communication)
ACCP/SCCM consensus conference1
Marshall & Sweeney6
Jnsson et al.8

Table II. Decision matrix for the two components of sepsis: invasive infection and systemic inflammation
Infection (invasive)

SIRS (systemic inflammation)

Clinical interpretation

Absent
Present

present
absent

Present

present

culture-negative SIRS, or non-infectious cause

infection without sepsis, or failed response, or
immunocompromised state
sepsis

Systemic inflammatory response syndrome

Table III. Definitions given by the ACCP/SCCM consensus conference. Modified from Bone et al.1
Term

Definition

SIRS

the systemic inflammatory response to a variety of severe clinical insults. The response is manifested
by two or more of the following conditions: temperature 38C or 36C; heart rate 90 beats/min;
respiratory rate 20 breaths/min or PaCO2 32 torr ( 4.3 kPa); WBC 12,000 cells/mm3, 4000
cells/mm3 or 10% immature (band) forms
microbial phenomenon characterized by an inflammatory response to the presence of microorganisms
or the invasion of normally sterile host tissue by those organisms
the systemic response to infection; this response is manifested by two or more of the SIRS criteria as a
result of infection
the presence of viable bacteria in the blood
sepsis associated with organ dysfunction, hypoperfusion or hypotension; hypoperfusion and perfusion
abnormalities may include, but are not limited to, lactic acidosis, oliguria or an acute alteration in
mental status
sepsis with hypotension, despite adequate resuscitation with fluids, along with the presence of
perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria or an acute
alteration in mental status; patients who are on inotropic or vasopressor agents may not be
hypotensive when perfusion abnormalities are measured
a systolic blood pressure of 90 mmHg or a reduction of 40 mmHg from baseline in the absence of
other causes for hypotension
presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained
without intervention

Infection
Sepsis
Bacteraemia
Severe sepsis

Septic shock

Hypotension
MODS

Abbreviations: SIRS, systemic inflammatory response syndrome; MODS, multiple organ dysfunction syndrome.

Table IV. The definition of sepsis syndrome after Bone et al.9

Clinical evidence of infection
Rectal temperature 38C or 36C
Tachycardia ( 90 beats/min)
Tachypnoea ( 20 breaths/min while spontaneously breathing)
At least one of the following manifestations of inadequate organ function/perfusion:
alteration in mental status
hypoxaemia (PaO2) 72 torr breathing room air) (overt pulmonary disease not direct cause of
hypoxaemia)
oliguria (urine output 30 mL or 0.5 mL/kg for at least 1 h)

shock present in patients with SIRS and hypotension that

is unresponsive to resuscitation with fluids.
Multiple organ dysfunction syndrome (MODS) is the
recognized diminished organ function associated with
acute illness, in which organ function is not capable of
maintaining homeostasis. The dysfunction may be absolute
or relative but is more readily identified as a gradual change
over time. An example of relative organ dysfunction is the
patient who has normal cardiac output and systemic
oxygen delivery but inadequate tissue oxygenation (e.g.
lactic acidosis). It is further recognized that organ dysfunction may be a direct result of a well-defined insult. The

secondary form of multiple organ dysfunction is an integral

part of the SIRS itself.
The consensus conference gave no indication of the
organ involvement or degree of dysfunction that identify
MODS.

Pathophysiology
The definition of sepsis syndrome as developed by Bone et
al.9 (Table IV) was originally seen as a diagnostic tool to be
used in many clinical studies of sepsis and trials of anti3

P.-O. Nystrm
infective agents to identify patients thought to have invasive infection.9 It was gradually realized that it was not a
diagnostic tool but merely identifies patients who match
the definition criteria. It does not identify all patients
thought to have sepsis, nor is there a specific prognosis
associated with sepsis syndrome. The APACHE III
database10 contains information for scoring patients either
by the sepsis syndrome or by the definition of the
APACHE III outcome model. In a subgroup of 519 ICU
patients from the database with sepsis but without specific
infection only about 60% had the sepsis syndrome or septic
shock. The prognoses for these patients ranged from near
zero risk to very high risk, with similar risk distributions for
those who satisfied the criteria and those who did not.11
However, the criteria for defining the sepsis syndrome are
closer to those of the severe SIRS/sepsis category of the
consensus conference: when the basic SIRS criteria were
applied nearly all of the 519 patients qualified as having
SIRS.1
The SIRS criteria cannot perform much better for diagnosis or as a measure of prognosis, perhaps because they
are too wide. A recent prospective survey identified
542857 episodes of SIRS/1000 patient-days in cardiovascular, medical and surgical intensive care units,3 and in
general surgical, cardiothoracic and medical oncology
wards 320671 episodes of SIRS/1000 patient-days were
identified. Only about half of the patients had proven infection, the others having culture-negative SIRS. SIRS is
common and may alert the clinician to patients who have
systemic inflammation which may be explained by the
working diagnosis or to those who need further diagnostic
or therapeutic measures. SIRS is not a diagnosis nor is it a
good indicator of outcome but its presence in individual
patients must be explained adequately. It will need to be
replaced by a more complete and comprehensive definition, or by terms that describe the pathophysiology of
individual cases.

The mediators of the triggerresponse concept

After an injection of bacteria or endotoxin, certain
cytokines appear briefly in circulating blood.12 The classical
sequence is tumour necrosis factor (TNF- ) followed by
interleukins 1 (IL-1), 6 (IL-6) and 8 (IL-8). These cytokines
have been named the pro-inflammatory or alarm cytokines
because they appear first. They, and other factors, mediate
various responses including the activation of numerous cell
populations and release of secondary cytokines and growth
factors.
It is important to understand whether the same mediator
is activated by different triggers and if different mediators
are associated with different pathophysiological responses.
Does the pathophysiological response to infection differ
from the response to other triggers? There are certain
differences: infection induces more TNFthan does
physical trauma, which releases more IL-6 and IL-8.1215
Thus primary infection is associated with higher fever than
in trauma, probably because of the different balance of
mediators produced. Hypovolaemic and hypotensive
patients, however, often initially suffer from hypothermia
and leucopenia whether triggered by infection or trauma.
After resuscitation all such patients develop fever and
leucocytosis. Initial differences in mediator patterns result
in different clinical presentations, but within hours or days
it is clinically no longer possible to associate these
responses with specific triggers.
Approaching the problem from a different standpoint,
attempts to correlate measurements of circulating
cytokines with pathophysiological changes and with prognosis have not been entirely successful. The concentrations
of these mediators vary widely probably because they have
short half-lives in the circulation and most are localized
within the inflamed body compartment where they cannot
readily be measured.
Patients admitted to intensive care with a diagnosis of
acute sepsis, i.e. SIRS following presumed infection, often
do not have positive blood cultures providing unequivocal
proof of invasive infection, nor do they have endotoxaemia. Many do not have detectable TNF- or IL-1 in
response to presumed invasive infection. Even elevated IL6 or IL-8 concentrations in circulating blood are not found
consistently. However, detectable bacteria, endotoxin or
inflammatory mediators are associated with increased
mortality.16

The acute phase response

This may be seen as the primary part of the systemic
inflammatory response. Tissue injury or bacteria at the site
will activate complement and induce tissue macrophages,
monocytes and other reactive cell elements such as mast
cells, endothelial cells and platelets to produce various
mediators.17 TNF- and IL-1 are secreted in large amounts
and appear in the circulation within 1 h. They have both

Figure 2. Clinical entities defined in the ACCP/SCCM consensus

paper showing the progression to more severe forms of sepsis
and the development of multiple organ dysfunction.

Systemic inflammatory response syndrome

Table V. The multiple organ dysfunction score developed by Marshall et al.28

System

Parameter

Respiratory
Renal
Hepatic
Cardiovascular
Haematological
Neurological

p(O2)/FI(O2) ratio
serum creatinine ( mol/L)
serum bilirubin ( mol/L)
PARa
platelet count
Glasgow coma score

Pressure-adjusted heart rate (PAR) is calculated as heart rate

300
100
20
10.0
120
15

226300
101200
2160
10.115.0
81120
1314

Score
2
151225
201350
61120
15.120.0
5180
1012

3
76150
351500
121240
20.130.0
2150
79

4
75
500
240
30.0
20
6

(right atrial (i.e. central venous) pressure/mean arterial pressure).

local and distant effects. Stromal cells at the site of injury

release a secondary wave of mediators that augment the
inflammatory signal. IL-6 now appears in the circulation
and also has systemic effects. The principal alarm cytokines
cause fever and stimulate the pituitary to release stress
hormones. They also stimulate the liver to synthesize a
number of acute phase proteins such as C-reactive protein,
fibrinogen and major antiproteases.18 IL-6 is the principal
signal for the hepatic acute phase response. At the site of
injury numerous mediators cause pain, vasodilation and
increased vascular permeability, and attract granulocytes
to the site.
The signs of local inflammation (pain, erythema,
increased temperature and oedema) are easily recognized.
In classical experiments Miles et al.19 showed that the early
underlying mechanisms were active over a very short
period (about 4 h) after which the local responses ceased.
The pathophysiological features of inflammation, however,
typically take 2448 h to develop fully.
The acute phase response involves additional mechanisms which reverse the inflammatory response. Interleukins 4 and 10 can turn off monocyte/macrophage
production of TNF- , IL-1, IL-6 and IL-8 and therefore
have potent anti-inflammatory action. In addition, the
acute phase response produces antagonists to the TNF
receptor and IL-1 receptor, which bind the circulating
cytokine or block receptors on target cells. The early events
also induce the production of cortisone. Through the combined action of these mechanisms and others the acute
phase response is attenuated and the homeostasic mechanisms return to normal.
It is clinically important to understand that the proinflammatory state of the acute phase response also
initiates anti-inflammatory activity involving mediators. If
the insult has been effectively controlled and contained by
host defences, or by means of surgery, then the acute
systemic inflammation will be attenuated and will clinically
resolve. This process takes several days and is best seen in
patients after major surgery. Fever resolves after 23 days,
bowel function is restored after 34 days and the patient
can soon return to full oral intake.

The extent of the pro- and anti-inflammatory events is

proportional to the magnitude of the insult. Constitutional
factors, both genetic and acquired, may cause particular
patients to overreact or respond inadequately. The proand anti-inflammatory mechanisms are often dysregulated
for reasons that are poorly understood.

Systemic inflammation and organ failure are on

a continuum
The SIRS criteria will serve only to sort patients into those
who display at least two of the criteria and therefore have
SIRS by definition, and those who do not have SIRS.
Further categorization is possible by identifying those who
satisfy two, three or all four criteria. Two additional variables, namely organ dysfunction and circulatory status, can
be used to characterize severe SIRS or SIRS shock. When
several organs fail to maintain their homeostatic function,
MODS can be said to have complicated the SIRS. The
various stages must be seen as phases in a continuum of
increasing disturbance of homeostasis (Figure 2).
The SIRS criteria may be seen as a crude stratification
system for patients with systemic inflammation as shown in
a recent prospective study of the epidemiology of SIRS in
medical and surgical patients.3 Mortality was 3% in
patients without SIRS but doubled in those with SIRS.
Mortality was increased to 10% in those with three positive
criteria and to 17% in those matching all four criteria.
Death rates were similar for patients with culture-negative
SIRS and those with culture-positive SIRS. This was true
also for culture-negative septic shock, which was associated
with 46% mortality.
The same authors also found evidence of an increase in
severity of SIRS with time. Half of the patients with two
criteria of SIRS developed a third criterion by day 7. Of
patients with two SIRS criteria 36% developed sepsis
(culture-proven infection) by day 14 and in those with all
four criteria 45% developed sepsis by day 14. The time
taken for sepsis to appear decreased as more SIRS criteria
were met.
5

P.-O. Nystrm
Several scoring systems have been introduced to assess
the physiological response, but the variables must be
weighted carefully so that increasing score values correlate
with worsening prognosis. Examples of such scoring
methods are the acute physiology and chronic health
evaluation (APACHE),10,20 the simplified acute physiology score (SAPS II)21 and the mortality probability model
(MPM II).22 The APACHE system is the most widely used
system for assessing acute physiological disturbances. The
pathophysiology scored is that which predicts the greater
mortality risk in patients with different initiating events or
diagnoses. The latest version, APACHE III, provides
updated risk assessments for the first 7 days of illness.23
The various scoring systems were recently reviewed for
their ability to identify septic patients.24 As most systems
have not been validated extensively their relative merits
are difficult to assess. The APACHE stands out as the best
validated system. Based on the APACHE III methodology two new sepsis-oriented scores were developed from
large populations of septic patients.25,26 However, these
scores were developed after sophisticated statistical modelling and they cannot be applied without access to computer support. There are probably no simplistic solutions
to predictive scoring of SIRS/sepsis. Simple scores that can
be used at the bedside are unreliable in individual patients,
while more precise scores are so complex that they are
unsuitable for routine use. As so many patients with SIRS
have a low mortality risk and are not treated in ICUs, such
sophisticated scoring is unnecessary. The clinician needs to
recognize the presence of systemic inflammation early
to diagnose and treat its cause before the SIRS progresses
to a more severe form.
The consensus conference gave no specific definition of
MODS. Mild degrees of organ dysfunction are common in
SIRS but the untreated patient may develop severe organ
failure, which is associated with poor outcome. The simultaneous failure of two organs is associated with widely
differing prognosis depending on the combination of
organs involved, ranging from 20% mortality for combined cardiovascular and haematological failure to 76%
mortality for combined cardiovascular and CNS failure.27
A score based simply on the number of failed organ systems is therefore an unreliable predictor, especially in the
absence of agreed definitions.
The various methods of grading organ dysfunction have
been recently reviewed for the development of a new score
of organ failure.28 This MOD score (Table V) considers six
organ systems. The function of each organ system is
weighted on a scale from 0 to 4. The weighting was
developed in one half of a surgical ICU population and
validated in the other half. For each variable a zero value
was associated with 5% mortality while a value of 4
represented severe dysfunction and a mortality of 50%
for patients managed in the ICU. This score showed excellent correlation both for patients treated in the ICU and
for those in general wards. Since the MOD score is based

on pathophysiology and not on therapeutic components, it

should be objective and produce consistent results in
different patient populations.

Conclusions
Systemic inflammation may be thought of as the presence
of signs that are clinically associated with inflammation
such as fever, tachycardia or leucocytosis. Other signs such
as the appearance of C-reactive protein are better
described as the acute phase response. Furthermore, many
patients with SIRS display varying degrees of organ dysfunction while some progress to develop multiple organ
failure. The clinical signs seen in SIRS arise through
many mechanisms, including inflammation, acute phase
response, metabolic dysfunction, shock, hypoxia and
organ system failure. While some physiological signs can
be recognized as primary and others as secondary, they all
contribute to disease severity, course and prognosis. The
definition of SIRS, while imperfect, implies variable levels
of risk depending on the degree of pathophysiological
disturbance. The production of anti-inflammatory mediators is triggered by inflammation and these will arrest the
SIRS and restore normal homeostasis, assuming that
medical intervention such as surgery, intensive care treatment or antibiotics has controlled the initial cause.

References
1. Bone, R. C., Balk, R. A., Cerra, F. B., Dellinger, R. P.,
Fein, A. M., Knaus, W. A. et al. (1992). Definitions for sepsis and
organ failure and guidelines for the use of innovative therapies in
sepsis. ACCP/SCCM consensus conference committee. Chest
101, 164455.
2. Beal, A. L. & Cerra, F. B. (1994). Multiple organ failure
syndrome in the 1990s. Systemic inflammatory response and
organ dysfunction. Journal of the American Medical Association
271, 22633.
3. Rangel-Frausto, M. S., Pittet, D., Costigan, M., Hwang, T.,
Davis, C. S. & Wenzel, R. P. (1995). The natural history of the
systemic inflammatory response syndrome (SIRS): a prospective
study. Journal of the American Medical Association 273, 11723.
4. Pittet, D., Rangel-Frausto, S., Li, N., Tarara, D., Costigan, M.,
Rempe, L. et al. (1995). Systemic inflammatory response syndrome, sepsis, severe sepsis and septic shock: incidence, morbidities and outcomes in surgical ICU patients Intensive Care Medicine
21, 3029.
5. Goris, R. J., te Boekhorst, T. P., Nuytinck, J. K. & Gimbrre,
J. S. (1985). Multiple-organ failure: generalized autodestructive
inflammation? Archives of Surgery 120, 110915.
6. Marshall, J. & Sweeney, D. (1990). Microbial infection and the
septic response in critical surgical illness. Sepsis, not infection,
determines outcome. Archives of Surgery 125, 1723.
7. Nieuwenhuijzen, G. A., Haskel, Y., Lu, Q., Berg, R. D., van
Rooijen, N., Goris, R. J. et al. (1993). Macrophage elimination
increases bacterial translocation and gut-origin septicemia but
attenuates symptoms and mortality rate in a model of systemic
inflammation. Annals of Surgery 218, 7919.

Systemic inflammatory response syndrome

8. Jnsson, B., Berglund, J., Skau, T. & Nystrm, P. O. (1993).
Outcome of intra-abdominal infection in pigs depends more on
host responses than on microbiology. European Journal of
Surgery 159, 5718.

19. Miles, A. A., Miles, E. M. & Burke, J. (1957). The value and
duration of defence reactions of the skin to the primary lodgement
of bacteria. British Journal of Experimental Pathology 38, 7996.
20. Knaus, W. A., Draper, E. A., Wagner, D. P. & Zimmerman,
J. E. (1985). APACHE II: a severity of disease classification. Critical Care Medicine 13, 81829.

9. Bone, R. C., Fisher, C. J., Clemmer, T. P., Slotman, G. J., Metz,

C. A. & Balk, R. A. (1989). The sepsis syndrome: a valid clinical
entity. Critical Care Medicine 17, 38993.

21. Le Gall, J. R., Lemeshow, S. & Saulnier, F. (1993). A new

Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. Journal of the American
Medical Association 270, 295763.

10. Knaus, W. A., Wagner, D. P., Draper, E. A., Zimmerman, J. E.,

Bergner, M., Bastos, P. G. et al. (1991). The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill
hospitalized adults. Chest 100, 161936.

22. Lemeshow, S., Teres, D., Klar, J., Avrunin, J. S., Gehlbach,
S. H., Rapoport, J. et al. (1993). Mortality Probability Models
(MPM II) based on an international cohort of intensive care unit
patients. Journal of the American Medical Association 270,
247886.

11. Knaus, W. A., Sun, X., Nystrm, P. O. & Wagner, D. P. (1992).

Evaluation of definitions for sepsis. Chest 101, 165662.
12. Michie, H. R., Spriggs, D. R., Manogue, K. R., Sherman, M. L.,
Revhaug, A., ODwyer, S. T. et al. (1988). Tumor necrosis factor
and endotoxin induce similar metabolic responses in human
beings. Surgery 104, 2806.

23. Wagner, D. P., Knaus, W. A., Harrell, F., Zimmerman, J. E. &

Watts, C. (1994). Daily prognostic estimates for critically ill adults
in intensive care units. Critical Care Medicine 22, 135972.

13. Bone, R. C. (1996). Toward a theory regarding the pathogene sis of the systemic inflammatory response syndrome: what we do
and do not know about cytokine regulation. Critical Care Medicine
24, 16372.

24. Barriere, S. L. & Lowry, S. F. (1995). An overview of mortality

risk prediction in sepsis. Critical Care Medicine 23, 37693.

14. Dinarello, C. A. & Cannon, J. G. (1993). Cytokine measurements in septic shock. Annals of Internal Medicine 119, 8534.

25. Knaus, W. A., Harrell, F. E., Fisher, C., Wagner, D. P., Opal,
S. M. Sadoff, J. C. et al. (1993). The clinical evaluation of new
drugs for sepsis: a prospective study design based on survival
analysis. Journal of the American Medical Association 270,
123341.

15. Roumen, R. M., Hendriks, T., van der Ven-Jongekrijg, J.,

Nieuwenhuijzen, G. A., Sauerwein, R. W., van der Meer, J. et al.
(1993). Cytokine patterns in patients after major vascular surgery,
hemorrhagic shock, and severe blunt trauma. Relation with subsequent adult respiratory distress syndrome and multiple organ failure. Annals of Surgery 218, 76976.

26. Knaus, W. A., Harrell, F. E., LaBreque, J. F., Wagner, D. P.,

Pribble, J. P., Draper, A. E. et al. (1996). Use of predicted risk of
mortality to evaluate the efficacy of anticytokine therapy in sepsis.
Critical Care Medicine 24, 4656.

16. Casey, L. C., Balk, R. A. & Bone, R. C. (1993).

Plasma cytokines and endotoxin levels correlate with survival in
patients with sepsis syndrome. Annals of Internal Medicine 119,
7718.

27. Zimmerman, J. E., Knaus, W. A., Wagner, D. P., Sun, X.,

Hakim, R. B. & Nystrm, P. O. (1996). A comparison of risks and
outcomes for patients with organ system failure: 19821990. Critical Care Medicine 24, 163341.

17. Baumann, H. & Gauldie, J. (1994). The acute phase response.

Immunology Today 15, 7480.

28. Marshall, J. C., Cook, D. J., Christou, N. V., Bernard, G. R.,

Sprung, C. L. & Sibbald, W. J. (1995). The multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome.
Critical Care Medicine 23, 163852.

18. Steel, D. M. & Whitehead, A. S. (1994). The major acute

phase reactants: C-reactive protein, serum amyloid P component
and serum amyloid A protein. Immunology Today 15, 818.