1. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 Critical Care 27 Blood Cultures and Infection— 1
27 BLOOD CULTURES AND INFECTION
IN THE PATIENT WITH THE SEPTIC
RESPONSE
Donald E. Fry, M.D.
Approach to Blood Cultures in Patients with the Septic Response
It has been well established that infection the microorganism or microorganisms responsible for the septic
and sepsis are distinct events [see 8:14 response, organization of the discussion according to the proven
Clinical and Laboratory Diagnosis of or suspected pathogen that may be recovered in a blood culture
Infection and Discussion, below]. is a convenient way of addressing treatment options.
Infection is local activation of the human
GRAM-POSITIVE COCCI
inflammatory response secondary to
local proliferation and invasion of tissue
by microorganisms. When infection Staphylococci
reaches a critical threshold of severity, the inflammatory The identification of gram-positive organisms from a blood
response may be activated at a systemic level. Systemic activation culture immediately arouses suspicion that a Staphylococcus
of inflammation is called the systemic inflammatory response species is the likely pathogen. Because staphylococci ordinarily
syndrome (SIRS); when infection is the putative agent for SIRS, colonize the skin and integument, infection from those sources
the resulting state is called sepsis.1 must be considered responsible for the bacteremia.
SIRS secondary to infection occurs when (1) whole microor- In surgical patients, a blood culture positive for staphylococci
ganisms are disseminated from the primary site of infection, usu- must be assumed to indicate infection arising from an intravas-
ally via the vascular or lymphatic system (e.g., bacteremia); (2) cular device until proven otherwise [see Table 2].3 Peripheral I.V.
structural components of the cell wall (e.g., gram-negative endo- catheters, subclavian lines, Swan-Ganz catheters, systemic arte-
toxin) or secreted exotoxins are systemically disseminated (as in rial lines, and even transvenous pacemaker wires are all docu-
toxic shock); or (3) normal autocrine and paracrine proinflam- mented sources of staphylococcal bacteremia [see Table 3]. All
matory signals (e.g., tumor necrosis factor [TNF]) from a severe lines must be removed and their sites changed. The line and
local inflammatory focus reach high systemic concentrations, catheter tips should be cultured by semiquantitative methods4 to
activating SIRS by virtue of their exaggerated endocrine domain document the role of the device in question [see 8:16
of action. Nosocomial Infection]. Although this semiquantitative method
Although biologic factors other than infection may cause uses a count of 15 colony-forming units as the threshold for a
SIRS and provoke a syndrome that is virtually identical to that positive culture of the catheter, devices responsible for bac-
resulting from invasive infection, infection is the most common teremia will usually demonstrate a solid sheet of bacterial growth
cause of SIRS in acutely ill surgical patients. Effective manage- on the agar [see Figure 2].
ment of infection in these patients requires recognition of the Septic thrombophlebitis may occur at the site of a previously
primary site of infection, control of the source of microbial con- placed device even though the foreign body has been removed.5,6
tamination and dissemination (i.e., source control); character- Pus within the vein becomes a source of persistent bacteremia
ization of the causative microorganism or microorganisms);
drainage and debridement of inflammatory exudates and
necrotic tissue at the primary site; and antibiotic therapy specif- Table 1—Most Common Nosocomial Bacteremia
ic for the pathogen. Pathogens Isolated from All Sites
in 12,243 Patients2
Positive Blood Culture with
Infection Pathogen Prevalence (%)
A positive blood culture in a patient Coagulase-negative staphylococci 31.9
with the septic response identifies the Staphylococcus aureus 15.7
putative cause of the infection [see Table Enterococcus species 11.1
1].2 This identification not only permits Candida species 7.6
institution of appropriate systemic Escherichia coli 5.7
antibiotic therapy [see Figure 1] but also facilitates assessment of Klebsiella species 5.4
Enterobacter species 4.5
potential primary sources of the infection because of the estab-
Pseudomonas aeruginosa 4.4
lished associations between specific anatomic sites and specific Serratia species 1.4
microbial isolates. Although it is not always possible to identify

2. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 Critical Care 27 Blood Cultures and Infection— 2
Approach to Blood Cultures in
Patients with the Septic Response
Patient has septic response
Perform blood culture to identify putative
cause of infection.
Blood culture is positive Blood culture is negative
Common pathogens include Attempt to determine whether there is a
• Gram-positive cocci (staphylococci, primary source of infection:
streptococci) • Perform careful physical examination
• Gram-negative Enterobacteriaceae • Order appropriate diagnostic studies
(Escherichia coli, Klebsiella, for each anatomic area
Proteus, Serratia) • Aggressively culture suspicious fluids
• Anaerobes (Bacteroides, clostridia, or exudates
certain streptococci) Pay particular attention to
• Fungi (Candida) • Surgical site
Attempt to determine whether there is a • Insertion sites for monitoring
primary focus of infection. and support devices
Infectious focus is No infectious focus is Infectious focus is No infectious focus is
identified identified identified identified
Initiate therapy as Presume GI microbial Drain primary focus Consider noninfectious
appropriate for pathogen translocation. Likelihood of mechanically. causes of septic response,
identified [see Figure 1]. this diagnosis is increased Initiate empirical antibiotic such as
by presence of “trilogy of therapy directed at • Acute pancreatitis
translocation” in blood suspected pathogens while • Aspiration pneumonitis
culture: culture and sensitivity data • Multiple trauma with
• Enterococcus are pending. extensive soft tissue
• Staphylococcus Maintain constant vigilance damage
epidermidis for changing clinical • Extracorporeal
• Candida findings, and observe membrane oxygenation
Rule out intravascular response to empirical Do not give antibiotics.
device infection. therapy carefully. Provide supportive care:
Continue to search for • Fluids
primary infectious focus. • Ventilatory assistance
Reinforce gut barrier
function via
• Enteral nutritional support
• Patient mobilization
• Addition of glutamine and
short-chain fatty acids to
nutritional solution
• Possible alteration of
antibiotic regimen

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8 Critical Care 27 Blood Cultures and Infection— 3
Positive blood culture identifies putative source of infection
Staphylococcus aureus
S. epidermidis
Causes soft tissue infection, commonly with a foreign body (e.g.,
intravascular device or prosthesis). Infected device will have to be Infection of intravascular device is presumed until proved otherwise;
removed; may have to excise infected vein. remove infected foreign body. May need to excise infected vein.
Antibiotic selection: Antibiotic selection:
If organism is methicillin sensitive, give either nafcillin, 1 g q. 4 hr; S. epidermidis shows a high frequency of methicillin resistance;
oxacillin, 1 g q. 4 hr; or cefazolin, 1–2 g q. 8 hr. If organism is vancomycin, 0.5–1.0 g q. 6 hr, will likely be necessary.
methicillin resistant, give vancomycin, 0.5–1.0 g q. 6 hr.
Enterococcus
Escherichia coli, Klebsiella species Infection of intravascular device (remove device), heart valve, or
Infection usually arises in peritoneal cavity, biliary tract, or urinary biliary tract is likely. May occur with Candida species as primary
tract. Must ensure adequate drainage and debridement of primary bacteremia without anatomic site of infection.
focus of infection. Antibiotic selection:
Antibiotic selection: Give piperacillin, mezlocillin, or ticarcillin at 12–16 g/day; consider
Choice of antibiotic is based on sensitivity data. Empirical therapy: ampicillin-sulbactam
gentamicin, 3–5 mg/kg (pharmacokinetically dosed), cefotaxime,
2 g q. 6–8 hr, or ceftizoxime, 2 g q. 8–12 hr.
Pseudomonas species, Serratia species
Pulmonary sepsis (usually with pulmonary failure), urinary tract
Bacteroides species, clostridia, anaerobic streptococci sepsis, or infection of intravascular device is likely. Treatment
requires aggressive pulmonary toilet, ensurance of unobstructed
Intra-abdominal sepsis, polymicrobial soft tissue infection, or female urinary tract, and removal of potentially infected devices.
genital tract infection is likely. Adequate drainage and debridement
of primary site of infection is mandatory. Antibiotic selection:
Antibiotic selection: Give gentamicin, 3–5 mg/kg/day, or amikacin, 15 mg/kg/day
(depending on sensitivity; pharmacokinetically dosed). The
Give clindamycin, 900–1,200 mg q. 6–8 hr, or metronidazole, addition of expanded-spectrum penicillin (ticarcillin, mezlocillin, or
500 mg q. 6 hr. piperacillin, 12–16 g/day) may be desirable in severe infections.
Candida species
Primary source of infection is infected central catheters or
gastrointestinal translocation. Remove catheters at risk.
Antifungal selection:
Give amphotericin B, 0.5 mg/kg/day (after test dose documents
patient tolerance), or fluconazole, 200–800 mg/day.
Figure 1 Identification of the putative cause of infection permits institution of appropriate antibiotic therapy.
until appropriate therapy is employed. Persistent evidence of delayed nature of some infections, particularly those involving S.
gram-positive bacteremia after removal of all intravascular lines epidermidis, has become more readily apparent. These indolent
gives rise to a high index of suspicion for suppurative throm- infections are consequences of intraoperative contamination but
bophlebitis. Previous I.V. sites must be examined for evidence of may not be clinically evident for months to years after implanta-
pus; suspicious sites may even have to be explored with the tion. Because selected species of S. epidermidis produce biofilm,7
patient under local anesthesia.When identified, the entire length even culturing the microorganism from the infected prosthesis
of septic vein must be surgically excised. Although many differ- that has been removed can be very difficult, and recovery of the
ent species of bacteria may be responsible for suppurative microorganism from a blood culture is quite uncommon in the
thrombophlebitis, S. aureus is decidedly the most common. period before the infection becomes clinically apparent.8
The implantable synthetic prosthetic materials that are now Diagnosis of arterial graft, heart valve, and total-joint arthro-
such a major part of vascular, cardiac, and orthopedic surgery plasty infections can be very difficult. Once infection has been
may become sources of bacteremia secondary to infections established, however, prompt removal of the prosthesis is manda-
resulting from intraoperative contamination. When gram-posi- tory. Removal of an actively infected prosthesis is invariably asso-
tive organisms are identified in the blood of a patient at risk, the ciated with major morbidity because the infection limits the recon-
synthetic implant should be considered the source of blood- structive options available. Antibiotic therapy alone will not eradi-
borne infection. As the use of synthetic devices has increased, the cate the infection, and it may lead to a delay in the decision to

4. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 Critical Care 27 Blood Cultures and Infection— 4
Table 2—Pathogens in 159 Cases of Intravascular
Device–Associated Bacteremia3
Organism No. of Isolates
Staphylococcus aureus 78
S. epidermidis 33
Serratia marcescens 18
Klebsiella/Enterobacter species 16
Candida species 11
Enterococcus species 8
Proteus species 6
Others 6
Total 176*
*The total exceeds 159 because of polymicrobial isolates in several patients.
remove the prosthesis; this can result in arterial graft failure (e.g.,
Figure 2 Illustrated is a blood agar plate 24 hours after an infect-
thrombosis or pseudoaneurysm), cardiac valvular insufficiency, or
ed catheter has been cultured by semiquantitative technique.
extensive arthroplasty infection (e.g., extrusion or osteomyelitis).
Although colony counts higher than 15 are associated with a posi-
Because S. epidermidis normally colonizes skin, it is also a poten- tive culture, the prolific growth shown here is commonly seen.
tial contaminant in the blood culture process. Accordingly, close
attention to proper culturing technique is crucial for minimizing
this potential diagnostic artifact. A frequent cause of false positive ence) or intramuscularly, is the agent of choice [see 1:1
cultures of S. epidermidis is use of the arterial line or the central Prevention of Postoperative Infection]. With lengthy operations,
venous catheter for drawing blood samples instead of a separate repeat doses should be given at 4-hour intervals. Prolonged post-
and carefully prepared venopuncture site. When more than one operative administration is of no value.
culture shows S. epidermidis or when cultures taken at separate Methicillin-resistant staphylococci are becoming increasingly
times show the same organism, however, the clinician must prevalent; in some series, they account for more than 50% of
assume that the organism is participating in clinical infection. clinical isolates. Consequently, presumptive antimicrobial thera-
Staphylococcal bacteremia is a preventable complication of py for bacteremia arising from an intravascular or implantable
indwelling devices and implants. Aseptic placement of intravas- device requires vancomycin, 1 g every 8 to 12 hours. If the
cular devices cannot be compromised. Peripheral I.V. catheters patient is intolerant of or unresponsive to vancomycin, then
should be changed routinely every 48 to 72 hours. Arterial lines either linezolid, 600 mg every 12 hours,9 or quinupristin-dalfo-
that have been in place for more than 72 hours are at consider- pristin, 7.5 mg/kg every 8 to 12 hours,10 may be given instead.
able risk for being foci for bacteremia. Catheters devoted to par- The antimicrobial choice may be modified when culture and
enteral nutrition must receive ongoing care to prevent septic sensitivity data subsequently become available. If methicillin-
morbidity [see 8:22 Nutritional Support]. resistant species are not a concern, nafcillin, 1 g every 4 hours, is
The primary therapy for device-related infection is removal of appropriate. Because of the risks of metastatic infectious com-
the infected device. Systemic antibiotics cannot overcome the plications from staphylococcal bacteremia, systemic antibiotics
adjuvant effects of the foreign body in supporting bacterial should be continued for a minimum of 7 days.
growth. Antimicrobial therapy thus becomes adjunctive to The toxic-shock syndrome, caused by S. aureus, gives the clin-
removal of the primary nidus of infection. ical impression of being a bacteremic illness.11 However, positive
To prevent infection from prosthetic implants, efforts must be blood cultures are uncommon with this syndrome because the
made to minimize development of a microenvironment in the SIRS is created by the exotoxin produced by the microorganism,
wound that favors bacterial proliferation. Meticulous technique, not by bacteremia per se. Initially associated with vaginal tam-
appropriate hemostasis, conservative use of the electrocautery, pons, the toxic-shock syndrome can be seen wherever body cav-
judicious use of suture ligatures, and antibiotics given immedi- ities or open wounds are filled with gauze or other packing.
ately before operation will reduce infectious morbidity. Diagnosis of this syndrome requires a high index of suspicion in
Cefazolin, 1 g preoperatively, administered either I.V. (by prefer- the septic, hypotensive patient with body packing. Treatment
requires removal of the packing, aggressive systemic supportive
care of shock and associated organ failure, and systemic admin-
Table 3—Sites of Intravascular Device– istration of suitable antibiotics.
Associated Bacteremia in 159 Patients3 Streptococci
Site No. of Patients Streptococcal bacteremia occurs less frequently than staphy-
lococcal blood-borne infection, though some areas of the United
Peripheral I.V. catheter 72 States have experienced an apparent increase in these infections.
Central venous catheter 49 Invasive group A streptococcal infections with bacteremia are
Arterial line 18 seen in patients with necrotizing soft tissue infections, invasive
Subclavian dialysis catheter 12 pharyngeal infections, bone and joint infections, and severe and
Swan-Ganz catheter 4
rapidly advancing pneumonia. About 20% of bacteremias with
Broviac catheter 3
Transvenous pacemaker wire 1
group A streptococci are without a primary source of infection12
and probably arise from the oropharynx.

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8 Critical Care 27 Blood Cultures and Infection— 5
Necrotizing soft tissue infection is the most common setting blood, I.V. devices should be changed and semiquantitatively
for a positive blood culture with group A streptococci.These ful- cultured. Potential biliary sources must be evaluated, with all
minant infections are seen after seemingly trivial cutaneous available clinical data, including those from ultrasound examina-
injuries but may also complicate chickenpox in children13 and tion of the gallbladder [see 8:18 Intra-abdominal Infection],
may even be seen as complications of elective surgical wounds. taken into account.
The necrotizing infection is characterized by pain, tenderness, Gangrenous acalculous cholecystitis must be kept in mind
and induration around a wound that is out of proportion to the because of the type of patient likely to have enterococcal bac-
size or mechanism of the injury. The infection dissects along the teremia.20 Intra-abdominal abscesses and serious soft tissue
fascial plane and can evolve from injury to a fatal illness in 24 infections are customarily associated with polymicrobial isolates,
hours.The diagnosis requires a high index of suspicion in a toxic which may include Enterococcus. The urinary tract, however,
patient with rapidly advancing cellulitis. The induration of the appears to be an infrequent cause of enterococcal bacteremia in
advancing infection may be palpable in thin patients and serves the absence of anatomic obstruction of urine flow.
to distinguish this condition from clostridial gas gangrene. Once the primary focus has been identified, removal of the
Necrotizing soft tissue infections are associated with a toxic- foreign body, drainage and debridement of infected material,
shock–like syndrome, but unlike patients with true toxic shock, and specific antibiotic therapy are indicated. Piperacillin-
these patients usually have blood cultures that are positive for tazobactam, 3.375 g every 6 hours, is recommended. Although
group A streptococci.11 Unfortunately, the positive blood culture ampicillin appears to have nearly uniform activity against
result is not available until the patient’s fate has already been dic- Enterococcus in vitro, the production of β-lactamase by synergis-
tated by earlier clinical decisions. tic pathogens in the polymicrobial milieu raises serious questions
Therapy requires aggressive local debridement of necrotic tis- about the effectiveness of this choice. Addition of sulbactam to
sue, systemic antibiotic therapy, and systemic supportive thera- ampicillin improves enterococcal coverage in mixed infections.
py for the shock and organ failure characteristic of severe infec- In about 40% of patients with blood cultures positive for
tions. The recommended antibiotic regimen includes both peni- Enterococcus, no primary site of infection can be identified.21 This
cillin, 12 to 24 million U/day, and clindamycin, 900 to 1,200 mg observation has led to considerable speculation as to whether
every 6 hours in adult patients. The addition of clindamycin is this organism is a marker of microbial translocation from the gut
believed to reduce toxin production by inhibiting protein syn- [see Positive Blood Culture without Infection, below] or whether
thesis in the rapidly multiplying bacteria. Another reason why the infection derives from a clinically obscure primary focus
clindamycin is useful is that large inocula of group A streptococ- (e.g., a catheter).
ci are believed not to express penicillin-binding proteins.14 The emergence of vancomycin-resistant enterococci is a matter
α-Hemolytic streptococcal bacteremia is well known in of great concern,22 and considerable effort has been expended on
patients with endocarditis and is generally associated with this finding newer agents that are effective against these organisms.23
condition when blood cultures are positive for these organisms. Both linezolid, 600 mg every 12 hours,24 and quinupristin-dalfo-
Echocardiographic confirmation of the diagnosis sets the stage pristin, 7.5 mg/kg every 8 to 12 hours,25 have been successfully
for treatment with penicillin. Therapy is continued until there is used in small treatment groups. The addition of rifampin may
conclusive evidence that the infection has been eradicated. enhance the therapeutic effect.26 Vancomycin resistance is medi-
Other groups of streptococci may be noted in positive blood ated by two separate genes, and there is substantial concern in the
cultures, usually reflecting infections secondary to GI contami- academic community regarding the possible transfer of these
nation. Group B streptococci, long identified as bacteremic genes into staphylococci or other gram-positive organisms.
pathogens in neonates, are now being seen with greater frequen-
GRAM-NEGATIVE ENTEROBACTERIACEAE
cy in adults. In adult bacteremia, group D streptococci are iden-
tified in circumstances similar to those associated with group B The gram-negative Enterobacteriaceae represent a group of
pathogens. Gut-derived streptococcal pathogens are usually facultative bacteria that are associated with infections of the
quite sensitive to penicillins. abdominal cavity, the biliary tract, and the genitourinary tract.
Infections tend to be monomicrobial when the urinary and bil-
Enterococci iary tracts are involved27,28 but are nearly always polymicrobial
Although there is disagreement regarding the true virulence and with peritonitis and intra-abdominal abscess.29 The common
pathogenicity of Enterococcus when it is isolated as part of the gram-negative Enterobacteriaceae include Escherichia coli,
polymicrobial microflora of a clinical exudate,15,16 no one would Klebsiella species, Enterobacter species, and Proteus species.
deny the need for antimicrobial chemotherapy when it is isolated Because intra-abdominal infection is a polymicrobial process,
in blood cultures. Mortalities exceeding 40% clearly underscore bacteremia with one of these organisms in patients with such
the severity of enterococcal bacteremia, though it is likely that infection represents only the tip of the iceberg, with a polymi-
impaired host status contributes significantly to the poor outcome. crobial flora presumed to be present at the focus [see 8:18
The primary foci of infection in enterococcal bacteremia Intra-abdominal Infection].
include intravascular devices and the biliary and GI tracts.
Enterococcal bacteremia ordinarily occurs in elderly or chroni- In the surgical patient, eradication of gram-negative bac-
cally ill patients receiving broad-spectrum antibiotics. Cephalo- teremia requires identification of the primary focus. The intra-
sporins in particular have been implicated as favoring entero- abdominal compartment must be the primary consideration.
coccal overgrowth.17 Enterococcus is usually associated with other Ultrasound examination of the biliary tract may be useful.
bacterial species at the primary site of intra-abdominal or soft Abdominal computed tomography is approximately 90% accu-
tissue infection, and a synergistic relation with other organisms rate in defining abscess. Urinary cultures may be useful but must
may be part of its pathogenic expression.18,19 be cautiously interpreted because a well-drained urinary tract is
Therapy for enterococcal bacteremia requires definition of the an improbable focus for bacteremia. P vulgaris is a urease-pro-
.
primary infectious focus.When Enterococcus is a solitary isolate in ducing organism, and its presence in patients with ileal conduits

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8 Critical Care 27 Blood Cultures and Infection— 6
Table 4—Expanded-Spectrum β-Lactam Antibiotics to lesser drugs, a combination of an expanded-spectrum penicillin
Effective against Enterobacteriaceae with an aminoglycoside is commonly chosen [see Table 5] because
of the synergism between these two types of agents. Culture and
Half-life Dose Interval Total 24-Hr sensitivity data from the primary source of infection are particu-
Drug larly important for guiding modification of drug therapy. Because
(hr) (hr) Dose (g)
a complex patient in the surgical ICU typically has an expanded
Cephalosporins volume of distribution and an altered pattern of antibiotic excre-
Cefoxitin 0.7–1.0 4–6 12–18 tion,31 it is essential that aminoglycoside therapy be pharmacoki-
Cefotetan 3.5 12 2–4
netically dosed. Considerable interest has been expressed regard-
Cefotaxime 1.0 6 8–12
Ceftizoxime 1.5 8 6
ing once-daily dosing of aminoglycosides for gram-negative hos-
Ceftazidime 2.0 8 6 pital-acquired infections33; at present, however, there is only testi-
Ceftriaxone 6.5–8.0 12–24 2–4 monial evidence to support this approach for intra-abdominal
infection.
Penicillins
Ampicillin-sulbactam 1.0 6 12
Nosocomial gram-negative bacteremia is a significant compli-
Ticarcillin-clavulanate 1.0 4 18.6 cation in surgical patients [see 8:16 Nosocomial Infection]. The
Piperacillin-tazobactam 1.0 6 13.5 principal sites are usually the respiratory and urinary tracts and
intravascular devices; the surgical site is a common locus for
Monobactams
Aztreonam 2.0 8 6
nosocomial infection but is only infrequently responsible for the
septic response or bacteremia.
Carbapenems
Imipenem-cilastatin 1.0 6 2–4 ANAEROBES
Meropenem 1.0 6 2–4
Ertapenem 4.0 24 1
The anaerobes of particular significance to surgeons as bacte-
remic pathogens are principally colonists of the human GI tract
and the female genital tract. Oral and cutaneous anaerobes (e.g.,
or staghorn calculi strongly favors a urinary tract source. Gram- diphtheroids) are rarely identified as bacteremic pathogens,
negative bacteremia from hospital-acquired pneumonitis is though diphtheroids are common skin contaminants of the blood-
always a possibility but is less common with the Enterobacteri- culturing process. Bacteroides species, anaerobic streptococci, and
aceae than with Pseudomonas or Serratia species. In general, bac- Clostridium species are the anaerobic pathogens more commonly
teremia from nosocomial pneumonia is relatively uncommon in identified in blood.
surgical patients. Klebsiella and Enterobacter species are known Among all anaerobes, Bacteroides species, particularly B. frag-
pathogens for bacteremia from intravascular devices; appropriate ilis, are the preeminent pathogens. They are customarily identi-
cultures of the primary device are necessary to establish this fied in infections involving distal ileal or colonic contamination.
potential source. Intra-abdominal infection must be considered the primary focus
Mechanical treatment is necessary at the primary focus of of B. fragilis bacteremia.34 Soft tissue infections may also be the
infection.30 Defects in the GI tract must be managed, pus drained, source of Bacteroides bacteremia, particularly in the presence of
necrotic tissue debrided, urinary obstruction relieved, and infect- a polymicrobial infection or necrotic tissue and especially in soft
ed catheters removed. Empirical exploration of the abdomen may tissue infections of the perineum. In one series of patients with
be necessary in bacteremic patients with a high index of suspicion B. fragilis bacteremia, 80% required operative drainage and
for an intra-abdominal source, though at present, it is infrequent- debridement as primary treatment.34
ly required, thanks to ongoing improvements in the technology Selection of antimicrobial therapy for B. fragilis must be based
used to visualize the abdominal compartment (i.e., CT). on an understanding of the pathogenesis of anaerobic infections.
Considerable latitude surrounds appropriate antibiotic thera- Anaerobic infection in the abdomen and soft tissues is synergistic
py for gram-negative bacteremia, particularly when the bac- in that both anaerobic and aerobic organisms benefit from the
teremia is secondary to intra-abdominal infection. When the polymicrobial environment. The aerobes reduce the oxidation-
infectious process is community-acquired, an expanded-spec- reduction potential of the environment, thereby optimizing condi-
trum β-lactam antibiotic is appropriate [see Table 4]. Although
anaerobic coverage is a necessary prerequisite in intra-abdomi-
nal infection, the expanded-spectrum β-lactam agents appear to
yield results equivalent to those of drug combinations that might Table 5—Expanded-Spectrum Penicillins
appear to have superior anaerobic activity. Furthermore, single- and Aminoglycosides Used in Combination
agent treatment with expanded-spectrum β-lactam antibiotics is Regimens in Treatment of Nosocomial
less expensive than multiple-drug therapy and eliminates the Gram-Negative Bacteremia
toxicity and pharmacokinetic dosage complexities of the amino-
glycoside alternatives.31 Ertapenem, a newer carbapenem that Drug Half-life (hr) Total 24-Hr Dose
can be given once daily, may become a desirable choice in the
initial management of peritoneal infection.32 Ticarcillin 1.0 16–18 g
For patients with bacteremia from infections that are hospital- Penicillins Mezlocillin 1.0 16–18 g
Piperacillin 1.0 12–18 g
acquired or represent failures of previous antimicrobial therapy,
specific treatment addressed to these more resistant isolates is Gentamicin 2.0 3–5 mg/kg
required. Single antibiotics that may be chosen to cover hospital- Aminoglycosides* Tobramycin 2.0 3–5 mg/kg
acquired gram-negative bacteria include aminoglycosides, Amikacin 2.0 15–20 mg/kg
expanded-spectrum penicillins, ceftazidime, aztreonam, quino- *Dosing interval and total dose per day are variable: pharmacokinetic dosing is required to
lones, and carbapenems. Even though the isolate may be sensitive prevent toxicity or underdosing.

7. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 Critical Care 27 Blood Cultures and Infection— 7
tions for anaerobic proliferation. The anaerobes may then elabo- dence for primary bacteremia from the GI tract without a pri-
rate factors that accelerate the aerobes’ growth cycle, or they may mary focus of infection, and nonhistotoxic clostridial bacteremia
shed a portion of their capsular polysaccharide into the environ- may be an expression of failed GI barrier function rather than
ment, thereby retarding phagocytosis of all components of the infection in the classic sense.
infection.35 The complexity of this synergistic relation may be fur-
FUNGI
ther compounded by interactions between Enterococcus and either
the gram-negative rod18 or the anaerobic organism.19 Candida species are the most common fungal organisms cul-
Antimicrobial therapy must address both halves of the syner- tured from the blood in surgical patients. Candidemia is typical-
gistic pair, with coverage of the aerobic Enterobacteriaceae being ly seen in a severely ill patient who has had or continues to have
a vitally important component of treatment for the anaerobe.The bacterial infection and is being treated with a prolonged course
expanded-spectrum β-lactam antibiotics appear to provide ade- (more than 7 days) of broad-spectrum antibiotics.37,38 Parenteral
quate polymicrobial coverage. Clindamycin, 900 to 1,200 mg nutrition and corticosteroid therapy are associated with can-
every 6 to 8 hours, or metronidazole, 500 mg every 6 hours, in didemia. The bacterial microflora becomes suppressed, and col-
combination with an aminoglycoside has been the traditional onization of the alimentary tract by Candida organisms becomes
treatment but, as noted, poses special problems. B. fragilis bac- the reservoir for dissemination.
teremia arising from unusual sites (e.g., endocarditis) or bac- Candidemia appears to occur principally via two mechanisms.
teremia in the face of β-lactam antibiotic therapy both call for In the first, indwelling catheters (particularly central lines)
specific clindamycin or metronidazole therapy. It is of the utmost become colonized. Catheter removal and appropriate culture
importance that treatment of anaerobic bacteremia include com- will document the process and likewise be effective treatment. In
plete drainage and debridement of the primary focus. the second, GI overgrowth with Candida leads to impairment of
Peptostreptococci and, to a lesser degree, peptococci are host barrier function and resultant fungemia.38 Although peri-
anaerobic streptococcal species that may cause bacteremia from tonitis and intra-abdominal abscess with Candida organisms
infection after GI contamination. More commonly, their pres- have been identified,39 translocation of the organisms across the
ence should arouse suspicion that bacteremia may be arising gut barrier is the probable source of contamination.
from the female genital tract. Either of these anaerobes may par- Prevention of candidemia requires aseptic care of catheters
ticipate in puerperal sepsis and pelvic inflammatory disease, with and prompt catheter removal when fungemia is suspected or
common gram-negative Enterobacteriaceae, enterococci, or documented. A reduction in the spectrum and duration of sys-
both acting as synergistic partners in the infection. Bacteroides temic antibiotic therapy is probably the most important method
species may also participate in such infections. of reducing fungal overgrowth and subsequent risk of dissemi-
Bacteremia with anaerobic streptococci secondary to infection nation. Oral nystatin, ketoconazole, and fluconazole have been
in the female genital tract mandates a search for a drainable pri- recommended for prophylaxis in patients at risk for candidemia
mary focus. For puerperal sepsis, dilatation and curettage may be but remain unproven.
required to eliminate retained products of conception. Pfannen- Diagnosis and treatment of candidemia are discussed in detail
stiel flaps may become sources of surgical site infection (SSI) that elsewhere [see 8:19 Fungal Infection].
may cause bacteremia and thus must be drained and debrided.
Pelvic inflammatory disease may be complicated by tubo-ovarian
abscess or extrauterine abscess within the pelvis that will have to Positive Blood Culture without
be drained. Infection
Appropriate antibiotic therapy for anaerobic streptococcal In the late 1950s, Jacob Fine proposed
bacteremia remains unclear. Most anaerobic species likely to the theory that acute physiologic pertur-
cause infection in the female genital tract are sensitive to peni- bations (e.g., hemorrhagic shock) could
cillin, with Bacteroides species being a notable exception.Therapy disrupt GI barrier function to the point
with an anaerobe-specific agent (e.g., clindamycin or metronida- where bacteria and their cellular prod-
zole) in combination with an aminoglycoside, however, appears ucts could escape from the gut reser-
to offer better clinical results in puerperal infection. The role of voir40-42 and contribute to clinical illness. In other words, the sep-
the expanded-spectrum β-lactam agents remains poorly defined. tic response could be triggered by bacteria or their products (e.g.,
Because Enterococcus is commonly identified in infections involv- endotoxin) in the absence of infection, as it is traditionally under-
ing the female genital tract, ampicillin is frequently added to the stood. Although this theory was discredited in the 1960s in germ-
antibiotic regimen, but this measure is of unproven value. free rat experiments,43,44 it enjoyed a considerable resurgence in
Clostridium species are gram-positive anaerobic rods that are the late 1980s, as both experimental45-49 and clinical50,51 studies
relatively uncommon in blood cultures and are ordinarily associ- demonstrated that GI microbial translocation appears to be a valid
ated with clostridial myonecrosis or cellulitis. Usually, the fulmi- biologic event. Consequently, it has been proposed (although not
nant nature of the infection is readily identifiable at the primary universally accepted52) that some surgical patients may have the
soft tissue focus, and blood culture is of little assistance in diag- septic response secondary to microorganisms while lacking a pri-
nosis. Therapy consists of radical debridement of the primary mary infectious focus.
site of infection and aggressive administration of penicillin [see
MECHANISMS OF GUT BARRIER FUNCTION
3:2 Soft Tissue Infection].
Nonhistotoxic clostridial bacteremia has been identified with For microbial translocation to be clinically relevant, gut barri-
increased frequency. In a series of 47 patients with such bac- er function must be impaired. At its most distal site, the lumen
teremia, only 25% had a focus of infection36; the remaining 75% of the human GI tract may contain as many as 1010 bacteria/g
had no clinically identifiable source. The patients in this latter colon contents. The biologic partition that prevents microbes
group either were severely, chronically ill or were alcoholics; from escaping from this reservoir is complex and consists of
thus, the presence of a colonic anaerobe in blood may be evi- anatomic, physiologic, and immunologic mechanisms.

8. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 Critical Care 27 Blood Cultures and Infection— 8
The physical barrier of the gut consists of a contiguous layer of remain vigilant and continue to search for infectious foci that
enterocytes and colonocytes. An intercellular matrix exists may be driving the septic response.
between the cells. Both types of cell appear to obtain a large part The presence of certain opportunistic microbes in blood cul-
of the nutrients they need directly from the gut lumen. tures strongly implies that GI microbial translocation may have
Enterocytes have a specific nutrient requirement for glutamine,53 occurred. The organisms making up the so-called trilogy of
and colonocytes require short-chain fatty acids.54 Deficiencies of translocation—namely, Enterococcus, S. epidermidis, and Candida
these critical nutrients lead to atrophy of the gut lining, which species—are common overgrowth organisms after long-term
results in a defective physical barrier. broad-spectrum antibiotic therapy and are commonly identified
The surface of the gut mucosal cells is covered with the glyco- together in blood cultures. Obviously, when blood cultures are
protein mucin,55 which is an important component of the gut positive for these organisms, any potential infectious source must
barrier.The mucin layer has a nonspecific retarding effect on bac- be ruled out, particularly bacteremia from intravascular devices.
terial adherence to mucosal cells; in addition, it has a nonspecific Fundamental to the prevention and treatment of microbial
inhibitory effect on bacterial proliferation at the mucosal cell sur- translocation is reinforcement of the gut barrier. Enteral rather
face, thereby helping prevent invasion by luminal bacteria. than parenteral nutritional support is always recommended if the
Secretory IgA also prevents the binding of bacteria to mucos- clinical circumstances permit [see 8:22 Nutritional Support].59
al cells.56 Presumably produced as nonspecific antibody from Intraluminal nutrients are delivered directly to the mucosal cells
submucosal gut lymphocytes, IgA does not fix complement and and promote GI motility60; moreover, they foster proliferation of
does not have cytotoxic effects on bacteria. Rather, it is thought a more normal intestinal microflora. Mobilization of the patient
to bind to bacteria and impede their binding to the mucosal from the recumbent position likewise promotes GI motility and
cell lining. The IgA concentration is highest at the mucosal cell is a critical feature of early fixation of long-bone fractures in mul-
surface. tiple-trauma patients.58,61 Immunonutritional regimens enhanced
The normal microflora that colonizes the GI lumen appears with glutamine, arginine, omega-3 fatty acids, and nucleotides
to make a significant contribution to normal gut barrier func- have yielded encouraging results in prospective clinical trials.62
tion. Anaerobic bacteria play a positive role by virtue of their It is also important to reevaluate patterns of antibiotic use.
species-specific adherence to mucosal cell-binding sites and their Although anaerobes act synergistically with aerobes in intra-
ability to prevent more noxious aerobic species from adhering to abdominal and soft tissue infections, the anaerobes in the GI
mucosal cells via competitive inhibition.57 This positive role cre- tract are important components of the gut barrier.63,64 Because
ates a real dilemma for clinicians attempting to formulate anti- anaerobes are seldom nosocomial pathogens, systemic antibi-
microbial regimens for critically ill patients. otics that act against anaerobes should not be used for ICU-
Normal GI motility is perhaps the most important of the phys- acquired infections unless clearly necessary. Some clinicans
iologic components of the gut barrier. Movement of luminal con- advocate selective gut decontamination (SGD), in which intra-
tents distally within the gut keeps intraluminal bacterial concen- luminal antibiotics are employed to reduce aerobic colonization
trations relatively low in the proximal gut and reduces the risk of of the gut while preserving the anaerobic species.65,66 One meta-
adherence and translocation. There is, in fact, considerable evi- analysis found this technique to improve survival.67 In the United
dence suggesting that ileus and intestinal obstruction may be States, however, concerns about potential resistance problems
important factors in the so-called gut origin septic response.58 from using antibiotics in this way within the critical care envi-
ronment has limited the use of SGD.
FACTORS COMPROMISING BARRIER FUNCTION
In critically ill surgical patients, numerous associated clinical
factors compromise the various components of barrier function. Negative Blood Culture with
Critical illness and injury lead to disordered GI motility and Infection
ileus. Antibiotic therapy frequently covers the common aerobic A positive blood culture is generally
and anaerobic members of the normal microflora, which results accepted as proof that microbial dis-
in overgrowth of the gut with resistant aerobic species. Parenteral semination has occurred and that this
nutrient solutions are characteristically deficient in glutamine process is the stimulus for the septic
and short-chain fatty acids, and sustained use of such solutions response (though, as noted [see Positive
can cause atrophy of the mucosal barrier. IgA and mucin pro- Blood Culture without Infection,
duction may be compromised by the catabolism typical of severe above], such an assumption is not always warranted). However,
illness. In essence, all of the components of the gut barrier are most patients who manifest the septic response secondary to
potentially vulnerable, and microbial translocation (and, subse- severe infection do not have positive blood cultures. In such
quently, the systemic septic response) can result from impair- cases, it is the septic response, rather than the blood culture
ment of any or all of them. itself, that is the most useful clinical indicator of a systemic reac-
tion to infection.
RECOGNITION AND MANAGEMENT OF MICROBIAL
TRANSLOCATION REASONS FOR NEGATIVE CULTURE
The clinical basis for the diagnosis of microbial translocation Patients with the septic response secondary to infection may
is imprecise: there is no distinctive clinical marker of this event. have negative blood cultures for any of several reasons. First, the
Essentially, the diagnosis is one of exclusion. When all conven- septic response may have been activated by disseminated
tional infectious sources for a septic response have been exclud- microorganisms that are sensitive to concurrently administered
ed by careful clinical evaluation, microbial translocation is con- antibiotics.The patient may actually be bacteremic, but the pres-
sidered to be the cause. This clinical diagnosis is a treacherous ence of active antibiotic in the blood prevents bacterial growth in
one and can only be made presumptively. Even when one is con- the culture. For certain antibiotics, there are laboratory methods
vinced that microbial translocation is operative, it is vital to for neutralizing the effects of their concurrent administration

9. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 Critical Care 27 Blood Cultures and Infection— 9
Table 6—Common Bacteria Cultured from ed. Special emphasis must be placed on the surgical site and on sites
ICU Patients with Pneumonia: NNIS System where invasive monitoring devices (e.g., a Foley catheter) or support
Report, 1990–199970 instruments (e.g., an endotracheal tube) have been introduced into
the patient. Nonbacteremic patients may indeed have the septic
Type of ICU response without being infected [see Septic Response without Micro-
organisms, below], but this can only be determined after systematic
Organism Cardiothoracic General Trauma (%) evaluation for a primary infectious focus.
(%) Surgery (%) Once a presumptive source of infection has been identified,
the primary focus should be drained mechanically, and empiri-
Pseudomonas aeruginosa 13.1 17.2 17.1
Enterobacter species 13.1 12.8 13.4
cal antimicrobial therapy directed toward the anticipated
Staphylococcus aureus 11.3 17.0 18.1 pathogens should be initiated while culture and sensitivity data
Candida albicans 6.3 3.9 1.5 are pending. For intra-abdominal infections, the antibiotic regi-
Klebsiella pneumoniae 5.9 7.2 7.0 men must cover both enteric aerobes and anaerobes. For post-
Haemophilus influenzae 5.8 4.4 7.4 operative pulmonary infection, multiresistant gram-negative
Escherichia coli 4.8 4.9 4.4 rods and S. aureus are the most common pathogens [see Table
Enterococcus species 2.3 1.8 1.1 6].70 Postoperative urinary tract infections are usually caused by
All others 37.4 30.9 29.9 enteric aerobic gram-negative rods, but more and more often,
they are being caused by Candida species [see Table 7]. Intelligent
antibiotic selections for these infections requires a working
(e.g., penicillinase), but for most, this is not the case. Second, it
knowledge of the antibiogram of the ICU.
may have been dissemination of bacterial cellular products (most
Many critically ill patients who have undergone operation
notably, endotoxin) rather than whole, viable microorganisms
have already received antibiotic therapy at some point during
that activated the septic response. Third, the response may have
management. Culture and sensitivity information must therefore
been activated by systemic distribution of cytokine signals from
be continuously obtained because the pathogens found in com-
an intense infectious focus (e.g., severe peritonitis), without dis-
plex ICU patients with the septic response are often resistant to
semination of either bacteria or their products from the focus.
multiple conventional antibiotics.
Fourth, given that bacteremia is an episodic process and blood
Although in many cases the source of the infection and the
culture a random event, the culture sample may simply have been
attendant septic response is readily apparent, in many others the
obtained at a time when the patient was temporarily nonbac-
diagnosis can only be presumptive. Constant vigilance for
teremic. The frequency of positive blood cultures in critically ill
changing clinical findings and careful observation of the
SICU patients is so low and the value of the occasional positive
response to empirical therapy are essential. For example, if a
culture so minimal that several authors have recommended not
postoperative patient with the septic response has a urinary tract
even drawing blood samples for culture in this population.68,69
culture that is positive for E. coli at 105 colony-forming units/ml,
EVALUATION AND MANAGEMENT it does not necessarily follow that the urinary tract is the source
of the septic response. In my experience, a well-drained urinary
Nonbacteremic patients who manifest the septic response must
tract is seldom the source of a postoperative septic response;
still be evaluated just as thoroughly as bacteremic patients would be,
other sources must be considered even when a positive urinary
with the aim of ascertaining whether there is a primary source of
tract culture has been obtained.
infection.The lungs, the urinary tract, surgical or traumatic wounds,
In the absence of a diagnosis, it is generally difficult to handle
visceral compartments, and I.V. devices must all be sequentially
either the infection or the septic response effectively; thus, contin-
evaluated. Careful physical examination, appropriate diagnostic
ued intensive surveillance is essential.The objective of management
studies for each anatomic area (e.g., CT scans for the abdomen),
is to control, by mechanical and pharmacologic means, the prima-
and aggressive culturing of suspicious fluids or exudates are indicat-
ry infectious source or sources of the disseminated whole microor-
ganisms, microbial cellular products, or inflammatory cytokines
that are responsible for the clinical septic response. Unfortunately,
Table 7—Common Bacteria Cultured from ICU this objective is not equally appropriate for all nonbacteremic sep-
Patients with Urinary Tract Infections: NNIS System tic patients: as is now well established, the septic response can be
Report, 1990–199970 activated by processes other than clinical infection.
Type of ICU
Septic Response without
Cardiothoracic General Microorganisms
Organism Trauma (%)
(%) Surgery (%) Traditional assumptions notwith-
Candida albicans 21.0 16.3 10.8
standing, there is no necessary associa-
Pseudomonas aeruginosa 12.6 13.1 13.5 tion between the activation of the septic
Escherichia coli 12.5 14.6 20.1 response and the presence of infection:
Enterococcus species 8.5 14.5 15.5 any physiologic event that can trigger a
Klebsiella pneumoniae 6.1 6.1 4.5 severe local inflammatory response is
Enterobacter species 5.9 6.2 6.5 potentially capable of activating the septic response.71-73 Extreme
Coagulase-negative 1.6 1.9 3.5 local tissue inflammation without a microbial component can
staphylococci
cause the release of inflammatory cytokines into the circulation in
Staphylococcus aureus 0.6 1.3 1.7
All others 31.2 26.0 23.9
sufficient quantities to evoke the septic response. The clinical
manifestations of the septic response are essentially the same

10. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 Critical Care 27 Blood Cultures and Infection— 10
whether it is caused by infection or not; thus, the diagnosis of the Effective supportive care is essential to the management of the
septic response secondary to sterile inflammation must be one of septic response secondary to sterile inflammation. Volume sup-
suspicion and exclusion. port to maintain an adequate cardiac output and tissue perfusion
Of the common clinical entities that can trigger the systemic is vital.The pulmonary microcirculation is the early target of the
septic response, perhaps the most notable is acute pancreatitis. septic response; accordingly, support of systemic oxygenation
The clinical course of severe acute pancreatitis managed with with mechanical ventilation is often necessary.
aggressive volume resuscitation includes loss of peripheral vas- A vexing problem associated with severe pancreatitis or aspi-
cular resistance, elevated cardiac output, elevated white blood ration pneumonia is that a number of separate stimuli capable of
cell counts, and fever. Indeed, Ranson’s criteria reflect charac- activating the septic response will present themselves during the
teristics of systemic inflammation, including end-organ damage course of protracted management. In a patient with severe pan-
to the lungs, the liver, and the kidneys.74 Patients with severe creatitis, for example, the primary inflammatory focus gives rise
acute pancreatitis often clearly illustrate the rapid physiologic to an initial septic response characterized by pulmonary failure.
progression from the septic response to the multiple organ dys- The patient is effectively resuscitated and appears clinically
function syndrome (MODS) [see 8:13 Multiple Organ Dysfunc- improved by the fourth or fifth day of hospitalization. By this
tion Syndrome]. Other conditions that can activate the septic point, however, an infectious focus, in the form of a pancreatic
response are severe aspiration pneumonitis, which initially is a abscess, has often developed, and this infectious focus evokes a
chemical event that evokes an intense inflammatory response, second septic response. Multiple operations and prolonged
and multiple trauma with extensive soft tissue injury, necrosis at antibiotic therapy then set the stage for microbial translocation
the injury site, and tissue hematoma. Even extracorporeal mem- from the gut, which results in candidemia and a third septic
brane oxygenation can be associated with acute activation of the response.
complement cascade and a postoperative septic response leading What is more, not only may a single pathologic condition give
to end-organ failure, without infection or bacteria being involved rise to various stimuli that can elicit the septic response, but
at all. severely ill surgical patients may also have additional separate
When the septic response occurs in one of these settings, the inciting causes (which can occur either sequentially or simulta-
clinician often is anxious about the possibility of infection and is neously) during management, each of which may be associated
tempted to initiate antimicrobial therapy, at the very least. How- with one or more septic stimuli. Indeed, a major challenge for
ever, it is the response itself, rather than any infection, that is the the future—perhaps the major challenge—is the necessity
fundamental problem to be dealt with in these patients. Obviously, of achieving better definition of clinical markers for specific
then, antibiotic therapy will be ineffective in such cases, and spe- stimuli of the septic response so that treatment can be better
cific treatment must be directed toward the septic response. directed.
Discussion
Sepsis as Nonspecific Systemic Inflammatory Response ly injured patients to a biologic point never before reached. As a
Infection has traditionally been viewed as a local inflammato- result, the septic response may now be seen as a consequence of
ry response within tissue that is initiated and perpetuated by (1) microorganisms in the context of infection, (2) microorgan-
microorganisms. It is generally agreed that the numerous ele- isms in the absence of infection, and (3) inflammatory events not
ments of host defense are designed to both contain and eradicate associated with either microorganisms or clinical infection.
the microbial provocateurs of this inflammatory process. It is
also generally recognized that a threshold exists, the breaching of
Elements of the Septic Response
which results in the dissemination of the infectious process and
the elicitation of a systemic inflammatory response. The precise The septic response represents an evolution of multiple physio-
point at which this threshold is passed has not been well defined logic and metabolic changes. These changes do not constitute an
clinically; however, the clinical expressions of this event are eas- either-or phenomenon but instead take place along an ever-chang-
ily recognized [see 8:14 Clinical and Laboratory Diagnosis of ing continuum. Consequently, it is difficult to determine exactly
Infection]. when a patient ceases to manifest an appropriate stress response
There is considerable evidence to support the theory that in and begins to manifest a deleterious septic response.The key phys-
the so-called septic patient, there occurs a generalized, systemic iologic elements of the septic response are (1) reduced peripheral
activation of the inflammatory cascade. The intricate inflamma- vascular resistance, (2) hyperdynamic cardiac performance, and
tory response to injury that is so salutary at the tissue level actu- (3) narrowing of the arteriovenous oxygen content difference.The
ally becomes a self-destructive process when activated at the sys- metabolic features of the septic response are quite complex but
temic level.75 Although these septic events have been associated can be simplified into five main elements: (1) hypermetabolism,
most often with uncontrolled infection, it is now appreciated that (2) accelerated hepatic gluconeogenesis, (3) accelerated hepatic
the systemic inflammatory response is in fact a nonspecific host ureagenesis, (4) increased urinary nitrogen loss, and (5) insulin
response in the same way that soft tissue inflammation is non- resistance.These metabolic changes are discussed in greater detail
specific. elsewhere [see 8:25 Metabolic Response to Critical Illness].
We can now identify a changing perspective with respect to Reduced peripheral vascular resistance—contrasting dramati-
the stimuli of the septic response in the SICU. Current support cally with the increased resistance associated with hypovolemia
technology permits sustained survival of critically ill and severe- and cardiac failure—is the sine qua non of the septic response.

11. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 Critical Care 27 Blood Cultures and Infection— 11
Natural History of the Septic Response
Cardiac Output
In the predominant view of the natural history of the septic
response,84 exaggeration of the fundamental stress response is
the basis for deterioration of the patient from a compensated
state (i.e., the stress response) to a decompensated state (i.e., the
septic response). The key element in the natural history of the
septic response is the relation between cardiac output and
peripheral vascular resistance [see Figure 3].
State A represents the normal adaptive stress response, the
first-order response to biologic insults. Cardiac output is mod-
A B C D
estly elevated, and peripheral vascular resistance is modestly
Systemic Vascular Resistance reduced. Systemic oxygen consumption is increased, but lactate
concentration is not. State A reflects the postresuscitative physi-
ology of the injured or postoperative patient. The hemodynamic
profile progressively returns to normal over several days, provid-
ed that there is no intercurrent insult (e.g., infection).
State B represents the exaggerated stress response and marks
the transition to the beginning of biologic decompensation.
Peripheral vascular resistance is profoundly reduced. A total
A B C D peripheral vascular resistance lower than 800 dynes-sec/cm5 is
the commonly recognized threshold for the septic response;
Figure 3 Illustrated is the relation of cardiac output to peripheral resistance may decline to 400 dynes-sec/cm5 or even lower. The
vascular resistance during the natural history of the septic
afterload reduction results in dramatic elevation of cardiac out-
response. The areas indicated by the light-red boxes are state C,
reflecting the onset of clinical septic shock.
put. An acceptable arterial blood pressure can usually be sus-
tained unless intrinsic myocardial disease or hypovolemia is
present.The increased capacitance typical of state B necessitates
(It must be emphasized that whereas resistance is reduced for considerable preload support, which often calls for aggressive
the vascular system as a whole, this may not be the case for each fluid administration. Measurement of the pulmonary capillary
individual tissue bed.) The loss of resistance is particularly inter- wedge pressure is often necessary to facilitate the expansion of
esting in light of the elevated catecholamine concentrations that intravascular volume.
are simultaneously identified in these patients. These elevations State B is also characterized by accumulation of lactate species
reflect the counterregulatory metabolic milieu of the septic in the blood before the evolution of frank clinical hypotension.
response.76,77 The alpha-adrenergic effects of the catecholamines Blood lactate concentrations reflect net lactate production in
are obviously overridden by other peripheral mechanisms. selected tissues minus lactate utilization in other tissues. Because
The systemic vasodilatation appears to be caused primarily by not all tissues are necessarily affected equally by the septic
nitric oxide from endothelial cells in the microcirculation.78-81 response process, oxidation of lactate by selected well-perfused
Nitric oxide is a paracrine signal that mediates relaxation of vas- tissues may compensate for production of lactate by others. Lactic
cular smooth muscle. Its synthesis and release are stimulated by acidemia preceding lactic acidosis is usually seen in patients with
several agonists, including endotoxin, bradykinin, and acetyl- sustained state B; compensatory mechanisms prevent acidosis
choline. Although prostacyclin and histamine are also potential until later in the process. These patients are actually in a state of
mediators of vasodilatation, at present, nitric oxide appears to be shock, even though their arterial blood pressure is considered nor-
the principal mechanism. mal, because tissue oxygen utilization is clearly impaired.
Hyperdynamic cardiac performance is the obligatory response State C heralds the beginning of septic shock as traditionally
of the left ventricle when peripheral vascular resistance declines. defined—that is, as hypotension in a nonhypovolemic patient
For cardiac output to increase, however, intravascular volume that is secondary to severe infection. State C patients fulfill this
must be replenished, and the myocardium must possess suffi- definition: they have mild to severe hypotension, with systolic
cient physiologic reserve. Thus, elderly patients may not be able arterial blood pressure lower than 80 mm Hg. In this setting,
to meet the physiologic demands imposed by sepsis-induced however, septic shock is secondary to the severe and exaggerat-
afterload reduction, and such inability results in the hypody- ed loss of peripheral vascular resistance; although cardiac output
namic septic shock state. Even in young, healthy patients, sus- may be normal or slightly increased (8 to 10 L/min), it is insuf-
tained hyperdynamism ultimately leads to ventricular failure and ficient to compensate for this loss.
low cardiac output. State C patients are in so-called hot shock. They are warm to
Narrowing of the arteriovenous oxygen content difference in the touch and usually show evidence of diaphoresis. Their cuta-
the hyperdynamic patient is perhaps the most important of the neous tissues appear well perfused, even though the arterial
critical mechanisms responsible for the septic response. Oxygen blood pressure is low. The loss of perfusion pressure acts syner-
consumption is inadequate to meet the demands of hyperme- gistically with the peripheral defect in oxygen utilization to cre-
tabolism,82,83 and lactate production is the result.When intravas- ate a severe peripheral oxygen debt that is clearly reflected in the
cular volume is fully expanded, further increases in cardiac severe lactic acidosis seen in state C.
output result in further narrowing of the arteriovenous oxygen State D represents the final phase in the process, in which frank
content difference. Failure of peripheral oxygen utilization is congestive heart failure emerges. Cardiac performance is consid-
fundamental to the septic process and underscores that this erably depressed. Autonomic mechanisms override the vasodila-
response is not characterized by inadequate myocardial perfor- tory influences seen in state C, and peripheral vascular resistance
mance until its very latest stages. is now increased. In state D, low cardiac output, peripheral vaso-

12. © 2003 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice
8 Critical Care 27 Blood Cultures and Infection— 12
constriction, and peripheral defects in oxygen utilization work
Stimulus (bacteria,
simultaneously to produce profound tissue hypoxemia and lactic bacterial cell products,
acidosis. In the absence of dramatic therapeutic and supportive dead tissue)
measures, this is the preagonal period before death.
Pathophysiology of the Septic Response
C3a
Fundamental to our understanding of the septic response is Complement Macrophage
activation C5a activation
the idea that its negative and destructive features are simply the
systemic manifestations of what is otherwise a positive and bene- C3
a,
ficial local inflammatory response to tissue injury. This crucial PA C5a
point can be illustrated by considering the local events that attend F
soft tissue injury.These events, in essence, are the septic response
in microcosm. Focal tissue Neutrophil Cytokine
necrosis activation release
LOCAL EVENTS
OH •
Soft tissue injury triggers a local inflammatory response that H2O2
O2–
includes disruption of blood vessels, exposure of the collagen
matrix, extravasation of red blood cells and plasma proteins, acti- Microcirculatory Endothelial
vation of the coagulation cascade, aggregation of platelets, and arrest injury
activation of the complement cascade via the alternative path-
way. It is likely that by-products of coagulation and complement
activation, among other potential biochemical signals, stimulate
mast cells to initiate the first phases of the inflammatory
response; the specific cleavage products of complement proteins Microaggregation
C3, C4, and C5 (the soluble anaphylatoxins C3a, C4a, and C5a) Microvasoconstriction (TXA2)
are known to be the most potent stimuli of mast cell degranula-
tion.85-87 The production of bradykinin from plasma protein pre- Figure 4 Shown is the self-energized cycle of tissue-level injury
cursors occurs via the stimulation of activated factor XII from that becomes the end-organ consequences of the septic response.
the coagulation cascade. The activation of these five initiators of Activation of the inflammatory cascade via several different stim-
uli results in neutrophil activation, which leads to autodestructive
inflammation (coagulation cascade, platelets, complement pro-
inflammation, tissue ischemia, tissue necrosis, and reactivation of
teins, mast cells, and bradykinin) have the specific effects of (1) the process.
local vasodilatation, which increases local flow but reduces flow
velocity in the area of injury; (2) increased capillary permeabili-
ty, which results in extravasation of protein-rich plasma into the hanced phagocytic activity and elicit the extracellular release of
injured area, thereby initiating edema formation; and (3) gener- reactive oxygen intermediates and lysosomal enzymes.The accel-
ation of numerous inflammatory enzyme and protein cleavage erated phagocytic activity results in the death of the neutrophils
products, which act as chemoattractants. and the formation of pus. Suppuration at the epicenter of the
Diffusion of the chemoattractant signals from the epicenter of injury is further enhanced when the TNF signal diffuses into the
injury begins the process of phagocytic infiltration of the injured adjacent microcirculation, where marginated neutrophils, recruit-
area. Chemoattractants bind to specific receptor sites on vascular ed into the inflammatory focus, are fully activated, resulting in
endothelial cells and initiate the interaction of the endothelial cell thrombosis of the adjacent microcirculation.This microcirculato-
with the intravascular neutrophil [see 8:26 Molecular and Cellular ry thrombosis is actually beneficial in that it prevents bacteria or
Mediators of the Inflammatory Response].The gradient of chemoat- their products from gaining systemic access. Indeed, the ultimate
tractant signals from the epicenter of the injury then serves as a function of the inflammatory response is the containment and
beacon to direct phagocytic diapedesis toward the site of injury subsequent eradication of bacterial contaminants.
and contamination.The severity of the injury, the extent of necro-
SYSTEMIC EVENTS
sis, and the degree of exogenous microbial contamination dictate
the intensity of the summed chemoattractant signals that govern The systemic septic response comprises the same sequence of
the rapidity and the quantity of neutrophil infiltration. events just described, except that the activation of the inflamma-
Approximately 24 hours after injury, macrophages infiltrate the tory cascade is generalized and lacks the clear directional focus
area via the same mechanisms for margination and chemotaxis that characterizes the local response. In severe infection, dissemi-
that mobilized the neutrophils. Macrophages orchestrate the nation of bacteria and endotoxins leads to systemic activation of
severity of the inflammatory response. If necrotic tissue and for- the initiator pathways of inflammation. Systemic activation of co-
eign elements (e.g., bacteria) are minimally present in the area of agulation, platelets, complement proteins, mast cells, and brady-
injury, then the magnitude of the chemoattractant signal is small, kinin results in generalized edema, systemic vasodilatation, and a
macrophages are minimally activated, and the neutrophils pro- generalized release of chemoattractant signals. Generalized neu-
ceed with phagocytosis in an orderly fashion. If, however, bacte- trophil margination occurs. The upregulation of the generalized
rial contamination is severe and there is considerable necrotic tis- inflammatory response results in full activation of marginated
sue, then the amplitude of chemoattractant effects will be great, neutrophils. From their intravascular and perivascular positions,
which results in full activation of macrophages. Fully activated the activated neutrophils subsequently release reactive oxygen
macrophages elaborate multiple proinflammatory signals that intermediates and lysosomal enzymes. The resulting inflammato-
induce the neutrophils to enter a state of accelerated and en- ry injury to the microcirculation leads to aggregation of platelets,