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Sepsis: A Clinical Update

Corey E. Ventetuolo and Mitchell M. Levy


Department of Medicine, Brown University, Providence, Rhode Island
Clin J Am Soc Nephrol 3: 571-577, 2008. doi: 10.2215/CJN.01370307

he burden of sepsis on our health care system is significant, with approximately 750,000 cases per year in the
United States, 215,000 resultant deaths, and annual
costs of $16.7 billion nationally (1). Organ failure is a significant
contributor to mortality, with renal failure occurring in approximately 15% of patients (2). In a large registry of critically ill
patients with acute renal failure, in 19% of whom was sepsis
identified as the presumed cause, in-hospital mortality was
37% with a combined outcome of death or dialysis dependence
in 50% (3). Clinicians are challenged to manage this disease in
an aging population with multiple comorbidities, immunosuppression, and a changing pattern of causative microorganisms
(2,4).
The increasing incidence of sepsis and the unacceptably high
mortality rates associated with the disease have led to global
efforts to understand pathophysiology, improve early diagnosis, and standardize management (5). Understanding the spectrum of the disease is important for gauging severity, determining prognosis, and developing methods for standardization
of care in sepsis. At an international consensus conference in
1991, sepsis was defined as the systemic inflammatory response
syndrome (SIRS) with a suspected source of infection. SIRS is
defined as two or more of the following perturbations: Temperature 38 or 36C; heart rate 90 beats per minute; respiratory rate 20 breaths per minute or Paco2 32 mmHg; and
white blood cell count 12,000/mm3, 4000/mm3, or 10%
immature band forms. Organ dysfunction and hypoperfusion
abnormalities characterize severe sepsis, and septic shock includes sepsis-induced hypotension despite adequate fluid resuscitation (6). These definitions allowed for a more uniform
approach to clinical trials, hypothesis generation, and the care
of the patient with sepsis.
The use of SIRS criteria for the identification of sepsis have
been believed by many to be arbitrary and nonspecific. In 2001,
the terminology was revisited in another consensus conference.
At that time, the primary categories of sepsis, severe sepsis, and
septic shock were confirmed as the best descriptors for the
disease process. The primary change introduced was a more
comprehensive list of signs and symptoms that may accom-

Published online ahead of print. Publication date available at www.cjasn.org.


Correspondence: Dr. Mitchell M. Levy, Rhode Island Hospital/Brown University, 593 Eddy Street, Providence, RI 02903. Phone: 401-444-2776; Fax: 401-4443002; E-mail: mitchell_levy@brown.edu.
Copyright 2008 by the American Society of Nephrology

pany the disease. In addition, a staging system was proposed


for the purpose of incorporating both host factors and response
to a particular infectious insult. This concept, termed PIRO
(predisposition, infection, response, organ dysfunction) (7)
speaks to the need to define, diagnose, and treat patients with
sepsis more precisely because a variety of evidence-based interventions now exist to improve outcomes (8 10) in severe
sepsis and septic shock. The PIRO model remains hypothetical
and is being evaluated in several studies.

Pathophysiology: Mediators of Sepsis


Integral to the development of diagnostic and management
strategies is an understanding of the interplay among the hosts
immune, inflammatory, and procoagulant responses in sepsis.
When a given infectious agent invades the host, an innate
response is triggered via toll-like receptors (TLR). TLR are
transmembrane proteins with the ability to promote signaling
pathways downstream (11), triggering cytokine release and
neutrophil activation and stimulating endothelial cells. Activation of humoral and cell-mediated immunity follows with specific B and T cell responses and both pro- and anti-inflammatory cytokine release (12). Proinflammatory mediators,
including TNF-, IL-1, and IL-6, and anti-inflammatory mediators, including IL-10, IL-1 receptor antagonists, and soluble
TNF receptors, both are significantly upregulated in patients
with severe sepsis (13).
As adaptive immunity is triggered and the inflammatory
cascade of sepsis unfolds, the balance is shifted toward cell
death and a state of relative immunosuppression. At this late
stage, accelerated lymphocyte apoptosis occurs (14), and proinflammatory mediators, including TNF-, IL-1, and IL-6, may
be downregulated (15). Innate defects in neutrophil response
and host immunity may also play a role (16). End-organ dysfunction ensues. Various mediators, including TNF- and IL-1
(17), induce nitric oxide (18) and cause myocardial depression
and left ventricular dilation with decreased ejection fraction
and systemic vascular resistance. The end result of these hemodynamic changes is an elevated cardiac output and generalized
vasodilation. This is often described as high-output shock. As
the inflammatory response progresses, myocardial depression
becomes more pronounced and may result in a falling cardiac
output. Altered Starling forces from vasodilation and endothelial dysfunction prompted by mediator release lead to capillary
leak and pulmonary edema that may progress to acute lung
ISSN: 1555-9041/3020571

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Clinical Journal of the American Society of Nephrology

injury and acute respiratory distress syndrome (ARDS). A


surge in catecholamines, angiotensin II, and endothelin causes
renal vasoconstriction and increases risk for nephrotoxicity
with renal failure (19). These changes are accompanied by
alterations in the coagulation cascade toward a procoagulant
and antifibrinolytic state. Increased thrombin, via tissue factor
upregulation, leads to endothelial and platelet activation as
well as vascular smooth muscle changes. As a result, there is
fibrin deposition and microvascular thrombosis, which may
threaten end organs. The development of disseminated intravascular coagulation in severe sepsis is a predictor of death and
the development of multiorgan failure (20). Antithrombin III,
protein C, protein S, and tissue factor pathway inhibitor levels
are decreased in severe sepsis, leading to a prothrombotic,
antifibrinolytic state (20,21). Formation of activated protein C
(APC) is also impaired (22). In the normal state, APC acts as an
important anticoagulant (23) and inhibits fibrinolysis via plasminogen activator inhibitor inactivation (24). In addition, APC
has been shown to reduce proinflammatory cytokine release
and inhibit leukocyte adhesion (25) and endothelial cell apoptosis (25,26).

Diagnostic Challenges in Sepsis


Despite advances in our understanding of the diseases mechanisms, it remains difficult to apply these lessons clinically
toward early diagnosis and treatment. Addressing this dilemma is paramount given the availability of life-saving interventions (8), interventions that lose their mortality benefit
when delivered late (27,28). As the hosts initial compensatory
mechanisms are overwhelmed and a patient moves through the
disease spectrum, tissue beds become hypoxic and injury occurs at the microvascular level. The resultant tissue hypoperfusion, which characterizes severe sepsis and septic shock, can
occur despite normal clinical parameters, including vital signs
and urine output, and may continue after initial resuscitation
(8,29). Failure to intervene at this stage, before or early in the
development of organ dysfunction, results in increased morbidity and mortality (30). Poor outcomes in severe sepsis have
been correlated to the development of organ failure on as early
as day 1 of presentation (31).
In addition to developing a more comprehensive definition
and staging system for identifying patients early, lactate and
central venous (superior vena cava; ScvO2) or mixed venous
oxygen saturation (SvO2) have been used as surrogate markers
to identify patients with an imbalance of oxygen supply and
demand, who are, therefore, at risk. Although lactate itself lacks
precision, in the appropriate clinical setting, an elevated level
(4 mmol/L) is indicative of tissue hypoperfusion and an
independent predictor of mortality (32,33). In the initial inflammatory phase, there is often an increase in oxygen delivery,
which may be associated with a fall in ScvO2 or SvO2 as a result
of an inadequate cardiovascular response. As the inflammatory
response progresses, there are regional alterations in the microcirculation, leading to an elevation in ScvO2 or SvO2 (34).
Knowledge of the relationships between these surrogates and
efforts to optimize oxygen supply and demand in patients with
severe sepsis evolved into goal-directed therapy. Rivers et al. (8)

Clin J Am Soc Nephrol 3: 571-577, 2008

found a significant reduction in 28-d mortality when applied


early (within 6 h of emergency department presentation) versus
standard therapy (30.5 versus 46.5%; P 0.009). Early goaldirected therapy (EGDT) refers to a protocol that targets a
normal central venous pressure and ScvO2 or SvO2 in these
critical early hours of sepsis. When intravenous fluids fail to
achieve these targets, red blood cells are transfused and inotropic support with dobutamine is added to augment oxygen
delivery. Although there was no direct assessment of the impact of EGDT on renal outcomes, various physiologic scoring
systems (Acute Physiology and Chronic Health Evaluation II
[APACHE II], Simplified Acute Physiologic Score II, and Multiple Organ Dysfunction Score) were assessed serially between
7 and 72 h and were significantly improved (P 0.001) in the
EGDT group. As discussed next, EGDT is considered a critical
intervention in the early treatment of patients with severe sepsis.

Management of Severe Sepsis: A New


Standard of Care
The publication of several randomized, controlled trials demonstrating mortality reduction with certain interventions in
severe sepsis (8 10), along with the desire to integrate evidence-based medicine into clinical practice, led to the development of the Surviving Sepsis Campaign guidelines (5). In partnership with the Institute for Healthcare Improvement, the
Surviving Sepsis Campaign designed the resuscitation and management bundles in an effort to facilitate knowledge transfer and
establish best-practice guidelines. They are to be completed
within the first 6 and 24 h, respectively, of a patients care
(Table 1). Evidence supporting each element of the bundles is
beyond the scope of this review, but some key discussion
points follow.

Appropriate Antibiotics
Broad-spectrum intravenous antibiotics should be administered promptly after appropriate cultures are obtained. Although it is widely recognized that failure to initiate adequate
antimicrobial coverage results in adverse outcomes (35,36), recent epidemiologic studies have shown a significant increase in
the frequency of severe sepsis from polymicrobial infection (4).
Multidrug-resistant bacteria, such as Pseudomonas species and
methicillin-resistant Staphylococcus aureus, as well as other
Gram-positive and fungal organisms, are also increasing (2).
Knowledge of these changing microbiologic patterns, as well as
host and local patterns of susceptibility, are critical in selecting
initial therapy. Institution of timely antimicrobial therapy is
equally important in the care of the patient with sepsis. A recent
retrospective review of 2731 cases of septic shock demonstrated
a strong relationship between delay in appropriate antibiotics
and in-hospital mortality; administration of antibiotics beyond
the first hour of presentation resulted in decreased survival
with each additional hour that therapy was delayed (37).

EGDT
After the original publication detailing EGDT (8), controversy has surrounded some aspects of the protocol. An in-

Clin J Am Soc Nephrol 3: 571-577, 2008

Sepsis

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Table 1. Surviving Sepsis Campaigna


Sepsis Resuscitation Bundle

The goal is to perform all indicated tasks 100% of


the time within the first 6 h of identification of
severe sepsis.
measure serum lactate
obtain blood cultures before antibiotic
administration
administer broad-spectrum antibiotic within 3
h of ED admission and within 1 h of
identification of sepsis on the hospital floor
in the event of hypotension and/or a serum
lactate 4 mmol/L
deliver an initial minimum of 20 ml/kg
crystalloid or equivalent
apply vasopressors for hypotension not
responding to initial fluid
resuscitate to maintain MAP 65 mmHg
in the event of persistent hypotension despite
adequate fluid resuscitation (septic shock)
and/or lactate 4 mmol/L
achieve a CVP 8 mmHg
achieve an ScvO2 70% or SvO2 65%

Sepsis Management Bundle

Efforts to accomplish these goals should begin


immediately, but these items may be completed within
24 h of presentation for patients with severe sepsis or
septic shock.
administer low-dosage steroids for septic shock in
accordance with a standardized ICU policy; if not
administered, then document why the patient did
not qualify for low-dosage steroids based on the
standardized protocol
administer rhAPC-Xigris in accordance with a
standardized ICU policy; if not administered, then
document why the patient did not qualify for rhAPC
maintain glucose control 70 but 150 mg/dl
maintain a median IPP 30 cmH2O for mechanically
ventilated patients

a
CVP, central venous pressure; ED, emergency department; ICU, intensive care unit; IPP, inspiratory plateau pressure;
MAP, mean arterial pressure; rhAPC, recombinant human activated protein C; ScvO2, central venous oxygen saturation; SvO2,
mixed venous oxygen saturation

depth discussion of such issues was recently published (38),


but some are worth noting here. There is a need for lactate as
the primary measure for determining tissue hypoperfusion
in the critically ill patient. Anion gap is an insensitive screen
for the presence of lactic acidosis, as demonstrated previously by Iberti et al. (39). In recent review by Otero et al. (38),
the use of anion gap or base deficit to predict lactic acidosis
was again shown to be imperfect. A normal bicarbonate level
and anion gap were found in 22.5 and 25.0%, respectively, of
patients with lactate levels 4 to 6.9 mmol/L. Although the
initial resuscitation (first 6 h) resulted in a greater amount of
volume given, at 72 h, the EGDT and standard care groups
were equivalent in the dosages of fluid and red blood cells
received. Moreover, a significantly larger proportion of patients in the standard care group ultimately required mechanical ventilation. These disparities were confirmed in a
subset analysis of 18 patients from the original trial who had
ESRD and were on hemodialysis (HD). Although it is understandable that clinicians may be hesitant to flood HD
patients, it is worth noting that the standard care group
received fewer fluids, required more mechanical ventilation,
and had a significantly higher mortality rate (70 versus 14%
in the standard care versus EGDT group, respectively; P
0.01) (40); therefore, even in the HD population and in the
absence of urine output as a target for resuscitation, it is
imperative to intervene early and with aggressive volume
resuscitation.

Vasopressin
For patients who have been fluid resuscitated, have achieved
optimal central venous pressure, and continue to have vasopressor refractory shock, consideration can be given to adding
low-dosage, time-limited vasopressin. Unlike traditional catecholamines, vasopressin causes direct vasoconstriction,
through a variety of mechanisms (19). Its effects are organ
system specific, however, with vasoconstriction occurring in
the splanchnic beds and vasodilation occurring in the pulmonary and coronary circulation. GFR is increased via efferent
arteriole constriction and increased filtration pressure. In early
sepsis, there is an excess of endogenous vasopressin. Ultimately, levels return to normal range, creating a state of relative
vasopressin insufficiency in the patient with severe septic shock
(41). When appropriate, the addition of vasopressin allows for
a reduction in standard vasopressors and may improve urine
output and creatinine clearance (42). It should be used with
caution in patients who are at risk for cardiac ischemia and low
cardiac output. The dosage in clinical practice is 0.01 to 0.04
U/min, with a usual dosage of 0.03 U/min. There is no advantage to dosage titration beyond 0.04 U/min, and some studies
have suggested a deleterious impact on organ perfusion at
higher dosages.

Corticosteroids
There is controversy surrounding the use of corticosteroids in
severe sepsis. The appropriate dosage and timing of therapy, as

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Clinical Journal of the American Society of Nephrology

well as how best to evaluate the adrenal axis, has been studied
and debated. High-dosage corticosteroids (300 mg/d hydrocortisone) are not recommended and may cause harm (43).
There has been a renewed interest in corticosteroids as we have
come to understand sepsis as a state of relative adrenal insufficiency, albeit a state that is difficult to diagnose and define on
the basis of various measurements of cortisol secretion (44).
A single, multicenter, randomized, controlled trial in which
patients with refractory shock despite vasopressors and volume resuscitation received either hydrocortisone (50 mg intravenously every 6 h) and fludrocortisone (50 g/d) or placebo
for 7 d showed a mortality benefit at 28 d (53 versus 63%
respectively; P 0.02) (9). In addition, vasopressors were withdrawn more frequently in the treatment group (57 versus 40%;
P 0.001). This benefit was seen only in patients who did not
respond appropriately to adrenocorticotropic hormone stimulation, with 229 of 299 patients classified as nonresponders
(defined as a cortisol increase 9 g/dl). A recent meta-analysis that included 16 trials and 2063 patients confirmed similar
results and, importantly, noted no increase in the rate of adverse effects from corticosteroids (45); therefore, it is recommended that the use of low-dosage corticosteroids (hydrocortisone 200 to 300 mg/d in divided doses for 7 d) be considered
in hypotensive patients with vasopressor-dependent septic
shock. If a corticotropin stimulation test is obtained, then the
clinician may elect to discontinue steroids in patients who
respond appropriately.

APC
Therapeutic attempts to target the procoagulant nature of sepsis have been disappointing (46,47), with the exception of drotrecogin (activated) or recombinant human APC (rhAPC).
This may be due in part to alternative mechanisms of action.
Recalling the pathophysiology of severe sepsis, rhAPC has
antiapoptotic and anti-inflammatory activity and modulates
endothelial dysfunction (25,26).
rhAPC is approved for the treatment of severe sepsis in
patients with a high risk for death (defined as an APACHE II
score 25), sepsis-induced multiple organ failure, septic shock,
or sepsis-induced ARDS. In a multicenter, randomized, controlled trial of 1690 patients, treatment with drotrecogin
(activated) was associated with a 19.4% relative reduction and
a 6.1% absolute reduction in the risk for death (P 0.005) (10).
Although renal outcomes were not specifically examined, subgroup analysis, including APACHE II scores and number of
dysfunctional organs or systems, demonstrated a persistent
treatment effect. This mortality benefit was not seen in patients
with a low risk for death (i.e., APACHE II score 25 or singleorgan failure) and resulted in the termination of the Administration of Drotrecogin Alfa (Activated) in Early Stage Severe
Sepsis (ADDRESS) trial at interim analysis (48).
The risk for bleeding must be considered, and the drug is
contraindicated in certain settings. The Recombinant Human
Activated Protein C Worldwide Evaluation in Severe Sepsis
(PROWESS) trial (10) excluded patients with platelet counts
30,000/mm3, surgery within the past 12 h, stroke within 3 mo,
uncorrected gastrointestinal bleeding within 6 wk, and trauma.

Clin J Am Soc Nephrol 3: 571-577, 2008

Patients who had ESRD and were on HD were also excluded. A


higher incidence of serious bleeding events in the treatment
group (3.5 versus 2.0%; P 0.06) occurred in PROWESS and
was confirmed in a follow-up study (49).
Although considerable controversy exists, current consensus
guidelines recommend rhAPC (5). In the appropriate clinical
setting, rhAPC should be considered in the treatment of severe
sepsis. It is recommended that hospitals develop a standardized policy to guide the use of rhAPC. Bedside assessment
should inform decisions about risk assessment. Once a patient
is determined to be at high risk for death, infusion of rhAPC
should begin. Benefits of treatment are seen irrespective of
pathogen or site of infection (50), and the drug is cost-effective
(51) when used appropriately.

Glucose Control
Critical illness is often characterized by hyperglycemia and
insulin resistance. Hyperglycemia may have detrimental effects
at the cellular level and contribute to organ failure and morbidity and ultimately death. In a landmark randomized, controlled trial that investigated intensive (blood glucose level 80
to 110 mg/dl) versus conventional (blood glucose 180 to 200
mg/dl) insulin therapy in a surgical intensive care unit (ICU),
intensive therapy resulted in a significant reduction in ICU and
in-hospital mortality (52). This benefit was most pronounced in
patients with a demonstrable septic focus and multiorgan failure, although the study involved primarily cardiac surgery
patients. Several markers of morbidity were also significantly
improved. Renal injury, defined as peak plasma creatinine 2.5
mg/dl, peak plasma urea nitrogen 54 mg/dl, or the need for
renal replacement therapy, was significantly reduced in the
intensive insulin group. Post hoc analysis demonstrated a more
modest but persistent treatment effect with the maintenance of
blood glucose levels 150 mg/dl, and, in the interest of avoiding hypoglycemia, current recommendations suggest this as a
target (5,53). It seems that mortality benefit is derived from
normoglycemia rather than insulin replacement itself, whereas
in the prevention of renal injury, insulin dosing seems to play
a role (53).
More recently, Van den Berghe et al. (54) examined intensive
insulin therapy in the medical ICU population. Using the same
targets for blood glucose control, intensive insulin therapy
failed to provide a mortality benefit. Renal injury was significantly reduced (8.9 to 5.9%; P 0.04) as was duration of
mechanical ventilation. There was an increase in mortality
among patients in the intensive insulin group who stayed 3 d
in the ICU. When ICU length of stay exceeded 3 d, rate of death
was decreased. The authors speculated that this disparity may
have resulted from earlier withdrawal of care among those
with short lengths of stay (suggested on post hoc analysis) or
that the effects of intensive therapy may take more time to be
realized (54). Although more data are needed on the medical
population to establish ideal targets for blood glucose, moderate control (blood glucose 150 mg/dl) is reasonable and likely
to provide morbidity and, in patients with extended ICU stays,
mortality benefit.

Clin J Am Soc Nephrol 3: 571-577, 2008

Mechanical Ventilation
Acute lung injury (ALI) or ARDS complicating severe sepsis or
septic shock should be managed with a goal to avoid large tidal
volumes and elevated plateau pressures. The largest trial that
examined a volume- and pressure-limited ventilation strategy,
by the ARDS Clinical Trials Network, demonstrated a significant mortality benefit in the group treated with a low tidal
volume strategy (tidal volume of 6 ml/kg predicted body
weight and plateau pressure 30 cmH2O) as compared with a
traditional ventilation strategy (12 ml/kg predicted body
weight and plateau pressure 50 cmH2O; 31.0 versus 39.8%,
respectively; P 0.007) (55). In addition, the group that was
treated with lower tidal volumes experienced less organ, including renal, failure. In an animal model of ARDS, those that
were subjected to higher tidal volumes had higher rates of
epithelial cell apoptosis in the kidney and small intestine, as
well as elevated levels of biomarkers correlated with renal
injury (56). This strategy may occur at the expense of a normal
pH and partial pressure of arterial carbon dioxide (so-called
permissive hypercapnea)abnormalities that may be tolerated when modest or offset with sodium bicarbonate infusion
when severe.

Considerations for the Nephrologist


The development of acute renal failure is common in severe
sepsis and has a significant impact on morbidity, mortality, and
cost (1,19). Administration of bicarbonate does not improve
hemodynamic instability, lactic acidosis, or response to vasopressors (57,58), and the use of low-dosage dopamine does not
provide sustainable renal protection or improve outcomes in
critically ill patients (59,60). Although the use of erythropoietin
has not been studied specifically in severe sepsis, it has been
shown to reduce transfusion requirements in critical illness but
has no effect on outcome (61,62). It is therefore not recommended for patients with sepsis.
There is evidence for equivalence of continuous and intermittent renal replacement therapies for critically ill patients,
although hemodynamic considerations are likely to dictate
mode of therapy (63,64). Although preliminary data suggested
that deleterious inflammatory mediators could be removed
with the use of continuous hemofiltration (65), a randomized,
controlled trial that examined the use of early continuous hemofiltration before the development of renal failure failed to
show a reduction in circulating mediators or prevention of
organ dysfunction (66).

Future Directions
The future management of sepsis will most likely involve therapies directed at newer inflammatory targets. Several such
molecules are under investigation and include, among others,
TLR4; the receptor for advance glycation end products; and
high mobility group box 1 (HMGB1), a cytokine-like molecule
that promotes TNF release from mononuclear cells. HMGB1 is
actively secreted by immunostimulated macrophages and enterocytes and is also released by necrotic but not apoptotic cells.
HMGB1 is now recognized as a proinflammatory cytokine (67).
The use of biomarkers to diagnose, stage, and assess risk is an

Sepsis

575

important new field of study. Pro-calcitonin, C-reactive protein,


IL-6, and other mediators may be used in combination to develop an ECG of sepsis that may ultimately help guide clinicians to early diagnosis and assist in determining appropriate
treatment strategies (68).
Another important area of ongoing and future research is
endothelial cells and the microcirculation. Better insight into
endothelial cell and microcirculatory dysfunction may direct
interventions that will facilitate enhanced restoration of tissue
perfusion, a primary pathophysiologic lesion in the inflammatory process that contributes to multiorgan failure and cellular
dysfunction in sepsis.

Conclusions
Severe sepsis and septic shock are common and increasing
among the critically ill. The opportunity now exists for clinicians to adopt an evidence-based approach to diagnosis and
management. Mortality may be reduced by focusing on early
diagnosis, targeted management, and standardization of the
care process.

Disclosures
Grant Support: Novartis, ESAI, Brahms. Speakers bureau: Eli Lilly,
Brahms.

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