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GM Clarke
Sepsis has traditionally implied infection accomp anied by systemic inflammatory
manifestations. However, the systemic changes are indistinguishable from those of non-
infective inflammatory conditions (e.g. pancreatitis, acute hepatic failure, immunol ogical
reactions and gross trauma including bums). Consequently, much confusion arose when
terms such as sepsis and septic syndrome were applied to these conditions.1 This led to a
consensus conference of the American College of Chest Physicians and Society of Critical
Care Medicine to define terms related to infection and the systemic response (Table 61.1; Fig.
61.l).2 Thus, sepsis is the systemic inflammatory respanse to infection. It is the comm onest
contributor to death in the ICU.3
Aetiology and epidemiology
Sepsis may be caused by Gram-negative and Gram- positive bacteria, fungi, Rickettsia,
viruses and spiro chaetes. In the ICU, common infective Gram- negative organisms include
Escherichia coli, Pseudomonas, Kiebsiella, Proteus, Enterobacter and Bacteroides; Gram-
positive organisms include stap hylococci, streptococci and Clostridium. Systemic infection
with fungi, especially Candida, is a risk in immunodeficient patients receiving broad-
spectrum antibiotics. The EPIC study reported that 17% of ICU patients had fungal and/or
protozoal infection.4
Nosocomial infection rates in ICU patients are 5—10 times higher than among general ward
patients. Organisms posing serious resistance problems in the rcu setting include methicillin-
resistant staphyloc occi, enterococci, certain Enterobacteriaceae, Pseud omonas aeruginosa,
P cepacia, Xanthomonas malt ophilia, Acinetobacter and Candida species.5
danv infcction acquircd in hc IC .irc iidogen ous and follow colonization of the alimentary
tract by organisms usually insignificant in healthy individu als (e.g. E. coli, Kiebsiella,
Proteus and Pseudomon as).6 Sepsis related to intravascular catheters is
commonly due to Staphylococcus epidermidjs, a normal skin commensal.
Pathogenesis
The host response, rather than the infecting organism, predominantly determines the severity
of an infect ion.7 Pathogenesis of the extremely complex syst emic inflammatory response
involves host defence mechanisms, products of infecting organisms (e.g. exotoxins and
endotoxins) and a multitude of mediat ors (Fig. 61.2).
Host defence mechanisms
Local organ defences
These may be impaired by critical illness or therap eutic interventions.
Respiratory system
Coughing may be impaired by pain, illness or drugs. The mucociliary escalator system may
be depressed by opioids, aspirin, inspired oxygen, inadequate humidification or endotracheal
suctioning. Laryngeal dysfunction, from neurological dysfunction, drugs or nasogastric or
endotracheal tubes, can lead to aspiration.
Alimentary tract
Gastrointestinal tract (GIT) mucosa and motility, secretion of mucus and immunoglobulin A,
and indigenous anaerobes resist gut colonization by aerobic bactena.6 GIT flora may rapidly
alter in the ICU patient. Following hospitalization, mouth flora changes from predominantly
anaerobic to Gramn egatis C organisms such ON E. to/i. Kiebsiella and Pseudomonas.
Staphylococcus aureus and Candida albicans may become part of the flora. The stomach,
which is normally sterile, becomes colonized with similar organisms if the gastric p1-I is
above 4.0 —
Table 61.1 Definitions of sepsis2
Infection
Microbial phenomenon characterized by an inflammatory response to the presence of
microorganisms or the invasion of normally sterile host tissue by those olganisms
Bacteraem,a
The presence of viable bacteria in the blood
Systemic inflamniarory response syndrome
The systemic inflammatory response to a vanety of severe clinical insults. The response is
manifested by two or more of the following conditions:
Temperature >38°C or <36°C
Heart rate >90 beats/mm
Respiratory rate >20 breaths/rain or Paco2 <4.3 kPa (<32 Torr)
White blood cell count >12000 cells/mm3, or> 10% immature (band) forms
Sepsis
The systemic response to infection. This systemic response is manifested by two or more of
the following conditions as a result of infection:
Temperature >38°C or <36°C
Heart rate >90 beats/mm
Respiratory rate >20 breaths/mm or Paco2 <4.3 kPa (<32 Torr)
White blood cell count >12 000 cells/mm3, or> 10% immature (band) forms
Severe sepsis -
Sepsis associated with organ dysfunction, hypoperfusjon or hypotension. Hypoperfusion and
perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria or an
acute alteration in mental status
Septic shock
Sepsis with hypotension, despite adequate fluid resuscitation, along with the presence of
perfusion abnormalities that may include, but are not limited 10, lactic acidosis, oliguria or
an acute alteration in menta] status. Patients who are on inotropic or vasopressor agents may
not be hypotensive at the time when perfusion abnormalities are measured
Hypotension
A systolic blood pressure of <90 mnilig or a reduction of>40 mmFlg from baseline in the
absence of other causes for hypotension
Multiple organ dysfunction syndrome
Presence of altered organ function in an acutely ill patient such that homeostasis cannot be
maintained without intervention.
Fig. 61.1 Interrelationship of systemic inflammatory response syndrome (SIRS), sepsis and
infection. From American College of Chest Physicians/Society of Critical Care Medicine,2
with permission.
526
61 Severe sepsis
Insult
I
macrophage/monocyte activation
I
Interleu kin-i
TN F
Others
+
Systemic inflammatory response
(if very severe)
Tissue damage Altered haemodynamics
Altered cellular metabolism NO1SVR
Impaired oxygen extraction
I
Multiple
organ
dysfunction syndrome
Fig. 61.2 Simplified scheme of events from insult to systemic inflammatory respons{ to
multiple organ
dysfunction syndrome. TNF = Tumour necrosis factor; NO = nitric oxide; SVR = systemic
vascular resistance.
likely if antacids or H2-blockers are prescribed. Antibiotics rapidly alter normal gut flora.
Overgrowth of Candida is common; overgrowth with Clostridium d/ficile in the large bowel,
though uncommon, may cause pseudomembranous colitis due to its toxins.
Eyes
Impaired blinking results in drying of cornea and conjunctiva. Loss of the irrigating and
antibacterial properties of tears predisposes to infection.
Genitourinary tract
The uredwal catheter is a common route of urinary tract infection, especially by perineal
faecal bacteria.
Skin
This may be breached by invasive catheters, all of which increase the risk of infection from
skin organisms.
General body defence mechanisms
Defects in immune competence are frequently seen in the critically ill (see Chapters 59 and
90). Some defects are set out below, but considerable overlap and interaction occur.
Reticuloendothelial system
Reticuloendothelial blockade results in defective phagocytic activity. This is partly related
to ]owered opsonh aLtivit3 i.e. promotion ol phagocytosis is decreased). Sepsis itself can
result in consumption of opsonic proteins, termed consumptive opsoninopathy. Apart from
diminished phagocytic activity, defects in polymorph chemotaxis and intracellular killing
may be present.
Cell-mediated immunity
Anergy (failure of delayed hypersensitivity), possibly reflecting defective T-helper cell
function, has proven to be a marker for altered host resistance, sepsis and mortality in
surgical patients.8 Age, cancer, sepsis, major trauma, malnutrition and increased T-supp
ressor cell activity have been implicated.8 The’ presence of a T-cell suppressive factor
(possibly a peptide) has been demonstrated in sera of trauma and cancer patients.9 Steroids,
immunosuppressive agents, halothane and antibiotics (e.g. tetracycline, chioramphenicol and
clindamycin) may Impair ccll ular immunity. Protein-calorie malnutrition may be associated
with anergy, diminished complement leve ls and impaired immunoglobulin synthesis.1°
Infections by well-encapsulated bacteria (e.g. stap hylococci and streptococci) are generally
handled by humoral defence mechanisms. Cell-mediated immun ity is important in infections
by poorly encapsulated Gram-negative organisms, such as Pseudomontis and intestinal
anaerobes — common causes of severe sepsis in the critically ill.
Humoral immunity
Defects in humoral immunity are seen in posts plenectomy patients)’ Immunoglobulin
(especially immunoglobulin M; 1gM) and complement defic iencies and diminished
properdin activity have been reported in these patients. The latter alternative complement
pathway factor is important, as pneumoc occi are more efficiently opsonized via the altern
ative pathway in the immunedeficient host. The asplenic patient is thus predisposed to
overwhelming bacterial sepsis, with pneumococci, Neisseria mening itidis, E. coli,
Haemophilus influenzae and Staphyloc occus aureus having been reported. The risk of
splenectomy-associated sepsis is considerably higher in trauma than in Hodgkin’s disease,
idiopathic thrombocytopenia and acquired haemolytic anaemic.
Exotoxins
Exotoxins are products of microorganisms harmful to the host, usually being high-molecular-
weight, heat- labile and antigenic proteins. (The toxins of Staphyloc occus are poorly
antigenic; fungal toxins are nona ntigenic of low molecular weight.2)
Some bacteria produce only one significant toxin to cause disease (e.g. tetanus, diphtheria,
cholera and
botulism). Other bacteria may produce an array of toxins, the significance and action of many
being ill understood (e.g. Staphylococcus, Streptococcus and Clostridiun perfringen.r). A
group may harm the host throiith thc actions of both cxoloxins and cttdotoxins (e.g.
Pseudomonas).
Endotoxin
Endotoxin is part of the outer membrane of Gram- negative bacteria. Whereas exotoxins are
heat-labile proteins, endotoxin is a lipopolysaccharide (LPS) and is much more heat-stable.
LPS is known to consist
I a lipid moiety (lipid A) which is responsible for most, if not all of the biological activity of
bacterial endotoxin;
2 a core polysaccharide;
3 oligosaccharide side chains which confer 0-antig en specificity to the molecule and differ
widely from strain to strain.
However, core polysaccharide—lipid A complexes of most Gram-negative bacteria are very
similar in structure. Reasons given for implicating LPS in the pathophysiology of Gram-
negative sepsis include the following:
1 Endotoxins on the surface of circulating bacteria are in a position to activate biological
mediators of shock, even if endotoxin is below detectable levels.
2 Clinical features of Gram-negative bacteraemia are identical to the effects of endotoxin
administered
Iv.
3 Antibiotics cannot reverse, and may possibly even aggravate, these features when bacteria
are killed. ‘
Mediators’4
There are over 100 known mediators which may be involved in the systemic inflammatory
response. Known important ones are listed in Table 61.2. Some cytokines exist in both
circulatory and cell-associated forms (e.g. interleukin- 1 (IL- 1), tumour necrosis factor
(TNF)). Actions and interactions are complex, with some mediators inducing the release of
others. A variety of feedback systems moderate the whole response. Primary mediators such
as TNF can induce toxic responses by activating neutrophils and the coagulation system, and
endothelial cells to produce nitric oi4e(NO; see below). Natural inhibitors also exist, e.g. Ci-
esterase inhibitors, soluble TNF recept ors and IL-i receptor antagonists (IL-Ira). IL-lO is a
potent macrophage-deactivating factor inhibiting the production of TNF and ‘interferon--y
(IFN-’y). IL-4, being a primary B-cell stimulant, reduces IL-I and TNF production, and is
thus anti-inflammatory.
Table 61.2 Important mediators in severe sepsis
Cytokines (e.g. tumour necrosis factor. interleukins. intcrfern-
Complement system
Contact system and extrinsic pathways of coagulation
Fibrinolytic system
Cells such as mononuclears. macrophages, microphages (predominantly neutrophils),
endothelial cells and platelets
Prostaglandin
Leukotrienes
Platelet-activating factor
Oxygen free radicals
Proteases
Nitric oxide
Cardiovascular pathophysiology
The systemic response of sepsis has significant cardiovascular effects which reflect some of
the pathogenetic mechanisms.
Systemic vascular resistance
Severe sepsis is commonly associated with a decreased systemic vascular resistance index
(SVRI), which results in hypotension despite- a normal or increased cardiac index (G1).’5
This is now believed to be due principally to NO production in endothelial and vascular
smooth muscle cells, via NO synthase, an enzyme that can be induced by endotoxin and
certain cytokines (e.g. IFN-’y, TNF and some interl eukins).’6 Other mediators implicated
include histam ine, 3-endorphins, decreased C3 complement, C3 proactivator and decreased
prekallikrein.’7 Most non- survivors of severe sepsis show persistent vasodilatat ion with
refractory hypotension.
Venous capacitance
Increased venous capacitance, due to decreased venous tone (probably due to increased NO
product ion), results in relative hypovolaemia.
Pulmonary vascular resistance (PVR)
PVR may be normal initially, but frequently rises at a later stage of sepsis.’8 The mechanisms
of increased PVR are ill understood; PVR may still be increased in the absence of
hypoxaemia or acidosis. Postulated causative factors include microthrombi, vasoactive
amine, endotoxin, angiotensin, platelet-activating
528
factor (PAF), thromboxane A2 and endothelin- I. Increased PVR has been associated with
increased mortality. 8
Capillary permeability
Capillary permeability of both systemic and pulmon ary capillary beds may increase rapidly
so that fluid is lost from the circulation. Clearance of radioi odinated serum albumin has been
shown to increase from a normal of 5—10%/h to 20—35%/h in severe sepsis. 9
Myocardial function
Myocardial dysfunction is common with severe sepsis and is usually associated with high
mortality. Radionuclide scans showed that survivors had an initially depressed biventricular
ejection fraction with biventricular dilatation.2° These changes returned towards normal over
7—10 days with recovery. Non- survivors had minimally increased biventricular eject ion
fraction and ventricular size, without significant change over time, and most died of
refractory hypotension. Why functionally worse patients parad oxically survived is not clear;
ventricular dilatation may be a beneficial compensatory mechanism to improve stroke voume.
Possible causes of myocardial dysfunction include a myocardial depressant factor (MDF) and
diminv 02
ished coronary blood flow.’7 The latter is not supported by coronary sinus catheter studies
reporti ng normal mvocardial blood flow and increased niyocardial Ia.aatc uptake. Systemic
acidosis and hypoxaemia will have added delçterious effects on myocardial function. Some
mediators (e.g. ‘fNF and PAF) directly or indirectly depress the myocardiuni. TNF and IL-i
inhibit myocardial respones to f3-adrenergic stimulation.14 In vitro studies have also
implicated NO.23
Global oxygen transport and consumption
In severe sepsis, and especially in septic shock, there are major disturbances in oxygen
transport and consumption. Correction of hypovolaemià usdally results in a hyperdynamic
circulation — high CL and low SVRI. Oxygen consumption (Vo2) is frequently normal or
decreased relative to metabolic demands.2
None the less, the presence of hyperlactic acidaemie suggests inadequate oxygen delivery
(Do2) and utilization in some regional vascular beds.25’26 Decreased oxygen extraction (i.e.
increased mixed venous oxygen saturation with decreased arteriov enous oxygen difference)
is a common finding. This may result from peripheral arteriovenous shunts (due to
maldistribution of blood flow secondary to impaired vasoregulation and interstitial oedema),
and cellular metabolic defects limiting the cell’s ability to utilize oxygen.
Acutely Ill Patients
? CoMfinued Supely
—. Dependency
SUPI* Independent
Supptj Dependent
DO2
‘Nomial” Subjects
Fig. 61.3 Relationship of oxygen consumption (Vo2) to oxygen delivery (Do2).
injections ana immune aisoruers
The concept of pathological supply dependency of oxygen uptake (reflected by Vo2) on
oxygen delivery has been proposed in sepsis (Fig. 61.3)2728 Vo2 is dependent on Do,.
denoting inadequate oxygen upp1y to tissue. Thus, the implication is to use high
(supranormal) Do2 and haemodynamic values as therapeutic targets (see below). However,
this supply dependency concept has not been demonstrated in more recent studies (see below
and Chapter 22). Also, should oxygen demand vary (as it does in a febrile, septic, restless
patient) then oxygen supply is expected to co-vary, i.e. Do2 would follow or be dependent
uon Vo2 (as in exercise), and not the other way around.
Regional perfusion and oxygen consumption
Regional changes in oxygen transport in septic shock cannot be predicted from whole-body
changes. Splanchnic blood flow, oxygen extraction and Vo2 can increase during the acute
phase of septic shock, despite reduced whole-body oxygen extraction.3° This marked
splanchnic hyperrnetabolism may cont ribute to a regional mismatch between oxygen
demand and supply. Noradrenaline produces a more favourable splanchnic haemodynainic
profile than dopamine,3’ with increased gastric intramucosal pH (pHi), indicating improved
regional oxygen tissue utilization. Dopamine, while increasing splanchnic blood flow,
decreases pHi, indicating an uncomrn sated increase in regional oxygen requirements.
Clinical presentation
Sepsis, severe sepsis and septic shock (Table 61.1) are stages in a spectnlm of
pathophysiological disturbances in the infected patient. Sepsis is common and can present
many faces. Many septic patients are referred to the ICU with such labels as cardiogenic
shock, pulmonary embolism, hypovolaemic shock, profound hypothermia and haemolytic—
uraemic synd rome. Conversely, there are many causes of syst emic inflammatory response
syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) other than sepsis.
However, as sepsis requires specific therapy, the patient with signs consistent with sepsis
should be considered as being infected until proven otherwise.
Sepsis may present with a wide spectrum of manifestations. Body temperature may be
normal, increased or decreased. Tachycardia and tachypnoea are common. A leukocytosis
and increased numbers of immature (band) forms is usual, although leukop enia may be seen.
Other signs and symptoms may relate to the site of infection (e.g. productive cough,
dyspnoea, cyanosis and pleuritic pain with pneumon ia). Other features often relate to organ
dysfunction (MODS), e.g. encephalopathy, renal impairment and gut dysfunction.
Coagulopathy is occasionally prese nt. Glucose intolerance is common, although if
hepatic dysfunction is present, hypoglycaemia may occasionally occur.
The picture of a septic patient with warm skin, bounding pulses and a hvperdvnamic
circulation is nut alsv;o present. I—Tx pu1eniun. ascunstritin and peripheral cyanosis (i.e.
cold shock) may present if the patient is hypovolaemic, has pre-existing myocardial
dysfunction, or has been referred late.
Management
Septic shock has a high mortality rate and efforts should be made to diagnose and treat sepsis
before shock occurs. As with any critically ill patient, these management principles are
important:
1 initial assessment with resuscitation;
2 steps to ensure adequate oxygen delivery to meet oxygen demands (Table 61.3):
3 attempts to diagnose and eradicate the cause of illness.
General measures
Oxygenation and ventilation
Hypoxaemia is common. If oxygen by mask is inadequate, then continuous positive airway
pressure (CPAP) by mask may be employed. Where respirat ory failure is severe,
endotracheal intubation and either CPAP or mechanical ventilatory support is necessary. An
adequate haemoglobin level must also be maintained.
Table 61.3 General measures in septic shock
Administer oxygen, ventilatory support if indicated Basic clinical monitoring
ECO, systemic arterial pressure (SAP)
Central venous pressure (CVP)
Pulmonary artery pressure (PAP)
Pulmonary capillary wedge pressure (PCWP)
Cardiac output (CO)
Oxygen delivery (Do2)
Temperature, urine output
Chest X-ray
Basic laboratory monitoring
Arterial blood gas/acid-base
Lactate
Electrolytes, creatinine
Blood sugar, haemoglobin
Platelet and white blood cell count
INR
Liver function tests
ECG = Electrocardiogram; INR = intemational normalized ratio.
530
61 Severe sepsis
Clinical monitoring and intervention
A central venous (preferably multi-lumen) and arter ial line and a urethral catheter are
inserted. Heart nile. rhythm. n1emn rterm:ml pressure MAP. central venous pressure (CVP)
and urine output are cont inuously monitored.
Haemodynamic manipulation
There is no consensus view on the correct haemodyn amic goals in septic shock, but a plan of
haemodyn amic management is needed. Tachycardia is comm on in sepsis, so increasing
heart rate is usually not an issue. Volume loading is usually with colloids, such as 5%
albumin or Haemaccel (1—2 I) followed by normal saline. If MAP is inadequate (i.e. <65—
8OmmHg or 8.6—lO.6kPa) despite attaining a CVP of 15cm H20 (l0—l2mmHg or l.3—
I.6kPa),an inotrope infusion should be started — usually adrenal ine initially, at 5 i.g/kg per
mm and varying the dose as necessary. A pulmonary artery catheter should be inserted to
monitor pulmonary capillary wedge press ure (PCWP), CI and SVRI, if inotropes are started.
Volume loading is continued if necessary, to a PCWP of l2mmHg (1.6kPa). A PCWP of l0—
l2mmHg (1.3—1.6 kPa) is associated with peak left ventricular stroke work and CI in septic
patients.32 Sustained PCWP over 12 mmHg (1.6 kPa) may lead to pulmon ary oedema due to
increased pulmonary capillary leak.
An adequate MAP (i.e. 65—8OmmHg or 8.6—lO.6kPa) and CI (>4.0) should be aimed for.
Blood pressure is important; blood flow to most organs is pressure-dependent, and
autoregulation is probably lost with the profound vasodilatation in septic shock. Arterial
pressure and SVRI have been shown to correlate directly with survival in septic shock.33’34
Noradrenaline vasopressor is reported to improve SVRI, blood pressure, regional blood flow,
oxygen extraction and urine output.°’3135 Haemoglob in concentration should be maintained
above 10 g/dl for adequate Do2. Haemodynamic interventions should avoid:
1 overdriving the heart with excessive catecholam ines which are cardiotoxic,
arrhythmogenic and increase oxygen requirements;
2 using inappropriate agents, e.g. dobutamine (an inodilator) instead of noradrenaline in a
patient with profoundly low SVRI.
Afterload reduction to improve right ventricular function is a consideration in pulmonary
hypert ension, which is associated with a high mortality)8 Vasodilators such as hydralazine,
sodium nitropruss ide and prostacyclin lower PVR and also SVRI, and are prone to cause
hypotension and increase pulmon ary shunt. NO, by inhalation, is a selective pulmon ary
vasodilator,36 but its use is still experimental.
Urine output
A urine output over 0.7 mllkg per h should be maintained. If severe oliguria persists despite
the above measures. IV mannitol (0.3 e/ke) and/or TV frusemide 250—500mg is commonly
given. These agents may increase renal blood flow and promote diuresis. However, frusemide
can precipitate hypot ension (by causing vasodilatation) and may worsen toxic nephropathy.
Chest X-ray
An early erect chest X-ray may show evidence of raised pulmonary venous pressure. In
severe sepsis, considerable tachypnoea and hypoxaemia may exist despite a deceptively
normal-looking chest film.
Laboratory monitoring
Increases in blood lactate suggest severe tissue hypoxaemia, and may indicate an advanced
stage of decompensation. However, in severe sepsis, lactate may be increased by other
mechanisms. For example, increased circulating catecholamines promote glycoly sis (by
stimulating cyclic adenosine monophosphate to augment glycogen phosphorylase). The
increased concentration of pyruvate so produced leads to increased production of lactate.
Conversely, in maln ourished patients with low glycogep stores, the increase in lactate for a
given level of hypoxia may be less. Hence, lactate may be an insensitive marker of tissue
hypoxia.37
Controversies in haemodynamic management
It has been suggested that the optimal goals of therapy in septic patients may be supranormal
values (Table Using these goals, better survival has been reported, and pathological supply
depende ncy was demonstrated (i.e. increases in Do2 were reflected by increases in
Vo2).40’4’ However, these recommendations have been challenged. Other worke rs have
shown no differences in outcome.42-47 In one study, target Vo2 values could not be attained
in some patients despite achieving target CI and Do2,48
Table 61.4 Supranormal values (normal values in brackets)
Cardiac index > 4.5 11mm per m2 (2.5—3.5)
Do2 > 600 mllmin per m2 (400—700)
1/02> 170 mI/mm per m2 (130—150)
PCWP = l8mmHg; 2.4kPa (l5mmHg; 2.OkPa)
Severe trauma and septic patients may require greater
increases39
Do2 = Oxygen delivery; 1/02 = oxygen consumption; PCWP = pulmonary capillary wedge
pressure.
531
Infections and immune disorders
suggesting that Increasing Do, does not affect the inability of tissues to extract or utilize
oxygen. Future efforts should be directed away from global values of Cl. Do. and Vo. towards
monitors and markers of individual olgan o\ygcnanon and function. Currenti). pHi is of much
interest. It is more likely to benefit patients at risk of developing shock rather than those
already in shock,49 but further evaluation of its role is necessary.
Dobutamine has been the most common inotropic agent used in reported studies. The
possibility exists that dobutamine may have worsened peripheral maldistribution of blood in
those patients. Also, aggressive use of dobutamine to achieve supranormal goals may have
been detrimental.47 In clinical practice, the choice of inotrope should be influenced by the
initial MAP, CI and SVRI following volume loading, and by the clinical response.
Specific measures
Blood cultures
Blood cultures are taken repeatedly before antibiotics are given. A set of cultures consists of
six bottles — three aerobic and three anaerobic — each bottle receiving 5 ml of blood.
Gram stain and culture
Appropriate specimens of sputum, urine, peritoneal dialysis fluid, cerebrospinal fluid (CSF)
and pus should be examined microscopically, Gram-stained and cultured.
Specimens for specific antigens and
serology
Specific serological tests should be requested if appropriate. Similarly, a search for specific
antigens (e.g. pneumococcal and meningococcal) may be relevant, especially in CSF
specimens of patients with suspected bacterial meningitis who were previously given
antibiotics.
Antibiotics
Adequate antibiotics are given following collection of blood and specimens for cultures. The
regimen is initially a best guess based on:
1 the possible site of infection;
2 whether the infection was acquired outside or within the hospital;
3 the age of the patient;
4 any history of hypersensitivity;
5 renal function;
6 whether previous antibiotics have been given.
The regimen may need to be changed once the organism and sensitivities are known (see
Chapter
64).
Surgical drainage
Surgical debridement or drainage of in ‘ection source is vital. If intra-abdominal abscesses
are left undrained. rnortalii approaches lOO.50 Locating sources ol infection can prove
diflicult and frustrati ng. In suspected intra-abdominal sepsis, plain abdominal X-rays,
ultrasonography, computed tomography (CT) scan, gallium 67 citrate scan and indium 111-
labelled leukocytes may be helpful,5’ but may also be misleading. The choice of
investigation is guided by availability, expertise and the clinical situation. If intra-abdominal
sepsis is strongly susp ected despite negative clinical findings, exploratory laparotomy should
be undertaken.52 Direct percutan eous drainage may be attempted in selected cases, when a
definite abscess is located by ultrasonography or CT scan.
Severe diffuse peritonitis has a high mortality, and aggressive forms of therapy have been
thed. Howe ver, radical peritoneal debridement or postoperative continuous pentoneal lavage
offers no benefit. Repeated laparotomies also confer poor results.53 Electively staged
laparotomies and open management of the abdomen (possibly with use of a mesh zipper)54
are also proposed.55’56 Advantages claimed for open management include maximal
drainage, ease of repeated debridement and lowered intra-abdominal pressure.55 This method
should be resrved for severe cases; mortality remains high and its superiority remains
unestablished.56
Measures for specific infections
Additional measures are relevant to the following infections.
Gas gangrene
Massive doses of crystalline penicillin are given with clindamycin, and urgent radical
debridement or amputation is undertaken. Hyperbaric oxygen may be beneficial, but
prospective evidence to support its use is lacking (see Chapter 63).
Systemic candidiasis
This is usually seen in immunodepressed patients receiving antibiotics. As fungaemia may
arise by translocation from the bowel,57 ICU patients on broad-spectrum antibiotics should
be given prophyl actic oral or nasogastric nystatin suspension or amphotericin B. In suspected
systemic candidiasis, ophthalmitis, osteomyelitjs, arthritis, myocarditis, meningitis and
macronodular skin lesions must be excluded. Established agents for treating Candida
infections are amphotericin B, flucytosine and flucon azole58 (see Chapter 64).
Necrotizing fasciitis
Necrotizing fasciitis is a fulminant infection of subcutaneous tissues with extensive
undermining of
532
Hypercatabolism
skin, usually occurring on the extremities, perineum and abdominal wall. Patients with
cirrhosis, diabetes and immunocompromised conditions are more likely victims. Infecting
organisms are usually enteric howel oreumms. tht’u pp.. LmLlp A streptococci.
and occasionally Staphylococcus aureus. Exteimive early debridement and antibiotic therapy
are the essential components of therapy (see Chapter 63).
Meningococcal meningitis and
meningococcaemia
These fulminant conditions have a high mortality. Antibiotics must be given immediately;
ceftriaxone 1—2g 12-hourly or cefotaxime I—2g 6—8-hourly is usually appropriate.
Dexamethasone 0.15 mg/kg 6-hourly for 2 days should be started before antib iotics in
children, but not for adults. Lumbar puncture will be unsafe if coagulopathy is present (see
Chapter46).
Complications of sepsis
Metabolic acidosis
This is commonly present because of lactic acidaemia from anaerobic metabolism. Measures
to improve Do2 will usually reverse this. However, severe metabolic acidosis worsens
myocardial depression and increases PVR and venoconstriction. Use of bicarbonate remains
controversial.59
Hyperglycaemia
Glucose intolerance is commonly precipitated by severe sepsis, and aggravated by steroids
and hypert onic glucose infusions. A low-dose insulin infusion may be necessary.
Hypoglycaemia may occasionally be seen, especially in the very young and those with severe
hepatic dysfunction.
Coagulopathy
Mild to severe disseminated intravascular coagulation may occur in septic shock. Platelets,
fresh frozen plasma and other factors are given if necessary (see Chapter 89). Vitamin K and
folate are routinely given if no contraindication exists.
Gastrointestinal bleeding
Antacids, H2-receptor blockers and sucralfate are effective in reducing GIT bleeding in
sepsis (see Chapter 35). Sucralfate has a minimal effect on intragastric pH and has
antimicrobial properties. Whether it is associated with less gastric colonization and
nosocomial pneumonia in ventilated patients is debatable.60’6’
Severe sepsis is associated with a hypercatabolic state. Muscle wasting can be profound.
Negative nitrogen balance can be minimized by providing
lequiiie nutri jonul support.
Multiple organ dysfunction and failure
Multiple organ dysfunction and/or failure is a feature of severe sepsis and septic shock.
Virtually any organ may be involved (see Chapter 85).
Novel, experimental and controversial therapies
Antiendotoxin antibodies
Antiendotoxin antibodies have not improved survival in several clinical trials.62 These
included polyclonal antiendotoxin anticore antibodies against E. coli J5,6268 and monoclonal
antiendotoxin antibodies ES (Xoma)69’7° and HA-IA (Centocor).71’72 The CHESS HA-lA
study was stopped because mortality in the treated group exceeded that of patients given plac
ebo.73 At present, agents with a higher binding affinity with endotoxin than antibodies
previously studied are being developed.62
Anticytokine therapies
Cytokines are small proteins produced by macrop hages and other immune cells, and are
primary mediators of inflammation with an important role in regulating host defences. Levels
of TNE IL-I and IL- 6 are increased in septic shock.74 Anticytokine therapy is thus based on
the assumption that suppress ion of an exaggerated inflammatory response is beneficial.
However, anti-TNF antibodies and soluble TNF receptors did not affect 28-day mortality in a
multicentre trial.62 Although increasing doses of ILI ra were reported to relate to improved
survival,75 no difference in mortality was shown in a larger IL-lra trial.76
Modifying neutrophil function
Experimental studies of monoclonal antibodies to inhibit neutrophil adhesion have shown
varying beneficial and adverse effects.Th78 Granulocyte colo ny-stimulating factor (GCSF)
has been shown to be beneficial in animal experiments.79’80 However, evid ence of clinical
benefit is lacking.
Nitric oxide
NO has important roles in neurotransmission, regulat ion of vascular tone, platelet inhibition
and leukocyte adhesion, with antitumour and bactericidal effects in higher concentrations.
Blocking its production in
Infections and immune disorders
sepsis is rationalized by its implications in myoc ardial depression23 and vasoplegia.8’ NO
synthase inhibitors have been used in sepsis to treat hypotens ion.8284 However, improved
survival has vet to be shov n convilkillg1. Indeed, ann-NO therap) could well be harmful.
Steroids
The use of high-dose steroids (e.g. methyiprednisol one 30 mg/kg and dexamethasone 6
mg/kg) does not improve overall survival in septic shock.85 Moreover, steroid treatment is
associated with more deaths related to secondary infection.8687 Use of steroids cannot be
recommended except for bacterial meningit is in children88 and Pneumocystis pneumonia.89
Prostaglandins
Prostaglandins participate in the pathophysiology of septic shock. Indomethacin and
ibuprofen, prostag landin cyclooxygenase inhibitors, have not been shown to improve human
survival in sepsis.909’ Prostacyclin (prostaglandin; PGI2) is a vasodilator; it antagonizes
thromboxane A2 and inhibits platelet aggregation, and is reported to improve peripheral
oxygen utilization in critically ill patients,2 but evidence of benefits in sepsis is lacking.
Alprostadil (prostaglandin E,) produced no improvement in survival in patients with acute
respiratory distress syndrome (ARDS).93
Naloxone
Endogenous opioid peptides derived from 3-lipo- tropin are released in septic shock and other
stress states. Despite earlier encouraging reports, naloxone, an opioid receptor blocker, offers
no real therapeutic benefits in septic shockY
Thyrotrophin-releaSing hormone (TRH)
TRH, like naloxone, opposes many opioid-mediated actions. Although it has been studied in
experimental shock, its clinical role is unknown.
Phospholipase A2 inhibitors
Endotoxin and bacterial products activate cell phosp holipases to liberate arachidonic acid
(and initiate synthesis of leukotrienes, prostaglandins and thromb oxanes) and, with
phospholipase A2, activate PAF. Drugs that inhibit phospholipase Aa have been shown to
prevent lung injury in animals,9’96 but usefulness in human sepsis is unknown.
Antioxidants
Free radical production is increased in sepsis and produces a toxic effect by interacting with
cell structure, processes or genetic activity. Endogenous
protective antioxidants include vitamins C, E, B carotene, sulphydryl group donors (e.g.
glutathione), proteins with sulphydryl group and enzymes (e.g. superoxide disniutase and
catalasel Encouraging results ha e been repoited in ARDS, and ant,ox,dants may have
potential benefits in sepsis,97 but pros pective clinical trials are required.
Ketoconazole
Ketoconazole, a thromboxane A2 synthetase inhibitor, has been shown to reduce the
incidence of ARDS98’99 and mortality in septic patients.98 Ketoconazole also inhibits the
synthesis of leukotrienes and interacts with other mediators such as IL-I and TNF.
Pentoxifylline
Pentoxifylline is a phosphodiesterase inhibitor, thus blocking chemotaxis and activation of
neutrophils. It reduces the formation of TNF and increases survival in murine endotoxic
shock,’°° and has been safely given to patients with ARDS.’°’ Further investigation of this
agent is needed.
Haemofiltration
Haemofiltration can remove certain circulating cytok ines from septic patients,’°2”°3 and
benefits have been suggested.l03_l05 In particular, plasma exchange has been used in the
treatment of meningococcal infection.’06 However, haemofiltration will not affect cytokines
that are fixed to cells, and many mediators of sepsis are cell-associated. Prospective
controlled clinical trials on dialytic therapies for sepsis are required.’°7
Prognosis
Mortality increases with increasing severity score (e.g. APACHE II), number of
dysfunctionallfailed organs and duration of such failure. 108.109 Several factors influence
the prognosis in bacteraemia and fungaemia in tsdults:0.W source of infection, where
acquired, blood pressure, organism isolated, body temperature, age and predisposing factors.
Survival is improved by appropriate use of antibiotics and surgical drainage (where
applicable).” The ability to maintain an increased CI, Do2 and Vo2 is associated with better
pronosis.33 Pulmonary hypertension is an adverse factor. 8 Peripheral vascular failure may
be a major haemodynamic determinant of mortality, as survivors of septic shock are more
able to augment
svlu.34
Prevention of sepsis in ICUs
Four main facets are important: reducing available routes of infection; preventing transfer of
pathogenic organisms and development of resistant strains;
61 Severe sepsis
improving host defences; and reducing risk of endogenous infection from the gut.
Reducing available routes of infection
All invasive cannulae and tubes should be removed when no longer necessary. Subclavian
central lines have lower rates of infection than femoral sites and are preferred.’’2 Triple-
lumen central venous cathe ters induce a higher sepsis rate than single-lumen catheters.
Preventing transfer of pathogenic
organisms and development of resistant strains
Hand-washing must be performed by staff members before and after attending each patient.
All invasive procedures, including endotracheal suctioning, must be done aseptically. If
prophylactic antibiotics are employed, narrow-spectrum agents should be used with a limited
duration. Indiscriminate use of antib iotics leads to serious outbreaks of infection within the
ICU (see Chapter 64).
Improving host defences
Potentially valuable measures include:
1 nutritional repletion;
2 surgery, e.g. drainage, control of haemorrhage and resection of colonic cancer;
3 active immunization, e.g. pneumococcal,’ “ Haem ophilus influenzae type B,°5 and
meningoc occal”6 vaccination of splenectomized patients; tetanus and hepatitis B vaccines;
4 passive immunization (e.g. human antitetanus, and pneumococcal and hepatitis B globulin);
5 granulocyte transfusion in the profoundly leuk openic patient.
Immunostimulation with agents such as levamisole, bacillus Calmette-Guérin (BCG) and
Corynebacter ium parvum may be useless or even dangerous.9 Infusions of fibronectin,
cryoprecipitate, fresh frozen plasma, -y-globulin and transfer factor are of unprov en benefit.
Reducing risk of endogenous infection from the gut
Early enteral feeding
Early enteral feeding can reduce bacterial and endotoxjn translocation from the gut, and
infection rates in animals and humans.’’7 Larger studies are
needed on outcome and influence of food composition.
Improving gut blood flow
Bacteraemia commonly occurs in patients with haemo rrhagtc shock,”8 Decreased intestinal
blood flow may be important in bacterial gut translocation. Early adequate resuscitation aims
to improve gut blood flow.
Selective oropharyngeal and
gastrointestinal decontamination
Organisms commonly causing infections in the compromised patient may be community-
acquired (e.g. Streptococcus pneumoniae, Haemophilus influe nzae, Branhamella catarrhalis,
E. coli, Staphyloc occus aureus and Candida albicans) or nosocomial (hospital/ICU-
acquired, e.g. Kiebsiella, Proteus, Morganella, Enterobacter, Citrobacter, Serratia, Acin
etobacter and Pseudomonas).”9 Normal indigenous flora of the throat and alimentary tract
are anaerobic (>99%), and are rarely involved in infection. Select ive decontamination aims
to prevent or eradicate colonization by community/hospital-acquired pathog ens, and preserve
protective normal flora.
Community flora are eradicated by short-term parenteral antibiotics. Therapy against
hospital- acquired flora is by topical application of non- absorbable antimicrobial agents
(Table 61.5). 120 Init ial repots’20-’22 and meta-analysis of available studies’23”24 are
favourable, but outcome has remained unchanged.’25
Table 61.5 A regimen for oropharyngeal and gastrointestinal decontamination
Systemic antibiotic (first 4 days) cefotaxime IV
50—100mg/kg per day in four divided doses
Topical antimicrobial (whole of ICU stay)
Oropharyngeal:
Cleanse mouth with 0.1% chlorhexidine aqueous solution
Apply carboxymethylcellulose (Orabase) containing:
2% polymyxin E
2% tobramycin
2% amphotericin B
A small quantity on a gloved finger is applied to buccal mucosa four times a day.
Gastrointestinal:
100mg polymyxin E
80mg tobramycin
500mg amphotericin B
as a 10-mi mixture, delivered four times a day via a nasogastric tube
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