Sepsis, SIRS and MODS
Severe sepsis: Sepsis with evidence of organ dysfunction or
Septic shock: Sepsis-induced hypotension which persists despite
adequate ﬂuid resuscitation.
Iain D Anderson
Multiple Organ Dysfunction Syndrome (MODS): the failure of
two, or more, organs which are unable to maintain homeostasis
SIRS is triggered by an insult to the body which may be
ischaemic, inﬂammatory, traumatic or infective. In healthy individuals the neuroendocrine and immune systems combine to
eradicate the insult, resulting in resolution, but if this local control
fails then the patient can progress down the sepsis pathway. The
inﬂammatory cascade is a complex process that involves humoral
and cellular responses, complement and cytokine cascades.
Important mediators include platelet-activating factor (PAF),
tumour necrosis factor alpha (TNFa) and the interleukins 1, 6, 8
and 10. SIRS may be seen in emergency admissions but is also
often seen in ward patients who have developed a complication.
In the UK, many wards now use an early warning score system
(EWS) to identify patients with abnormal physiology and there is
some overlap with SIRS criteria enabling clinical staff to rapidly
target patients at risk.
We recommend a structured approach as outlined in
CCrISP,1 to facilitate early identiﬁcation, rapidly restore normal
physiology and halt progression. While simple cases may be
resolved by prescribing oxygen, a ﬂuid bolus and antibiotics,
many are more complex. Should the patient fail to improve
quickly or deteriorate, then senior members of the surgical
team should be informed and the critical care team alerted. In
complex patients several episodes of SIRS or sepsis are expected and the structured approach should be employed over and
over again to avoid important omissions. The most common
cause of sepsis is bacterial infection but viruses, fungi and
parasites should always be considered. The most common sites
are chest, abdomen, genitourinary tract and infected intravascular lines. Emergency cases, operations involving contaminated sites and patients with co-morbidities are also more
While milder sepsis often responds to simple treatments,
deterioration is unpredictable and mortality from severe sepsis
remains high (28e50%) e the Surviving Sepsis Campaign
(international consensus group) guidelines2 are now widely used
to reduce this. They provide evidence-based ‘care bundles’ which
should be delivered expediently to septic patients as outlined
below, Table 1. These targets emphasize the importance of
speed: failure to achieve them is associated with poor outcome.
Some steps require critical care unit management. Patients
should always be managed in an appropriate area but waiting for
transfer should not delay the commencement of necessary
Sepsis, a systemic inﬂammatory process triggered by infection, is the
commonest mode of death in modern surgical practice. Sepsis exists as
a spectrum of severity from the Systemic Inﬂammatory Response
Syndrome (SIRS) through to Multiple Organ Dysfunction Syndrome
(MODS). The surgeon must be able to recognize patients within this spectrum rapidly because early identiﬁcation and intervention is the key to
reducing mortality. Rapid, accurate assessment and management are
facilitated by using a structured approach such as that described in the
Care of the Critically-Ill Surgical Patient (CCrISP) programme. Control of
the source of sepsis is fundamental to success and this should be led
by senior surgeons. Key steps and timelines are described in the
evidence-based ‘care bundles’ of the Surviving Sepsis Campaign.
Keywords resuscitation; source control; sepsis; SIRS; MODS
Sepsis is a major cause of morbidity and mortality worldwide
with around 36,800 sepsis-related deaths in the UK per annum.
Only coronary heart disease kills more people in the UK and it is
anticipated that worldwide rates of sepsis will increase year on
year. Sepsis is the leading mechanism of death in modern
surgical practice and the surgeon must understand common
deﬁnitions and their place in the sepsis spectrum. SIRS is
extremely common and patients will be seen with this on most
ward rounds. The surgeon should aim to identify cases early by
conducting structured ward rounds (progress/history, examination, observations, laboratory results) with the aim of preventing
the slide of a patient with SIRS on the surgical ward to a critically-ill patient with MODS on ICU. This slippery slope from SIRS
to MODS can be rapid and difﬁcult to halt but the earlier the
intervention the better the outcome.
Systemic Inﬂammatory Response Syndrome (SIRS) d can be
diagnosed when any two of the following criteria exist:
body temperature 36 C or 38 C
heart rate 90 beats/min
respiratory rate 20 breaths/min or PCO2 4.3 kPa
white cell count 4 or 12 Â 109/l OR the presence of greater
than 10% immature neutrophils.
Sepsis: SIRS in the presence of infection, either proven or
Ben Grifﬁths FRCS is a Specialist Registrar in General Surgery on the
North-West England rotation, UK. Conﬂict of interests: none declared.
Serum lactate is produced by anaerobic metabolism and is
a marker of tissue hypoperfusion. It helps to identify inadequate
oxygen delivery and has prognostic value for patients in septic
Iain D Anderson FRCS is a Consultant Colorectal Surgeon at the
Intestinal Failure Unit, Salford Royal Hospital, Salford, UK. Conﬂict of
interests: none declared.
Ó 2009 Elsevier Ltd. All rights reserved.
Next steps in management
Sepsis resuscitation bundle
After resuscitation, controlling the source of sepsis is essential to
halting progress down the sepsis slope. Experienced surgical
input is needed to lead the search for the source of sepsis and
arrange urgent control. This may involve appropriate imaging if
the site is not obvious or immediate intervention once the source
has been identiﬁed (see Table 2). Source control may simply
involve removal of an in-dwelling vascular or urinary catheter or
a course of appropriate antibiotics. Radiologically-guided
drainage is a minimally invasive technique used to drain suitable
solitary intra-abdominal/pelvic abscesses. Clearly, in a patient
with perforated diverticular disease and faecal peritonitis the
only effective method of source control will be an urgent
laparotomy and deﬁnitive surgical management of the source is
the gold standard. However, a limited damage control
laparotomy may occasionally be necessary for rapid control of
sepsis in a patient too ill (acidotic, coagulopathic) to survive
complex deﬁnitive surgery. The patient returns to the ICU for
physiological improvement before delayed deﬁnitive surgery.
The goal is to perform all indicated tasks within the ﬁrst 6 h of
identiﬁcation of severe sepsis in all patients.The tasks are:
1. Measure serum lactate
2. Obtain blood cultures prior to antibiotic administration
3. Administer broad-spectrum antibiotic, within 3 h of emergency
admission and within 1 h otherwise
4. In the event of hypotension and/or a serum lactate 4 mmol/l
a. Deliver an initial minimum of 20 ml/kg of crystalloid or an
b. Apply vasopressors for hypotension not responding to initial
ﬂuid resuscitation to maintain mean arterial pressure (MAP)
5. In the event of persistent hypotension despite ﬂuid resuscitation
(septic shock) and/or lactate 4 mmol/l
a. Achieve a central venous pressure (CVP) of 8 mmHg
b. Achieve a central venous oxygen saturation (ScvO2) 70 %
or mixed venous oxygen saturation (SvO2) 65%
(Reproduced with permission. Copyright 2008. European Society of Intensive Care Medicine, International Sepsis Forum and Society of Critical Care
Nutrition should be considered as part of every deﬁnitive
management plan. All septic patients are catabolic and their
calorie requirement increases signiﬁcantly. The enteral route
should be utilized wherever possible and this may involve
accessing the gastrointestinal tract by tube (typically nasogastric/
nasojejunal tube, or radiological or open gastrostomy/jejunostomy). The enteral route also maintains mucosal integrity and
may protect against further septic complications originating from
the gut, through colonisation/translocation, but if unavailable,
then parenteral nutrition should be used with meticulous care of
central venous catheters to prevent further sepsis.
Immuno-modulating feeds containing immunonutrients such
as arginine, glutamine, and omega-3 fatty acids are conceptually
appealing but data from multiple individual trials and several
meta-analyses have failed to produce convincing evidence of
Intravenous ﬂuid and vasopressors
If the serum lactate is 4 mmol/l (or the patient is underperfused) then an intravenous ﬂuid bolus of 20 ml/kg crystalloid should be given rapidly and the response evaluated.
Crystalloid or colloid can be used as there is no evidence that
one is superior to the other, but 5% dextrose should be
avoided. In patients unresponsive to ﬂuid challenges, vasopressors should be started to aim at a mean arterial pressure
(MAP) of 65 mmHg. In sepsis the most common ﬁrst-line
vasopressor is noradrenaline which raises MAP primarily by
vasoconstriction. Goals in patients with septic shock are
a central venous pressure of 8 mmHg and either a central
venous oxygen saturation (ScvO2) of 70% or a mixed venous
oxygen saturation (SvO2) of 65%.
Source control in sepsis.
Two sets of peripheral blood cultures should be taken as well as
cultures from any in-dwelling vascular device. Blood cultures are
positive in 30e50% of septic patients and the identiﬁcation of the
correct organism in these patients enables antibiotic therapy to
be targeted subsequently.
Urinary tract infection
Aspiration of breast abscess
Radiological paracolic abscess drainage
Central venous catheter
Hernia mesh excision
Amputation gangrenous limb
Colonic resection with stoma
Small bowel anastomosis
Stapling ends of bowel
Drain pus, leave abdomen open
Drainage of pus
Give broad-spectrum antibiotics as soon as blood cultures
have been sent, the choice depending on local policy. If
necessary, get advice from your microbiologist. There is good
evidence that outcome is improved if antibiotics are given
within an hour of ward admission and within 3 h if seen in
Accident and Emergency.
Ó 2009 Elsevier Ltd. All rights reserved.
Prevention of complications
Septic patients are at increased risk of venous thromboembolism
and peptic ulceration. National Institute of Health and Clinical
Excellence (NICE) guidelines recommend mechanical prophylaxis with low molecular weight heparin in patients with severe
infection.3 Gastric acid suppression or preferably cytoprotective
therapy is used for ulcer prophylaxis. Meticulous intravascular
line care reduces line sepsis, and hand washing by medical and
nursing staff reduces cross-infection.
This has led to a relaxation of the acceptable range as shown in
the bundle above.
The critical care team should be informed of the presence of
a patient with severe sepsis as early as possible to enable them to
plan appropriate intervention and to decide on the appropriate
level of care. They may employ the sepsis management ‘bundle’
for ICU care of severe sepsis, Table 3.
Multiple organ dysfunction syndrome (MODS)
Inspiratory plateau pressure goal
Most septic patients need to be intubated and ventilated and
approximately 50% will have either acute lung injury or acute
respiratory distress syndrome (ARDS). Studies have shown that
aiming for a mean inspiratory plateau pressure of 30 cm H2O
improves all-cause mortality.8
Once initiated, MODS often follows a predictable clinical course,
irrespective of the precipitating event. The ﬁrst evidence of
organ dysfunction is usually changes in the respiratory and
cardiovascular systems. The resulting pulmonary failure and
ensuing hypoxaemia are followed by hepatic and renal
dysfunction and disorders of the haemostatic, gastrointestinal
and central nervous systems. Bone marrow failure and
myocardial dysfunction are usually late manifestations of MODS.
Support for the failing organs is the cornerstone of modern ICU
practice, and prognosis is most directly related to the number of
failed organs. Mortality from septic shock approaches 50% and
each subsequent failing organ probably adds a further 15% to
that ﬁgure. In surgical patients with MODS, source control is
vital for success. Additionally, each failing organ has to be
Intravenous corticosteroids (hydrocortisone 200e300 mg/day,
for 7 days in divided doses or by infusion) are recommended in
patients with septic shock who, despite adequate ﬂuid replacement, require vasopressor therapy to maintain adequate blood
pressure. A meta-analysis has shown signiﬁcant reductions in
ICU and all-cause mortality as well as numbers of patients whose
septic shock was reversed.4
Activated protein C (APC)
APC has anticoagulant, anti-inﬂammatory and ﬁbrinolytic properties. It is used in patients with severe sepsis and multiple organ
dysfunction in addition to standard care. Its anticoagulant action
means it is contraindicated in patients with a risk of signiﬁcant
bleeding. The PROWESS study5 demonstrated a 6.1% absolute
reduction in 28-day mortality using recombinant human activated protein C in patients with severe sepsis and a recent Canadian study has shown improved mortality if activated protein C
was given within the ﬁrst 24 h of developing sepsis-induced
organ dysfunction.6 NICE has recommended APC for patients
with severe sepsis and organ failure.
Signiﬁcant derangement in autoregulation of circulation is typical
of sepsis. Vasoactive mediators cause vasodilatation and increase
the microvascular permeability, resulting in oedema. Myocardial
depression is a late feature of septic shock. Treatments include
adequate volume replacement and optimisation of haemodynamic parameters using vasoactive drugs (inotropes,
Endothelial injury and neutrophil entrapment in the alveoli lead
to local injury, disturbed capillary blood ﬂow and enhanced
microvascular permeability, resulting in interstitial and alveolar
oedema. Acute lung injury and acute respiratory distress
syndrome (ARDS) are a frequent manifestation of these effects.
Ventilatory techniques aim to optimize oxygenation whilst preventing trauma to the lungs.
Hyperglycaemia is common in septic patients and there is
evidence that maintaining blood glucose levels within a very
tight range (4.4e6.1 mmol/l) reduces morbidity and mortality in
critically-ill surgical patients.7 Maintaining glucose in such a tight
range is difﬁcult and hypoglycaemic events are more common.
Sepsis management bundle
Efforts to accomplish these goals should begin immediately, but these items may be completed within 24 h of presentation for patients with
severe sepsis or septic shock
1. Administer low-dose steroids for septic shock by a standardized ICU policy.
2. Administer human recombinant activated protein C by a standardized ICU policy.
3. Maintain glucose control 3.9 mmol/l, but 8.3 mmol/l.
4. Maintain a median inspiratory plateau pressure (IPP) 30 cm H2O (22.8 mmHg) for mechanically ventilated patients.
(Reproduced with permission. Copyright 2008. European Society of Intensive Care Medicine, International Sepsis Forum and Society of Critical Care Medicine.)
Ó 2009 Elsevier Ltd. All rights reserved.
The GI tract may help propagate the septic process. Bacteria in
the upper GI tract may be aspirated into the lungs, producing
nosocomial pneumonia and this process is made worse by the
necessary gastric acid suppression in critical illness. Alternatively, cytoprotective therapy with drugs such as sucralfate can
be prescribed. There is evidence from animals that the normal
barrier function of the gut may be affected by splanchnic hypoperfusion or reperfusion injury allowing translocation of bacteria
and endotoxins into the systemic circulation.
are being used more commonly in ICUs to monitor haemostasis
as a dynamic process.
It is hoped that widespread use of the evidence-based Surviving
Sepsis Campaign care bundles will translate into improvements in
mortality from sepsis over the next decade. Surgical advances are
likely to involve minimally invasive techniques of obtaining
source control. In the critical care setting there is interest in
improving understanding of the genetic polymorphisms which
have been shown to be important in an individual’s susceptibility
and response to sepsis. There is interest in administering APC in
the inhaled form to patients with ALI as there is improved
oxygenation in animal models. Hydrogen sulphide has been
identiﬁed as the third gaseous transmitter (after nitric oxide and
carbon monoxide) and has been shown to be a signalling molecule
of the cardiovascular, neurological and inﬂammatory systems.
Animals continue to be studied in various shock models and we
wait to see whether any application in humans emerges.
By virtue of the role of the liver in host defence, the abnormal
synthetic functions caused by liver dysfunction can contribute to
both the initiation and progression of sepsis. The reticuloendothelial system of the liver acts as a ﬁrst line of defence in clearing
bacteria and their products; liver dysfunction leads to a spill-over
these products into systemic circulation. Markers of liver
synthetic function can be useful in assessing response to treatment (C-reactive protein, serum albumin).
Acute renal failure often accompanies sepsis due to acute tubular
necrosis. Systemic hypotension, direct renal vasoconstriction,
release of cytokines and activation of neutrophils by endotoxins
and other peptides all contribute to renal injury. Treatment
involves limiting ischaemic injury to the kidney, reducing iatrogenic injury (nephrotoxic medication) and the use of renal
replacement therapy. Common methods of renal replacement on
the ICU include continuous veno-venous haemoﬁltration
(CVVH), continuous veno-venous diaﬁltration (CWHDF) and
continuous veno-venous haemodialysis (CVVHD).
1 Anderson ID. Care of the critically ill surgical patient. Hodder Arnold:
Royal College of Surgeons; 2003. p. 7e15.
2 Also available at: www.survivingsepsis.org.
3 Also available at: www.nice.org.
4 Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for treating
severe sepsis and septic shock. Cochrane Database Syst Rev 2005; 1:
5 Bernard GR, Vincent JL, Laterre PF, et al. Efﬁcacy and safety of
recombinant human activated protein C for severe sepsis. N Engl J Med
2001; 344: 699e709.
6 Hodder RV, Hall R, Russell JA, Fisher HN, Lee B. Early drotrecogin alpha
(activated) administration in severe sepsis is associated with lower
mortality: a retrospective analysis of the Canadian ENHANCE cohort.
Crit Care 2009; 13: R78.
7 Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin
therapy in critically ill patients. N Engl J Med 2001; 345: 1359e67.
8 The Acute Respiratory Syndrome Network. Ventilation with lower tidal
volumes as compared with traditional tidal volumes for acute lung
injury and the acute respiratory distress syndrome. N Engl J Med 2000;
Central nervous system
Involvement of the CNS in sepsis produces encephalopathy and
peripheral neuropathy, the pathogeneses being poorly
Subclinical coagulopathy signiﬁed by a mild elevation of the
thrombin or activated partial thromboplastin time (APTT) or
a moderate reduction in platelet count is extremely common, but
overt disseminated intravascular coagulation (DIC), with a diagnostic rise in D-dimers, is less common. Thromboelastograms
Ó 2009 Elsevier Ltd. All rights reserved.