Original article

Association between early systemic inflammatory response,

severity of multiorgan dysfunction and death in acute
pancreatitis
R. Mofidi, M. D. Duff, S. J. Wigmore, K. K. Madhavan, O. J. Garden and R. W. Parks
Department of Clinical and Surgical Sciences, University of Edinburgh, Royal Infirmary of Edinburgh, Old Dalkeith Road, Edinburgh EH16 4SA, UK
Correspondence to: Mr R. W. Parks (e-mail: R.W.Parks@ed.ac.uk)

Background: Mortality in patients with acute pancreatitis is associated with the number of failing organs
and the severity and reversibility of organ dysfunction. The aim of this study was to assess the significance
of early systemic inflammatory response syndrome (SIRS) in the development of multiorgan dysfunction
syndrome (MODS) and death from acute pancreatitis.
Methods: Data for all patients with a diagnosis of acute pancreatitis between January 2000 and December
2004 were reviewed. Serum C-reactive protein (CRP), Acute Physiology And Chronic Health Evaluation
(APACHE) II scores and presence of SIRS were recorded on admission and at 48 h. Marshall organ
dysfunction scores were calculated during the first week of presentation. Presence of SIRS and raised
serum CRP levels on admission and at 48 h were correlated with the cumulative organ dysfunction
scores in the first week.
Results: A total of 759 patients with acute pancreatitis were identified, of whom 45 (5·9 per cent) died
during the index admission. SIRS was identified in 162 patients on admission and was persistent in 138
at 48 h. The median (range) cumulative Marshall score in patients with persistent SIRS was significantly
higher than that in patients in whom SIRS resolved and in those with no SIRS (4 (0–12), 3 (0–7) and
0 (0–9) respectively; P < 0·001). Thirty-five patients (25·4 per cent) with persistent SIRS died from
acute pancreatitis, compared with six patients (8 per cent) with transient SIRS and four (0·7 per cent)
without SIRS (P < 0·001). No correlation was observed between CRP level on admission and Marshall
score (P = 0·810); however, there was a close correlation between CRP level at 48 h and Marshall score
(P < 0·001).
Conclusion: Persistent SIRS is associated with MODS and death in patients with acute pancreatitis and
is an early indicator of the likely severity of acute pancreatitis.

Presented to the Quincentenary Congress of The Royal College of Surgeons of Edinburgh, Edinburgh, UK, June 2005
Paper accepted 16 November 2005
Published online in Wiley InterScience (www.bjs.co.uk). DOI: 10.1002/bjs.5290

Introduction with the number of failing organs as well as the severity

Acute pancreatitis has a spectrum of clinical presentations
ranging from mild self-limiting disease to severe pancreati-
tis, which results in the development of local and systemic
complications with a significant risk of death1 – 4 . Mortal-
ity from acute pancreatitis follows a bimodal distribution.
Early death is related to the development of severe and irre-
versible multiorgan dysfunction, and late mortality occurs
in the second phase of illness dominated by sepsis and the
consequences of organ failure3 . Regardless of the timing,
death in patients with acute pancreatitis is associated closely
and reversibility of organ failure.
In patients with acute pancreatitis, progression to
a severe course appears to be associated with the
inappropriate activation of an inflammatory cascade
leading to the development of a systemic inflammatory
response5 – 7 , which in turn results in the development
of multiorgan dysfunction and death. The term systemic
inflammatory response syndrome (SIRS) was developed to
imply the presence of the clinical response to a non-specific
inflammatory insult8 . SIRS has a precise clinical definition,
which has been validated in large patient populations9 .

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Published by John Wiley & Sons Ltd
Severity of acute pancreatitis
Similarly the severity of multiorgan dysfunction has been
described in terms of clear physiological and biochemical
variables. Marshall et al.10 have developed a widely used
and validated multiorgan dysfunction score to classify
the degree of physiological derangement associated with
organ dysfunction. A recent review of 121 patients with
severe acute pancreatitis emphasized the dynamic nature
of multiorgan dysfunction in this patient population11 .
Buter et al.11 found that some patients who presented
with significant organ dysfunction made a complete
recovery with appropriate therapy, and documented that
persistent or deteriorating organ dysfunction was the only
independent predictor of death in patients with severe
acute pancreatitis. The criterion for recruitment to the
above study was an admission Acute Physiology And
Chronic Health Evaluation (APACHE) II score greater
than 6; therefore, the presence and significance of an early
systemic inflammatory response and its relationship with
multiorgan dysfunction syndrome (MODS) and death in
an unselected population of patients with acute pancreatitis
remains to be determined.
The aim of the present study was to examine the
prevalence of SIRS in patients with acute pancreatitis
regardless of aetiology and severity, and to assess the
significance of the inflammatory response during the first
48 h in the development and severity of MODS and death
from acute pancreatitis.
Patients and methods
All patients who presented with acute pancreatitis between
January 2000 and December 2004 were identified from a
prospectively collected Lothian surgical audit database12
and reviewed retrospectively. Acute pancreatitis was
defined as an increase in serum amylase concentration
of three times the upper limit of the normal value in
association with typical symptoms of acute pancreatitis,
computed tomographic evidence of acute pancreatitis, or
the diagnostic finding of pancreatic inflammation and
saponification made at the time of laparotomy in patients
with a normal serum amylase level. Patients with chronic
or recurrent acute pancreatitis were excluded.
Data for all surgical admissions during the study period
were recorded on standard admission proformas, which
were supplemented by retrospective chart review and
cross-referenced against the hospital laboratory database.
For each patient with acute pancreatitis, details of age,
sex, variables pertaining to APACHE II and Glasgow
outcome scores13 , serum C-reactive protein (CRP) levels,
and presence or absence of SIRS were collected in the first
24 h and at 48 h. SIRS was deemed to be present if the
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Published by John Wiley & Sons Ltd
739
patient had two or more of the following8 : temperature
greater than 38◦ C or less than 36◦ C, heart rate greater
than 90 beats per min, respiratory rate above 20 breaths
per min, arterial partial pressure of carbon dioxide of less
than 32 mmHg, and white cell count greater than 12 000
or less than 4000 cells/mm3 .
Organ dysfunction scores were calculated at 24 h, 48 h
and 1 week using the criteria proposed by Marshall et al.10 .
This widely used and validated system employs defined
physiological measures for each of five organ systems;
however, in this study the hepatic score was excluded to
avoid the possibility of confounding effects due to biliary
obstruction. Organ dysfunction was defined as a Marshall
score of 2 or more for each organ system10 . If this score
increased during the first 7 days or if organ dysfunction
(Marshall score of 2 or more) developed in another organ
system, the patient was considered to have deteriorating
MODS11 . Cumulative Marshall organ dysfunction scores
were calculated as the sum of organ dysfunction scores for
each of the four organ systems10 .
Severe acute pancreatitis was defined as acute pancre-
atitis associated with an APACHE II score greater than
6, a Marshall score greater than 2 affecting one or more
organ system, or the development of local complications of
pancreatitis in line with the Atlanta consensus document
definition14 . Mortality was calculated as the number of
patients dying during the index hospital admission with
pancreatitis.
Statistical analysis
Statistical analysis was performed using SPSS version
12 (SPSS, Chicago, Illinois, USA) statistical software.
To avoid distributional assumptions, values were stated
as median (range) and non-parametric statistical tests
(χ2 , Mann–Whitney, Kruskal–Wallis) were used. Survival
was analysed with the Kaplan–Meier method and log
rank test. Cox’s regression analysis was used to identify
factors collected in the first 48 h that were independent
predictors of mortality during the index presentation, and
stepwise logistic regression analysis was used to identify
independent predictors of the development of persistent
or deteriorating MODS. The diagnostic odds ratio was
determined for each predictor at the optimal cut-off levels
(age greater than 60 years, APACHE II score of less than
8, persistent SIRS, and Glasgow outcome score below 4).
Univariate linear regression analysis was used to assess
the relationship between serum CRP levels and maximal
cumulative Marshall scores. P < 0·050 was considered
statistically significant.
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740 R. Mofidi, M. D. Duff, S. J. Wigmore, K. K. Madhavan, O. J. Garden and R. W. Parks

Results
Circulatory system Renal system
Between January 2000 and December 2004, 759 con- 114 patients 78 patients
secutive patients (388 men and 371 women) with a Median score 2 (2–4) 14 Median score 2 (2 – 4)
median age of 57 (range 18–93) years presented with
acute pancreatitis. The aetiology of acute pancreatitis was 3

gallstones in 359 patients (47·3 per cent), alcohol related 48

52
in 249 (32·8 per cent), postendoscopic retrograde cholan-
giopancreatography in 19 (2·5 per cent), other cause in 37 13
(4·9 per cent) and idiopathic in 95 (12·5 per cent). At the
time of presentation, the median serum amylase level was 79
Respiratory system
906 (range 177–13 703) units/l, median APACHE II score
192 patients
was 4 (range 0–23) and the median CRP level was 99·7 Median score 2·5 (2–4)
(1–560) mmol/l. The median duration of hospital stay
was 6 (range 2–194) days. Forty-five patients (5·9 per cent) Fig. 1Distribution of multiorgan dysfunction involving the three
died from acute pancreatitis or its complications during the main organ systems in the study population. Seventeen patients
index admission. Of these, 14 died within 1 week of admis- also had coagulopathy (median score 2 (range 2–4)) as part of a
sion, nine died during the second week and the remaining multiorgan dysfunction syndrome
22 thereafter. The median time between admission and
death was 15 (range 1–124) days. 1·0
SIRS was identified at admission in 162 patients
(21·3 per cent) and resolved within the first 48 h in 74 0·8
patients. A further 50 patients had no clinical evidence of
Cumulative survival

SIRS on admission but developed SIRS in the first 48 h 0·6

after admission. Thus, a total of 138 patients (18·2 per cent)
had persistent SIRS at 48 h after presentation (Table 1). 0·4
Significant organ dysfunction was present in 209 No MODS
Transient MODS
patients (27·5 per cent) on admission and in 148 patients 0·2 Deteriorating MODS
(19·5 per cent) at 48 h. Eighty-nine patients (11·7 per cent)
had persistent or deteriorating MODS at 1 week. Fig. 1
0 20 40 60 80 100
illustrates the distribution and severity of organ dysfunction
Time (days)
in the study population in the first week of presentation. No. at risk
Of the 120 patients in whom MODS improved during No MODS 550 548 547 546 546
the first week, four patients (3·3 per cent) died, all of Transient MODS 120 117 117 116 116
Deteriorating MODS 89 63 59 53 52
which were late deaths as a result of infected pancreatic
necrosis, whereas 37 patients (42 per cent) with persistent Fig. 2Kaplan–Meier survival plot of the effect of the presence
or deteriorating MODS during the first week died and deterioration of multiorgan dysfunction syndrome (MODS)
(χ2 = 238·4, 2 d.f., P < 0·001) (Fig. 2). Four patients on survival from acute pancreatitis (P < 0·001, log rank test)
without significant multiorgan dysfunction did not survive.
All four of these deaths occurred late; one was a result of
pulmonary embolus, one from myocardial infarction and
two from late local complications of pancreatitis.
The median (range) cumulative Marshall score was
Table 1 Survival of patients with clinical evidence of systemic
significantly higher in patients who presented with SIRS
inflammatory response syndrome
than in those who did not have SIRS on admission (4
No. alive No. dead Total (0–12) versus 0 (0–7); P < 0·001). Similarly, higher median
cumulative Marshall scores were observed in patients who
No SIRS 543 (99·3) 4 (0·7) 547
Transient SIRS 68 (92) 6 (8) 74
had SIRS at 48 h 4 (0–12) than those in whom SIRS
Persistent SIRS 103 (74·6) 35 (25·4) 138 did not develop 0 (0–9), or had resolved by 48 h (3
Total 714 (94·1) 45 (5·9) 759 (0–7); P < 0·001) (Fig. 3). A close correlation was observed
between serum CRP level at 48 h and cumulative Marshall
Values in parentheses are percentages. χ2 = 120·6, 2 d.f., P < 0·001. score (R2 = 0·350, P < 0·001) (Fig. 4), whereas there was

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Severity of acute pancreatitis 741

Table 2 Clinical predictors of the development of persistent or

12
deteriorating multiorgan dysfunction syndrome identified using
backward stepwise logistic regression analysis
10
Cumulative Marshall score

Odds ratio P
8
Age 0·99 (0·97, 1·00) 0·095
APACHE II score 0·74 (0·56, 0·98) 0·030
6 Glasgow outcome score (48 h) 1·09 (0·97, 1·23) 0·156
Persistent SIRS (48 h) 8·24 (5·47, 12·43) <0·001
Serum CRP (48 h) 1·00 (0·97, 1·00) 0·790
4

Values in parentheses are 95 per cent confidence intervals. APACHE,

2 Acute Physiology And Chronic Health Evaluation; SIRS, systemic
inflammatory response syndrome; CRP, C-reactive protein.

0
Table 3 Clinical predictors of survival in the first 48 h of
No SIRS Transient SIRS Persistent SIRS
presentation assessed using Cox’s regression analysis
Fig. 3 Box and whisker plot comparing the cumulative Marshall
Odds ratio P
multiorgan dysfunction scores between patients who had no
systemic inflammatory response syndrome (SIRS) (n = 543 Age 0·73 (0·6, 0·89) 0·005
patients), patients with transient SIRS (n = 74) and those with APACHE II score 5·15 (2·40, 11·10) <0·001
persistent SIRS (n = 138). The thick black lines represent Glasgow outcome score (48 h) 0·91 (0·72, 1·15) 0·450
Persistent SIRS (48 h) 3·63 (2·50, 5·25) <0·001
median values, boxes represent the interquartile range, whiskers
Serum CRP (48 h) 1·00 (0·99, 1·01) 0·310
represent the outliers, and the individual circles denote extreme
values. P < 0·001 (Kruskal–Wallis test)
Values in parentheses are 95 per cent confidence intervals. APACHE,
Acute Physiology And Chronic Health Evaluation; SIRS, systemic
inflammatory response syndrome; CRP, C-reactive protein.
600

with the development of persistent or deteriorating MODS

500 (Table 2).
There was a strong association between persistent SIRS
and death from acute pancreatitis (Fig. 5). The mortality
400
CRP level (mmol/l)

rate was significantly higher in patients who developed or

had persistent SIRS at 48 h after admission (25·4 per cent)
300 than in patients who had transient SIRS (8 per cent)
and those with no SIRS in the first 48 h (0·7 per cent)
(χ2 = 120·6, 2 d.f., P < 0·001). Cox’s regression analysis
200
using age, admission APACHE II score, persistent SIRS,
Glasgow outcome score and serum CRP level at 48 h
100 indicated that only age (P = 0·005), admission APACHE
II score (P < 0·001) and presence of persistent SIRS (P <
0·001) were associated with death from acute pancreatitis
0 1 2 3 4 5 6 7 8 9 10 11 12 during the index admission (Table 3).
Cumulative Marshall score

Fig. 4Correlation between serum C-reactive protein (CRP) level Discussion

at 48 h and cumulative Marshall score (R2 = 0·350, P < 0·001)
no significant correlation between serum CRP level on
admission and Marshall score (R2 = 0·010, P = 0·810).
Logistic regression analysis revealed that APACHE II
scores at admission (P = 0·030) and persistent SIRS within
the first 48 h (P < 0·001) were the only variables associated
It is widely accepted that local pancreatic inflammation
is the initiating stimulus for a systemic inflammatory
response. This in turn results in the development of
multiorgan dysfunction and contributes to death from
acute pancreatitis. Although the development of SIRS
is central to the pathophysiology of organ dysfunction,
its incidence and relationship with the development of

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742
1⋅0
0⋅8
Cumulative survival
0⋅6
No SIRS
0⋅4
Transient SIRS
Persistent SIRS
0⋅2
0 20 40 60
Time (days)
No. at risk
No SIRS 547 544 543 542
Transient SIRS 74 69 69 68
Persistent SIRS 138 112 109 104
Fig. 5Kaplan–Meier survival plot of the effect of the presence
and persistence of the systemic inflammatory response syndrome
(SIRS) in the first 48 h of presentation on survival from acute
pancreatitis (P < 0·001, log rank test)
severe pancreatitis has not been determined previously
in a large cohort of patients. In this study the incidence
of SIRS was 21·3 per cent of patients on admission and
18·2 per cent at 48 h after admission, confirming that the
systemic inflammatory response is a dynamic process8,11 .
Notably it was observed that, although SIRS does resolve
after appropriate resuscitation in some patients, a small
proportion of patients develop features of SIRS after initial
presentation despite supportive therapy. These patients,
together with those with persistent SIRS, are at highest
risk of multiorgan failure and death.
SIRS is caused by the activation of an inflammatory
cascade mediated by cytokines such as tumour necrosis
factor (TNF) and interleukin (IL) 6, mononuclear cells and
the complement system4,8 . This inflammatory response
involves the activation of macrophages, which are recruited
into tissues distant to the pancreas and result in the
development of MODS. de Beaux et al.15 , in a study of 59
consecutive patients with acute pancreatitis, found a close
correlation between serum TNF, soluble TNF receptors
(TNFR55 and TNFR75 ) and serum IL-6 levels and the
development of multiorgan failure15 . A rise in the serum
levels of these cytokines has been shown to precede the
acute inflammatory response and predict the severity of
acute pancreatitis16,17 .
CRP is an acute-phase reactant synthesized by hepa-
tocytes following induction by IL-1 and IL-6. It is the
most popular and widely available marker of severity of
the acute inflammatory response14,17,18 . However, as CRP
Copyright  2006 British Journal of Surgery Society Ltd
Published by John Wiley & Sons Ltd
R. Mofidi, M. D. Duff, S. J. Wigmore, K. K. Madhavan, O. J. Garden and R. W. Parks
is synthesized in response to an acute inflammatory event,
peak serum levels lag behind the initiation of an acute sys-
temic inflammatory response7,17 . de Beaux et al.15 reported
that, although serum CRP level at 48 h correlated closely
with severity of acute pancreatitis, the level at presentation
was unhelpful in predicting the severity of acute pancreati-
tis or the development of organ failure. This finding was
substantiated in the present study as there was a significant
correlation between serum CRP concentration and cumu-
lative Marshall score at 48 h, but no such correlation was
demonstrated on admission.
80 100 In the present study, persistent or developing SIRS
in the first 48 h was associated with higher cumulative
organ dysfunction scores and correlated with poor survival.
542
68 This is consistent with previous observations made by
103 Buter et al.11 , although no attempt was made to assess
the temporal relationship between SIRS and multiorgan
dysfunction. The finding that a significantly higher
proportion of patients with persistent SIRS in the first 48 h
had deteriorating Marshall scores during the first week
after admission suggests that such a relationship may exist.
Despite the close correlation between persistent SIRS
and survival from acute pancreatitis, Buter et al.11
reported that this relationship was not independent of
deteriorating organ dysfunction. Current paradigms of
the pathophysiology of acute pancreatitis suggest that
death in the early phase of severe acute pancreatitis,
before the onset of local pancreatic infection, results from
increasing multiorgan dysfunction4 . Therefore, increasing
organ dysfunction may not be predictive in terms of
pathophysiology, but rather reflects the presence of the
most severe spectrum of disease in patients who are
likely to succumb to acute pancreatitis. Johnson and Abu-
Hilal19 studied 290 patients with predicted severe acute
pancreatitis and documented that persistent organ failure,
whether present on admission or arising within the first
week, was significantly associated with a fatal outcome, as
had been observed by Buter et al.11 . They also found that
persistent organ failure in the first week of presentation was
significantly associated with the subsequent development
of local complications of pancreatitis19 .
Improvements in intensive care have resulted in a
significant reduction in the mortality rate from acute
pancreatitis over the past 25 years20 . In the present study,
the overall mortality rate from acute pancreatitis was
5·9 per cent. Timely organ support may be able to reverse
the physiological and biochemical features of MODS in
some patients, and therefore it is important to identify
those who are at risk of deteriorating MODS and death
despite supportive therapy early in the course of their
disease. The cumulative Marshall score can be used as a
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Severity of acute pancreatitis
surrogate marker of the severity of the consequences of
the systemic inflammatory response and identify the larger
number of patients who, without close monitoring and
organ support, are at risk of death from acute pancreatitis.
The close association between early persistent SIRS and
cumulative Marshall score highlights the usefulness of this
observation as an early prognostic indicator. Moreover,
these data suggest that persistent SIRS and admission
APACHE II score are independent predictors of the
development of persistent MODS and death from acute
pancreatitis.
In recent years there has been increasing interest in
the use of early goal-directed therapy in the management
of patients with SIRS and septic shock in the intensive
care setting21 . Goal-directed therapy involves adjustments
of cardiac preload, afterload and contractility to optimize
the delivery of oxygen to the tissues. Recent randomized
controlled trials have revealed that early goal-directed
therapy is associated with stabilization of physiological
resuscitation endpoints such as heart rate, mean arterial
pressure, central venous oxygen saturation, arterial lactate
concentration and base deficit22,23 , as well as improvements
in the subsequent APACHE II and organ dysfunction
scores23 . Rivers et al.23 reported that early goal-directed
therapy in the setting of severe sepsis and septic shock
was associated with a reduced in-hospital mortality rate.
The presence of persistent or developing SIRS in patients
with acute pancreatitis could be used to identify a cohort
of patients who might similarly benefit from early goal-
directed therapy. This hypothesis remains to be examined
by a randomized clinical trial.
This study has highlighted the association between
the acute systemic inflammatory response and the
development and severity of multiorgan dysfunction in
acute pancreatitis. The presence of SIRS as the clinical
manifestation of this inflammatory response can provide
a bedside indicator of the severity of acute pancreatitis
during the first 48 h of presentation.
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