British Journal of Anaesthesia 105 (6): 73443 (2010)

Advance Access publication 27 October 2010 . doi:10.1093/bja/aeq305

REVIEW ARTICLE

Anaesthetic management of patients with severe sepsis

D. Eissa, E. G. Carton and D. J. Buggy *
Division of Anaesthesia, Mater Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland
* Corresponding author. E-mail: donal.buggy@nbsp.ie, dbuggy@mater.ie

Key points
Patients with sepsis often
require surgical
interventions.

Preoperative optimization
and intraoperative and
postoperative care need
to be planned before
starting.
Techniques that preserve
cardiovascular and
respiratory function are
required.

Keywords: anaesthesia; emergency service; anaesthesia, general; infection; surgery;

perioperative period

Epidemiology
Severe sepsis and septic shock are major healthcare problems with a reported incidence of 66 132 per 100 000
population in the USA and UK, respectively.1 2 In 2001, a consensus conference (Society of Critical Care Medicine, European Society of Intensive Care Medicine, American College
of Chest Physicians, American Thoracic Society, and Surgical
Infection Society) concluded that the basic definitions of systemic inflammatory response syndrome (SIRS), as originally
described in 1992 by the American College of Chest Physicians and the Society of Critical Care Medicine,3 should
remain largely unchanged4 (Table 1). Because of the limitations of the definitions of SIRS and infection, the 2001 consensus conference suggested an expanded list of possible
signs of systemic inflammation that may be observed in
septic-looking patients (Table 2).
Severe sepsis occurs in 1 2% of all hospitalizations and
accounts for as much as 25% of intensive care unit (ICU)
bed utilization. It is common in elderly, immunecompromised, and critically ill patients and is a major

cause of death in ICUs worldwide.5 Sepsis is the second

leading cause of death in non-coronary ICU patients. Mortality remains high at 3050% despite improved care in
the past 1015 yr.1 5 6

Causes of sepsis
Severe sepsis may have infective and non-infective causes
(Table 3). Infections are common and amenable to treatment; therefore, in patients presenting with clinical signs of
systemic inflammation (SIRS), an infective cause should be
actively sought. Community-acquired infections in previously
well patients are easier to recognize than nosocomial infections in debilitated hospitalized patients. Infections leading
to sepsis include central nervous system (CNS) infections,
for example, meningitis or encephalitis, cardiovascular infections (e.g. infective endocarditis), respiratory infections (e.g.
pneumonia), gastrointestinal infections (e.g. peritonitis), or
urinary tract infections (e.g. pyelonephritis).1 7 Although bacterial infections are the most common infective cause,
viruses and fungi can also cause septic shock. Non-infective

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Anaesthesia can be
hazardous in these
cardiovascularly unstable
patients.

Summary. Severe sepsis, a syndrome characterized by systemic inflammation and acute

organ dysfunction in response to infection, is a major healthcare problem affecting all age
groups throughout the world. Anaesthetists play a central role in the multidisciplinary
management of patients with severe sepsis from their initial deterioration at ward level,
transfer to the diagnostic imaging suite, and intraoperative management for emergency
surgery. The timely administration of appropriate i.v. antimicrobial therapy is a crucial step
in the care of patients with severe sepsis who may require surgery to control the source of
sepsis. Preoperative resuscitation, aimed at optimizing major organ perfusion, is based on
judicious use of fluids, vasopressors, and inotropes. Intraoperative anaesthesia
management requires careful induction and maintenance of anaesthesia, optimizing
intravascular volume status, avoidance of lung injury during mechanical ventilation, and
ongoing monitoring of arterial blood gases, lactate concentration, haematological and
renal indices, and electrolyte levels. Postoperative care overlaps with ongoing
management of the severe sepsis syndrome patient in the intensive care unit. These
patients are by definition, high risk, already requiring multiple supports, and require
experienced and skilful decision-making to optimize their chances of a favourable
outcome. Similar to acute myocardial infarction, stroke, or acute trauma, the initial hours
(golden hours) of clinical management of severe sepsis represent an important
opportunity to reduce morbidity and mortality. Rapid clinical assessment, resuscitation
and surgical management by a focused multidisciplinary team, and early effective
antimicrobial therapy are the key components to improved patient outcome.

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Anaesthetic management of patients with severe sepsis

Table 1 2001 sepsis definitions by the American College of Chest

Physicians (ACCP) and the Society of Critical Care Medicine
(SCCM)3 4

Table 2 Diagnostic criteria for sepsis

Documented or suspected infection with some of the following
clinical signs or laboratory data

Pathological entity

Definition

1. Infection: documented or suspected infection

Bacteraemia

Presence of bacteria in the bloodstream

2. Signs of systemic inflammation

Septicaemia

The presence of large numbers of bacteria

in the bloodstream often associated with
systemic signs and symptoms such as
fever, rigors, and headache

SIRS

The threshold definition is two or more of

the following criteria:
o temperature .388C or ,368C
o heart rate .90 beats min21
o ventilatory frequency .20 bpm or PaCO2
,4.3 kPa
o WBC ,4109 litre21 or .12109 litre21
or .10% immature forms
SIRS with clinical evidence of infection

Severe sepsis

Sepsis associated with organ dysfunction,

hypotension, or hypoperfusion
abnormalities

Septic shock

Sepsis-induced
hypotension

Sepsis-induced hypotension, despite fluid

resuscitation, plus hypoperfusion
abnormalities
A systolic arterial pressure ,90 mm Hg or
a reduction of . 40 mm Hg from baseline
in the absence of other causes for
hypotension

Fever (core temp. .38.88C)

Hypothermia (core temp. ,368C)
Tachycardia (.90 beats min21)
Tachypnoea (.30 bpm)
Altered mental status
Significant positive fluid balance (.20 ml kg21 over 24 h)
Hyperglycaemia (.7.7 mmol litre21) in non-diabetic
patients
(b) Inflammatory parameters
WCC ,4 or .12, .10% immature forms
C-reactive protein .2 SD above normal value
Plasma procalcitonin .2 SD above normal value
(c) Haemodynamic parameters
Arterial hypotension (SAP ,90 mm Hg)
SvO2 .70%
CI.3.5
(d) Organ dysfunction parameters:
Hypoxic (PaO2 /FIO2 ,40)
Oliguria (,0.5 ml kg21 h21)
Creatinine increase (.0.5 mg dl21)
Coagulopathy (INR .1.5, aPPT.60 s, plt count,100)
Absent bowel sounds

causes include severe trauma or haemorrhage and acute

systemic disease, including myocardial infarction, pulmonary
embolus, and acute pancreatitis. Table 4 summarizes the
presentation of severe sepsis syndrome, the pathophysiology
underpinning the symptoms and signs, and the organisms
most commonly implicated.

Pathophysiology of sepsis
A detailed discussion of the physiology of sepsis is beyond
the scope of this review, but has itself been recently reviewed
comprehensively.8 This review concentrates on anaesthetic
management of patients with severe sepsis syndrome.

Anaesthetic management
Anaesthetists are frequently involved in the care of severely
septic patients in the emergency department, operating
theatre, or ICU. Infection source control, involving surgical
drainage of an abscess or debridement of necrotic tissue
coupled with early effective antimicrobial therapy, is central
to the successful treatment of a patient with severe sepsis.
In high-risk surgical or trauma patients with sepsis, early
haemodynamic optimization before the development of
organ failure reduced mortality by 23% in comparison with
those who were optimized after the development of organ
failure.9 10

Hyperbilirubinaemia
(e) Tissue hypoperfusion parameters
Lactate.3 mmol litre21
Decreased capillary refill
Mottling of skin

Preoperative assessment
Although not all patients with severe sepsis have an infective
focus, it is prudent to examine patients systematically
looking for a source of infection (Table 4). The primary
source may be self-evident (e.g. trauma, burns, recent
surgery) or may be more difficult to identify (e.g. empyema
of the gall bladder, pancreatitis, gynaecological sepsis, soft
tissue, and bony infections), particularly in agitated
un-cooperative patients. The examination should focus on
the severity of SIRS, the state of intravascular hydration,
the presence of shock or multi-organ dysfunction, and the
adequacy of haemodynamic resuscitation.

Surviving Sepsis Campaign

Following an international process of consultation to standardize the management of critically ill septic patients, the
Surviving Sepsis Campaign suggested that therapies be
grouped or bundled for particular subsets of patients. The
concept is not unlike that of Advanced Trauma Life Support
(ATLS), where somewhat didactic therapies are proposed in

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Sepsis

(a) General parameters

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Eissa et al.

Table 3 Aetiology of severe sepsis

Infective causes

Non-infective causes

CNS infections

Severe trauma

CVS infections

Haemorrhage

Respiratory infections

Complication of surgery

Renal infections

Complicated aortic aneurysm

GIT infections

Myocardial infarction

Skin and soft tissue infections

Pulmonary embolism

Bone and joint infections

Cardiac tamponade
Subarachnoid haemorrhage
Burns
Acute pancreatitis
Drug overdose/toxicity
Diabetic ketoacidosis
Adrenal insufficiency
Anaphylaxis

Antibiotic therapy
It is imperative that i.v. antibiotics should be started as early
as possible after the diagnosis of severe sepsis and septic
shock. There is no evidence that delaying until the start of
the surgical procedure or until microbiology culture results
are available is beneficial. Appropriate samples should be
obtained for culture before giving first-line anti-microbial
therapy.14 Anti-microbial drugs are best given i.v. and in sufficient dosage to achieve therapeutic concentration. The
choice of agents should be based on the clinical history,
physical examination, likely pathogen(s), optimal penetration
of anti-microbial drugs into infected tissues, and the local
pattern of sensitivity to anti-microbial agents. Broadspectrum agents should be used initially with one or more
agents active against all likely bacterial/fungal pathogens.

Haemodynamic resuscitation
The objective of preoperative resuscitation measures is to
rapidly restore adequate oxygen delivery to peripheral
tissues. If the patient is haemodynamically unstable, invasive
arterial pressure monitoring, central venous access, and ICU
or high dependency unit admission must be considered. Placement of a central venous catheter (CVC) will allow
measurement of central venous pressure (CVP), mixed
venous oxygen saturation (SvO2 ), administration of i.v.
fluids, and vasopressor medication.15 17 Resuscitation
measures begun in the emergency room can be continued
even if the patient requires diagnostic imaging studies or

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given clinical situations. Although its detractors point out

that bundled therapies are not individualized to a particular
patients needs, and the lack of evidence-based medicine
to underpin its guidelines, there is nonetheless some evidence that the process of care and outcomes improved
after educational programmes were instituted based on the
Surviving Sepsis Campaign.11 13

admission to the ICU before transfer to the operating

theatre. The first 6 h of resuscitation of septic patients, the
so-called golden hours, are crucial and frequently coincide
with the time for emergency surgery.11 18 There is little disagreement among clinicians that in the hypotensive septic
patient with lactate .3 mmol litre21, volume resuscitation
using crystalloids or colloids should be used initially, aiming
to reach the following clinical endpoints: CVP 8 12 mm Hg,
mean arterial pressure 65 mm Hg, urine output 0.5 ml kg21
h21, central venous oxygen saturation: .70% (Table 5).
There is no evidence-based support for one type of i.v. fluid
over another with regard to ICU stay, duration of mechanical
ventilation, duration of renal replacement therapy, and 28
day outcome.11 16 Colloid with pentastarch therapy was
associated with higher rates of acute renal failure and renalreplacement therapy than Ringers lactate and its toxicity is
increased with accumulating doses.7
Vasopressor support with norepinephrine may be considered even before optimal i.v. fluid loading has been
achieved. Low-dose vasopressin (0.03 units min21) may be
subsequently added to reduce the requirement for high-dose
norepinephrine alone.10 18 19 Inotropes are added to volume
resuscitation and vasopressors, if there is evidence of continued low cardiac output despite adequate cardiac filling and
fluid resuscitation. The Surviving Sepsis Campaign recommends that dobutamine is the first-line inotrope
therapy to be added to vasopressors in septic patients.11
However, a study in septic patients showed no difference
in efficacy and safety with epinephrine alone compared
with norepinephrine plus dobutamine (28 day mortality:
40% vs 34% respectively, P0.31) in the management of
septic shock.19 There is no evidence to support the use of
dobutamine to achieve supernormal oxygen delivery in
terms of improving outcomes.16 18 Resuscitation efforts
should be continued as long as haemodynamic improvement accompanies each step in the process. Further i.v.
fluid administration should be stopped when filling pressures
are high and no further improvement seen in tissue perfusion is seen (e.g. serum lactate not decreasing). Transfusion of red blood cells may be considered if tissue oxygen
delivery remains inadequate.20 21
Levosimendan may be a useful adjunct to conventional
inotropic therapy in cases of refractory myocardial dysfunction in sepsis. Its inotropic effect is attributable to increased
cardiac troponin C sensitivity to calcium. The systemic and
pulmonary vasodilator effect is attributable to its opening
of ATP-dependent potassium channels.22 A single randomized controlled trial in 28 patients with septic shock and ejection fraction ,45% persisting .48 h after conventional
treatment found that cardiac index and renal function
indices improved after levosimendan, compared with dobutamine.22 23 However, further larger clinical studies are
required before levosimendan becomes a widely accepted
therapy in septic shock.
Supplemental oxygen therapy is valuable in severely
septic patients even if they do not have signs of respiratory
distress. Immediate tracheal intubation and mechanical

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Anaesthetic management of patients with severe sepsis

Table 4 Common presentation, pathophysiology, and pathogens in severe sepsis

System affected

Signs and symptoms

Mechanism

Common system pathogens

Central nervous
system

Confusion, drowsiness, irritability coma

headache, neck stiffness, photophobia

Alteration in: blood brain barrier

neurotransmitter levels; receptor
function energy availability

Community-acquired pathogens:
Streptococcus pneumoniae; Neiserria
meningitides; Listeria monocytogenes
Nosocomial pathogens: Pseudomonas
aeruginosa; Escherichia coli

Cardiovascular
system

Hypovolaemia, impaired myocardial

contractility, tachycardia, increased
cardiac output, decreased systemic
vascular resistance (SVR), impaired
responsiveness to vasopressor agents,
short of breath, orthopnoea, raised
venous pressure

Major community-acquired pathogens:

Enterococcus; Streptococcus bovis;
Streptococcus spp.; coagulase-negative
staphylococci; Coxiella burnetii; Staphylococcus
aureus; Campylobacter; E. coli; fungus

(b) Increase in microvascular

permeability and
hypoalbuminaemia

Major nosocomial pathogens: Staphylococcus

spp.; methicillin-resistant S. aureus;
methicillin-resistant Staphylococcus
epidermidis; methicillin-resistant coagulase
negative Staphylococcus

(c) Myocardial depression

(d) Down-regulation of adrenergic
receptors heart valve dysfunction
Respiratory
system

Hypoxaemia, cyanosis, tachypnoea, use

of accessory muscles, change in
sputum: volume, purulance

(a) Increase in capillary

permeability; alveolar flooding

Major community-acquired pathogens:

S. pneumoniae, Haemophilus influenzae,
Legionella sp.

(b) Neutrophils recruited to the

lung

Major nosocomial pathogens: aerobic

Gram-negative bacilli

(c) Pulmonary microemboli

platelet aggregates
Gastrointestinal
system

Vomiting, diarrhoea, abdominal pain,

tenderness, liver failure, cholestasis

GU system

(a) Frequency, dysuria, haematuria,

flank pain, renal failure

Major community-acquired pathogens: E. coli; Bacteroides fragilis

Major nosocomial pathogens: aerobic Gram-negative bacilli anaerobes
Mechanisms?

Major community-acquired pathogens: any of

the above-mentioned organisms as a result of
bacteraemia
Major nosocomial pathogens: any of the
above-mentioned organisms as a result of
bacteraemia

Table 5 Goal-directed therapy: a summary of clinical targets

Clinical parameter

Goal

Central venous
pressure

8 12 mm Hg (8 mm Hg in
spontaneously breathing patient, 12
mm Hg in ventilated patients)

Mean arterial pressure

Between 65 and 90 mm Hg

Central venous
oxygen saturation

70 mm Hg

Urine output

0.5 ml kg21 h21

Haematocrit

30%

ventilation of the lungs can be considered if the patients

level of consciousness is low or if there is progressive distress
and hypoxia.24 If there is an inadequate response to these
resuscitation measures, it is important to consider the presence of an alternative diagnosis. The non-infective causes

of SIRS or an iatrogenic complication, for example, tension

pneumothorax after CVC placement, should also be considered (Table 3).

Diagnostic imaging
Diagnostic imaging studies are increasingly important in confirming the site of infection, excluding alternative pathology
and guiding radiological or surgical source control procedures. If diagnostic imaging studies are considered appropriate, it is important that all other therapeutic measures
(e.g. i.v. fluid resuscitation, antimicrobial therapy, mechanical
ventilation) are continued in a comprehensive manner. Computerized tomography is the most useful imaging modality
for complex soft-tissue infections and deep-seated infections
in the abdomen and thorax. Ultrasound imaging of the biliary
and urinary tract may also be considered. Expert interpretation of all imaging studies should be sought to assist in
planning the optimal management strategy.

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(a) Poor intake, inadequate

replacement, excessive insensible
losses

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Source control

Intraoperative management
The primary goal of the anaesthetist during the intraoperative period is to provide safe and optimal care for critically
ill septic patients so that they may benefit maximally from
the surgical or radiological source control procedure. The
majority of surgical source control procedures are optimally
carried out in the operating theatre under general anaesthesia.

Before induction
Many source control procedures are done out of hours, so it is
important that the anaesthetist has appropriate help available in the operating theatre. Some thought should be
given early to whether the patient may require ICU management after operation. Awareness of the microbiological
samples sent for culture, the anti-microbial agents which
were started, and timing of the next scheduled dose is
important to optimize type and timing of intraoperative

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antimicrobial therapy.28 Therapeutic concentrations of effective antimicrobial agents should be maintained throughout
the perioperative period as the procedure itself may cause
further bacteraemia and clinical deterioration. Invasive
haemodynamic monitoring is likely to be indicated in
addition to standard intraoperative monitoring. Serial
measurements of arterial blood gases and lactate concentration should be readily available from near-patient testing
equipment. If large volume loss is anticipated during the surgical procedure, it is worth considering placement of an
appropriate volume resuscitation intravascular device.

Induction of anaesthesia and initiation of

mechanical ventilation
Patients undergoing source control procedures are in an
inherently unstable cardiovascular state due to the combined effects of sepsis, anaesthesia, intravascular volume
loss, bleeding, and surgical stress. De-nitrogenation of the
lungs, breathing 100% O2 through a tightly fitted facemask
for up to 3 min, may be considered before induction of
anaesthesia. Because many surgical procedures on severely
septic patients occur on an emergency basis, a modified
rapid sequence induction, perhaps using rocuronium rather
than succinylcholine to facilitate tracheal intubation, may
be required. Options for the induction technique are many,
including ketamine, etomidate, and slow administration of
more commonly used agents such as propofol. Most i.v. or
inhalation anaesthetic agents cause vasodilation or impaired
ventricular contractility. Induction of anaesthesia is ideally a
deliberate step-wise process, using small doses of i.v. anaesthetic agents, titrated to clinical response. The choice of
induction agent or narcotic is less important than the care
with which they are administered. Ketamine or midazolam
may provide a degree of haemodynamic stability and shortacting opioids such as fentanyl or alfentanil will enable a
reduction in the dose of anaesthetic induction agent. With
the exception of remifentanil, the effects and duration of
action of i.v. opioids may be increased by impaired hepatic
and renal perfusion. Remifentanil infusion, either as a
primary agent or as a background adjunct to another induction drug, has much to recommend it in the setting of induction of anaesthesia in the septic, unstable patient. Although
it can cause bradycardia, many of these patients are tachycardic, and its effects on myocardial contractility are
minimal. Further, remifentanil avoids sudden reductions in
systemic vascular resistance.29 Placement of a cuffed tracheal tube is facilitated by the use of neuromuscular blocking
agents (preferably non-histamine releasing agents).
Continued volume resuscitation and incremental doses of
vasopressors are helpful to counteract the hypotensive effect
of anaesthetic agents and positive pressure mechanical ventilation. Options for the use of vasopressors include ephedrine, phenylephrine, and metaraminol, but there is no
evidence base to support the use of any of these in preference to another. Norepinephrine infusion may be used for
a more prolonged effect.10 18 The goal of mechanically

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Source control measures include drainage or debridement

procedures and definitive correction of anatomical abnormalities leading to ongoing contamination of previously
sterile tissue. Drainage procedures apply to wellcircumscribed infections that can be drained either percutaneously under image-guidance or by an open surgical
approach. Debridement refers to the physical removal of
non-viable solid tissue usually by an open surgical approach.
Definitive surgical interventions are indicated to correct anatomical abnormalities and prevent further contamination.
A surgeon with experience in dealing with complex infections in critically ill patients is best placed to be involved in
the decision-making process regarding a particular source
control procedure.25 The immediate goal is to achieve adequate control of the source of infection with the least physiological embarrassment. Source control intervention may
cause further complications such as bleeding, fistulas, or
inadvertent organ injury. The optimal timing of any surgical
intervention depends on the diagnosis and the clinical
course of the patient. In some patients, immediate surgery
or within 1 2 h of presentation (e.g. upper airway infections
leading to airway compromise, necrotizing fasciitis) is lifesaving.25 26 There are also a number of commonly occurring
severe infections (intra-abdominal abscess, infections associated with intravascular or prosthetic device, infective endocarditis with structural heart damage leading to
cardiogenic shock) which may require urgent surgical intervention. The exception to this rule is peripancreatic necrosis
associated with acute pancreatitis, where percutaneous drainage and full supportive therapy facilitate delayed surgical
intervention, which is associated with improved outcome.27
Clear and timely communication between the anaesthetist, surgeon, microbiologist-infectious disease physician,
and radiologist is essential for rapid implementation of an
effective treatment plan, which can be discussed with the
patient and their family. It is vital that the anaesthetist
assumes a central role in the multidisciplinary team.

Eissa et al.

Anaesthetic management of patients with severe sepsis

ventilating patients with severe sepsis is to use sufficiently

high fractional inspired oxygen concentration (F IO2 ) to maintain adequate oxygenation (PaO2 .12 kPa). There is now
strong evidence supporting a low tidal volume ventilatory
strategy, to minimize the impact of positive pressure ventilation on the lung tissue itself, and also on venous return
and cardiac output.30 Shear forces caused by high tidal
volumes or high inspiratory pressures will exacerbate lung
injury. Therefore, where oxygenation is adequate, the
concept of permissive hypercapnia has arisen, where low
alveolar minute ventilation to minimize ventilatory lung
damage inevitably results in a degree of hypercapnia (typically PaCO2 .89 kPa), which is tolerated and appears relatively safe in the short term (i.e. more than 34 days).31

Maintenance of anaesthesia

mixed-venous O2 saturation). Throughout the surgical procedure, cardiovascular parameters (heart rate, cardiac
filling pressures, inotropic state, systemic arterial pressure)
can be adjusted to optimize tissue oxygen delivery rather
than to achieve set values of cardiac output or arterial
pressure. The adequacy of global oxygen delivery may be
assessed by serum lactate ,2 mmol litre21 and mixedvenous O2 saturation .70%.
Oxygenation may be impaired by non-cardiogenic pulmonary oedema, which is caused by the increased capillary
permeability in sepsis. Management options for hypoxaemia
during maintenance of anaesthesia include increasing the
inspired oxygen concentration and incrementally increasing
PEEP. The inspired oxygen concentration can be increased
until SaO2 is at least 90% and the use of PEEP may be considered during the surgical procedure. The PEEP may be cautiously increased in haemodynamically stable patients if
there is still hypoxia despite increasing the FIO2 . Hypercarbia
should be avoided specifically in patients with raised intracranial pressure, compensated metabolic acidosis, or the
later stages of pregnancy. In all other circumstances, hypercarbia may be well tolerated and there is some evidence that
permissive hypercapnia may have inherent protective
effects.31 35
Protective lung strategies are advisable for mechanical
ventilation of the lungs. The difference between the pressure
inside and outside the alveolar air space at end-inspiration is
the transpulmonary pressure. Plateau airway pressure,
measured during volume-control mechanical ventilation
when an end-inspiratory pause has been applied, is an indicator of the maximal pressure applied inside the alveolar sac.
The pressure outside the alveolar sac cannot be measured
directly but is estimated clinically by assessing changes in
pleural pressure. Extra-alveolar or pleural pressure can be
abruptly increased by placing the patient in the Trendelenberg position or by the increased intra-abdominal pressure
associated with inflation of a pneumoperitoneum for laparoscopic surgery. Pulmonary gas exchange may deteriorate if
pleural pressure is increased and plateau pressure remains
constant (i.e. a reduction in transpulmonary pressure). On
the other hand, high transpulmonary pressures are associated with lung injury. In patients with early acute lung
injury, the ventilatory strategy should aim to strike an expedient balance between significant reduction in transpulmonary airway pressure (e.g. ,2025 cm H2O, with associated
reduction in alveolar ventilation), and excessive transpulmonary pressures (e.g. .2530 cm H2O, and the associated
risk of barotraumas).30 35 36 Recruitment of collapsed alveoli
by manually ventilating the patient to a peak airway pressure
of 3040 mm Hg for short periods may reduce shunt and
improve intraoperative oxygenation. Caution is advisable in
undertaking this manoeuvre in patients at risk of pneumothorax, such as patients with emphysematous bullae or
severe chronic obstructive pulmonary disease. During the
surgical procedure, regular near-patient testing of arterial
blood gases, full blood count, coagulation screen, electrolytes, lactate, and glucose concentration is advisable. Every

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There is no evidence to suggest an outcome benefit when

anaesthesia is maintained by the inhalation or i.v. route.
Options for maintaining anaesthesia include inhalation
agents, i.v. agents, and opioids, for example, remifentanil
infusion using 0.25 0.5 mg kg21 min21. The anaesthetist
should choose the technique which they believe best fits
with their assessment of the individual patients risk factors
and co-morbidities, and their own experience and expertise.
The MAC of inhalation anaesthetic agents is reduced in
severe sepsis.32 In patients with significant lung dysfunction,
maintenance of stable concentrations of anaesthetic agents
in the brain may be more reliably achieved when using i.v.
rather than inhalation agents. Whatever technique is used,
the depth of anaesthesia achieved can be estimated using
bispectral index monitoring. During surgery, the haemodynamic state may be further complicated by blood loss or
systemic release of bacteria or endotoxins. Transfusion of
blood products should proceed without delay if the surgical
procedure is complicated by excessive blood loss.
Intravascular volume resuscitation should continue as
indicated throughout the surgical procedure. Although a
CVP of 812 cm H2O is a commonly used haemodynamic
goal in the initial resuscitation of septic patients, intraoperative CVP values may be increased by raised intra-thoracic and
intra-abdominal pressure. Changes in dynamic markers
(pulse pressure variation, stroke volume variation) have
been shown to predict volume responsiveness more accurately than pressure-based estimates (CVP or pulmonary
artery occlusion pressure). Changes in dynamic markers of
volume responsiveness can be used intraoperatively to
guide i.v. volume therapy, especially in patients with
regular sinus heart rhythm and whose lungs are ventilated
by controlled mechanical ventilation. Concurrent transoesophageal echocardiography or oesophageal Doppler may be
used to define changes in stroke volume variation.33 34
There are many devices available to monitor changes in
cardiac output either continuously (pulmonary artery catheter, oesophageal Doppler, impedance plethysmography) or
at discrete time intervals (trans-thoracic or transoesophageal echocardiography, or serial measurement of

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effort should be implemented to avoid intraoperative
hypothermia as it is associated with impaired platelet and
coagulation factor dysfunction.37

Role of regional anaesthesia and nerve blocks in

anaesthesia for septic patients

End of surgical procedure

At the conclusion of the surgical procedure, administration of
further neuromuscular blocking agents to facilitate surgical
closure of the abdomen or thorax may be considered. The
rate of blood loss should be minimal before leaving the operating theatre. Supplemental doses of antimicrobial agents
may be considered. In patients who will require further
surgery and in all severely ill patients, analgesia, sedation,
and mechanical ventilation are maintained at the conclusion
of the surgery. Safe transfer of the patient to the ICU is
essential. A focused hand-over report is helpful for the ICU
colleagues which highlights the clinical presentation,
response to resuscitation measures, antimicrobial agents
used, details of the surgical procedure preformed, blood products used intraoperatively, and any specific problems that
should be anticipated in the postoperative period.

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Postoperative management of patients

with severe sepsis
It is important to note that pre-resuscitation measurements
should be used to calculate the Intensive Care admission
APACHE score and not those that have improved after resuscitation and the surgical procedure. Ongoing infusions of
vasopressor medication should be adjusted to match the
present intravascular volume and the new mechanical ventilator settings. Having secured the patients airway, mechanical ventilation settings can be decided, with the
objective of minimizing ventilation-induced volutrauma
and barotraumas to the lungs. This is most likely to be
achieved using low-pressure settings, a high fractional
inspired oxygen concentration (F IO2 ), and suitably
set alarm limits. Low tidal volumes (up to 6 ml kg21 of the
predicted body weight) and permissive hypercapnia may
be considered, provided that arterial pH does not decrease
below 7.20.36 Pressure-controlled or volume-control mode
of mechanical ventilation can be used. When an endinspiratory pause is included in the respiratory cycle in the
volume-control mode, the achieved transpulmonary
pressure (plateau pressure pleural pressure) should be
limited to 25 30 cm H2O to minimize lung parenchymal
ventilatory damage.41 The use of high PEEP (10 15 cm
H2O) may be limited by the degree of associated haemodynamic instability. The F IO2 can be decreased (i.e. ,60%)
to achieve an SpO2 of 93 95%.35 36 41
It is obviously important that antimicrobial therapy, which
was started before operation, should be continued in the ICU
and the time of the next scheduled dose was noted. Antimicrobial regimens can be reassessed daily in light of microbiological results, and adjusted to ensure efficacy, prevent
resistance, and to avoid toxicity.
Duration of therapy should be limited to 710 days.14 28 It
has been shown that patients who had a restrictive red blood
cell transfusion strategy (transfusion avoided unless Hb ,7 g
dl21) had a significantly lower mortality rate (22% vs 28%)
than those who were transfused at higher Hb levels, with
the possible exception of patients with acute myocardial
infarction and unstable angina.42 Fresh-frozen plasma may
be used to correct laboratory clotting abnormalities only if
there is clinical bleeding or an invasive procedure is
planned.20 Platelets are transfused if counts are 5000
mm23 regardless of bleeding, or if between 5000 and
30 000 mm23 with significant bleeding risk.20 Deep venous
thrombosis thromboprophylaxis should usually be considered
when concerns about coagulopathy have abated. Recombinant human activated protein C (rhAPC) may be considered
in adult patients with sepsis-induced organ dysfunction
with clinical assessment of high risk of death (typically
APACHE score .25 or multiple organ failure) if there are no
contraindications to rhAPC. Adult patients with severe
sepsis and low risk of death (typically, APACHE II ,20 or
one organ failure) should not receive rhAPC.43 44
Continuation of adequate glycaemic control (,8.5 mmol
litre21) is important in the control of the septic process. In

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Peripheral nerve block may be effective at minimizing the

sympathetic response to a painful stimulus, while avoiding
the systemic effects of opioid and may be used if an individual assessment of the risk benefit balance suggests that it
may be justified in their particular circumstances. However,
the presence of coagulopathy, local or systemic spread of
infection, and the fact that local anaesthetics may not
work properly in the presence of infection or acidosis may
limit the application of regional techniques in septic patients.
Neuraxial block (spinal and epidural anaesthesia) should be
undertaken with caution, since the haemodynamic effects
of these techniques in the setting of sepsis-induced cardiovascular compromise may be difficult to reverse.38 39
Recent blood tests confirming normal coagulation are
essential.
More than 700 000 central neuraxial blocks are conducted
annually in the UK. The incidence of permanent injury from
CNB was 4.2 (95% CI 2.96.1) per 100 000 and that of paraplegia or death was 1.8 (95% CI 1.0 3.1) per 100 000 cases.
Of the 52 cases which were the focus of follow-up for permanent injury from CNB, 22 made a complete recovery from
their serious complication within the follow-up period.40 48
Therefore, while epidural anaesthesia appears to have a
very low risk of permanent neurological sequelae overall,
severely septic patients may be at increased risk of this and
other serious complications. Although there is no evidence
that placement of an epidural catheter in severely septic
patients increases the risk of epidural abscess or haematoma
formation, a substantial proportion of clinical opinion would
seem to believe that the risks associated with using it in
the context of severe sepsis is not justifiable.

Eissa et al.

BJA

Anaesthetic management of patients with severe sepsis

Acute renal failure occurs in 23% of patients with severe

sepsis. Renal replacement therapy may be initiated to
correct acidosis, hyperkalaemia, or fluid overload and may
be continued until acute tubular necrosis has recovered.
Sodium bicarbonate is not recommended for correcting
acidosis unless pH ,7.1. Continuous veno-venous haemodiafiltration does not confer any survival benefit when compared with intermittent haemodialysis, the observed
mortality being 67% for intermittent haemodialysis vs 65%
for continuous haemodiafiltration, with an RR of 1.03 (95%
CI 0.94 1.14), P0.54.46 However, continuous renal replacement may be more practical in hemodynamic unstable
patients. A study comparing daily with alternate-day haemodialysis found that daily haemodialysis resulted in better
control of uraemia, fewer hypotensive episodes during haemodialysis, and more rapid resolution of acute renal failure
[mean (SD), 9 (2) vs 16 (6) days; P0.001] than did conventional intermittent haemodialysis on alternate days.47
Although the weight of current evidence suggests that
higher doses of renal replacement may be associated with
improved outcomes, these results may not apply specifically
to patients with severe sepsis.
Analgesia and sedative medication is continued by infusion, but excessive use of sedation or neuromuscular blocking agents is not recommended. Finally where applicable, it
is wise to raise the subject of advanced care planning with
the patient and his family, and realistic expectations and
outcomes targeted.
In conclusion, severe sepsis is a major healthcare issue,
with a persistently high mortality. Patients with severe
sepsis syndrome often require surgery for source of infection
control. The anaesthetist has a crucially important role in
coordinating and delivering resuscitation and therapeutic
strategies to optimize patient survival outcome. Early i.v.
administration of effective antimicrobial therapy is essential.
Preoperative resuscitation, aimed at optimizing major organ
perfusion, is based on judicious use of fluids, vasopressors,
and inotropes. Intraoperative management requires careful
induction of anaesthesia, using lowest effective doses of a
range of agents. Maintenance of anaesthesia is challenging,
requiring achievement of optimal volume status, avoidance
of lung injury during mechanical ventilation, and ongoing
monitoring of arterial blood gases, haematological and
renal indices, and electrolyte levels. Postoperative care overlaps with ongoing management of the severe sepsis syndrome patient in the ICU. The care of critically ill septic
patients requiring anaesthesia and surgery will be further
enhanced by testing promising therapeutic strategies, e.g.
use of levosimendan for intraoperative inotropic support, in
well-designed clinical trials.

Conflict of interest
D.J.B. is a member of the Editorial Board of BJA.

Funding
D.J.B.s time was supported by The Sisk Foundation.

741

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a large, international, randomized trial of ICU patients, there

was no significant difference between strict glycaemic
control (blood glucose 46 mmol litre21) and more liberal
glycaemic control (blood glucose 610 mmol litre21) in the
rate of death or the mean organ failure score. However,
the rate of severe hypoglycaemia (glucose level 2.2 mmol
litre21) was higher in the intensive-therapy group than in
the conventional-therapy group (17% vs 4%, P,0.001), as
was the rate of serious adverse events (11% vs 5%,
P0.01). Therefore, in severely septic patients, blood
glucose should be maintained in the range 610 mmol
litre21.7
Nutrition is one of the cornerstones of management in
critically ill septic patients. Enteral nutrition via a nasogastric
tube is the best choice to maintain enterocyte integrity and
nourish the patient. Gastrointestinal protective measures
(stress ulcer prophylaxis) and antiemetic drugs are also
prescribed. Total parenteral nutrition (TPN) should be considered if there is a surgical contraindication to enteral
nutrition or if nutritional requirements are not fully met by
enteral nutrition alone. Patients may become rapidly
hypoglycaemic if TPN or enteral nutrition is stopped during
the perioperative period.44
I.V. hydrocortisone may be considered when hypotension
responds poorly to fluid resuscitation and vasopressors. A 7
day trial treatment with low doses of hydrocortisone and fludrocortisone significantly reduced the risk of death in
patients with septic shock and relative adrenal insufficiency
without increasing adverse events (P,0.05).30 In this study,
there were 81 deaths (70%) in the placebo group and 66
deaths (58%) in the corticosteroid group at the end of ICU
stay [relative risk (RR) 0.82; 95% CI 0.68 1.00; adjusted
odds ratio (OR) 0.50; 95% CI 0.28 0.89; P0.02]. Although
this study was conducted in the ICU setting, it seems
prudent to extrapolate the finding to appropriately selected
patients in the perioperative period.45
Hydrocortisone in a dose of 200 mg per day in four divided
doses or as a continuous infusion in a dose of 240 mg per day
(10 mg h21) for 7 days is recommended for septic shock in
the ICU setting.10 45 Whether administration of low-dose
steroids during intraoperative management of the septic
patient would improve haemodynamic stability or outcome
is unknown and seems unlikely. The role of glucocorticoids
in the management of patients with severe sepsis requires
further investigation. In a multicentre, randomized, blinded,
controlled trial of patients with septic shock who were
treated with corticosteroids, there was significantly
decreased mortality in patients who received vasopressin
compared with norepinephrine (36% vs 45%, respectively,
P0.03). In contrast, in septic patients who did not receive
corticosteroids, vasopressin use was associated with
increased mortality compared with norepinephrine (34% vs
21%, respectively, P0.05).10 There appears to be a benefit
to the use of low-dose glucocorticoids (e.g. hydrocortisone
50 mg, four times daily, where normovolaemic septic
patients seem refractory to vasopressor therapy to maintain
major organ perfusion and haemodynamic stability).

BJA
References

742

15 Finfer S, Bellomo R, Boyce N, et al. The SAFE study: a comparison

of albumin and saline for fluid resuscitation in the intensive care
unit. N Engl J Med 2004; 350: 2247 56
16 Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented hemodynamic therapy in critically ill patients. N Engl J Med 1995; 333:
1025 32
17 Rivers E, Nguyen B, Havstad S, et al. Early Goal-Directed Therapy
Collaborative Group. Early goal-directed therapy in the treatment of
severe sepsis and septic shock. N Engl J Med 2001; 345: 136877
18 LeDoux D, Astiz ME, Carpati CM, et al. Effects of perfusion pressure
on tissue perfusion in septic shock. Crit Care Med 2000; 28:
2729 32
19 Djillali A, Vigno P, Renault A, et al. for the CATS Study Group.
Norepinephrine plus dobutamine versus epinephrine alone for
management of septic shock: a randomized trial. Lancet 2007;
370: 67684
20 American Society of Anaesthesiologists: Task Force on Blood
Component Therapy: practice guidelines for blood component
therapy. Anesthesiology 1996; 84: 732 47
21 Fernandes CJ, Akamine N, DeMarco FVC, et al. Red blood cell
transfusion does not increase oxygen consumption in critically
ill septic patients. Crit Care 2001; 5: 3627
22 Hunter JD, Doddi M. Sepsis and the heart. Br J Anaesth 2010; 104:
311
23 Morelli A, De CS, Teboul JL, et al. Effects of levosimendan on systemic and regional haemodynamics in septic myocardial
depression. Intensive Care Med 2005; 31: 638 44
24 Hayes MA, Timmins AC, Yau EHS, et al. Elevation of systemic
oxygen delivery in the treatment of critically ill patients. N Engl
J Med 1994; 330: 1717 22
25 Marshall JC, Al Naqbi A. Principles of source control in the management of sepsis. Crit Care Clin 2009; 25: 753 68, viiiix
26 Natanson C, Shelhamer JH, Parrillo JE. Intubation of the trachea
in the critical care setting. J Am Med Assoc 1985; 253: 1160 5
27 Mier J, Leon EL, Castillo A, Robledo F, Blanco R. Early versus late
necrosectomy in severe necrotizing pancreatitis. Am J Surg
1997; 173: 71 5
28 Kumar A. Optimizing antimicrobial therapy in sepsis and septic
shock. Crit Care Clin 2009; 25: 73351, viii
29 Kollef MH, Levy NT, Ahrens TS, et al. The use of continuous IV
sedation is associated with prolongation of mechanical ventilation. Chest 1998; 114: 5418
30 The Acute Respiratory Distress 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; 342: 13018
31 Laffey JG, OCroinin D, McLoughlin P, Kavanagh BP. Permissive
hypercapniarole in protective lung ventilatory strategies. Intensive Care Med 2004; 30: 34756
32 Allaouchiche B, Duflo F, Tournadre JP, Debon R, Chassard D. Influence of sepsis on sevoflurane minimum alveolar concentration in
a porcine model. Br J Anaesth 2001; 86: 832 6
33 Biais M, Nouette-Gaulain K, Cottenceau V, Revel P, Sztark F.
Uncalibrated pulse contour-derived stroke volume variation
predicts fluid responsiveness in mechanically ventilated patients
undergoing liver transplantation. Br J Anaesth 2008; 101: 761 8
34 Derichard A, Robin E, Tavernier B, et al. Automated pulse pressure
and stroke volume variations from radial artery: evaluation
during major abdominal surgery. Br J Anaesth 2009; 103: 678 84
35 Grasso S, Stripoli T, De Michele M, et al. ARDSnet ventilatory protocol and alveolar hyperinflation: role of positive end-expiratory
pressure. Am J Respir Crit Care Med 2007; 176: 7617

Downloaded from bja.oxfordjournals.org by guest on November 18, 2010

1 Dombrovskiy VY, Martin AA, Sunderram J, Paz HL. Rapid increase

in hospitalization and mortality rates for severe sepsis in the
United States: a trend analysis from 1993 to 2003. Crit Care
Med 2007; 35: 1414 5
2 Harrison DA, Welch CA, Eddleston JM. The epidemiology of severe
sepsis in England, Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high quality clinical database, the ICNARC
Case Mix Programme Database. Crit Care 2006; 10: R42
3 Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ
failure and guidelines for the use of innovative therapies in sepsis.
The ACCP/SCCM Consensus Conference Committee. American
College of Chest Physicians/Society of Critical Care Medicine.
Chest 1992; 101: 1644 55
4 Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/
SIS International Sepsis Definitions Conference. SCCM/ESICM/
ACCP/ATS/SIS. Crit Care Med 2003; 31: 1250 6
5 Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of
sepsis in the United States from 1979 through 2000. N Engl J
Med 2003; 348: 1546 54
6 Brun-Buisson C, Doyon F, Carlet J, et al. Incidence, risk factors,
and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group
for Severe Sepsis. J Am Med Assoc 1995; 274: 96874
7 Brunkhorst FM, Engel C, Bloos F, et al. German Competence
Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358:
125 39
8 Levi M, van der Poll T. Inflammation and coagulation. Crit Care
Med 2010; 38(2 Suppl): S26 34
9 Kern JW, Shoemaker WC. Meta-analysis of hemodynamic
optimization in high-risk patients. Crit Care Med 2002; 30:
1686 92
10 Russell JA, Walley KR, Gordon AC, et al. Dieter Ayers for the Vasopressin and Septic Shock Trial Investigators. Interaction of vasopressin infusion, corticosteroid treatment, and mortality of
septic shock. Crit Care Med 2009; 37: 8118
11 Dellinger RP, Levy MM, Carlet JM, et al. International Surviving
Sepsis Campaign Guidelines Committee; American Association
of Critical-Care Nurses; American College of Chest Physicians;
American College of Emergency Physicians; Canadian Critical
Care Society; European Society of Clinical Microbiology and Infectious Diseases; European Society of Intensive Care Medicine;
European Respiratory Society; International Sepsis Forum; Japanese Association for Acute Medicine; Japanese Society of Intensive Care Medicine; Society of Critical Care Medicine; Society of
Hospital Medicine; Surgical Infection Society; World Federation
of Societies of Intensive and Critical Care Medicine. Surviving
Sepsis Campaign: international guidelines for management of
severe sepsis and septic shock: 2008. Crit Care Med 2008; 36:
296 327. Erratum in: Crit Care Med 2008; 36: 1394 6
12 Ferrer R, Artigas A, Levy MM, et al. Edusepsis Study Group.
Improvement in process of care and outcome after a multicenter
severe sepsis educational program in Spain. J Am Med Assoc
2008; 299: 2294 303
13 Levy MM, Dellinger RP, Townsend SR, et al. Surviving Sepsis Campaign. The Surviving Sepsis Campaign: results of an international
guideline-based performance improvement program targeting
severe sepsis. Crit Care Med 2010; 38: 6834
14 Handelsman J, Maki DG. Does combination antimicrobial therapy
reduce mortality in Gram-negative bacteraemia? A meta-analysis. Lancet Infect Dis 2004; 4: 51927

Eissa et al.

Anaesthetic management of patients with severe sepsis

44 Laterre PF, Levy H, Clermont G, et al. Hospital mortality and

resource use in subgroups of the Recombinant Human Activated
Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial.
Crit Care Med 2004; 32: 220718
45 Annane D, Sebille V, Charpentier C, et al. Effect of treatment
with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. J Am Med Assoc 2002; 288:
862 71
46 Schiffl H, Lang SM, Fischer R. Daily hemodialysis and the outcome
of acute renal failure. N Engl J Med 2002; 346: 30510
47 Tonelli M, Manns B, Feller-Kopman D. Acute renal failure in the
intensive care unit: a systematic review of the impact of dialytic
modality on mortality and renal recovery. Am J Kidney Dis 2002;
40: 87585
48 Cook TM, Counsell D, Wildsmith JA. Major complications of
central neuraxial block: report on the Third National Audit
Project of the Royal College of Anaesthetists. Royal College of
Anaesthetists Third National Audit Project. Br J Anaesth 2009;
102: 17990

Downloaded from bja.oxfordjournals.org by guest on November 18, 2010

36 Hager DN, Krishnan JA, Hayden DL, et al. Tidal volume reduction
in patients with acute lung injury when plateau pressures are not
high. Am J Respir Crit Care Med 2005; 172: 12415
37 Insler SR, Sessler DI. Perioperative thermoregulation and temperature monitoring. Anesthesiol Clin 2006; 24: 823 37
38 Guay J. Benefits of adding epidural analgesia to general anesthesia: a meta-analysis. Br J Anaesth 2006; 20: 33540
39 Schuz-Stubner S, Pottinger JM, Coffin SA, Herwaldt LA, et al.
Nosocomial infections and infection control in regional anaesthesia. Acta Anaesthesiol Scand 2008; 52: 114457
40 Buggy DJ. Central neuraxial block: defining risk more clearly. Br J
Anaesth 2009; 102: 1513
41 Ferguson ND, Frutos-Vivar F, Esteban A, et al. Airway pressures,
tidal volumes, and mortality in patients with acute respiratory
distress syndrome. Crit Care Med 2005; 33: 21 30
42 Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical
care. N Engl J Med 1999; 340: 40917
43 Farimani MR, Bajestani NN. Comparison of early enteral feeding
versus parenteral nutrition after resection of esophageal
cancer. J Crit Care 2008; 23: 4489

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