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22 Sepsis, Severe Sepsis, and Septic Shock
263
Table 22.3 RIFLE criteria for renal failure
Creatinine criteria Urine output criteria
Risk Increased Cr × 1.5 UOP<0.5 mL/kg × 6 h
Injury Increased Cr × 2 UOP<0.5 mL/kg × 12 h
Failure Increased Cr × 3 or Cr ≥4 mg/dL UOP<0.3 mL/kg/h × 24 h
or Anuria × 12 h
Loss Persistent ARF = complete loss of renal function >4 weeks
ESRD End-stage renal disease
the setting of sepsis will do so in the fi rst 7 days of the ICU
course. Hypotension at the time of diagnosis is strongly
associated with subsequent AKI and likely refl ects the end
result of hypoperfusion of the renal tissues. When acute kidney injury complicates sepsis, the risk of hospital mortality
increases to 25 %. Additionally, patients with surgical sepsis
complicated by AKI are more prone to other infections,
multi-organ failure, increased ICU days, and decreased likelihood of discharge to home [ 47 ].
Treatment of AKI is supportive. Judicious fl uid and electrolyte management, cautious use of diuretics for volume
overload, and continued management of sepsis are necessary
until the acute phase resolves. Consultation with the nephrologist should occur early in the course of acute kidney injury,
and dialysis should be initiated if indicated. Fluid and electrolyte clearance are equivalent in both continuous and intermittent renal replacement therapy. However, due to decreased
fl uid shift and the ability to manage fl uid removal on an
ongoing basis, continuous renal replacement therapy is more
appropriate in the patient with unstable hemodynamics due
to septic shock [ 12 ].
ARDS and Sepsis
Acute respiratory distress syndrome, fi rst defi ned by
Ashbaugh in 1967, is broadly defi ned as acute hypoxemic
respiratory insuffi ciency with bilateral pulmonary infi ltrates
on chest radiograph, not explained by left atrial hypertension. Multiple defi nitions and classifi cations have evolved
since its description. The most recent iteration, the Berlin
Defi nition, classifi es ARDS on partial pressure of arterial
oxygen to fractional concentration of inspired oxygen (P:F
ratio) as mild (200<P:F≤300), moderate (100<P:F≤200),
and severe (P:F≤100) [ 48 ]. Severe sepsis is the most com-
mon risk factor for ARDS in all patients and carries a mortality rate of nearly 40 %. Although a full iteration of the
management of ARDS is outside the scope of this chapter,
the general principles of ventilator management include
lung-protective ventilation strategies (VT = 6 ml/kg IBW and
Pplat ≤30 cm H20), liberal use of PEEP to assist oxygenation, and recruitment maneuvers and prone positioning for
severe refractory hypoxemia [
12 ]. Although concerns have
been raised for intravenous fl uid volumes causing or worsening ARDS, end-organ perfusion of the patient in septic shock
should remain the top priority in resuscitation [
24 ].
Neurologic Dysfunction in Severe Sepsis
Like all organ systems affected by the deleterious, systemic
response to infection, the central nervous system may also be
affected. The patterns of brain dysfunction in severe sepsis
range from acute delirium to coma. Less commonly, severe
sepsis or septic shock may cause focal neurologic defi cits or
seizures. These patterns of central nervous system dysfunction may be seen in up to 60 % of patients who develop severe
sepsis or septic shock during their hospital course [ 49 ].
The neurological manifestations of severe sepsis and septic shock are thought to arise secondary to disseminated
intravascular coagulation, and imaging fi ndings are often
similar to those in microvascular ischemic events. Although
the initial workup for many of these patients will include a
CT scan, MRI has been recommended as the test of choice
due to its ability to reveal diffuse white matter lesions and
increased sensitivity for ischemic stroke. These fi ndings are
associated with increased risk of inpatient mortality and
decreased likelihood of discharge to home [ 50 ].
Multi-organ Dysfunction Syndrome
Like sepsis, severe sepsis, and septic shock, the damaging
immune response associated with an infectious insult affects
the organ systems along a continuum of severity. Multiple
organ dysfunction syndrome (MODS) exists when organ function is compromised to an extent in the acutely ill patient that
homeostasis cannot be maintained without intervention. The
majority of deaths in the ICU due to septic shock are the end
result of multiple failed organ systems. As discussed earlier in
this chapter, the Sequential Organ Failure Assessment or SOFA
score can be used to objectively quantify the degree of dysfunction in the cardiovascular, pulmonary, hepatic, renal, coagulation, and neurologic systems. This score can be easily
recalculated daily based on the above parameters and provides
an additional metric that accounts for the amount of global dysfunction of the patient with complicated sepsis. SOFA scores
of greater than 15 points are associated with 90 % mortality.
Persistent Infl ammation/
Immunosuppression Catabolic Syndrome
The successful management of severe sepsis and septic
shock has allowed more patients with more severe degrees of
organ dysfunction to survive much longer than in previous
264
A.C. Gaugler and N. Namias
decades. Often, these patients remain in the ICU for weeks to
months with ongoing need for ventilator and renal support,
low to moderate doses of vasopressors, and smoldering
organ dysfunction. They develop secondary infections and
receive multiple courses of antibiotics, drainage procedures,
and numerous lines and catheters. This prolonged critical illness leads to progressive protein catabolism, muscle wasting, and failure to regain strength. We redefi ne success in
these patients as discharge to a long-term acute-care facility,
rather than return to meaningful functional status.
This syndrome of persistent infl ammation, immunosuppression, and catabolism has been termed PIICS by Moore
and colleagues. Their criteria include a prolonged hospital
course greater than 14 days, laboratory evidence of persistent infl ammation as a C-reactive protein>150 mcg/dL,
immunosuppression with total lymphocytes <800/mm3, and
catabolism with weight loss>10 % over hospital stay, marked
by albumin<3 mg/dL, prealbumin<10 mg/dL, or retinolbinding protein<10 mcg/dL. Correcting the trajectory for
these patients is diffi cult and their potential for rehabilitation, at this time, is dismal. As the therapeutic management
of severe sepsis and septic shock continues to advance, caring for these patients will provide new challenges for rehabilitation and surgical nutritional support [
51 ] .
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Source Control and Supporting Therapeutics: Integrating Bacterial Invasion, Host Defense, and Clinical Interventions with Source Control Procedures
Lewis J. Kaplan , Addison K. May , and Lena M. Napolitano
2 3
Introduction
Surgeons are integrally involved in addressing devitalized,
perforated, or infected organs and tissue. The integrated
moniker appended to this practice regardless of complexity
is “source control” [ 1 , 2 ]. Nonetheless, such undertakings
have not occurred in a vacuum and have relied on and benefi tted from the synergistic effects of fl uid resuscitation and
adjunctive antimicrobials agents to improve patient outcome.
Advances in technology, particularly in catheter-based and
imaging technology, have changed the landscape of source
control by eliminating or delaying operative therapy for certain conditions that would have been previously managed
primarily by an operative procedure. Prime examples include
the postoperative abscess or diverticular perforation and/or
abscess where drainage by interventional radiology instead
of early operation may be performed.
Such practices, while designed to limit patient morbidity
and hailed as routinely benefi ting patients by reducing
operative risk, may engender other practices that may not
be as benefi cial. Repeated imaging with ionizing radiation,
prolonged periods of partially controlled infection with
persistent activation of pro- and anti-infl ammatory cascades, extended courses of antimicrobial agents with sub-
L. J. Kaplan , MD, FACS, FCCM, FCCP
Department of Surgery , Perelman School of Medicine, University
of Pennsylvania, Corporal Michael J. Crescenz VA Medical
Center , Philadelphia , PA 19104 , USA
Lewis.Kaplan@uphs.upenn.edu; Lewis.Kaplan@va.gov
e-mail:
A. K. May , MD (
Division of Trauma and Surgical Critical Care,
Department of Surgery , Vanderbilt University Medical Center ,
Nashville , TN 37212 , USA
addison.may@vanderbilt.edu
e-mail:
L. M. Napolitano , MD
Department of Surgery , University of Michigan Health System ,
Ann Arbor , MI 48109 , USA
lenan@umich.edu
e-mail:
*)
sequent induction of multidrug-resistant organisms
(MDRO), and the multiple readmissions for catheter malposition or dislodgement are all potentially anticipated but
undesired consequences of less invasive approaches that
consume resources and may engender poor outcomes [ 3 , 4 ].
Prolonged antibiotic therapy in particular is associated with
untoward outcomes characterized by increased infectionrelated morbidity and mortality, especially if prior therapeutic administration is not considered when prescribing
empiric therapy [ 5 , 6 ].
The ability to effectively clear incompletely drained or
débrided foci of pathogens is altered by the presence of
biofi lm, specifi c organism virulence factors, neutrophil
delivery and function, and the ability (or inability) to adequately deliver antibiotics to the site of infection [ 7 ].
Advances in human genome typing and the integration of
genomics and proteomics with clinical circumstances have
improved our understanding of how individual pheno- and
genotypes respond to self and nonself bacterial challenges.
As an example, individuals who are at higher risk for persistent postoperative hyperalgesia following thoracotomy
can now be identifi ed by preoperatively examining their
DNA profi le. Armed with that data, the anesthesiologist
may craft an appropriate anesthetic and analgesic technique to mitigate that risk. This conceptual approach has
been identifi ed as the “perioptome” [ 8 ]. The Research
Outcomes Consortium is delineating the host response to
injury and infl ammation at the genome level; no similar
analysis is underway related to infection [ 9 ]. Since genome
manipulation to improve outcome after infection is not
realistic at present, the clinician must rely on standard
approaches to infection management. Accordingly, this
manuscript will review existing source control practices
and integrate them with factors that may infl uence the host
response to infection including metabolic derangements,
plasma volume expansion, organ failure, biofi lm, immunonutrition, immunomodulators, evolving organism virulence factors, and epigenetics.
© Springer International Publishing Switzerland 2016
N.D. Martin, L.J. Kaplan (eds.), Principles of Adult Surgical Critical Care, DOI 10.1007/978-3-319-33341-0_23
267
268
L.J. Kaplan et al.
Source Control
In 2001, John Marshall popularized the term “source control” to encompass all of the physical interventions (surgical
and other) that are used to treat infection, including those to
eliminate the infection source, control ongoing contamination when present, and restore premorbid anatomy and function [ 10 ]. He described a standard approach to surgical
infection that embraced (a) fl uid resuscitation to ensure adequate delivery of neutrophils, oxygen, and antibiotics to the
site of infection; (b) adjunctive antibiotics to support host
defenses and control bacterial tissue invasion; and (c) the key
element – control of the source of infection [ 11 ]. This
approach has been used successfully for decades and is well
applied to the debridement of devitalized tissue as in a necrotizing soft tissue infection, resection of a perforated or
ischemic intestinal segment, or drainage of a localized peritoneal abscess.
Application of the source control conceptual framework
is less clear in some circumstances that complicate surgical
critical care. These problematic circumstances include but
are not limited to central vein catheter-related infection
with an intravascular biofi lm sheath, tertiary peritonitis,
entero- atmospheric fi stula in a patient with an open abdomen, and MDRO pneumonia in a patient with persistent
respiratory failure. Other circumstances that may provide
similar challenges include peri-prosthetic spinal hardware
infection with osteomyelitis where hardware removal
would create an unstable spine, a percutaneously drained
abscess with a persistently positive drain culture, as well as
sinusitis in an orally intubated patient in the ICU. Infection
resolution failure may refl ect the inability to resect the
infected structure, an inability to respond to therapy due to
immunoincompetence, or the inability to deliver antibiotics
to the intended site.
Changes in Source Control Procedures
Despite the importance of adequate source control in the
management of surgical infections, particularly intraabdominal infections, there is a trend toward nonoperative
methods of source control. Percutaneous image-guided
drainage procedures are now the standard for the initial, and
perhaps fi nal, management of most isolated and even multiple intra-abdominal abscesses [ 12 – 17 ]. Similarly, a mini-
mally invasive step-up approach (percutaneous drainage
followed, if necessary, by minimally invasive retroperitoneal
necrosectomy), as compared with open necrosectomy in
patients with necrotizing pancreatitis and infected necrotic
tissue, reduced the rate of the composite endpoint of major
complications or death [ 13 ]. However, the appropriate selec-
tion of patients for this approach is complex, and current
studies frequently do not include severely critically ill
patients or those with multiple complex collections. In
poorly selected patients, such approaches may not achieve an
ideal outcome.
Recent data has improved our understanding of patients
that may respond to antibiotics without complete drainage.
In a meta-analysis of the nonsurgical management of patients
with perforated appendicitis with either localized appendiceal abscess or phlegmon, more than 80 % were treated without any source control procedure. In these patients, the lack
of source control was related to either the presence of a
phlegmon without abscess, small abscess size, or the lack of
an access route for abscess drainage. Interestingly, in these
patients, nonsurgical treatment failed in only 7.2 % of
patients, and the risk of recurrence was 7.4 % [
meta-analysis comparing nonoperative treatment versus
acute appendectomy for complicated appendicitis (abscess
or phlegmon) with 1,572 patients found a decreased complication and reoperation rate with conservative management
[ 15 ]. These data support the practice of nonsurgical treat-
ment without interval appendectomy in patients with appendiceal abscess or phlegmon in patients similar to those who
met the inclusion/exclusion criteria of these studies.
In contrast, a meta-analysis of randomized controlled trials (RCTs) comparing antibiotic therapy with appendectomy
for acute uncomplicated (no abscess or phlegmon) appendicitis reported that nonoperative management with antibiotics
was associated with signifi cantly fewer complications, better
pain control, shorter sick leave, but overall had inferior effi cacy because of a high rate of recurrence in comparison with
appendectomy [ 16 ]. Other systematic reviews have con-
fi rmed these fi ndings [ 17 , 18 ]. Additionally, the dramatic
increase in the use of computerized tomography to diagnose
appendicitis complicates the interpretation of recent studies
versus older studies due to the increase in identifi cation of
appendiceal infl ammation. Since only a small number of
RCTs of poor methodological quality are available, additional well-designed RCTs are required.
We have clearly entered a new era in which less invasive
strategies for source control are increasingly utilized. The
adequacy of source control must be considered in the conduct of clinical trials in surgical infections for the future to
appropriately interpret results of therapeutic interventions
and strategies.
14 ]. Another
Source Control and Clinical Trials
Inadequate source control has been identifi ed as a signifi cant
risk factor for adverse outcome in surgical trials. The importance of source control in the management of intra- abdominal
infections is evident, and the failure or inability to achieve
adequate source control is associated with worse clinical out-
23 Source Control and Supporting Therapeutics: Integrating Bacterial Invasion
269
Table 23.1 Adequacy of initial source control in the PROWESS trial
Drotrecogin-alfa Placebo Total
N = 177 N = 182 N = 359
n (%) n (%) n (%)
Adequate 90 (50.8) 86 (47.3) 176 (49)
Inadequate 38 (21.5) 51 (28) 89 (24.8)
Indeterminate 49 (27.7) 45 (24.7) 94 (26.2)
Data from Barie et al. [
22 ]
come in terms of increased rates of treatment failure and
increased mortality [ 19 , 20 ]. In this context, inadequate
source control represents the composite of several situations
including the inability or the unsuccessful attempt to drain or
remove all infected material, recurrence of infection despite
early control, and the failure to heal suture lines and anastomoses. A recent study of 224 patients with septic shock and
candidemia reported that hospital mortality for patients having adequate source control and antifungal therapy administered within 24 h of shock onset was 52.8 % ( n = 142)
compared to 97.6 % ( n = 82) in patients with inadequate ther-
apy ( p < 0.001) [ 21 ].
Inadequate source control may also explain a large portion of clinical failures in trials of antimicrobials and other
agents studied for sepsis treatment. A surgical evaluation
committee adjudicated the adequacy of source control of surgical patients in the Protein C Worldwide Evaluation in
Severe Sepsis (PROWESS) trial and determined that the initial source control procedure was adequate in only 50.8 % of
drotrecogin-alfa (activated) and 47.3 % of placebo patients
(Table 23.1 ). During the 28-day study period, source control
was defi nitively adjudicated as adequate in only 57.1 % and
56.6 % (103 of 182) of the drotrecogin-alfa (activated) and
placebo patients, respectively [ 22 ]. Despite these important
fi ndings, not all clinical trials of infections that require source
control have adopted the approach to include objective evaluation of adequacy of source control in the clinical trial
design and conduct.
Source Control Issues Related to Pathogens
Bacterial Invasion and Multidrug-Resistant Organisms (MDRO)
A brief review of bacterial resistance is in order as MDRO
pathogens are relatively new but occur in the context of conserved microbial constituents such as LPS or lipoteichoic
acid that trigger the repertoire of the human immune system’s response to bacterial invasion. A host of bacterial characteristics enable invasion despite the panoply of human host
defense mechanisms. Bacterial virulence factors that enable
either evasion of host defense agents (immune effector cells,
complement, immunoglobulins) cause the dysregulation of
host defenses (T helper cell activation by superantigens such
as streptococcal spe-A, spe-B, and spe-C), enable resistance
to administered antimicrobials agents, and enhance tissue
invasion are protean. Additionally, toxin production from
noninvasive organisms also may create severe disease without bacterial invasion. The prime example is Clostridium dif-
fi cile , in which C. diffi cile -associated colitis may cause
severe illness without tissue invasion, the incidence of which
and number of related hospital admissions have increased
signifi cantly over the last decade [ 23 – 27 ]. Over the past sev-
eral decades, patient acuity has steadily risen and is associated with a decrement in immune competence that may
signifi cantly compromise how an individual patient responds
to a bacterial challenge. Increasing patient acuity is also
accompanied by the rise of multidrug resistance in both
Gram-positive and Gram-negative organisms and directly
impacts resource utilization, care cost, as well as outcome
[ 28 ]. An abundance of data demonstrates that all areas of
patient care (home, outpatient offi ce, nursing home, skilled
nursing facility, rehabilitation facility, outpatient procedure
center, and acute care inpatient hospital) are beleaguered by
MDROs [ 29 ].
Both infection control practices and antibiotic stewardship programs have been employed as measures to reduce
the prevalence of MDRO and the antibiotic selection pressure that drives the genesis of resistant pathogens [ 30 , 31 ].
While few data conclusively support preemptive isolation of
all patients admitted to an acute care facility until proven to
be free of MDRO colonization or infection, isolation is a
common practice [ 32 ]. Variations include weekly swabs for
MDRO detection, isolation of those from chronic care facilities, isolation of all ICU patients, or isolation of those who
have previously been proven to have been colonized or
infected with MDRO (typically MRSA, VRE, or extended
spectrum beta-lactamase (ESBL)-producing Gram-negative
rods). For example, a major infection control intervention is
hand hygiene using alcohol-based cleansing agents that is
ubiquitous in acute care facilities, shopping malls, coffee
bistros, and grocery stores and is the subject of regular
review by hospitals organizations as well as patients and
visitors [ 33 , 34 ]. Nonetheless, infection control practices do
not alter MDRO genesis, instead only altering transmission
but may impact the empiric antimicrobial agents that are
selected to accompany source control procedures.
Antimicrobial prescriptive practice control may assume
many forms with varying degrees of success in reducing
resistance pressure and control of MDRO genesis. Formulary
control to limit the ability to prescribe certain antimicrobial
agents alone or in combination has been a time- and fi nancehonored practice in many institutions and is part of a practice known as antimicrobial stewardship [ 35 – 37 ]. Generally,
such control rests with an infectious disease specialist as
270
L.J. Kaplan et al.
well as with pharmacy. Such practices have demonstrated
some effi cacy in institutions with a low prevalence of
MDRO but may be less effective in those with high prevalence rates. Instead, formulary control may lead to the relatively homogeneous use of an only limited array of
antimicrobial agents. Instead, current data supports antibiotic heterogeneity as a means of reducing selection pressure
by presenting microbes with an array of antimicrobial
agents [
38 , 39 ]. Either no restriction or a preplanned
sequencing of antibiotics (undertaken with a wide variety of
methods) can achieve antibiotic heterogeneity. The degree
of heterogeneity may be calculated as an antibiotic heterogeneity index (AHI), with a target index exceeding 0.85,
where an index of 1.0 indicates complete heterogeneity.
Investigations into the deliberate management of antibiotic
heterogeneity note reduced MDRO genesis with such programs [
40 ]. As such, antibiotic heterogeneity may provide
one arm of an overarching source control program by deliberately infl uencing the spectrum of microbes that may need
to be addressed in hospitalized or long-term care facility
patients who require source control [
29 ].
Organism Virulence Factors
There are a host of traditionally identifi ed virulence factors
that span the elaboration of biofi lm, endotoxin, exotoxins, M
proteins, and superantigens. However, as genomic and proteomics analysis advances, our understanding of the molecular underpinnings of bacterial-host interactions is further
illuminated. Some examples include worsened acute lung
injury during pulmonary infection with P. aeruginosa related
to deletion of host aquaporin 5 from type I alveolar epithelial
cells, an aquaporin that appears related to mucin production
as well as dendritic cell antigen presentation – key actions in
host airway defense [ 41 ].
Relatedly, different strains of P. aeruginosa isolated from
critically ill patients were assessed for their relative virulence impact using a murine model. In this model, the type 3
secretion system (exotoxin release) and quorum sensing
regulated elastase appeared to confer the greatest virulence
and may be suitable targets for specifi c intervention [ 42 ].
Similarly, adhesin barrier-disruption activity (another quorum sensing regulated gene product) has been tied to the
ability of small bowel luminal Pseudomonas aeruginosa to
translocate and confer near uniform lethality in a murine
model of intestinal ischemia and reperfusion injury [ 43 ].
Understanding such mechanisms may help devise strategies
that target specifi c virulence factors to help manage the bacteria that remain behind in tissue or gain access to the bloodstream during source control procedures.
Acinetobacter has emerged as a major nosocomial MDRO,
facilitated by tolerance to desiccation and multidrug resis-
tance. Recent studies document that Acinetobacter produce
autoinducers, hormonelike molecules, as signals to sense cell
density and activate adaptations by quorum sensing (QS).
Quorum sensing by autoinducer-receptor mechanisms plays a
role in biofi lm formation in Acinetobacter infections [ 44 ].
Strategies that either inhibit QS or cause the premature
expression of QS-regulated genes (quorum quenching) could
provide broad-spectrum control of particular bacterial diseases such as Acinetobacter infections (Fig. 23.1 ). Inhibition
of quorum sensing signals, which further regulates biofi lm
production and possibly other virulence genes, has been targeted for development of novel therapeutics [ 45 ].
While there are a host of organism virulence factors, the
key feature is that as we augment our understanding of those
factors, we may derive specifi c interventions that inactivate
key virulence factors (including biofi lm) or enhance host
defense against those factors. Such interventions are not currently available but form the horizon of forward-looking
undertakings that potentially enable source control prior to
host invasion.
Biofi lm
Biofi lm is an extracellular exopolysaccharide matrix that is
elaborated by a wide variety of organisms that provides a
supportive matrix of nutrient sequestration enhancing bacterial proliferation, as well as a physical, chemical, and
electrostatic barrier to antibiotic ingress. As such, biofi lms
allow a community of disparate bacteria to function together
to channel water pathways for enhanced growth success
(even if at a reduced rate of division) and sharing of genetic
material between promiscuous strains [ 46 , 47 ].
Biofi lms have been noted to be a cause of persistent infection even after presumed appropriate therapeutic antimicrobial administration [ 48 ]. Biofi lm composition includes
polysaccharides, extracellular DNA, proteins, autolysins, and
adhesins that also facilitate bacterial communication using
quorum sensing molecules [ 49 ]. As such, biofi lm reduces the
effi cacy of administered antibiotics even when the target bacteria are judged susceptible both in vitro and in vivo.
Mechanical methods of biofi lm disruption in open body
cavities such as the peritoneal space or the pleural space
maybe partially effective, but such methods are not suitable
for the intravascular space. Perhaps most prominently, biofi lm is identifi ed coating the inner aspect of indwelling endotracheal tubes of all varieties where it reduces the available
inner diameter for gas fl ow and may result in increased airway pressures and reduced CO 2 clearance and may precipitate unplanned tube changes – a potentially dangerous event
in certain patient populations. Biofi lm-related diseases
involving the respiratory system include cystic fi brosis, diffuse panbronchiolitis, and bronchiectasis, all of which are
23 Source Control and Supporting Therapeutics: Integrating Bacterial Invasion
271
RNA
Polymerase
RIF ampicin
DNA synthesis
metronidazole
Inhibition of
signal
molecule
synthesis
Cell wall synthesis
D-cycloserine
Vancomycin
Bacitracin
Cephallosporin
Cephamycin
DNA gyrase
quinolones
Protein synthesis
(50s inhibitors)
Erythromycin
Chloramppenicol
Iincomycin
Cindamycin
Signal
diffusion
out of cell
Transcription
Replication
Quorum sensing molecule
Translation
Protein synthesis
(30s inhibitors)
Thtracyclin
Streptomycin
Spectinomycin
Kanamycin
Signal molecule
synthesiizing
gene
DNA
50s
30s
Degradation
of signal
molecule
Signal
diffusion
inside the
cell
Receptor
Signal
receptor
binding
R
Promoter
Cytoplasmic membrane
Polymyxins
R
R
Receptor
promoter
binding
Inhibition of signal
receptor binding
Signal molecule
inhibiting gene
Microbial cell
analogue
expression
expression
Signal
molecule
degrading
enzyme
Gene
Fig. 23.1 Modes of action of both antimicrobial agents and quorum quenchers in Acinetobacter (From Bhargava et al. [ 44 ] reprinted by permis-
sion of Taylor & Francis Ltd,
diffi cult to fully eradicate [ 50 ]. Biofi lms are also key in
implant-associated infections, particularly in orthopedic and
vascular surgery, and source control in implant-related infections commonly requires implant removal.
Organisms that are well known to elaborate biofi lm
include methicillin-resistant Staphylococcus aureus ,
coagulase- negative Staphylococcus spp., Pseudomonas spp.,
Klebsiella spp., E coli , Proteus spp., Morganella spp.,
Acinetobacter spp., and Streptococcus spp.; others have been
reported although less frequently than those above including
Salmonella spp. and Pasteurella spp. Note that many of the
reported organisms are members of the ESKAPE ensemble
http://www.tandfonline.com )
Biofi lm-associated bacterial growth plays a key role in bacterial adaptability and antibiotic resistance. Drugs that could
slow growth in biofi lm-associated infections could have signifi cant effi cacy in these infections. A recent study used a systems
biology approach to identify drug targets in biofi lm-associated
Pseudomonas infection using metabolic modeling to study the
effect of gene deletion on bacterial growth and served as a powerful tool to identify novel candidate antibiotic targets [ 54 ].
Promising strategies for biofi lm- associated infections may
include the use of compounds that can dissolve the biofi lm
matrix and quorum sensing inhibitors, which increases biofi lm
susceptibility to antibiotics and phagocytosis [ 55 ].
of pathogens noted for ESBL production or inducibility [ 51 ].
More importantly, novel delivery methods to penetrate
biofi lm to enhance antibiotic effi cacy are essential. Recently
Source Control Issues Related to the Host
the nonpathogenic bacterium B. subtilis has been found to
produce a quartite of D-amino acids that has effi cacy in dis-
Metabolic Derangements
ruption biofi lms and offers a potential method of biofi lm
management in clinical care [
methods of managing diffi cult bacterial infections such as
honey have been noted to impede biofi lm formation [
52 ]. In fact, time-honored
53 ].
Perhaps the most common serious metabolic derangement
that drives therapeutic decisions is metabolic acidosis. On
hospital entry, metabolic acidosis is most commonly related
272
L.J. Kaplan et al.
to hypoperfusion in the absence of underlying renal or
hepatic failure. In sharp contradistinction, patients who have
undergone fl uid resuscitation may have their acidosis establish by induced hyperchloremia instead of stemming from
lactic acid derived from anaerobic metabolism [
56 , 57 ].
Importantly, there is an increased mortality associated with
hyperchloremic metabolic acidosis in patients admitted to
the ICU regardless of admission diagnosis [ 58 ].
However, all acidoses are not alike with regard to host
response. In cultured RAW cells made acidotic with lactic
acid as opposed to chloride from hydrochloric acid, equivalent pHs were established, but very different nuclear and
intracellular signaling responses were identifi ed [ 59 ]. In par-
ticular, cells rendered acidotic with chloride demonstrated
differential activation of NF-kB as well as upregulation of
nuclear domains that are associated with infl ammation. Lactic
acid, the downstream effect of hypoperfusion, demonstrated
the opposite pattern consistent with an anti- infl ammatory
response despite an identical pH. Unchecked infl ammation is
thought to be maladaptive and related to multiple organ failure following infection or injury. Therefore, while these cell
data are devoid of a readily translatable clinical correlate,
modulation of the host immune response with avoidance of
hyperchloremia is a readily achievable and logically supported therapeutic goal that may help with managing untoward host responses (infl ammation) to infection.
On the other hand, there is clinical data with regard to
ICU relevant outcomes. Such a strategy is associated with a
shorter time to pH normalization, reduced total fl uid resuscitation, and importantly, reduced minute ventilation needs
[ 60 ]. Unfortunately, this study did not measure plasma or
bronchoalveolar lavage or aspirate fl uid levels of commonly
infl ammatory mediators such as TNF-α, IL-6, or IL-8.
Reduced minute ventilation may support reduced pulmonary
infl ammation by decreasing the opening and closing of
incompletely recruited alveolar segments, a process that
leads to infl ammation from shear stress along the common
wall and is known as intratidal shear [
61 , 62 ]. Decreasing the
frequency of intratidal shear in lungs that may have direct or
indirect lung injury, capillary leak, and increased extravascular lung water may be one important way to modulate overall
infl ammation in those requiring mechanical ventilation.
While intuitively attractive, the above hypothesis remains
unproved but a reasonable avenue of future research.
Plasma Volume Expansion
This topic is linked to metabolic derangements through
electrolyte- induced abnormalities of acid-base balance, specifi cally hyperchloremic metabolic acidosis (HCMA).
Normal saline solution (0.9 % NSS), the most ubiquitous
resuscitation fl uid utilized in the USA and the world, is asso-
ciated with the induction of HCMA through the delivery of
fl uids with a chloride concentration above that of plasma
[ 63 ]. Thus, avoiding inducing HCMA may be an appropriate
therapeutic target to achieve. Several studies have identifi ed
successful strategies to avoid or reduce HCMA including the
use of colloids (less chloride delivery), custom crafted fl uids
(lower chloride content than standard crystalloids), as well
as damage control resuscitation (DCR) since biologically
active colloids have a lower chloride content than crystalloids and are used in preference to crystalloids [ 64 ]. The
association of reduced HCMA as it impacts DCR has yet to
be explored.
The Saline versus Albumin Fluid Evaluation (SAFE) trial
randomized nearly 7,000 critically ill patients to albumin vs.
normal saline and demonstrated no difference in mortality.
However, in a subgroup analysis of 1,218 patients with
severe sepsis, albumin resuscitation was associated with a
trend toward reduced mortality (RR of death 0.87, 95 % CI
0.74–1.02) despite using a hyperchloremic diluent for the
albumin [ 65 ]. It is likely that any signal from hyperchloremia
would have been masked by the trial design that included
only hyperchloremic fl uids. Nonetheless, a recent systematic
review and meta-analysis regarding albumin as a resuscitation fl uid for patients with sepsis reported a signifi cant mortality benefi t (RR 0.82, 95 % CI 0.67–1.00) – an observation
that may be related in part to albumin’s pharmacologic and
toxic oxygen metabolite-scavenging properties [ 66 ].
There are currently at least two important randomized
clinical trials, including the Volume Replacement with
Albumin in Severe Sepsis trial (ALBIOS, n = 1,818, 4 %
albumin to achieve serum albumin 3 g/dL vs. saline) and the
Fluid Resuscitation in Early Septic Shock trial (PRECISE,
NCT00819416, phase II clinical trial, 5 % albumin vs. saline
for fi rst 7 days of ICU care). The pilot PRECISE trial met the
prespecifi ed feasibility targets for patient recruitment, and
the PRECISE team is planning the larger trial [ 67 , 68 ]. The
ALBIOS trial found no improvement in the rate of survival
regardless of resuscitation fl uid selection, but both fl uid arms
had signifi cant chloride loading since albumin is mixed in
saline. An additional study in France (Early Albumin
Resuscitation during Septic Shock, NCT00327704) completed enrollment in March 2010 (794 patients) and compared 20 % albumin (Vialebex) 100 ml every 8 h versus
saline 100 ml every 8 h during the fi rst 3 ICU days, but has
found no outcome benefi t.
Avoiding HCMA may have other benefi ts related to the
delivery of neutrophils, oxygen for oxidative burst-based
bacterial destruction, as well as antibiotic agents through
preserving an open microcirculation. Recall that RBC
deformability is essential for passage through capillary beds.
Such passage is upended by tissue edema and is impeded by
rouleaux formation, a key element in the “no refl ow” phenomenon identifi ed in reperfused beds [
69 ]. An elegant study
23 Source Control and Supporting Therapeutics: Integrating Bacterial Invasion
273
evaluating how acidosis interacts with RBC volume and
shear stress at low and high fl ow rates noted that acidosis
increased RBC volume by 7 % [
70 ]. Importantly, this
increase in size is reversible in the laboratory with NaOH,
with NaHCO 3 being the clinical correlate. This increase in
volume and the effects of acidosis on protein structure and
function may be suffi cient to uncouple the spectrin linkage
system that is critical for microtubular array anchorage and
membrane deformation to enable RBC passage through
small capillary channels [ 71 , 72 ].
Interestingly, impeded RBC deformability is also noted
when RBC are superfused with lymph derived from the mesenteric system of rodents with peritonitis in a cecal ligation and
puncture model [ 73 ]. While the pH and chloride content of the
lymph was not assessed, the similar impact on RBC deformability is compelling. Thus, avoiding HCMA may be appropriate to explore as one means of supporting innate host defense
in the context of a source control procedure by enabling delivery of host defense agents as well as exogenous therapeutics. It
is important to note that virtually no study of surgical infection,
innate immunity, or source control is parsed on the basis of
acid-base status sorted by the presence or absence of HCMA
and perhaps therefore merits investigation.
Adequacy of resuscitation in infection and sepsis is a primary goal and is a major component of adequate source control [ 74 ]. Recent studies, however, have identifi ed that
overresuscitation may be harmful. A post hoc analysis of the
Vasopressin in Septic Shock Trial (VASST) study concluded
that a more positive fl uid balance both early in resuscitation
and cumulatively over 4 days is associated with an increased
risk of mortality in septic shock. Optimal survival in the
VASST study occurred with a positive fl uid balance of
approximately 3 L at 12 h [ 75 ].
Excessive fl uid resuscitation increases the risk of abdominal
compartment syndrome in critically ill surgical/trauma, burn,
and medical patients [ 76 – 78 ]. Similarly, in a multicenter study
of burn patients, administration of excessive fl uids (>25 % of
predicted) increased the odds of ARDS (odds ratio [OR] 1.7),
pneumonia (OR 5.7), multiple organ failure (OR 1.6), bloodstream infections (OR 2.9), and death (OR 5.3) [ 79 ].
It is now widely recognized that resuscitation fl uids are
not innocuous and may potentiate the cellular injury caused
by hemorrhagic shock [ 80 ]. This concept of “resuscitation
injury” has steadily gained attention since a report by the
Institute of Medicine (1999) described in detail the wide
spectrum of adverse consequences that can follow resuscitative efforts [ 81 ]. An ever-increasing basic science literature
supports the new paradigm that cellular injury is infl uenced
not only by shock but also by our resuscitation strategies.
Commonly used resuscitation fl uids can exaggerate immune
activation. Therefore, in addition to the immediate side
effects, delayed complications of fl uid resuscitation such as
systemic infl ammatory response, fl uid overload (leading to
compartment syndromes, pulmonary edema), dilutional anemia and thrombocytopenia, electrolyte and acid-base abnormalities, as well as cardiac and pulmonary complications
must be considered [
82 , 83 ].
Organ Failure
The infl uence of organ failure has been well described with
regard to its impact on infection, with hepatic failure and pulmonary failure incurring the greatest risk for infection- related
morbidity and mortality [ 84 , 85 ]. However, there is compara-
tively less data on how organ failure management hinders or
enables host defense. Since mechanical ventilation carries
with it a well-characterized risk of ventilator- associated pneumonia (now ventilator-associated conditions and events),
study in this organ system may be less ideal. Instead, those
requiring renal support techniques would seem to be an ideal
population in which to evaluate the impact of organ failure
mitigation or management on host defense. Unlike mechanical ventilation, renal support may be started or stopped in a
preplanned fashion to test specifi c hypotheses.
The majority of relevant data in renal failure derives from
those with continuous renal support technologies. In this subset of individuals with acute kidney injury (AKI), continuous
technologies allow one to collect, measure, and evaluate the
effl uent. Such analyses have identifi ed high concentrations of
both infl ammatory and anti-infl ammatory mediators in the
effl uent [ 86 ]. Patients who have severe sepsis or septic shock
and undergo continuous renal support may derive a signifi cant
improvement in hemodynamics and outcome. Specifi cally,
improvements in immune competence, antigen presentation
ability, leukocyte traffi cking, neutrophil oxidative capacity,
and responsiveness may be identifi ed in septic patients undergoing continuous renal support [ 87 ]. Patient selection for this
intervention remains unclear and is complicated by different
indications for renal support, different therapeutic targets, different dialysis doses, changes in fi lter bioincompatibility, and
different durations of therapy. Furthermore, unlike virtually all
other ICU therapies that are titrated off, continuous renal support is most commonly abruptly terminated without welldefi ned criteria or a weaning period. Nonetheless, since
current renal support technology can manage fl uids, electrolytes, pH, and a host of toxins, those with AKI both with and
without infection remain an ideal target population for study
of organ failure mitigation and infection.
Immunonutrition and Immunomodulation
While severe protein-calorie malnutrition is recognized to
impede host bacterial defense by reducing the effi cacy of
neutrophils in particular, the ability to enhance host defenses