SEPSIS
Sepsis
Whats new ?
Recent studies suggest that, in some patients with
sepsis, physiological doses of corticosteroids may be
valuable
Jonathan Cohen
Strict glycaemic control reduces mortality in some
patients with sepsis, even if they do not have diabetes
Definition
In selected patients, drotrecogin alfa (activated)
significantly reduces mortality
Sepsis is the systemic response to infection. Clinical features
include haemodynamic instability, mental confusion and tachypnoea. Terms used in the past to describe this syndrome are
septicaemia and bacteraemia. Only about 20% of cases of shock
are associated with bacteraemia; the remainder are secondary to
infection at other sites, most often the lower respiratory tract or
the abdomen.
The term systemic inflammatory response syndrome is used
to describe the early response to injury, which may be infective
or non-infective.
The term multi-organ dysfunction syndrome is used for more
severe infections.
Bacteraemia is the presence of bacteria in the bloodstream. The
incidence is about 7/1000 hospital admissions but is increasing,
largely as a result of hospital-acquired infections. Gram-negative
bacteria account for about 60% of cases and Gram-positive organisms for 40%; in some settings (e.g. ICUs) yeasts such as Candida
make a small but significant contribution.
Septic shock is the most severe form of sepsis syndrome and
is associated with marked hypotension and organ failure. It is
best viewed as a state of profound tissue hypoperfusion. Shock
complicates about 20% of cases of bacteraemia and increases the
mortality to 60% or more.
Bacterial cell walls stimulate macrophages and other cells of
the immune system to produce cytokines such as tumour necrosis
factor (TNF) and interleukin-1, which are important mediators of
the pathophysiological changes in septic shock and also lead to
activation of neutrophils. Activated neutrophils adhere to each
other and to the vascular endothelium, and probably contribute
to vascular and tissue injury. Among the many other mediators
activated are the coagulation cascade and vascular mediators such
as complement, the arachidonic acid pathway and nitric oxide.
Clinical features and diagnosis
The typical features of septic shock are:
altered mental status
fever (or hypothermia)
profound and/or prolonged hypotension
acidosis
tachypnoea
hypoxia.
Septic shock may be associated with acute respiratory distress
syndrome, disseminated intravascular coagulation and acute renal
failure, and diagnosis may not be straightforward (Figure 2).
The following bacteria are associated with a particularly fulminating course:
Neisseria meningitidis (WaterhouseFriderichsen syndrome of
intra-adrenal haemorrhage with meningococcal septicaemia)
Staph. aureus (toxic shock syndrome, usually without bacteraemia)
Strep. pyogenes (necrotizing fasciitis and/or streptococcal shock
syndrome)
Strep. pneumoniae (in splenectomized patients).
Aetiology
The most common Gram-negative bacteria associated with sepsis
and septic shock are Escherichia coli, Klebsiella and Pseudomonas
aeruginosa; the most common Gram-positive organisms are Staphylococcus aureus, Staph. epidermidis, Streptococcus pneumoniae
and enterococci. The epidemiology of infection, and antibiotic
susceptibility patterns, can vary markedly between countries. The
fact that shock can be caused by both Gram-positive and Gramnegative bacteria, in addition to fungi and other micro-organisms,
is important when considering empirical therapy.
Management
Pathogenesis
Immediate resuscitation: the initial treatment priority is control
of life-threatening abnormalities, the so-called ABC (airway,
breathing, circulation).
Oxygen first, secure the airway, particularly in patients with
depressed consciousness. Adequate oxygenation is essential. This
is not simply a matter of achieving a satisfactory arterial oxygen
tension; the aim is to ensure that tissue oxygenation is appropriate.
In septic shock, the patient is typically tachypnoeic, and hypoxaemia does not respond to inspired oxygen alone. Mechanical
ventilation is usually required.
Correction of acidosis the acidosis that commonly accompanies septic shock usually resolves (or at least improves substantially) relatively quickly when treatment for the underlying disease
The pathogenesis of sepsis is summarized in Figure 1.
In Gram-negative sepsis, the prime initiator is a lipopolysaccharide (LPS) bacterial cell wall component (i.e. an endotoxin).
Gram-positive bacteria do not have LPS in their cell wall, but
peptidoglycan and lipoteichoic acids can have similar effects. In
addition, some Gram-positive bacteria produce exotoxins (e.g.
staphylococcal toxic shock toxin).
Jonathan Cohen is Professor of Infectious Diseases and Dean at Brighton
and Sussex Medical School, Brighton, UK. Conflict of interests: none
declared.
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2005 The Medicine Publishing Company Ltd
SEPSIS
Pathogenesis of septic shock
Lipopolysaccharide and
other bacterial molecules
Complement system
Chemotaxis
Superoxide radicals
Lysosomal enzymes
Capillary leak
Neutrophil accumulation
Neutrophils
Adhesion molecules
Monocytic cells
Fever
Metabolic changes
Hormonal changes
Cytokines
Lipid mediators
Vasodilatation
Endothelial cells
Factor XII
Tissue factor
Coagulation system
Fibrinolysis
Bradykinin
Disseminated intravascular
coagulation
Sepsis syndrome
Hypotension
Adult respiratory
distress syndrome
Multiple organ failure
Death
Vasopressors and inotropes after volume resuscitation, drugs
such as dopamine are often used to sustain blood pressure and
reduce the complication risk. Dopamine, 220 g/kg/minute, can
be titrated against blood pressure. If the patient remains hypotensive, noradrenaline is added, typically at 0.010.5 g/kg/minute.
It is important to note that these drugs do not cure septic shock;
at most, they provide support during a critical period.
is instituted. Sodium bicarbonate is probably not helpful except
in very severe acidosis.
Fluid replacement is used with the aim of optimizing cardiac
output without increasing the risk of pulmonary oedema. Opinion
is divided on whether a crystalloid or a colloid should be used.
Bolus doses of 250500 ml are given, with careful monitoring to
ensure that there is no increase in pulmonary capillary pressure
leading to hypoxaemia. Packed RBCs are indicated only when
haemoglobin is less than 8 g/dl.
Important haemodynamic changes in septic shock
Pitfalls in the diagnosis of septic shock
None of the typical features is essential for diagnosis, and it is
uncommon for all to be present simultaneously, particularly in
the early stages
In certain groups (e.g. the very young, the elderly,
the immunosuppressed), the clinical changes may be subtle
Shock may present as a collapse or cardiac arrest
There are no consistent or reliable differences distinguishing
Gram-positive from Gram-negative infections, though
there may be clues to suggest the microbial aetiology
(e.g. the characteristic purpura of meningococcaemia)
In shock1
Cardiac index
(litres/minute.m2)
2.83.6
Systemic vascular resistance
index (dyn.second1/cm5.m2)
17602600
Oxygen delivery
(ml/minute.m2)
520720
Oxygen consumption
(ml/minute.m2)
110140
Values are variable and may change rapidly
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Normal
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2005 The Medicine Publishing Company Ltd
SEPSIS
Examples of empirical antibiotic regimens for sepsis or septic shock
Site of origin
Community-acquired
Hospital-acquired
Skin and soft tissue
Penicillin plus flucloxacillin
Flucloxacillin plus gentamicin
Urinary tract
Ampicillin plus gentamicin, or cephalosporin,
or quinolone
Ampicillin plus gentamicin, or cephalosporin,
or quinolone
Pneumonia
Ampicillin plus erythromycin
Third-generation cephalosporin or quinolone
Biliary tract
Anti-Pseudomonas penicillin plus gentamicin
Anti-Pseudomonas penicillin plus gentamicin
Neutropenia
Anti-Pseudomonas penicillin plus gentamicin,
or ceftazidime
Anti-Pseudomonas penicillin plus gentamicin,
or ceftazidime
Unknown
Flucloxacillin plus gentamicin metronidazole
or
Tazobactam or quinolone, plus vancomycin or
linezolid
Tazobactam or imipenem or meropenem
plus
Vancomycin or linezolid (if indicated, see text)
identify patients who would benefit from this treatment remains
controversial.
Septic patients are at risk of developing stress-associated gastric ulceration. H2-blockers or sucralfate are used, particularly in
patients receiving mechanical ventilation.
There is considerable dysregulation of metabolic control in
sepsis, and strict glycaemic control has been shown to significantly
improve the outcome, even in patients who were not previously
known to be diabetic. Intensive insulin therapy and maintenance of
blood sugar levels at 80110 mg/dl reduced mortality, particularly
in patients with multiple-organ failure with a proven septic focus.3
Coagulation is disturbed in sepsis, and much evidence suggests
that occlusion of small blood vessels leading to inadequate tissue
perfusion is a major cause of organ failure. Protein C is a natural
anticoagulant that is consumed in septic patients, and a large randomized controlled trial has shown that replacement of protein C
(as drotrecogin alfa (activated)) significantly reduces mortality,
most notably in patients with moderate-to-severe disease.4
Invasive monitoring techniques can provide information
helpful in improving control of physiological variables (Figure 3),
but this does not mean that SwanGanz-type catheters should be
inserted in all patients, and this practice remains controversial.
Early goal-directed therapy has been shown to improve outcome
in certain groups of septic patients,1 but there is no single correct
regimen for supporting the critically ill; instead, they need constant
monitoring and fine-tuning of fluid, oxygen and vasopressor
therapy. A reasonable therapeutic aim is a mean arterial pressure
of 6065 mm Hg, a high-normal cardiac index and reversal of lactic
acidosis.
Empirical antimicrobial therapy blood cultures should be
obtained before starting antibiotic therapy. There is no advantage
to obtaining arterial blood cultures. Other specimens should be
obtained from any potential source of the sepsis. No single antibiotic regimen can be recommended for all patients. The probable
site of origin of the sepsis is often apparent, and knowledge of the
likely microbial flora can help in the choice of appropriate antibiotics. The constantly changing pattern of antimicrobial resistance
means that newer, broad-spectrum agents may have to be used
until culture results become available. This is particularly problematic in Gram-positive infections, in which methicillin-resistant
staphylococci, and penicillin-resistant Strep. pneumoniae, have led
to increasing use of vancomycin and linezolid. Other factors that
must be considered include:
the presence of neutropenia
previous antibiotic therapy
the underlying disease
prevailing patterns of antibiotic resistance
whether the infection was acquired in the community or in
hospital.
Examples of suitable regimens are listed in Figure 4; the recommendations may vary between patients.
Drainage of abscesses is essential as soon as the patient has
been resuscitated.
Adjunctive therapy high-dose corticosteroids are contraindicated in the treatment of septic shock, but recent studies have suggested that lower-dose physiological replacement of corticosteroids
(hydrocortisone, 100 mg 6-hourly, with or without fludrocortisone)
may be beneficial.2 The need for a Synacthen stimulation test to
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REFERENCES
1 Rivers E, Nguyen B, Havstad S et al. Early goal-directed therapy in the
treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:
136877.
2 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. JAMA 2002; 288: 86271.
3 Van den Berghe G, Wouters P, Weekers F et al. Intensive insulin
therapy in critically ill patients. N Engl J Med 2001; 345: 135967.
4 Bernard G R, Vincent J-L, Laterre P F et al. Efficacy and safety of
recombinant human activated protein C for severe sepsis. N Engl J
Med 2001; 344: 699709.
FURTHER READING
Cohen J. The immunopathogenesis of sepsis. Nature 2002; 420: 88591.
Dellinger R P, Carlet J M, Masur H et al. Surviving Sepsis Campaign
guidelines for management of severe sepsis and septic shock.
Intensive Care Med 2004; 30: 53655.
Hotchkiss R S, Karl I E. The pathophysiology and treatment of sepsis.
N Engl J Med 2003; 348: 13850.
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