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Sepsis, SIRS and MODSBen Griffiths

Iain D Anderson

AbstractSepsis, 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 spec-

trum 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, examina-

tion, observations, laboratory results) with the aim of preventing

the slide of a patient with SIRS on the surgical ward to a criti-

cally-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

(32 mmHg)

� white cell count <4 or >12 � 109/l OR the presence of greater

than 10% immature neutrophils.

Sepsis: SIRS in the presence of infection, either proven or

suspected.

Ben Griffiths FRCS is a Specialist Registrar in General Surgery on the

North-West England rotation, UK. Conflict of interests: none declared.

Iain D Anderson FRCS is a Consultant Colorectal Surgeon at the

Intestinal Failure Unit, Salford Royal Hospital, Salford, UK. Conflict of

interests: none declared.

SURGERY 27:10 446

Severe sepsis: Sepsis with evidence of organ dysfunction or

tissue hypoperfusion.

Septic shock: Sepsis-induced hypotension which persists despite

adequate fluid resuscitation.

Multiple Organ Dysfunction Syndrome (MODS): the failure of

two, or more, organs which are unable to maintain homeostasis

without intervention.

SIRS is triggered by an insult to the body which may be

ischaemic, inflammatory, traumatic or infective. In healthy indi-

viduals 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 expec-

ted 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 intravas-

cular lines. Emergency cases, operations involving contam-

inated sites and patients with co-morbidities are also more

likely victims.

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

treatment.

Serum lactate

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

shock.

� 2009 Elsevier Ltd. All rights reserved.

Sepsis resuscitation bundle

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

equivalent

b. Apply vasopressors for hypotension not responding to initial

fluid resuscitation to maintain mean arterial pressure (MAP)

>65 mmHg

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 Inten-

sive Care Medicine, International Sepsis Forum and Society of Critical Care

Medicine.)

Table 1

Source control in sepsis.

Techniques Examples

Antibiotics Urinary tract infection

Cellulitis

Drainage of pus Aspiration of breast abscess

Radiological paracolic abscess drainage

Device removal Central venous catheter

Hernia mesh excision

Debridement of

dead tissue

Necrotising fasciitis

Amputation gangrenous limb

Definitive surgery Colonic resection with stoma

Small bowel anastomosis

Damage control

laparotomy

Stapling ends of bowel

Drain pus, leave abdomen open

Table 2

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Intravenous fluid and vasopressors

If the serum lactate is >4 mmol/l (or the patient is under-

perfused) then an intravenous fluid bolus of 20 ml/kg crystal-

loid 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, vaso-

pressors 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%.

Blood cultures

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.

Broad-spectrum antibiotics

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.

SURGERY 27:10 447

Next steps in management

Source control

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.

Nutrition

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/jejuno-

stomy). 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

general benefit.

� 2009 Elsevier Ltd. All rights reserved.

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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 prophy-

laxis 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.

Critical care

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.

Steroid therapy

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 replace-

ment, 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 prop-

erties. 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 activ-

ated protein C in patients with severe sepsis and a recent Cana-

dian 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.

Glycaemic control

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 it

severe sepsis or septic shock

1. Administer low-dose steroids for septic shock by a standardized ICU po

2. Administer human recombinant activated protein C by a standardized I

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.

(Reproduced with permission. Copyright 2008. European Society of Intensive Care M

Table 3

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This has led to a relaxation of the acceptable range as shown in

the bundle above.

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

Multiple organ dysfunction syndrome (MODS)

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

supported.

Cardiovascular

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 haemo-

dynamic parameters using vasoactive drugs (inotropes,

vasoconstrictors, vasodilators).

Lungs

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 pre-

venting trauma to the lungs.

ems may be completed within 24 h of presentation for patients with

licy.

CU policy.

8 mmHg) for mechanically ventilated patients.

edicine, International Sepsis Forum and Society of Critical Care Medicine.)

� 2009 Elsevier Ltd. All rights reserved.

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Gut

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. Alterna-

tively, 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 hypo-

perfusion or reperfusion injury allowing translocation of bacteria

and endotoxins into the systemic circulation.

Liver

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 reticuloendo-

thelial 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 treat-

ment (C-reactive protein, serum albumin).

Kidneys

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 iatro-

genic 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).

Central nervous system

Involvement of the CNS in sepsis produces encephalopathy and

peripheral neuropathy, the pathogeneses being poorly

understood.

Coagulation

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 dia-

gnostic rise in D-dimers, is less common. Thromboelastograms

SURGERY 27:10 449

are being used more commonly in ICUs to monitor haemostasis

as a dynamic process.

Novel therapies

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. A

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� 2009 Elsevier Ltd. All rights reserved.