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

535