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DOI 10.1378/chest.

06-2535
2007;132;1967-1976 Chest

Arthur P. Wheeler

Management of Severe Sepsis


Recent Developments in the Diagnosis and
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Recent Developments in the Diagnosis
and Management of Severe Sepsis*
Arthur P. Wheeler, MD, FCCP
The last 5 years have brought dramatic changes to the care of patients with severe sepsis. While
early diagnosis remains a challenge and, regrettably, a rapid, sensitive, and specific diagnostic
test is still lacking, the methods to identify those critically ill patients who are likely to die have
become clearer. The presence of multiple organ failure, vasopressor-dependent shock, and high
values in formalized scoring methods such as the APACHE (acute physiology and chronic health
evaluation) and sequential organ failure assessment systems all have some utility for outcome
prediction for groups of patients. Refinements in long-used supportive practices such as lower
tidal volume ventilation and enhanced glucose control have improved outcomes. A growing
appreciation of the importance of timely provision of antimicrobial therapy, circulatory resusci-
tation, and activated protein C administration have also improved survival. Optimal treatment
candidates for, and the timing and dose of some treatments (eg, corticosteroids) remain
controversial and are undergoing additional study. Perhaps the most important change in the
care of patients with severe sepsis is awareness that the syndrome is more common, lethal, and
expensive, than previously appreciated, and as such it warrants an organized approach to care
provided by experts. Although there is still much to learn, numerous studies now indicate that
improvements in outcomes are possible when treatment protocols that incorporate all known
beneficial therapies are applied in a timely fashion. (CHEST 2007; 132:19671976)
Key words: ARDS; sepsis; septic shock; severe sepsis
Abbreviations: ACTH adrenocorticotropic hormone; ALI acute lung injury; APACHE acute physiology and
chronic health evaluation; EGDTearly goal-directed therapy; PACpulmonary artery catheter; PEEPpositive end-
expiratory pressure; rhAPCrecombinant human activated protein C
S
everal aspects of severe sepsis treatment have
dramatically changed in the last decade, although
many things remain the same.
1
Then, as now, initial
treatment involved obtaining cultures, mechanically
eradicating infection sources, and giving antibiotics
directed at suspected pathogens. Historically, subse-
quent management was to support failing organ
systems. Patients with respiratory failure were intu-
bated and ventilated with a positive end-expiratory
pressure (PEEP)-fraction of inspired oxygen combi-
nation to maintain a Pao
2
of 60 mm Hg, or
hemoglobin saturation of 90%. A tidal volume of
10 to 15 mL/kg was mated to a respiratory rate
sufficient to achieve a normal pH and Paco
2
, which
were evaluated daily and after almost every ventila-
tor change. High airway pressures were tolerated if
necessary to achieve desired blood gas level targets,
and barotrauma was treated with tube thoracostomy.
Deep sedation alleviated visible discomfort and made
patients conform to ventilator selections, but even then
chemical paralysis was often administered. Weaning
was an intricate, highly individualized, process of grad-
ual ventilator withdrawal.
*From the Medical Intensive Care Unit, Division of Allergy,
Pulmonary, and Critical Care, Vanderbilt University, Vanderbilt
Medical Center, Nashville, TN.
Dr. Wheeler has acted as a consultant for Astra-Zeneca, Cubist
Pharmaceuticals, Cumberland Pharmaceuticals, Eli-Lilly, Sanofi-
Aventis, and Takeda. He has worked for the speakers bureaus of
Boehringer-Ingleheim, Eli Lilly, Pfizer, and Sanofi-Aventis.
Manuscript received October 16, 2006; revision accepted June 4,
2007.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Arthur P. Wheeler, MD, FCCP, Director,
Medical Intensive Care Unit, Associate Professor of Medicine,
Division of Allergy, Pulmonary, and Critical Care, Vanderbilt
University, T-1217 MCN Vanderbilt Medical Center, Nashville,
TN 37232250; e-mail: art.wheeler@vanderbilt.edu
DOI: 10.1378/chest.06-2535
CHESTRecent Advances in Chest Medicine
www.chestjournal.org CHEST / 132 / 6 / DECEMBER, 2007 1967
Frequently a pulmonary artery catheter (PAC)
was inserted to confirm a low intravascular pres-
sure and/or low systemic resistance before fluids
were given to achieve an arbitrary pulmonary artery
occlusion pressure (commonly, 18 mm Hg was tar-
geted). Persistently hypotensive patients were regularly
given dopamine, especially if they were oliguric. For
the treatment of refractory hypotension, norepineph-
rine was added to therapy to allow dopamine to remain
in a renal range. Often, even modest anemia was not
tolerated, and many physicians were in the habit of
transfusing at an arbitrary hemoglobin value.
So-called stress-dose corticosteroids were often ad-
ministered to patients receiving long-term glucocorti-
coid therapy, but only rarely would a formal adreno-
corticotropic hormone (ACTH) stimulation test be
performed. For many clinicians, nutrition support was
an afterthought, and, if given, was often provided IV
because it was accepted that the GI tract was nonfunc-
tional. A blood glucose level of 200 mg/dL was
satisfactory. Skin care and patient positioning were
low-priority measures, and preventative treatments for
deep venous thrombosis and GI bleeding were incon-
sistently used.
After initial interventions, a conversation with the
family communicated a poor prognosis, the belief
that severe sepsis was due to uncontrolled inflam-
mation, and the frustrating fact that there was no
specific treatment. Many clinicians desired a sepsis
drug, but pessimism over the prospect was perva-
sive given the failures of numerous high-profile
clinical trials.
How things have changed! The care of nearly
every failing organ has improved, new treatments
have been developed, older therapies have been
refined, and some long-used treatments are now all
but abandoned. More important than the refinement
of individual interventions is a growing awareness
that it is not one but the sum of all beneficial
treatments delivered in a timely manner that results
in recovery. Survival now has improved to the point
that long-term outcomes including quality of life and
cost-effectiveness can be studied.
2,3
Definition and Case Finding
Despite many advances, some things have not
changed. Clinicians still long for a simple, reliable
test to diagnose severe sepsis because medical history,
examination, routine laboratory studies, and radio-
graphs often leave the diagnosis in question. Procalci-
tonin and C-reactive protein have been advocated for
diagnosis, and while the former has better predictive
value, neither has gained widespread clinical use.
4
Measurements of the soluble triggering receptor ex-
pressed on myeloid cells-1 remain experimental.
5
d-Dimer and interleukin-6 determinations are sensitive
but nonspecific, and the latter test is not clinically
available.
6,7
Presently, the value of total protein Clevels
as a diagnostic tool for severe sepsis is limited because
assays are not generally available in a timely fashion and
many patients do not have reduced levels at the time of
diagnosis; it is more likely that protein C levels will
prove useful as a prognostic tool.
8
Ongoing studies seek
to define a sensitive and specific panel of diagnostic
biomarkers.
The diagnosis of severe sepsis remains ambiguous
in some physicians minds despite a well-accepted
consensus definition.
9
This is especially true for the
early stages of the disease, which can be as subtle as
altered mental status in an elderly patient. In part,
diagnostic confusion may stem from multiple defini-
tions of organ failure or dysfunction that are used
in clinical practice, research studies, and consensus
guidelines. For example, renal failure has been
alternatively defined by urine output, creatinine
level, or the need for renal replacement therapy. In
daily practice, difficulty recognizing the syndrome is
commonly voiced; however, because of the surpris-
ingly consistent patient presentation, identification is
usually straightforward. When recognized, the typi-
cal patient has two or more failing organs, and the
lungs and circulatory system are likely to be among
them.
10
These two vital organ failures are usually
manifested clinically by the use of a ventilator and
therapy with a vasoactive drug. Although using these
support technologies does not guarantee that the
patient has severe sepsis, when antibiotics are con-
comitantly administered it is not easy to imagine a
plausible alternative diagnosis. Granted, seeking this
treatment triad will miss some patients with single-
organ failure (eg, coagulopathy) and will delay diag-
nosis, but it will eventually find the patients who are
at high risk of dying. Earlier identification of high-
risk cases can be accomplished in the emergency
department by recognizing hypotension or elevated
lactate levels in patients with suspected infections;
however, the patient who is being taken care of on a
general medical or a surgical floor of a hospital often
goes unnoticed until respiratory or circulatory failure
are advanced.
11
Severity of Illness and Outcome
Prediction
Studies in the last 5 years have undercut the
long-held belief that microorganism characteristics
are the predominant determinants of prognosis. The
identity of the infecting organism is of little conse-
quence for most patients provided that appropriate,
prompt antimicrobial therapy is administered.
1214
1968 Recent Advances in Chest Medicine
The presence of coagulopathy is a powerful pre-
dictor of organ failure development and subsequent
death.
15
The occurrence of shock treated with vaso-
active drugs and the total number of failing organ
systems are also markers of a poor prognosis.
16,17
The
significance of these organ failures is so entrenched
that slang is sometimes used to refer to the sickest of
these patients (eg, five-organ failures). In addition
to the number of organ failures, the severity of each
or the intensity of support required correlates with
outcome. For example, higher doses of vasoactive
drugs are associated with a worse prognosis than
lower doses or no vasoactive drug therapy at all.
18
Understandably, advanced age and the presence of
cancer also worsen the prognosis.
1921
Substudies of large trials have also shown a rela-
tionship between the severity-of-illness scores, like
the modified acute physiology and chronic health
evaluation (APACHE) II score and outcome. Such
scoring systems are not designed to predict outcomes
in individual patients, and the same score may be
associated with a different mortality rate in different
countries or even among hospitals within the same
country.
22
The baseline value, or change in plasma lactate,
23
interleukin-6, and protein-C level
24
have been shown
to predict outcome. Of the commonly available
clinical tests, prothrombin time is perhaps the most
useful laboratory predictor of outcome.
13
Pathophysiology
The septic response was once believed to be
simply exaggerated inflammation. The last decade
has brought to light a major conceptual advance.
Sepsis pathophysiology is very complex and re-
mains incompletely understood, but clearly in-
volves inflammatory, procoagulant, antifibrino-
lytic, and microvascular components
25,26
that have
been nicely summarized elsewhere.
27,28
Infection Prevention
For hospitalized patients, many cases of severe
sepsis can be avoided by meticulous hand washing,
precautions for vascular catheter insertion, and ele-
vation of the head of the bed. Though these are not
new ideas, they have grown in importance. Soap and
water hand washing is more critical than ever with
the emergence of a virulent strain of Clostridium
difficile, the spores of which are resistant to alcohol-
based hand washes.
29,30
The prevention of vascular
catheter-related infection has proven to be an attain-
able goal by using a standardized protocol that
incorporates thoughtful site selection and insertion
by an experienced operator, using full barrier pre-
cautions with chlorhexidine skin preparation, fol-
lowed by careful dressing management.
31,32
The use
of specialized catheters that are impregnated with
antimicrobial agents may also be beneficial in some
settings.
33
Despite the seeming simplicity of raising
the head of the bed to decrease the risk of nosoco-
mial pneumonia, practical problems in achieving the
desired degree of elevation persist.
34,35
Recent data
36
also have indicated that enhanced oral hygiene using
hydrogen peroxide or antimicrobial agents can re-
duce the risk of nosocomial pneumonia.
Supportive Care
There are now numerous relatively safe, simple,
inexpensive measures to reduce morbidity, and in
some cases mortality, in ICU patients that arguably
should be applied broadly, even if they have not been
proven to reduce the risk of death specifically in
patients with severe sepsis. Many of these measures,
including deep venous thrombosis prophylaxis, GI
bleeding prophylaxis, conservative transfusion prac-
tices, sedation-and-weaning protocols, standardized
enteral feeding protocols, bed-sore and fall preven-
tion programs, and strategies to prevent acute
renal failure have been recommended in consen-
sus statements.
Potentiality Time-Sensitive Treatments
In the last few years, six beneficial therapies have
been identified that form the core of the Surviving
Sepsis Campaign, a joint effort of numerous profes-
sional organizations to expedite and standardize care
of the patient with severe sepsis.
37
Beneficial treat-
ments are advocated collectively in bundles, and
several studies outlined below have examined the
effectiveness of a standardized approach to care
compared to historical control subjects.
Antimicrobial Therapy
It makes sense to obtain cultures of blood and
other suspect body fluids before the institution of
antimicrobial therapy, provided the process does not
unduly delay treatment. Cultures are most useful
when a highly sensitive organism that can be treated
with a simplified regimen is grown, or when an
unexpected or highly resistant organism requiring
the modification of empiric therapy is recovered.
Despite prompt collection in the absence of antibi-
otics, findings from cultures of samples taken from
all sites remain negative in up to 20% of patients, and
blood culture findings are positive in only approxi-
mately one third of patients.
38
Even though the
majority of culture findings are negative, blood and
www.chestjournal.org CHEST / 132 / 6 / DECEMBER, 2007 1969
spinal fluid cultures are most useful because when
they grow an organism, it likely represents a true-
positive result, compared to urine or sputum cultures
in which contamination is much more common.
While it is seemingly preposterous to question the
importance of antimicrobial agents or source control,
data supporting these treatments are not of the same
scientific rigor as those for other sepsis therapies. It
is implausible that a randomized study will be con-
ducted comparing the outcomes of patients operated
on for a ruptured appendix vs those subjected to a
sham operation. Likewise, the lack of equipoise
dictates a study in which patients are randomized to
receive placebo vs optimal antimicrobial therapy; or
prompt vs intentionally delayed treatment will not
occur. Hence, inferring an antimicrobial therapy
benefit hinges on comparing the outcomes of pa-
tients who receive timely, adequate, sometimes
called appropriate, antimicrobial therapy to those of
patients who receive something less.
The problem inherent to all such nonrandomized
studies is that there may be some unknown patient
factor or characteristic of the setting in which pa-
tients are treated influencing outcomes that is inde-
pendent of antibiotic selection (ie, unmeasured co-
variates). Some possibilities are obvious. Patients
receiving inadequate therapy may have fungal dis-
ease or highly resistant bacteria, making the initial
antibiotic choices wrong. This situation often results
from patient characteristics such as immune compro-
mise or chronic illness with repeated antimicrobial
exposure.
3941
Another possibility relates to system
performance. For example, outcomes could be bet-
ter when patients are treated in hospitals with rapid
access to physicians and nurses and efficient labora-
tory and radiology services, all of which are factors
that could result in faster diagnosis and appropriate
antibiotic therapy.
42
Attempts to control for these
and other differences cannot eliminate the possibility
that patient groups may differ in ways that cannot be
discerned.
Despite study limitations, the ability of antimicro-
bial agents to effectively treat infection before the
development of organ failure is well accepted.
4345
Until the past few years, there was little evidence
that antimicrobial therapy conferred a significant
benefit to patients with established organ failure,
46
but now a large retrospective analysis
47
has sug-
gested that time to treatment with antibiotics, even
after the onset of shock, is a predictor of survival. In
this analysis,
47
meaningful survival differences were
observed with as little as a 1-h delay in antimicrobial
therapy. These data are perhaps the best that will
ever exist to support guidelines recommending
broad, rapid antimicrobial administration. These
findings will be controversial as some argue it will
lead to overuse and perhaps to the inappropriate
prescription of antibiotics. In addition, there is an
emerging body of literature
48
to suggest that dees-
calating antibiotic therapy when culture findings are
negative is a beneficial practice.
Hemodynamic Management
In the last few years, physicians treating patients
with severe sepsis have been reminded of what
trauma and burn physicians have espoused for
decades, which is that rapidly identifying patients
with inadequate circulation and providing prompt
resuscitation is a critical determinant of outcome.
Although numerous studies, including the large
randomized Saline versus Albumin Fluid Evalua-
tion study,
49
have failed to definitively prove the
superiority of colloids or crystalloids, studies in
severe sepsis consistently indicate that substantial
volumes (6 to 10 L of crystalloid or its colloid
equivalent) are required to restore and maintain
normal intravascular pressures.
11
For patients who are hypotensive or who have
persistent lactate elevations after administration of
an initial fluid bolus, the use of an explicit hemody-
namic protocol reduces hospital mortality by as
much as 16%.
11
This early goal-directed therapy
(EGDT) differs in numerous respects from older
unsuccessful studies
50,51
in which attempts were
made to boost oxygen delivery often long after
organs had failed. Although the difference in out-
comes might simply be prompt implementation, it is
possible that some or all protocol elements may be
essential. This strategy uses therapy with vasopres-
sors to achieve a mean arterial pressure of 65 mm
Hg after central venous pressure is raised to 8 to 12
mm Hg with fluids. A key distinction between this and
other approaches is the measurement of superior vena
caval oxygen saturation, targeting a value 70%. This
goal is pursued by RBC transfusion for anemic patients
(hematocrit, 30%) and dobutamine therapy for pa-
tients above that threshold. The application of these
rules for a mere 6 h reportedly reduces the following:
mortality; the fraction of patients requiring mechanical
ventilation and therapy with vasopressors; time in the
hospital; and costs.
11
Like many therapies for severe sepsis, controversy
and questions surround this approach. For example,
how does the protocol recommendation for transfu-
sion reconcile with studies suggesting that a lower
transfusion target may be acceptable or even bene-
ficial? The answer is not known; however, because
these patients are hemodynamically unstable, they
differ significantly from hemodynamically stable par-
ticipants who have been studied in previous transfu-
1970 Recent Advances in Chest Medicine
sion protocols.
52
Curious physicians seek to identify
which one protocol component is beneficial. While
this may be a germane research question, for the
practicing clinician trying to decide which protocol
component is critical it is of questionable impor-
tance, considering that the protocol is brief and
employs generally conventional, inexpensive inter-
ventions. However, one important unanswered ques-
tion is what is the maximum time window for the
application of this protocol beyond which benefit
wanes? This question is especially important given
that studies
50
in which later attempts to modify
oxygen delivery may have been harmful. Despite
impressive results, this protocol has not been widely
adopted.
53
Potential reasons for nonadoption of the
results are the relatively small number of patients
studied and the single-center, nonblinded design.
Yet, other potential reasons for nonimplementation
are an uncooperative or inadequately staffed emer-
gency department; the added expense of saturation
measuring catheters; general opposition to standard-
ization of care; and uncertainty over which protocol
element is responsible for benefits.
After initial resuscitation, data from the Fluid and
Catheter Treatment Trial
54
indicate that among pa-
tients with acute lung injury (ALI) a more conserva-
tive approach to fluid management is prudent. Al-
though not exclusively a study of severe sepsis, nearly
two thirds of participants met the criteria for severe
sepsis (pneumonia and ALI or sepsis as the ALI risk
factor). The application of an explicit hemodynamic
management protocol that targets a central venous
pressure ( 4 mm Hg) or pulmonary capillary occlu-
sion pressure ( 8 mm Hg) after the resolution of
shock resulted in a significantly less positive net
fluid balance during the first week of treatment.
Although the nominally lower mortality rate (ap-
proximately 3%) was not significantly different,
fluid-conservative patients had more ventilator and
ICU-free days and a reduced duration of mechanical
ventilation among survivors. These goals were reached
without increased risk of renal insufficiency or hypo-
tension.
54
Which tool is used to measure the vascular
pressure used to drive the protocol (ie, central venous
catheter vs PAC) did not seem to matter, except with
regard to complications where PAC-randomized pa-
tients had roughly twice as many nonfatal catheter-
related complications.
55
Some investigators have questioned how the
EGDT approach, advocating early and aggressive
fluid administration, reconciles with this more con-
servative approach to fluid management. Perhaps
the best explanation was articulated in an editorial
56
accompanying the Fluid and Catheter Treatment
Trial publication, which posits the phase of illness as
the critical difference. A liberal fluid approach ap-
pears to be beneficial over the first 6 h of shock as
part of early goal-directed therapy, and a conserva-
tive approach yields better outcomes after shock
resolution.
Although several studies now suggest that therapy
with dopamine does not offer significant protection
of the kidney at risk from shock or sepsis,
57
it is still
being used by some for that purpose. Unfortunately,
few data suggest that one vasopressor is superior to
another, but small randomized studies
58
have sug-
gested that norepinephrine is more likely to rapidly
achieve a desired BP target than other vasopressors,
and do so with less tachycardia. The Sepsis Occur-
rence in Acutely ill Patients study
59
has suggested
that the use of dopamine in uncontrolled practice is
associated with a higher mortality than the use of
norepinephrine; however, studies of vasopressor use
are ongoing.
The last few years have produced numerous re-
ports that some septic shock patients have low levels
of vasopressin
60
and that fixed-dose replacement can
reduce or eliminate the need for therapy with cat-
echolamines.
61
Preliminary data from a large, ran-
domized study evaluating norepinephrine vs vaso-
pressin, the Vasopressin and Septic Shock Trial (data
not published), have been presented and do not
suggest a significant generalized benefit from vaso-
pressin therapy. Hence, until the final results are
available, this author advocates caution in the use of
vasopressin since it is a potent vasoconstrictor that may
lead to splanchnic ischemia.
Normal Tidal Volume Ventilation
Some degree of ALI develops in most patients
with severe sepsis. In a study of ALI patients,
62
investigators established that the use of a normal
tidal volume (6 mL/kg) indexed to predicted body
weight reduces absolute mortality by 9% compared
to ventilation with a traditional tidal volume of 12
mL/kg. The beneficial effects of this strategy were
confirmed among patients with sepsis as the risk
factor for ALI.
63
In this approach, ventilation with 6
mL/kg predicted body weight was used initially, but
tidal volumes were reduced to as low as 4 mL/kg if
needed to maintain plateau pressures at 30 cm
H
2
O. Although volume-cycled ventilation was used,
it is reasonable to think that a pressure-cycled ap-
proach could yield similar results, provided that
inflation pressures are set to deliver a tidal volume of
6 mL/kg and corresponding plateau pressures are
not 30 cm H
2
O.
64
Contrary to speculation, no data
have suggested that there is a known safe plateau
pressure or that there is an optimal tidal volume
between 6 and 12 mL/kg.
65
It is important to recog-
www.chestjournal.org CHEST / 132 / 6 / DECEMBER, 2007 1971
nize that these studies also remind physicians that
tidal volume is determined predominately by height
not actual body weight, and that 6 mL/kg is not a
small tidal volume, but rather a normal tidal volume,
just one that has not traditionally been used. Data
from clinical practice also now suggest that the use of
a higher tidal volume in patients with ALI is associ-
ated with worse outcomes
66
and lung injury is more
likely to develop in patients without ALI who have
received ventilation with higher tidal volumes.
67
Given that a normal-tidal-volume strategy has no
added cost, does not require additional sedation or
paralysis,
68
and is quick and simple to implement for
the majority patients, it represents a reasonable
starting point for ventilation of ALI patients.
Because low-level PEEP has inhibited atelectasis
formation and has attenuated the development of
ALI in animal models of lung injury,
69,70
some
nominal level of PEEP (approximately 5 cm H
2
O)
should probably be supplied to all patients. Beyond
this minimal recommendation, the selection of PEEP
and inspired oxygen concentration should maintain
saturations in the range of 88 to 95% (or an equivalent
Pao
2
range) while avoiding potentially toxic inspired
oxygen concentrations and excessive lung stretch. Nei-
ther higher levels of PEEP nor the titration of PEEP to
lung compliance or lower inflection point of the pres-
sure-volume curve (or Pflex) values have been consis-
tently shown to produce superior outcomes compared
to a simpler approach, provided that tidal volumes are
reduced.
71
Ventilation strategies that give a high prior-
ity to recruitment clearly can improve radiographic
images of the lung and indexes of oxygenation, but, to
date, have not translated into improved patient out-
comes.
72
Glucocorticoids and Mineralocorticoids
for Septic Shock
Numerous trials
73
using short courses of high-
dose corticosteroids in patients with severe sepsis
have failed to improve survival. Nonetheless, in
the last few years interest in lower doses of
glucocorticoids has been revived as a concept
termed relative adrenal insufficiency. In a widely
discussed study
74
of septic shock, approximately
300 patients who were identified within 8 h of
shock onset were randomized to receive hydrocor-
tisone plus fludrocortisone or placebo for 7 days.
When evaluating all patients, the time to death
may have been altered somewhat, but there was no
difference in the 28-day, ICU, hospital, or 1-year
mortality rate between treated patients and pla-
cebo recipients. Subsequent analyses found that
for patients who failed to increase their total
plasma cortisol levels by at least 9 g/dL following
administration of a 250-g ACTH stimulation
dose, there was approximately a 10% absolute
reduction in adjusted mortality associated with
treatment.
74
The smaller group of responders to
ACTH had a nominally higher mortality rate if
they were treated compared to those receiving
placebo, although this difference was not statisti-
cally significant.
This study caused controversy and stimulated ad-
ditional study. Since the benefit appears confined to
ACTH nonresponders, perhaps the most pressing
unanswered question is whether it is necessary to
conduct an ACTH stimulation test. This is a signifi-
cant issue in many hospitals, where the results of
cortisol tests are not available for days. Another
problem is clinician skepticism about whether pa-
tients with high baseline cortisol values could benefit
from receiving even more glucocorticoid therapy
merely because they failed to raise plasma cortisol
levels after the administration of ACTH. Along those
lines, some researchers
75
have claimed that a more
relevant provocation test may be 1 g of ACTH.
Some publications
76
illustrating a poor correlation
between free and total cortisol levels have ques-
tioned the soundness of using total cortisol level as a
marker. Some physicians have also expressed doubt
regarding the need to include fludrocortisone be-
cause of the volume of fluids that has been admin-
istered.
The outcomes of patients who were given various
doses of corticosteroids in usual practice may be
substantially different. When examined as part of a
trial of activated protein C, corticosteroid-treated
patients had a lower survival rate than those not
treated with corticosteroids regardless of treatment
with activated protein C.
77
Despite these questions,
a number of clinicians have adopted glucocorticoid
therapy for the treatment of patients with severe
sepsis without shock, or with shock of prolonged
duration, perhaps based on the recommendations of
some authors for broad use.
78
Hopefully, the final results of a follow-up study
79
of glucocorticoid supplementation in patients with
septic shock will help to clarify the role of cortico-
steroids. Unfortunately, preliminary results suggest
little benefit. Nevertheless, for the time being it
seems prudent to this author to administer glucocor-
ticoids and mineralocorticoids to ACTH (250 g)
nonresponders with early shock that is refractory to
fluid administration, since that is how the primary
study showing benefit was conducted. Omitting the
mineralocorticoid or the ACTH stimulation test with
the assumption that they are unimportant implies
that one can discern which component of a complex
protocol accounts for the benefit.
1972 Recent Advances in Chest Medicine
Glucose Control
Substantial data indicate that long-term inade-
quate glycemic control in diabetic patients is associ-
ated with poor long-term prognosis and that the
outcomes of heterogeneous populations of critically
ill patients are worse if they are hyperglycemic.
80
Now this concept has been extended to patients with
or at risk of severe sepsis. In a prominent study
81
of
approximately 1,500 postoperative patients, a proto-
col in which glucose was targeted to a range of 80 to
110 mg/dL gained substantial benefits compared to
patients with less stringent control. An ICU and
hospital mortality rate reduction of slightly 3%
was observed, with the greatest differences seen in
the sickest patients.
81
Although this was not a study
of patients with established severe sepsis, the sug-
gestion that glucose control could reduce the inci-
dence of sepsis and improve outcomes is reasonable.
Many were disappointed when subsequent stud-
ies,
82
including one of medical ICU patients, failed
to show an overall mortality benefit even though
intensive insulin therapy reduced renal injury and
lessened time on the ventilator in the ICU and in the
hospital. Debate followed the observation that pa-
tients with shorter stays ( 3 days) may actually have
an increased mortality rate from treatment, whereas
benefit was observed for those with longer stays. The
relevance of this finding to practitioners caring for
patients with severe sepsis is questionable because
they rarely stay 3 days.
Because it is hard to think of a reason that patients
would benefit from hyperglycemia of a significant
degree, it makes sense to follow the recommenda-
tions for maintaining glucose levels at 150 mg/dL,
and maybe even in the range of 80 to 110 mg/dL.
Despite rapid widespread adoption, many questions
remain regarding glucose control, the most impor-
tant of which are the following: does glycemic con-
trol improve the outcomes of patients with estab-
lished sepsis, and what is the optimal glucose target
and protocol that maximizes benefit while minimiz-
ing hypoglycemia? Although it is not certain, a
protocol may be even more important if corticoste-
roids are utilized as part of therapy for shock. It
appears that the benefit results from the glucose
control, not the dose of insulin administered.
83,84
Drotrecogin Alfa Activated
The last few years have seen release of the first
drug for the treatment of severe sepsis. Drotrecogin
alfa activated, also known as recombinant human
activated protein C (rhAPC) has been shown in a
large randomized, multicenter, placebo-controlled
trial
85
to reduce the absolute mortality of patients
with severe sepsis by approximately 6%. Long-term
follow-up demonstrated a persistent survival benefit
2 to 3 years after treatment.
86
In addition, treated
patients had a shorter time spent receiving therapy
with vasopressors and ventilation compared to pla-
cebo.
87
When defined as a modified APACHE II
score of 25, the absolute mortality reduction in
high-risk-of-death patients was 13%. Similar to the
EGDT and glucocorticoid studies, designating a
subgroup with a larger survival benefit than the
whole dictates that there must be a complementary
group with a lesser benefit. Subsequent study of a
heterogeneous group of low-risk-of-death patients
confirmed that such patients do not experience a
survival benefit but still incur the roughly 1 to 2%
increase in serious bleeding risk compared to placebo.
88
In controlled trials,
85,88
the increase in the risk of
intracranial hemorrhage is in the range of 0.1 to
0.3%. Preliminary reports
89
have indicated that in a
relatively small study of a heterogeneous group of
children no survival benefit was observed.
Similar to the temporal effect seen in studies of
antimicrobial therapy, a large open-label trial and a
multihospital case series
90
found a that patients
treated with rhAPC within the first day after severe
sepsis developed had a higher survival rate compared
to the second day. Earlier treatment was also asso-
ciated with less time receiving ventilation in the ICU
and in the hospital. The results of a large retrospec-
tive analysis
91
of all patients treated in controlled
trials in the first 24 h of sepsis to those treated in the
second 24 h of sepsis support the observation that
earlier treatment is better than later treatment. For
many clinicians, the survival benefit, and data sug-
gesting that a shorter time spent receiving mechan-
ical ventilation in patients with shock in the ICU and
in the hospital compared to those receiving placebo,
is not sufficiently compelling to justify the costs of
rhAPC, despite numerous analyses suggesting cost-
effectiveness.
92,93
Changing Practice
Perhaps the most exciting development is the
demonstration by numerous institutions that a stan-
dardized procedure or protocol can be used to
improve process and outcomes, including survival
and time spent on the ventilator, in the ICU and in
the hospital. Collectively, hospitals initiating proto-
cols have shown that best practices are achieved in a
higher fraction of patients, and the time to begin
almost all beneficial treatments decreases; with early
intervention, many other treatments such as pulmo-
nary artery catheterization and mechanical ventila-
tion decrease in use. For institutions that have
www.chestjournal.org CHEST / 132 / 6 / DECEMBER, 2007 1973
investigated,
9497
costs are reduced by protocol-
directed care. Reports
98
are now emerging that the
failure to meet the treatment goals of the early or
late phase of the surviving sepsis bundles results in
increased mortality. Although some have questioned
the motivation for recommendations and protocol
development, published data
9498
support the find-
ing that a bundled approach to care is associated
with improved outcomes.
Conclusion
The last 5 years have produced significant im-
provements in the care of patients with severe sepsis,
including organ support and direct treatment of the
underlying inflammatory and coagulopathic process.
Although the treatments advocated today are almost
certainly not the best that will ever be known, they
are the best known now. Daily clinicians are faced
with the following simple choice: ignore existing
evidence because it may have some flaws and is
incomplete in favor of non-evidence-based practice,
or promptly provide all the treatments we now know
to increase our patients chance of survival unless
there is a compelling reason not to do so.
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1976 Recent Advances in Chest Medicine
DOI 10.1378/chest.06-2535
2007;132;1967-1976 Chest
Arthur P. Wheeler
Sepsis
Recent Developments in the Diagnosis and Management of Severe
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