Download Defeating Sepsis: 25 Percent by 2009 When someone contracts an

Defeating Sepsis: 25 Percent by 2009
When someone contracts an infection, the body’s natural defense system usually fights back, routing the
infection and restoring equilibrium. Not so for the estimated 750,000 Americans per year who develop
severe sepsis, septic shock, or septicemia. Because of what is thought to be a chemical reaction gone awry,
when these patients encounter a dangerous pathogen, passed along by an infected person or object, their
defense systems overreact, setting off chain reactions that can be catastrophic. The “sepsis syndrome,” as
it’s often called, includes gross inflammation, low blood pressure, and many dispersed, tiny blood clots, all of
which deprive the body of vital oxygen, damaging — even destroying — major organ function and body
tissue.[1]
Unusually lethal, severe sepsis quickly kills about 30 percent of those who develop it and, as a result of
lingering damage, another 20 percent die within six months. Quick diagnosis and thorough treatment are
key to saving lives but also can be difficult to achieve. Sepsis often develops suddenly, with symptoms —
fever, chills, nausea, diarrhea, rapid heart and respiration rates — that can easily be misinterpreted,
delaying treatment past the point of effective intervention. Once treatment begins, it may not be
comprehensive, leaving a patient vulnerable to ancillary insults, such as a depressed heart rate and
hyperglycemia. The disease can frustrate even the most vigilant caregivers. Common infection sites are the
lungs, urinary tract, abdomen, and pelvis, but, in 30 percent of patients, the infection source cannot be
traced and the course of the disease is often unpredictable.
Anyone whose immune system has been weakened by physical trauma, substance abuse, or debilitating
medical treatments is at higher risk for sepsis, but seriously ill hospitalized patients are the most vulnerable.
Surrounded by the drug-resistant pathogens often found in hospitals, these patients are the most likely to
suffer from other underlying diseases, have a history of extensive use of antibiotics, and tend to be hooked
up to invasive equipment — any one of which increases the odds of developing a serious infection.
With aging populations, increased use of invasive medical technologies, and a growing number of cancer and
HIV patients, experts predict a steady increase in the global incidence of severe sepsis — currently
estimated at 13 million cases — over coming decades. However, efforts to alter this bleak picture are
accelerating. In 2002 the US Society of Critical Care Medicine, the European Society of Intensive Care
Medicine, and the International Sepsis Forum launched the Surviving Sepsis Campaign (SSC), to reduce the
relative risk of sepsis deaths by 25 percent globally by 2009. The focus of the initiative has been to build
awareness of the issue, improve early and accurate diagnosis and treatment of sepsis, and develop global
standards of care.
By early 2004, evidence-based clinical guidelines for the resuscitation and management of patients with
severe sepsis were published in leading medical journals and on the SSC website (translated into six
languages), along with educational materials, advice, and support for both clinicians and families of patients.
Health systems around the world were invited to join the global effort, simply by implementing the site’s
recommendations or, if willing, by also sharing patient charts so the SSC can analyze what progress is being
made toward the goal of 25 percent reduction in the risk of death from sepsis.
To help integrate the clinical guidelines into bedside practice, the SSC joined forces with the Institute for
Healthcare Improvement (IHI), distilling the guidelines into articulated protocols, or “bundles.” In 2007, the
SSC unveiled two bundles for effective intervention and management of sepsis. “The objective of both
bundles is to improve blood and oxygen flow throughout the body, particularly to the organs,” explains Sean
Townsend, MD, an IHI faculty member who supervised the project and who serves on the SCC executive
committee. “One bundle addresses the acute phase of severe sepsis; the other addresses the non-acute
phase, which is just as important.”
The Severe Sepsis Resuscitation Bundle contains up to seven steps, depending on circumstances, which
must be started immediately and accomplished within six hours of when a patient first presents with the
infection. The steps include: confirming the presence of sepsis; identifying the exact type of infection and
administering the antibiotic appropriate to that infection; restoring blood pressure levels, generally by
administering fluids; and verifying that oxygen is reaching vital organs.
The Sepsis Management Bundle contains four back-up steps to be considered immediately and, if indicated,
completed within 24 hours of sepsis being diagnosed. These steps are: use of low-dose steroids if fluids
were not effective in restoring blood pressure; an evaluation to determine if other drug therapies are needed
based on disease severity; control of glucose levels; and, for patients on mechanical ventilation,
maintenance of proper settings to avoid tissue damage.
To date, 41 countries — from Brazil to Wales, including Colombia, Slovakia, and five hospitals in China —
are participating in the Surviving Sepsis Campaign, and roughly 10,000 patient charts have been submitted
via downloadable data collection software available on the SSC site. The US has the largest number of SSC
sites: 54 in 19 states, plus Washington, DC.
Among the first to sign on was the Colorado Critical Care Collaborative, a coalition of 14 hospitals across the
state affiliated with the Colorado Hospital Association. Dubbed “C4” by its members, the voluntary multiprofessional critical care provider organization seeks “to improve outcomes in the most cost-effective
manner through multidisciplinary efforts.” The SSC’s objectives and approach were considered a good fit as
an initial collaborative project. In 2005, C4 members agreed to adopt the SSC guidelines — now codified
into bundles. The experience of the intervening two years shows that they have the potential for significant
impact, according to Ivor Douglas, MD, MRCP (UK), vice-chair of C4 and Chief of Pulmonary and Critical Care
at Denver Health, an integrated community academic health care system. “Our data indicate that, when
both bundles are perfectly administered to a patient with severe sepsis, twice as many patients survive as
when only one or partial bundle of care is used.” Unfortunately, says Douglas, progress has been uneven in
both uptake of the bundles and perfect adherence to the protocol. “Unless there’s an in-house champion and
the hospital has really bought in to the notion of protocol-driven, bundled care for sepsis, it can be a
struggle,” he observes. “Even then, there may be competing interests that take attention away.”
Still, he says, “the sepsis domain has set an important precedent” for the entire C4 effort. “The strength of
the SSC approach has set up the framework for future campaigns.”
Sentara Healthcare
In September 2006, Sentara Healthcare — a network of seven hospitals in southeast Virginia — became the
largest, most integrated US system to join the Surviving Sepsis Campaign, adopting the SSC goals as part
of its 2007 performance improvement program. System-wide, 15 in-service educational sessions were held
for physicians, nurses, therapists, and administrators. Bolstering the training are new resources to
encourage and facilitate consistent use of the bundles, such as revamped order sets and the addition of
sepsis screenings to nursing shift change reports.
Sentara has implemented a data collection system that takes accumulated sepsis patient information from
each individual hospital site and submits it nightly into a system-wide database that ultimately merges it
with all other important clinical information about that patient (identifiers are scrubbed before the data is
submitted to the SSC). Bundle performance is monitored weekly at the individual hospital level to assess
compliance with the SSC goals and address local process-related issues. The merged database is utilized to
analyze system-level outcomes on a monthly basis and reported to Sentara’s system quality leadership
team. Based on early extrapolation, the clinical leaders at Sentara expect the SSC bundles will save about
200 lives per year.
University of Minnesota Medical Center
At the University of Minnesota Medical Center in Minneapolis, SSC guidelines have been used informally
since their 2004 publication, says Henry Mann, Pharm D, FCCP, FCCM, FASHD, Director of the Center for
Excellence in Critical Care at the University of Minnesota College of Pharmacy. “Sepsis management has
always been a focus of ours, but there wasn’t a formal move to promote these particular guidelines until
2006.”
In June of that year, Mann and others organized the Minnesota Surviving Sepsis Network to accelerate use
of the SSC guidelines. Conducting a survey of the state’s 15 largest hospitals, they found that nine were
already using at least some portion of the SSC guidelines, but six were not, and no hospitals had adopted all
of the guidelines. “Several of the sites that were not considering using the guidelines thought their outcomes
were already better than average,” says Mann, “but few had data to support that view.” During 2007, the
Center for Excellence in Critical Care provided educational programs on best practices in sepsis to develop
the Network throughout the state.
Mann has also applied for a grant from the federal Agency for Healthcare Research and Quality to underwrite
the cost of hiring “change agents” or improvement advisors at willing hospitals. Change can be slow work,
admits Mann. “I’m constantly surprised by how hard it is to get hospitals to do what they say they want to
do but, when it comes down to it, they just have other priorities. One of the major obstacles that sites who
have adopted the guidelines continue to identify is a lack of data collection resources. This factor has kept
submissions to the SSC databank low. We’re exploring ways that the Center for Excellence in Critical Care
can help overcome this hurdle.”
Survive Sepsis Program in the UK
The official launch of the SCC in the United Kingdom took place in Summer 2004. However, while initial buyin to the guidelines and take-up of the database were brisk, progress was slow outside units with local SSC
champions. To address this issue, a new education initiative was launched in September 2007 with the aim
of improving compliance with the SSC guidelines. Known as Survive Sepsis, the program has already trained
750 individuals with a four-part strategy consisting of a day’s worth of tutorials, workshops, lectures, and
case studies; a 45-minute bedside demonstration; a toolkit of evaluative screens and care pathways, plus a
provider manual.
The main goal of Survive Sepsis in the UK is to raise awareness of the Sepsis Resuscitation Bundle,
particularly among junior nursing and medical staff in acute care. “Of course, we’re interested in both
bundles,” says Ron Daniels, MD, who heads the project, “but the greatest gaps in delivery currently exist for
the Resuscitation Bundle, which demands early recognition and immediate action from individuals in all
disciplines and at all levels. Rarely, if ever, has such a wide-scale application of such a complex diagnostic
and therapeutic package been required.” The challenge, says Daniels, is “the identification of a response to a
disease, rather than simply the disease itself. The skills required are unfamiliar to many outside critical care
units. Achieving them requires a level of interdisciplinary cohesion previously unseen in the UK.”
In contrast, says Daniels, “When recognition and emergency therapy is timely, the Sepsis Management
Bundle will be more readily achieved.” Indeed, he points out, “At roughly 36 percent, compliance with the
Management Bundle in the UK and globally is already more than three times higher than with the
Resuscitation Bundle at 11 percent.”
So far, the Survive Sepsis program has trained more than 700 people, says Daniels. By the end of 2007, he
expects that another 360 will have been trained. “By the end of 2008, we should be providing training to
more than 400 staff per month.”
While some individual efforts are sure to progress faster than others, says IHI faculty Dr. Sean Townsend,
the global Surviving Sepsis Campaign is on track to deliver a huge impact in lives saved. “Based on the data
that’s coming in, I’m confident that we’re going to reach our 2009 goal of reducing the risk of dying from
sepsis by 25 percent. Worldwide, that’s a lot of people.”
[1] Surviving Sepsis Campaign
Implement the Sepsis Management Bundle
Reducing mortality due to severe sepsis requires an organized process that guarantees early recognition and
consistent application of evidence-based practices. The Severe Sepsis Bundles are a series of evidencebased therapies that, when implemented together, will achieve better outcomes than if implemented
individually.
There are two sepsis bundles. Each bundle articulates requirements for specific timeframes.

Sepsis Resucitation Bundle: Evidence-based goals that must be completed within 6 hours for patients
with severe sepsis, septic shock and/or lactate > 4 mmol/L (36 mg/dl).

Sepsis Management Bundle: Evidence-based goals that must be completed within 24 hours for patients
with severe sepsis, septic shock and/or lactate > 4 mmol/L (36 mg/dl).
For patients with severe sepsis, as many as seven Sepsis Resuscitation Bundle elements may be necessary
to accomplish within the first 6 hours of presentation, and as many as four Sepsis Management Bundle
elements must be accomplished within the first 24 hours of presentation. Some bundle elements may not be
completed if the clinical conditions described in the bundle do not prevail, but clinicians should still assess
for those conditions and make a determination. The intention in applying the Sepsis Management Bundle is
to perform all indicated tasks 100 percent of the time within the first 24 hours of indication for severe
sepsis.
Changes for Improvement
Administer Low-Dose Steroids by a Standard Policy
Administer Drotrecogin Alfa (Activated) by a Standard Policy
Maintain Adequate Glycemic Control
Prevent Excessive Inspiratory Plateau Pressures
Implement the Sepsis Management Bundle:
Administer Low-Dose Steroids by a Standard Policy
Corresponding Bundle Item:
Low-dose steroids administered for septic shock in accordance with a standardized ICU policy.
Related Measures
Low-Dose Steroid Administration
Background:
Intravenous corticosteroids (hydrocortisone 200–300 mg/day, for 7 days in three or four divided doses or by
continuous infusion) are suggested for adult septic shock patients after blood pressure is identified to be
poorly responsive to fluid resuscitation and vasopressor therapy. We believe hospitals should strive to
develop a standardized policy in their ICU for the administration of steroids in accordance with the available
evidence for use.
For decades, the rationale for the use of glucocorticoids in sepsis trials has been the fundamental role that
they play in the stress response to infection and the anti-inflammatory effects that they exert. Randomized,
controlled, high-dose glucocorticoid trials failed to improve outcomes, leading to skepticism and the
avoidance of using any glucocorticoids in septic patients by most intensive care unit physicians. However,
recent randomized, controlled trials with low doses of hydrocortisone in septic shock have evoked a renewed
interest.
In the context of corticosteroid therapy for septic shock, high doses of glucocorticoids mainly refer to 30
mg/kg methylprednisolone or equivalent steroid preparations administered up to four times during a short
course of 1 or 2 days. [1,2] Recent low-dose glucocorticoid trials refer to a daily dose of 200–300 mg of
hydrocortisone or equivalent administered for 5 to 7 days or longer. [3–8]
Possible Decreased Mortality:
Preliminary data from a 2005 Cochrane meta-analysis considering 15 randomized controlled trials of lowand high-dose corticosteroids in 2,022 patients with septic shock summarizes available evidence on the use
of steroids in septic shock. [9] Pooled 28-day all-cause mortality did not differ between placebo and verum
(relative risk, 0.98; 95 percent CI, 0.87–1.10; p=0.7). Subgroup analysis of five trials [3–7] with low-dose
corticosteroids reduced 28-day all-cause mortality significantly (relative risk, 0.8; 95 percent CI, 0.67–
0.95; p=0.01), whereas high-dose trials did not (relative risk, 0.99; 95 percent CI, 0.83–1.17; p=0.9). The
number needed to treat with low-dose corticosteroids to save one additional life was nine (95 percent CI, 5–
33). In addition, low-dose corticosteroids significantly reduced intensive care unit and hospital all-cause
mortality and significantly increased the number of patients with shock reversal on day 7 and day 28.
These data stand in contrast to results from a large European trial, CORTICUS, which failed to show a
mortality benefit from administration of low-dose steroids in septic shock. [12] In this multicenter,
randomized, double-blind, placebo-controlled trial, 251 patients were assigned to receive 50 mg of
intravenous hydrocortisone and 248 patients to receive placebo every 6 hours for 5 days; the dose was then
tapered during a 6-day period. At 28 days, the primary outcome was death among patients who did not
have a response to a corticotropin test. Of the 499 patients in the study, 233 (46.7 percent) did not have a
response to corticotropin (125 in the hydrocortisone group and 108 in the placebo group). At 28 days, there
was no significant difference in mortality between patients in the two study groups who did not have a
response to corticotropin (39.2 percent in the hydrocortisone group and 36.1 percent in the placebo group,
p=0.69) or between those who had a response to corticotropin (28.8 percent in the hydrocortisone group
and 28.7 percent in the placebo group, p=1.00). At 28 days, 86 of 251 patients in the hydrocortisone group
(34.3 percent) and 78 of 248 patients in the placebo group (31.5 percent) had died (p=0.51). Possible
interpretations and concerns about CORTICUS are detailed below.
Earlier Shock Reversal:
Low-dose corticosteroids promote more rapid shock reversal than when they are not administered to
patients with septic shock. Numerous randomized, controlled trials with low-dose corticosteroids in patients
with septic shock confirm shock reversal and reduction of vasopressor support within a few days after
initiation of therapy in most patients. [3–7] The median time to cessation of vasopressors decreased in one
study from 13 to 4 days [5] and, in the other study, from 7 to 3 days. [8] CORTICUS, although finding no
overall decreased mortality from low-dose steroid administration, confirmed the finding of more rapid shock
reversal. [12]
Choice of Steroid:
Hydrocortisone is preferred to other glucocorticoids in patients with septic shock in most clinical trials.
Although a comparative study of different corticosteroids has not been performed in patients with septic
shock, there are several reasons why hydrocortisone is preferred. First, most of the experience with lowdose corticosteroid treatment in septic shock has been with the use of hydrocortisone. [4–
6,8,10,11] Second, hydrocortisone is the synthetic equivalent to the physiologic final active
cortisol. Therefore, treatment with hydrocortisone directly replaces cortisol, independent of metabolic
transformation. Third, hydrocortisone has intrinsic mineralocorticoid activity, whereas dexamethasone does
not.
No Role for Corticotropin Stimulation Testing:
The use of a 250-μg ACTH stimulation test to identify responders (> 9 μg/dL increase in cortisol 30–60
minutes post-ACTH administration) and to discontinue therapy in these patients is no longer recommended.
Clinicians should not wait for results of ACTH stimulation to administer corticosteroids. See Grading the
Evidence below for a more detailed explanation and rationale.
Grading the Evidence: [See Ranking the Evidence]
The Grade 2 suggestions below are weaker recommendations for care based on a number of qualitative
considerations. “B” level evidence generally derives from randomized control trials with certain limitations or
very well-done observational or cohort studies. “C” level evidence reflects well-done observational or cohort
studies with controls. “D” level evidence generally reflects case series data or expert opinion.

The 2008 Surviving Sepsis Campaign Guidelines suggest intravenous hydrocortisone be given only to
adult septic shock patients after blood pressure is identified to be poorly responsive to fluid resuscitation
and vasopressor therapy (Evidence Grade 2C).
Rationale: One French multi-center, randomized, controlled trial (RCT) of patients in vasopressorunresponsive septic shock (hypotension despite fluid resuscitation and vasopressors) showed a significant
shock reversal and reduction of mortality rate in patients with relative adrenal insufficiency (defined as postadrenocorticotropic hormone [ACTH] cortisol increase 9 µg/dL or less). [4] Two additional smaller RCTs also
showed significant effects on shock reversal with steroid therapy. [3,5] However, a large European
multicenter trial (CORTICUS) failed to show a mortality benefit with steroid therapy of septic shock. [11]
CORTICUS did show a faster resolution of septic shock in patients who received steroids. The use of the
ACTH test (responders and nonresponders) did not predict the faster resolution of shock. Importantly, unlike
the French trial, which only enrolled shock patients with blood pressure unresponsive to vasopressor
therapy, the CORTICUS study included patients with septic shock, regardless of how the blood pressure
responded to vasopressors. Although corticosteroids do appear to promote shock reversal, the lack of a clear
improvement in mortality ― coupled with known side effects of steroids such as increased risk of infection
and myopathy ― generally tempered enthusiasm for their broad use. Thus, there was broad agreement that
the recommendation should be downgraded from the previous 2004 Surviving Sepsis Campaign Guidelines
(Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign Guidelines for management of severe
sepsis and septic shock. Critical Care Medicine. 2004;32:858-873.).

The Surviving Sepsis Campaign suggests the ACTH stimulation test not be used to identify the subset of
adults with septic shock who should receive hydrocortisone (Grade 2B).
Rationale: Although one study suggested those who did not respond to ACTH with a brisk surge in cortisol
(failure to achieve or > 9 µg/dL increase in cortisol 30-60 minutes post-ACTH administration) were more
likely to benefit from steroids than those who did respond, the overall trial population appeared to benefit
regardless of ACTH result, and the observation of a potential interaction between steroid use and ACTH test
was not statistically significant. [4] Furthermore, there was no evidence of this distinction between
responders and nonresponders in a more recent multicenter trial. [12] Commonly used cortisol
immunoassays measure total cortisol (protein-bound and free) while free cortisol is the pertinent
measurement. The relationship between free and total cortisol varies with serum protein concentration.
When compared to a reference method (mass spectrometry), cortisol immunoassays may over- or
underestimate the actual cortisol level, affecting the assignment of patients to responders or nonresponders.
[13] Although the clinical significance is not clear, it is now recognized that etomidate, when used for
induction for intubation, will suppress the HPA axis. [14]

The Surviving Sepsis Campaign suggests that patients with septic shock should not receive
dexamethasone if hydrocortisone is available (Grade 2B).
Rationale: Although often proposed for use until an ACTH stimulation test can be administered, we no longer
suggest an ACTH test in this clinical situation. Furthermore, dexamethasone can lead to immediate and
prolonged suppression of the HPA axis after administration. [15]

The Surviving Sepsis Campaign suggests the daily addition of oral fludrocortisone (50 µg) if
hydrocortisone is not available and the steroid that is substituted has no significant mineralocorticoid
activity. Fludrocortisone is considered optional if hydrocortisone is used (Grade 2C).
Rationale: One study added 50 μg of fludrocortisone orally. [4] Since hydrocortisone has intrinsic
mineralcorticoid activity, there is controversy as to whether fludrocortisone should be added.

The Surviving Sepsis Campaign suggests clinicians wean the patient from steroid therapy when
vasopressors are no longer required (Grade 2D).
Rationale: There has been no comparative study between a fixed duration and clinically guided regimen, or
between tapering and abrupt cessation of steroids. Three RCTs used a fixed duration protocol for treatment
[3,5,12], and in two RCTs [3,16] therapy was decreased after shock resolution. In four RCTs steroids were
tapered over several days [3,5,12,16], and in two RCTs [4,7] steroids were withdrawn abruptly. One crossover study showed hemodynamic and immunologic rebound effects after abrupt cessation of corticosteroids.
[16] It remains uncertain whether outcome is affected by tapering of steroids or not.
The Grade 1 recommendations below are based on strong evidence for care based on a number of
qualitative considerations. “B” level evidence generally derives from randomized control trials with certain
limitations or very well-done observational or cohort studies. “C” level evidence reflects well-done
observational or cohort studies with controls. “D” level evidence generally reflects case series data or expert
opinion.

The 2008 Surviving Sepsis Campaign Guidelines suggest doses of corticosteroids comparable to >300
mg hydrocortisone daily not be used in severe sepsis or septic shock for the purpose of treating septic
shock (Grade 1A).
Rationale: Two randomized prospective clinical trials and a meta-analyses concluded that for therapy of
severe sepsis or septic shock, high-dose corticosteroid therapy is ineffective or harmful. [2,18,19] Reasons
to maintain higher doses of corticosteroid for medical conditions other than septic shock may exist.

The Surviving Sepsis Campaign recommends that corticosteroids not be administered for the treatment
of sepsis in the absence of shock. There is, however, no contraindication to continuing maintenance
steroid therapy or to using stress does steroids if the patient’s endocrine or corticosteroid administration
history warrants (Grade 1D).
Rationale: No studies exist that specifically target severe sepsis in the absence of shock that offer support
for use of stress doses of steroids in this patient population. Steroids may be indicated in the presence of a
prior history of steroid therapy or adrenal dysfunction. A recent preliminary study of stress dose level
steroids in community-acquired pneumonia is encouraging but needs confirmation. [20]
References:
1.
2.
3.
Lefering R, Neugebauer EA. Steroid controversy in sepsis and septic shock: A meta-analysis. Critical
Care Medicine. 1995;23:1294–1303.
Cronin L, Cook DJ, Carlet J, et al. Corticosteroid treatment for sepsis: A critical appraisal and metaanalysis of the literature. Critical Care Medicine. 1995;23:1430–1439.</
DIV>
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
Briegel J, Kellermann W, Forst H, et al. Low-dose hydrocortisone infusion attenuates the systemic
inflammatory response syndrome: The Phospholipase A2 Study Group. The Clinical Investigator.
1994;72:782–787.
Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and
fludrocortisone on mortality in patients with septic shock. Journal of the American Medical Association.
2002;288:862–871.
Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic shock with supraphysiologic doses of
hydrocortisone. Critical Care Medicine. 1998;26:645-650.
Chawla K, Kupfer Y, Goldman I, et al. Hydrocortisone reverses refractory septic shock. Critical Care
Medicine. 1999;27(1S):33A.
Yildiz O, Doganay M, Aygen B, et al. Physiological-dose steroid therapy in sepsis. Critical Care.
2002;6:251–259.
Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock:
A prospective, randomized, double-blind, single-center study. Critical Care Medicine. 1999;27:723–
732.
Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for treating severe sepsis and septic shock.
Cochrane Database Systematic Review. 2005;1:CD002243.
Oppert M, Reinicke A, Gräf KJ, et al. Plasma cortisol levels before and during “low-dose”
hydrocortisone therapy and their relationship to hemodynamic improvement in patients with septic
shock. Intensive Care Medicine. 2000;26:1747–1755.
Rothwell PM, Udwadia ZF, Lawler PG. Cortisol response to corticotropin and survival in septic shock.
Lancet. 1991;337:582–583.
Sprung CL, Annane D, Keh D, et al. CORTICUS Study Group. Hydrocortisone therapy for patients with
septic shock. New England Journal of Medicine. 2008 Jan 10;358(2):111-124.
Briegel J, Vogeser M, Annane D, Keh D, Moreno R, Singer M, Weiss Y, Sprung CL. Measurement of
cortisol in septic shock: Interlaboratory harmonization. American Journal of Respiratory and Critical
Care Medicine. 2007;175:A436.
Allolio B, Dorr H, Stuttmann R, et al. Effect of a single bolus of etomidate upon eight major
corticosteroid hormone and plasma ACTH. Clinical Ednocrinology. 1985;22:281-286.
Reincke M, Allolio B, Würth G, Winkelmann W. The hypothalamic-pituitary-adrenal axis in critical
illness: Response to dexamethasone and corticotropin-releasing hormone. Journal of Clinical
Endocrinology and Metabolism. 1993;77:151-156.
Oppert M, Schindler R, Husung C, et al. Low dose hydrocortisone improves shock reversal and reduces
cytokine levels in early hyperdynamic septic shock. Critical Care Medicine. 2005;33:2457-2464.
Keh D, Boehnke T, Weber-Carstens S, et al. Immunologic and hemodynamic effects of “low-dose”
hydrocortisone in septic shock: A double-blind, randomized, placebo-controlled, crossover study.
American Journal of Respiratory and Critical Care Medicine. 2003;167:512–520.
Bone RC, Fisher CJ, Clemmer TP. A controlled clinical trial of high-dose methylprednisolone in the
treatment of severe sepsis and septic shock. New England Journal of Medicine. 1987;317:653-658.
The Veterans Administration Systemic Sepsis Cooperative Study Group. Effect on high-dose
glucocorticoid therapy on mortality in patients with clinical signs of sepsis. New England Journal of
Medicine. 1987;317:659-665.
Confalonieri M, Urbino R, Potena A, et al. Hydrocortisone infusion for severe community-acquired
pneumonia. A preliminary randomized study. American Journal of Respiratory and Critical Care
Medicine. 2005;171:242-248.
Content adapted extensively from:

Dellinger, RP, Levy, MM, Carlet, JM, et al. Surviving Sepsis Campaign: International guidelines for
management of severe sepsis and septic shock: 2008. Critical Care Medicine. 2008;36(1):296-327.

Keh D, Sprung CL. Use of corticosteroid therapy in patients with sepsis and septic shock: An evidencebased review. Critical Care Medicine. 2004;32[Suppl.]:S527–S533.
Tips
1.
Use the Interim Low-Dose Glucorticoid Policy until your
institution is able to devise an appropriate policy.
2.
3.
4.
5.
Create an ICU protocol that standardizes the use of low-dose
steroids in septic shock to eliminate variation in care.
Use a sufficient dose of glucocorticoid for efficacy, for
example, hydrocortisone 50 mg IV every 6 hours.
Resist deferring the use of low-dose steroids for fear of
worsening infection in patients who remain hypotensive
despite both adequate volume resuscitation and application
of vasopressors.
An ACTH stimulation is not recommended to ascertain
whether septic shock patients should receive low-dose
steroids.
Implement the Sepsis Management Bundle:
Administer Drotrecogin Alfa (Activated) by a Standard Policy
Disclosure:
The Surviving Sepsis Campaign has been underwritten in part by an unrestricted educational grant by Eli
Lilly, Inc., the manufacturer of Drotrecogin Alfa (Activated). During the deliberations of the 2004 and 2008
Surviving Sepsis Campaign Guidelines Committees, there was no industry input into guidelines development
and no industry presence at any of the meetings. In 2008, the Surviving Sepsis Campaign Guidelines
Committee meetings were made possible by a grant from the Society of Critical Care Medicine. In both 2004
and 2008, the industry sponsors of educational grants to the Surviving Sepsis Campaign did not see the
guidelines until the manuscript was peer reviewed and accepted for publication in final form.
Corresponding Bundle Element:
Drotrecogin Alfa (Activated) administered in accordance with a standardized ICU policy.
Related Measures
Drotrecogin Alfa (Activated) Administration
Background:
The 2008 Surviving Sepsis Campaign Guidelines suggest that adult patients with sepsis induced organ
dysfunction associated with a clinical assessment of high risk of death, most of whom will have APACHE II
≥25 or multiple organ failure receive Drotrecogin Alfa (Activated), also known as recombinant activated
protein C (rhAPC), if there are no contraindications. The Surviving Sepsis Campaign recommends that adult
patients with severe sepsis and low risk of death, most of whom will have APACHE II <20 or one organ
failure, do not receive rhAPC.
Mortality Benefit:
The first trial to assess the efficacy of rhAPC was the PROWESS trial. PROWESS was a phase 3,
multinational, double-blind, placebo-controlled trial of rhAPC (24 μg·kg-1·hr-1 during 96 hrs) in patients
with severe sepsis. The trial was powered to document a 15 percent reduction in the relative risk of 28-day
all-cause mortality. [1] The trial was stopped early due to a statistically significant difference observed
between the treatment and the placebo groups after the second interim analysis of 1,520 patients.
PROWESS demonstrated a significant reduction in the 28-day all-cause mortality: absolute reduction of
mortality, -6.1 percent (30.8 percent to 24.7 percent); relative risk reduction of mortality, 19.4 percent (95
percent confidence interval, 6.6-30.5; p=0.005); and a range of number needed to treat of 16 to 54.
Nevertheless, subsequent trials made interpretation of these results less straightforward. Please see Grading
the Evidence below.
APACHE II Score:
In the PROWESS trial, patients were prospectively stratified, in part, by their baseline Acute Physiology and
Chronic Health Evaluation (APACHE) II score. There are practical and methodologic limitations of the
APACHE II score, which is not typically used to clinically manage individual patients. Nevertheless, The US
Food and Drug Agency approved rhAPC for sepsis-induced organ dysfunction associated with high risk of
death, such as APACHE II of > 25. In Europe, the European Agency for the Evaluation of Medicinal products
approved rhAPC for the treatment of adult patients with two or more organ dysfunctions. The APACHE II
score may be calculated courtesy of the French Society of Anesthesia and Intensive Care (see
http://www.sfar.org/scores2/apache22.html).
Risk Assessment:
At present, risk assessment is best determined by bedside clinical evaluation and judgment. The use of a
standardized policy in intensive care units for the administration of rhAPC may help to clarify decision
making about when to apply rhAPC. See the Interim Drotrecogin Alfa (Activated) Administration Policy for a
policy that may be used until your intensive care unit or hospital creates one.
Cost-Effectiveness:
Cost-effectiveness appears to be related to the severity of illness as calculated by APACHE II score. The
cost-effectiveness analysis of the PROWESS trial could document a $27,400 cost per quality-adjusted lifeyear when limited to patients with an APACHE II score of 24, whereas rhAPC was considered cost ineffective
in patients with a lower risk of death. [2,3]
Exclusion Criteria:
Many patients were not included in trials establishing the efficacy of rhAPC in severe sepsis. Therefore, the
effect of rhAPC is not documented in morbidly obese patients, those patients admitted to an intensive care
unit in moribund state with an almost certain likelihood to die, in children, and in pregnant women. Patients
with acute pancreatitis were not included in the PROWESS trial, nor were patients who required
anticoagulation for a documented or suspected deep vein thrombosis or pulmonary embolism. In addition,
hematologic diseases that could interfere with the anticoagulant effects of rhAPC (resistance to activated PC
[Leyden mutation], hereditary deficiency of Protein C, Protein S, or antithrombin, known anticardiolipin
antibody, lupus anticoagulant, and homocystinemia) were considered as exclusion criteria.
Adverse Effects of Treatment with rhAPC:
Bleeding is the most frequent and serious adverse event that may be induced by rhAPC treatment, and
patients at high risk of serious bleeding events should not be treated with rhAPC. [1] The risk of bleeding
events should be carefully weighed at the time of the initial clinical evaluation of severely septic patients.
Clinicians should consider needed surgeries and/or invasive procedures. Intracranial bleeding is the most
severe bleeding event observed in clinical studies of rhAPC. The main risk factor for intracranial bleeding
was severe thrombocytopenia andmeningeal infection. Patients with a baseline platelet count of <
30,000/mm3 should not receive rhAPC; previous platelet transfusion should likely not be used to allow
rhAPC treatment; platelet count should be carefully monitored by short-time sequential measurements
during treatment to anticipate the platelets decrease; platelet transfusion should be used to maintain
platelet count at > 30,000/mm3.
Grading the Evidence: [See Ranking the Evidence]
The Grade 1 recommendations below are based on strong evidence for care based on a number of
qualitative considerations, while Grade 2 suggestions are weaker recommendations for care. “B” level
evidence generally derives from randomized control trials with certain limitations or very well-done
observational or cohort studies. “C” level evidence reflects well-done observational or cohort studies with
controls. “D” level evidence generally reflects case series data or expert opinion.

The 2008 Surviving Sepsis Campaign Guidelines suggests that adult patients with sepsis induced organ
dysfunction associated with a clinical assessment of high risk of death, most of whom will have APACHE
II ≥25 or multiple organ failure, receive rhAPC if there are no contraindications (Evidence Grade 2B,
except for patients within 30 days of surgery where it is Grade 2C). Relative contraindications should
also be considered in decision making.

The Surviving Sepsis Campaign recommends that adult patients with severe sepsis and low risk of
death, most of whom will have APACHE II <20 or one organ failure, do not receive rhAPC (Grade
1A).
Rationale: The evidence concerning use of rhAPC in adults is primarily based on two randomized controlled
trials (RCTs): PROWESS (1,690 adult patients, stopped early for efficacy) [1], and ADDRESS (stopped early
for futility). [4] Additional safety information comes from an open-label observational study called
ENHANCE. [5] The ENHANCE trial also suggested early administration of rhAPC was associated with better
outcomes.
PROWESS involved 1,690 patients and documented 6.1 percent in absolute total mortality reduction with a
relative risk reduction (RRR) of 19.4 percent (95 percent CI, 6.6-30.5, p=0.005), with a number needed to
treat (NNT) of 16. [1] Controversy associated with the results focused on a number of subgroup analyses.
Subgroup analyses have the potential to mislead due to the absence of an intent to treat, sampling bias, and
selection error. [6] The analyses suggested increasing absolute and relative risk reduction with greater risk
of death using both higher APACHE II scores and greater number of organ failures. [7] In Europe, this led to
drug approval for patients with high risk of death (such as APACHE II ≥25) and more than one organ failure.
The ADDRESS trial involved 2,613 patients judged to have a low risk of death at the time of enrollment.
Twenty-eight-day mortality from all causes was 17 percent on placebo vs. 18.5 percent on APC, relative risk
(RR) 1.08 (95 percent CI, 0.92-1.28). [4] Again, debate focused on subgroup analyses; analyses restricted
to small subgroups of patients with APACHE II score over 25, or more than one organ failure which failed to
show benefit. However, these patient groups also had a lower mortality than in PROWESS.
Relative risk reduction of death was numerically lower in the subgroup of patients with recent surgery
(n=502) in the PROWESS trial (30.7 percent placebo vs. 27.8 percent APC) [7] when compared to the
overall study population (30.8 percent placebo vs. 24.7 percent APC). [1] In the ADDRESS trial, patients
with recent surgery and single organ dysfunction who received APC had significantly higher 28-day mortality
rates (20.7 percent vs. 14.1 percent, p=0.03, n=635). [4]
Serious adverse events did not differ in the studies [1,4,5] with the exception of serious bleeding, which
occurred more often in the patients treated with APC: PROWESS, 2 percent vs. 3.5 percent (p=0.06) [1];
ADDRESS, 2.2 percent vs. 3.9 percent (p<0.01) [4]; and ENHANCE, 6.5 percent (open label). [5]
Intracranial hemorrhage (ICH) occurred in the PROWESS trial in 0.1 percent (placebo) and 0.2 percent
(APC) (n.s.) [1]; in the ADDRESS trial 0.4 percent (placebo) vs. 0.5 percent (APC) (n.s.) [4]; and in the
ENHANCE trial 1.5 percent. [5] Registry studies of rhAPC report higher bleeding rates than randomized
controlled trials, suggesting that the risk of bleeding in actual practice may be greater than reported in
PROWESS and ADDRESS. [8,9]
The two RCTs in adult patients were methodologically strong, precise, and provide direct evidence regarding
death rates. The conclusions are limited, however, by inconsistency that is not adequately resolved by
subgroup analyses (thus the designation of moderate quality evidence). Results, however, consistently fail
to show benefit for the subgroup of patients at lower risk of death, and consistently show increases in
serious bleeding. The RCT in pediatric severe sepsis failed to show benefit and has no important limitations.
Thus, for low risk and pediatric patients, the 2008 Surviving Sepsis Campaign Guidelines rate the evidence
as high quality.
For adult use there is probable mortality reduction in patients with clinical assessment of high risk of death,
most of whom will have APACHE II >25 or multiple organ failure. There is likely no benefit in patients with
low risk of death, most of whom will have APACHE II <20 or single organ dysfunction. The effects in patients
with more than one organ failure who have APACHE II <25 are unclear, and in that circumstance one may
use clinical assessment of the risk of death and number of organ failures to support a treatment decision.
There is a certain increased risk of bleeding with administration of rhAPC, which may be higher in surgical
patients and in the context of invasive procedures. Decision on utilization depends upon assessing likelihood
of mortality reduction versus increases in-bleeding and cost.
A European Regulatory mandated randomized controlled trial of rhAPC vs. placebo in patients with septic
shock is now ongoing. [10]
References:
1.
2.
Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein
C for severe sepsis. New England Journal of Medicine. 2001;344:699–709.
Manns BJ, Lee H, Doig CJ, et al. An economic evaluation of activated protein C treatment for severe
sepsis. New England Journal of Medicine. 2002;347:993–999.
3.
Angus DC, Linde-Zwirbie WT, Clermont G, et al. Cost-effectiveness of drotrecogin alfa (activated) in
the treatment of severe sepsis. Critical Care Medicine. 2003;31:1–11.
4.
Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, Francois B, Guy JS, Bruckmann M,
Rea-Neto A, et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death.
New England Journal of Medicine. 2005; 353:1332-1341.
5.
Vincent JL, Bernard GR, Beale R, et al. Drotrecogin alfa (activated) treatment in severe sepsis from
the global open-label trial ENHANCE: Further evidence for survival and safety and implications for
early treatment. Critical Care Medicine. 2005;33:2266-2277.
6.
Oxman AD, Guyatt GH. A consumer's guide to subgroup analyses. Annals of Internal Medicine.
1992;116:78-84.
7.
Ely EW, Laterre PF, Angus DC, Helterbrand JD, Levy H, Dhainaut JF, Vincent JL, Macias WL, Bernard
GR. Drotrecogin alfa (activated) administration across clinically important subgroups of patients with
severe sepsis. Critical Care Medicine. 2003;31:12-19.
8.
Kanji S, Perreault MM, Chant C, et al. Evaluating the use of Drotrecogin alfa activated in adult severe
sepsis: A Canadian multicenter observational study. Intensive Care Medicine. 2007;33:517-523.
9.
Bertolini G, Rossi C, Anghileri A, et al. Use of Drotrecogin alfa (activated) in Italian intensive care
units: The results of a nationwide survey. Intensive Care Medicine. 2007;33:426-434.
10. European Medicines Agency (EMEA). Committee for Medicinal Products for Human Use February 2007
Plenary Meeting Monthly Report. EMEA/85096/2007. London, 2 March 2007. Available at:
www.emea.europa.eu/pdfs/human/press/pr/8509607en.pdf.
Content adapted extensively from:

Dellinger, RP, Levy, MM, Carlet, JM, et al. Surviving Sepsis Campaign: International guidelines for
management of severe sepsis and septic shock: 2008. Critical Care Medicine. 2008;36(1):296-327.

Fourrier F. Recombinant human activated protein C in the treatment of severe sepsis: An evidencebased review. Critical Care Medicine. 2004;32(Suppl.):S534–S541.
Tips
1.
2.
3.
4.
Investigate whether the pharmacy has established
indications for use of Drotrecogin Alfa in the institution.
Create a standardized ICU policy for the use Drotrecogin Alfa
(Activated).
Use the Interim Drotrecogin Alfa (Activated) Administration
Policy until finalized.
Provide in-service training to ICU personnel on
administration, side effects, and expected laboratory
alterations when using Drotrecogin alfa.
Drotrecogin Alfa (Activated) Administration
Definition
Drotrecogin Alfa (Activated) has been shown to decrease mortality
in severely septic patients in some clinical trials. There are a
number of clinical criteria applied to patients to determine eligibility
best captured in a standardized ICU policy for administration.
Compliance with this bundle element is defined as the percent of
patients with severe sepsis or septic shock for whom Drotrecogin
Alfa (Activated) was administered in accordance with a
standardized ICU policy within 24 hours following the time of
presentation.
Note: It is possible that the standardized ICU policy that governs
Drotrecogin Alfa (Activated) administration concludes that the drug
should not be given in a particular case. In that case, as long as
there is annotation in the chart concluding that Drotrecogin Alfa
was not indicated by protocol, simply assign credit for following the
policy.
Numerator: The number of patients with severe sepsis or septic
shock for whom Drotrecogin Alfa (Activated) was administered in
accordance with a standardized ICU policy within 24 hours following
the time of presentation
Denominator: The total number of patients presenting with severe
sepsis and septic shock
Exclusion: Non-severe sepsis
Goal
Increase administration of Drotrecogin Alfa (Activated) in
accordance with a standardized ICU policy to 100 percent of
indicated severe sepsis cases.
Data Collection Plan
Data may be collected concurrently — that is, once a patient is
placed on the hospital’s severe sepsis protocol, data can be
abstracted from the patient chart in real time — or retrospectively
using a chart review, a method generally recommended for more
experienced improvement teams.
Sample Graph
Use Improvement Tracker to enter, save, and graph your
team's data
Implement the Sepsis Management Bundle:
Maintain Adequate Glycemic Control
Related Measures
Glycemic Control Goal
Background:
Effective glucose control in the intensive care unit (ICU) has been shown to decrease morbidity across a
large range of conditions and also to decrease mortality.
Hyperglycemia, caused by insulin resistance in the liver and muscle, is a common finding in ICU patients.
Some have considered it to be an adaptive response, providing glucose for the brain, red blood cells, and
wound healing. Traditionally, hyperglycemia has only been treated when blood glucose increases to >215
mg/dL (>12 mmol/L). Conventional wisdom in the ICU has been that some degree of hyperglycemia is
beneficial and that hypoglycemia is dangerous and should be avoided. The extent of appropriate glucose
control has been evaluated in recent years.
Initial Investigations — Intensive Insulin Therapy:
An initial investigation by Van den Berghe and colleagues [2] suggested that controlling blood glucose levels
by intensive insulin therapy decreased mortality and morbidity in surgical critically ill patients. The trial was
a large single-center study of postoperative surgical patients. The design employed a continuous infusion of
insulin to maintain glucose between 80 and 110 mg/dL (4.4–6.1 mmol/L). Exogenous glucose was begun
simultaneously with insulin, with frequent monitoring of glucose (every 1 hour) and intensity of monitoring
was greatest at the time of initiation of insulin. This protocol called for implementing a strategy to maintain
normoglycemia with an insulin infusion while providing for normal intake of glucose (9 g/hour) and calories
(19 kcal·kg-1·day-1).
A total of 35 of 765 patients (4.6 percent) in the intensive insulin group died in the ICU in Van den Berghe
et al., compared with 63 patients (8.0 percent) in the conventional therapy group.
Intensive insulin therapy halved the prevalence of:





Bloodstream infections
Prolonged inflammation
ARF requiring dialysis or hemofiltration
Critical illness polyneuropathy
Transfusion requirements
Patients receiving intensive insulin therapy were also less likely to require prolonged mechanical ventilation
and intensive care.
Rigorous insulin treatment reduced the number of deaths from multiple-organ failure with sepsis, regardless
of whether there was a history of diabetes or hyperglycemia.
Surgical vs. Medical Patients:
The same protocol used in the first Van den Berghe trial for surgical patients was subsequently tested in
medical patients. [3]
Patients who were considered to need intensive care for at least three days were enrolled in a prospective,
randomized, single-center, controlled study. On admission, patients were randomly assigned to strict
normalization of blood glucose levels (80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]) with the use of
insulin infusion or conventional therapy (i.e., insulin administered when the blood glucose level exceeded
215 mg per deciliter [12 mmol per liter], with the infusion tapered when the level fell below 180 mg per
deciliter [10 mmol per liter]).
Intensive insulin therapy reduced blood glucose levels but did not significantly reduce in-hospital mortality
(40.0 percent in the conventional treatment group vs. 37.3 percent in the intensive treatment group,
p=0.33). However, morbidity was significantly reduced by the prevention of newly acquired kidney injury,
accelerated weaning from mechanical ventilation, and accelerated discharge from the ICU and the hospital.
Although length of stay in the ICU could not be predicted on admission, among 433 patients who stayed in
the ICU for less than three days, mortality was greater among those receiving intensive insulin therapy. In
contrast, among 767 patients who stayed in the ICU for three or more days, in-hospital mortality in the 386
who received intensive insulin therapy was reduced from 52.5 to 43.0 percent (p=0.009) and morbidity was
also reduced.
The authors concluded that intensive insulin therapy significantly reduced morbidity but not mortality among
all patients in the medical ICU. Although the risk of subsequent death and disease was reduced in patients
treated for three or more days, these patients could not be identified before therapy.
Meta-Analyses and Severe Sepsis Specific Inquires:
A meta-analysis of 35 trials on insulin therapy in critically ill patients, including 12 randomized trials,
demonstrated a 15 percent reduction in short-term mortality (relative risk 0.85, 95 percent confidence
interval 0.75-0.97) but did not include any studies of insulin therapy in medical ICUs. [4]
A multi-center randomized control trial (VISEP) focusing on patients with severe sepsis failed to demonstrate
improvement in mortality. [5] In VISEP, the investigators randomly assigned patients with severe sepsis to
receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy. Of the 537
patients who could be evaluated, the mean morning blood glucose level was lower in the intensive therapy
group (112 mg per deciliter [6.2 mmol per liter]) than in the conventional therapy group (151 mg per
deciliter [8.4 mmol per liter], p<0.001). However, at 28 days, there was no significant difference between
the two groups in the rate of death or the mean score for organ failure.
Further, the VISEP investigators found that the rate of severe hypoglycemia (glucose level, < or = 40 mg
per deciliter [2.2 mmol per liter]) was higher in the intensive therapy group than in the conventional therapy
group (17.0 percent vs. 4.1 percent, p<0.001), as was the rate of serious adverse events (10.9 percent vs.
5.2 percent, p=0.01). The trial was stopped earlier than planned for these reasons.
NICE-SUGAR Study:
Based on the foregoing studies, most clinicians believed that there was a benefit to glucose control in terms
of mortality and morbidity. However, the optimal target range for blood glucose in critically ill patients
remained unclear.
The NICE-SUGAR study investigators [1] chose to evaluate whether there was a difference in mortality
between subjects randomly assigned to either intensive glucose control, with a target blood glucose range of
81 to 108 mg per deciliter (4.5 to 6.0 mmol per liter), or conventional glucose control, with a target of 180
mg or less per deciliter (10.0 mmol or less per liter). To be considered, patients were expected to require
treatment in the ICU on 3 or more consecutive days.
Of the 6,104 patients who underwent randomization, 3,054 were assigned to undergo intensive control and
3,050 to undergo conventional control. A total of 829 patients (27.5 percent) in the intensive-control group
and 751 (24.9 percent) in the conventional-control group died. Thus, the odds of dying with intensive
control were 1.14 times greater than with conventional control (p=0.02). In addition, severe hypoglycemia
(blood glucose level of 40 mg per deciliter [2.2 mmol per liter]) was reported in 206 of 3,016 patients (6.8
percent) in the intensive-control group and in 15 of 3,014 patients (0.5 percent) in the conventional-control
group (p<0.001). Thus, the incidence of hypoglycemia was lower in the conventional group.
With regard to morbidity and length of stay, NICE-SUGAR demonstrated that there was no significant
difference between the two treatment groups in the median number of days in the ICU or hospital, or the
median number of days of mechanical ventilation or renal-replacement therapy.
The NICE-SUGAR investigators concluded that that intensive glucose control increased mortality among
adults in the ICU and that a blood glucose target of 180 mg or less per deciliter resulted in lower mortality
than did a target of 81 to 108 mg per deciliter.
Grading the Evidence: [See Ranking the Evidence]
The Grade 1 recommendations are based on strong evidence for care based on a number of qualitative
considerations. “B” level evidence generally derives from randomized control trials with certain limitations or
very well-done observational or cohort studies. “C” level evidence reflects well-done observational or cohort
studies with controls. “D” level evidence generally reflects case series data or expert opinion.
The Surviving Sepsis Campaign formerly recommended in the 2008 Surviving Sepsis Campaign Guidelines
that, following initial stabilization, patients with severe sepsis and hyperglycemia who are admitted to the
ICU receive IV insulin therapy to reduce blood glucose levels (Evidence Grade 1B).
The Surviving Sepsis Campaign reviewed its specific recommendations and ranges for glucose control after
publication of NICE-SUGAR and issued a statement on glucose control ranges for severely septic patients in
June 2009:
“There is insufficient information from randomized controlled trials to determine the optimal target range of
blood glucose in the severely septic patient. [6] The NICE-SUGAR trial is the largest most compelling study
to date on glucose control in ICU patients given its inclusion of multiple ICUs and hospitals, and a more
general patient population. [1] Based on the results of this trial, we recommend against intravenous insulin
therapy titrated to keep blood glucose in the normal range (80-110 mg/dl) in patients with severe sepsis. It
is clear that attempts to normalize blood glucose with IV insulin during critical illness results in higher rates
of hypoglycemia. [6,7] Until additional information is available, teams seeking to implement glucose control
should consider initiating insulin therapy when blood glucose levels exceed 180 mg/dL with a goal blood
glucose approximating 150 mg/dl as was observed in the beneficial arm of the NICE-SUGAR trial.”
Similarly, IHI advocates for a target threshold less than <180 for criticially ill patients based on the NICESUGAR trial data.
References:
1.
2.
3.
4.
5.
6.
NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional
glucose control in critically ill patients. New England Journal Medicine. 2009 Mar 26;360(13):1283-1297.
Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients.
New England Journal of Medicine. 2001;345:1359–1367.
Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. New
England Journal of Medicine. 2006 Feb 2;354(5):449-461.
Pittas, AG, Siegel RD, Lau, J. Insulin therapy for critically ill hospitalized patients. Archives of Internal
Medicine. 2004;164:2005-2011.
Brunkhorst FM, Engel C, Bloos F, et al; German Competence Network Sepsis (SepNet). Intensive insulin
therapy and pentastarch resuscitation in severe sepsis. New England Journal of Medicine. 2008 Jan
10;358(2):125-139.
Griesdale DE, de Souza RJ, van Dam RM, et al. Intensive insulin therapy and mortality among critically
ill patients: A meta-analysis including NICE-SUGAR study data. Canadian Medical Association Journal.
2009 Apr 14;180(8):799-800.
7.
8.
Dandona P, Aljada A, Mohanty P, et al. Insulin inhibits intranuclear nuclear factor kappa-B and
stimulates I-kappa-B in mononuclear cells in obese subjects: Evidence for an anti-inflammatory effect?
Journal of Clinical Endocrinology and Metabolism. 2001;86:3257–3265.
Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in critically ill adults: A
meta-analysis. Journal of the American Medical Association. 2008;300:933-944.
Content adapted extensively from:

Dellinger, RP, Levy, MM, Carlet, JM, et al. Surviving Sepsis Campaign: International guidelines for
management of severe sepsis and septic shock: 2008. Critical Care Medicine. 2008;36(1):296-327.

Cariou A, Vinsonneau C, Dhainaut JF. Adjunctive therapies in sepsis: An evidence-based review. Critical
Care Medicine. 2004;32(Suppl.):S562–S570.
Tips
1.
2.
3.
4.
5.
6.
Create a standardized protocol that provides for continuous
intravenous insulin infusion and nutritional support for cases
of severe sepsis and septic shock .
Allow the protocol to be automatically adjusted by the
nursing staff to safely accomplish tight glucose control with a
reliable bedside presence.
Administer glucose or enteral feedings while the insulin
infusion is active, with frequent glucose monitoring by finger
stick.
Adopt a specific treatment plan for hypoglycemia.
Educate the nursing staff about the benefits of tight glucose
control and relieve the fear of increasing the incidence of
hypoglycemia. Tight glycemic control in patients can be so
foreign to routine clinical practice that fear can defeat the
success of the project.
Work closely with nursing in creating the protocols to make
sure the increased burden of frequent glucose checks can be
integrated into their workflow.
Implement the Sepsis Management Bundle:
Prevent Excessive Inspiratory Plateau Pressures
Corresponding Bundle Element:
Inspiratory plateau pressures maintained < 30 cm H2O for mechanically ventilated patients.
Related Measures
Inspiratory Plateau Pressure Goal
Background:
Patients with sepsis are at increased risk for developing acute respiratory failure, and most patients with
severe sepsis and septic shock will require endotracheal intubation and mechanical ventilation. Nearly 50
percent of patients with severe sepsis will develop acute lung injury (ALI)/acute respiratory distress
syndrome (ARDS). Patients with lung injury will have bilateral patchy infiltrates on chest x-ray, low
paO2:FIO2 ratios (less than 300 for ALI or less than 200 for ARDS), and pulmonary capillary wedge pressure
less than 18 cm H20, although this last measure is often clinically not available.
High tidal volumes that are coupled with high plateau pressures should be avoided in ALI/ARDS. Clinicians
should use as a starting point a reduction in tidal volumes over 1 to 2 hours to a “low” tidal volume (6
mL·kg-1·lean body weight-1) as a goal in conjunction with the goal of maintaining end-inspiratory plateau
pressures of < 30 cm H2O.
Mortality Reduction:
The largest trial of a volume- and pressure-limited strategy showed a 9 percent decrease of all-cause
mortality in patients ventilated with tidal volumes of 6 mL/kg of estimated lean body weight (as opposed to
12 mL/kg) while aiming for a plateau pressure of < 30 cm H2O. [1]
The formal ARDSnet protocol for mechanical ventilation is available at
http://www.ardsnet.org/system/files/Ventilator+Protocol+Card.pdf and is encouraged for use in septic
patients.
Permissive Hypercapnia:
Hypercapnia (allowing PaCO2 to increase above normal, so-called permissive hypercapnia) can be tolerated
in patients with ALI/ARDS if required to minimize plateau pressures and tidal volumes.
Although an acutely elevated PCO2 may have physiologic consequences that include vasodilatation and
increased heart rate, blood pressure, and cardiac output, allowing modest hypercapnia in conjunction with
limiting tidal volume and minute ventilation has been demonstrated to be safe in small, nonrandomized
series. [2,3] No upper limit for PCO2 has been established. Some authorities recommend maintaining pH at
> 7.20–7.25, but this has not been prospectively established. The use of hypercarbia is limited in patients
with preexisting metabolic acidosis and is contraindicated in patients with increased intracranial pressure.
[4] Sodium bicarbonate infusion may be considered in select patients to facilitate use of permissive
hypercarbia. [1] Experimental models suggest that respiratory acidosis may confer protection against
various forms of inflammatory injury. [6]
Positive End-Expiratory Pressure (PEEP):
Provide adequate supplemental oxygen to maintain a pulse oximetric saturation of > 90 percent. A minimum
amount of PEEP should be set to prevent lung collapse at end expiration. Setting PEEP based on severity of
oxygenation deficit and guided by the FIO2 required to maintain adequate oxygenation is one acceptable
approach.
For patients supported by mechanical ventilation or who are appropriate candidates for a pressurized face
mask, PEEP or continuous positive airway pressure may be used to increase mean and end-expiratory
airway pressures, allowing the reduction of the oxygen concentrations below potentially toxic levels (FIO2 <
0.60).
Grading the Evidence: [See Ranking the Evidence]
The Grade 1 recommendations below are based on strong evidence for care based on a number of
qualitative considerations. “B” level evidence generally derives from randomized control trials with certain
limitations or very well-done observational or cohort studies. “C” level evidence reflects well-done
observational or cohort studies with controls. “D” level evidence generally reflects case series data or expert
opinion.

The 2008 Surviving Sepsis Campaign Guidelines recommends that clinicians target a tidal volume of 6
ml/kg (predicted) body weight in patients with ALI/ARDS (Evidence Grade 1B). The Campaign also
recommends that plateau pressures be measured in patients with ALI/ARDS and that the initial upper
limit goal for plateau pressures in a passively inflated patient be less than or equal to 30 cm H2O. Chest
wall compliance should be considered in the assessment of plateau pressure (Grade 1C).
Rationale: Over the past 10 years, several multi-center randomized trials have been performed to evaluate
the effects of limiting inspiratory pressure through moderation of tidal volume. [1,6-9] These studies
showed differing results that may have been caused by differences between airway pressures in the
treatment and control groups. [1,10] The largest trial of a volume- and pressure-limited strategy showed a
9 percent decrease of all-cause mortality in patients with ALI or ARDS ventilated with tidal volumes of 6
mL/kg of predicted body weight (PBW), as opposed to 12 mL/kg, and aiming for a plateau pressure less
than or equal to 30 cm H2O. [1] The use of lung protective strategies for patients with ALI is supported by
clinical trials and has been widely accepted, but the precise choice of tidal volume for an individual patient
with ALI may require adjustment for such factors as the plateau pressure achieved, the level of positive endexpiratory pressure (PEEP) chosen, the compliance of the thoracoabdominal compartment and the vigor of
the patient’s breathing effort. Some clinicians believe it may be safe to ventilate with tidal volumes higher
than 6 ml/kg PBW as long as the plateau pressure can be maintained less than or equal to 30cm H2O.
[11,12] The validity of this ceiling value will depend on breathing effort, as those who are actively inspiring
generate higher trans-alveolar pressures for a given plateau pressure than those who are passively inflated.
Conversely, patients with very stiff chest walls may require plateau pressures higher than 30 cmH2O to
meet vital clinical objectives. One retrospective study suggested that tidal volumes should be lowered even
with plateau pressures that are less than or equal to 30 cm H20. [13] An additional observational study
suggested that knowledge of the plateau pressures was associated with lower plateau pressures; however,
in this trial, plateau pressure was not independently associated with mortality rates across a wide range of
plateau pressures that bracketed 30 cm H2O. [14] The largest clinical trial employing a lung protective
strategy coupled limited pressure with limited tidal volumes to demonstrate a mortality benefit. [1]
High tidal volumes that are coupled with high plateau pressures should be avoided in ALI/ARDS. Clinicians
should use as a starting point the objective of reducing tidal volumes over 1 to 2 hours from its initial value
toward the goal of a “low” tidal volume (≈6 mL per kilogram of predicted body weight) achieved in
conjunction with an end-inspiratory plateau pressure less than or equal to 30 cm H2O. If plateau pressure
remains >30 after reduction of tidal volume to 6 ml/kg/PBW, tidal volume should be reduced further to as
low as 4 ml/kg/PBW.
No single mode of ventilation (pressure control, volume control, airway pressure release ventilation, high
frequency ventilation, etc.) has been consistently shown advantageous when compared with any other that
respects the same principles of lung protection.

The Surviving Sepsis Campaign recommends that hypercapnia (allowing PaCO2 to increase above its
pre-morbid baseline, so-called permissive hypercapnia) be allowed in patients with ALI/ARDS if needed
to minimize plateau pressures and tidal volumes (Grade 1C).
Rationale: An acutely elevated PaCO2 may have physiologic consequences that include vasodilation as well
as an increased heart rate, blood pressure, and cardiac output. Allowing modest hypercapnia in conjunction
with limiting tidal volume and minute ventilation has been demonstrated to be safe in small, nonrandomized
series. [2,3] Patients treated in larger trials that have the goal of limiting tidal volumes and airway pressures
have demonstrated improved outcomes, but permissive hypercapnia was not a primary treatment goal in
these studies. [1] The use of hypercapnia is limited in patients with preexisting metabolic acidosis and is
contraindicated in patients with increased intracranial pressure. Sodium bicarbonate or tromethamine
infusion may be considered in selected patients to facilitate use of permissive hypercarbia. [15,16]

The Surviving Sepsis Campaign recommends that positive end-expiratory pressure (PEEP) be set so as
to avoid extensive lung collapse at end-expiration (Grade 1C).
Rationale: Raising PEEP in ALI/ARDS keeps lung units open to participate in gas exchange. This will increase
PaO2 when PEEP is applied through either an endotracheal tube or a face mask. [17-19] In animal
experiments, avoidance of end-expiratory alveolar collapse helps minimize ventilator-induced lung injury
(VILI) when relatively high plateau pressures are in use. One large multi-center trial of the protocol-driven
use of higher PEEP in conjunction with low tidal volumes did not show benefit or harm when compared to
lower PEEP levels. [20] Neither the control nor experimental group in that study, however, was clearly
exposed to hazardous plateau pressures. A recent multi-center Spanish trial compared a high PEEP, lowmoderate tidal volume approach to one that used conventional tidal volumes and the least PEEP achieving
adequate oxygenation. A marked survival advantage favored the former approach in high acuity patients
with ARDS. [21] Two options are recommended for PEEP titration. One option is to titrate PEEP (and tidal
volume) according to bedside measurements of thoracopulmonary compliance with the objective of
obtaining the best compliance, reflecting a favorable balance of lung recruitment and overdistention. [22]
The second option is to titrate PEEP based on severity of oxygenation deficit and guided by the FIO2
required to maintain adequate oxygenation. [1] Whichever the indicator — compliance or oxygenation —
recruiting maneuvers are reasonable to employ in the process of PEEP selection. Blood pressure and
oxygenation should be monitored and recruitment discontinued if deterioration in these parameters is
observed. A PEEP >5 cm H20 is usually required to avoid lung collapse. [23]
References:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared
with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. New
England Journal of Medicine. 2000;342:1301–1308.
Hickling KG, Henderson S, Jackson R. Low mortality rate in adult respiratory distress syndrome using
low-volume, pressure-limited ventilation with permissive hypercapnia: A prospective study. Critical Care
Medicine. 1994;22:1568–1578.
Bidani A, Cardenas VJ, Zwischenberger JB. Permissive hypercapnia in acute respiratory failure. Journal
of the American Medical Association. 1994;272:957–962.
Tasker RC. Combined lung injury, meningitis and cerebral edema: How permissive can hypercapnia be?
Intensive Care Medicine. 1998;24:616–619.
Laffey JG, et al. Therapeutic hypercapnia reduces pulmonary and systemic injury following in vivo lung
reperfusion. American Journal of Respiratory and Critical Care Medicine. 2000;162:2287–2294.
Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the
acute respiratory distress syndrome. New England Journal of Medicine. 1998;338(6):347-354.
Brochard L, Roudot-Thoraval F, Roupie E, et al. Tidal volume reduction for prevention of ventilatorinduced lung injury in acute respiratory distress syndrome. American Journal of Respiratory and Critical
Care Medicine. 1998;158(6):1831-1838.
Brower RG, Fessler HE, Shade DM, et al. Prospective, randomized, controlled clinical trial comparing
traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients.
Critical Care Medicine. 1999;27:1492-1498.
Stewart TE, Meade MO, Cook DJ, et al. Evaluation of a ventilation strategy to prevent barotrauma in
patients at high risk for acute respiratory distress syndrome. New England Journal of Medicine.
1998;338:355-361.
Eichacker PQ, Gerstenberger EP, Banks SM, et al. Meta-analysis of acute lung injury and acute
respiratory distress syndrome trials testing low tidal volumes. American Journal of Respiratory and
Critical Care Medicine. 2002;166:1510-1514.
Tobin MJ. Culmination of an era in research on the acute respiratory distress syndrome. New England
Journal of Medicine. 2000;342:1360-1361.
Marini JJ, Gattinoni L. Ventilatory management of acute respiratory distress syndrome: A consensus of
two. Critical Care Medicine. 2004;32:250-255.
Hager DN, Krishnan JA, Hayden DL, et al. Tidal volume reduction in patients with acute lung injury when
plateau pressures are not high. American Journal of Respiratory and Critical Care Medicine.
2005;172:1241-1245.
Ferguson ND, Frutos-Vivar F, Esteban A, et al. Airway pressures, tidal volumes, and mortality in patients
with acute respiratory distress syndrome. Critical Care Medicine. 2005 Jan;33(1):21-30.
Kallet RH, Jasmer RM, Luce JM, Lin LH, Marks JD. The treatment of acidosis in acute lung injury with
tris-hydroxymethyl aminomethane (THAM). American Journal of Respiratory and Critical Care Medicine.
2000 Apr;161(4 Pt 1):1149-1153.
16. Weber T, Tschernich H, Sitzwohl C, et al. Tromethamine buffer modifies the depressant effect of
permissive hypercapnia on myocardial contractility in patients with acute respiratory distress syndrome.
American Journal of Respiratory Critical Care Medicine. 2000;162:1361-1365.
17. Marini JJ, Ravenscraft SA. Mean airway pressure: Physiologic determinants and clinical importance—Part
I: Physiologic determinants and measurements. Critical Care Medicine. 1992;20:1461-1472.
18. Gattinoni L, Marcolin R, Caspani ML, Fumagalli R, Mascheroni D, Pesenti A.. Constant mean airway
pressure with different patterns of positive pressure breathing during the adult respiratory distress
syndrome. Bulletin Europeen dePhysiopathologie Respiratoire. 1985;21:275-279.
19. Pesenti A, Marcolin R, Prato P, Borelli M, Riboni A, Gattinoni L.. Mean airway pressure vs. positive endexpiratory pressure during mechanical ventilation. Critical Care Medicine. 1985;13:34-37.
20. The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Higher versus lower positive
end-expiratory pressures in patients with the acute respiratory distress syndrome. New England Journal
of Medicine. 2004;351(4):327-336.
21. Villar J, Kacmarek RM, Pérez-Méndez L, Aguirre-Jaime A, for the ARIES Network. A high PEEP-low tidal
volume ventilatory strategy improves outcome in persistent ARDS. A randomized controlled trial. Critical
Care Medicine. 2006 May;34(5):1311-1318.
22. Amato MB, Barbas CS, Medeiros DM, et al. Beneficial effects of the “open lung approach” with low
distending pressures in acute respiratory distress syndrome. A prospective randomized study on
mechanical ventilation. American Journal of Respiratory and Critical Care Medicine. 1995;152:18351846.
23. Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with acute respiratory distress
syndrome. New England Journal of Medicine. 2006;354:1775-1786.
Content adapted extensively from:

Dellinger, RP, Levy, MM, Carlet, JM, et al. Surviving Sepsis Campaign: International guidelines for
management of severe sepsis and septic shock: 2008. Critical Care Medicine. 2008;36(1):296-327.

Sevransky JE, Levy MM, Marini JJ. Mechanical ventilation in sepsis-induced acute lung injury/acute
respiratory distress syndrome: An evidence-based review. Critical Care Medicine.
2004;32[Suppl.]:S548–S553.
Tips
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2.
3.
4.
5.
6.
7.
Create a standardized protocol that prompts users to use
tidal volumes no greater than 6 ml/kg IBW and to maintain
plateau pressures less than 30 cm H20.
Make execution of an ARDSnet-like protocol the primary
responsibility of the respiratory therapists, if possible.
Have stakeholders work in concert with the respiratory
therapy department to create and deploy a clinical protocol
for ALI/ARDS ventilation.
Avoid synchronized intermittent mandatory ventilation
(SIMV) during the acute phase of illness. Instead, use
mandatory modes of ventilation such as assist control (ACV)
or pressure control (PCV) to prevent spontaneously large
tidal volumes.
Do not allow peak pressures to govern ventilator
management. The key value is the plateau pressure.
The weight for determining the Vt should be the ideal body
weight. The ideal body weight is calculated from the patient’s
height.
Do not worry about the pCO2 unless the pH is less than a
threshold the clinical team cannot accept. Some intensivists
are comfortable with pH as low as 7.10. Most clinicians like
to see pH greater than 7.21. Some more
conservative clinicians use pH in the range of 7.25 or 7.30.
Where renal dysfunction prevents compensation, bicarbonate
or tromethamine can be used to help maintain the
pH. However, constant bicarbonate infusions can also
contribute to CO2 production. Tromethamine does not have
this side effect.
Inspiratory Plateau Pressure Goal
Definition
ARDS Net clinical trials suggest that maintaining inspiratory plateau
pressures < 30 cm H2O (when accompanied by a low-tidal volume
ventilation strategy of 6 ml/kg) reduces mortality in patients with
lung injury. Many mechanically ventilated patients with severe
sepsis and/or septic shock will meet criteria for lung injury or acute
respiratory distress syndrome and could benefit from inspiratory
plateau pressures < 30 cm H2O.
Compliance with this bundle element is defined as the percent of
patients requiring mechanical ventilation who have a median IPP <
30 cm H2O over the first 24 hours following presentation with
severe sepsis and/or septic shock.
Numerator: Number of mechanically ventilated patients with severe
sepsis and/or septic shock who had a median IPP < 30 cm H2O
over the first 24 hours following presentation with severe sepsis
and/or septic shock
Denominator: Number of mechanically ventilated patients
presenting with severe sepsis and/or septic shock
Exclusion: Patients not mechanically ventilated
Goal
Increase the number of cases of mechanically ventilated patients
with severe sepsis and/or septic shock who maintain inspiratory
plateau pressures < 30 cm H2O to 100 percent.
Data Collection Plan
Data may be collected concurrently — that is, once a patient is
placed on the hospital’s severe sepsis protocol, data can be
abstracted from the patient chart in real time — or retrospectively
using a chart review, a method generally recommended for more
experienced improvement teams.
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