Objectives: TreaTmenT of SepSiS: How To make Goal DirecTeD

Treatment of Sepsis: How to Make Goal Directed
Therapy a Consistent Approach in Your ED
Emanuel P. Rivers, MD, MPH
Vice Chairman and Director of Research, Department of Emergency Medicine
Senior Staff Attending, Emergency Medicine, and Critical Care
Henry Ford Health Systems, Detroit, Michigan
1. Quantify the prevalence and magnitude of sepsis mortality as it relates to Emergency Medicine.
2.Understand the pathogenesis of early sepsis which provides the therapeutic rationale for early
goal-directed therapy.
3.Understand the components of a sepsis quality initiative and its salutary impact on patient
outcomes and health care resource consumption.
A Change in the Paradigm of Treating
Severe Sepsis and Septic Shock
Improvement in mortality for acute
and stroke have been realized by a
coordinated team approach, beginning
in the emergency department (ED), to
provide early identification of high risk
patients and time sensitive evidencebased therapies. Over 500,000 patients
present each year to the ED with severe
sepsis and septic shock, having a
resulting mortality ranging from 20%The same approach provided
for acute myocardial infarction (AMI),
trauma and stroke has been lacking for
early sepsis management until recently.
Early goal-directed therapy (EGDT)
was developed as a quality initiative
which includes 1) assessment of the
hospital sepsis prevalence and mortality,
2) early identification of high-risk
patients, 3) mobilization of resources
for intervention, 4) reversal of early
hemodynamic perturbations, 5) assessing
compliance, 6) dedicated education of
health providers, 7) quantifying health
care resource consumption and 8)
assessing outcomes (Figure 1).
The Early Hemodynamics of Sepsis
The early stages of sepsis can manifest as
a hypodynamic state of oxygen delivery
dependency causing elevated lactate
concentrations and low venous oxygen
saturations. Depending on the stage of
disease presentation and the extent of
resuscitation, however, a hyperdynamic
state, where oxygen consumption is
independent of systemic oxygen delivery
having normal to increased lactate
concentrations and high venous oxygen
saturation, may be more commonly
recognized.5,6 Thus, sepsis evolves as
a progression of hemodynamic phases
where lactate and central venous oxygen
saturation (ScvO2)/mixed central venous
oxygen saturation (SvO2) represent
the balance between systemic oxygen
delivery and demands and quantifying
the severity of global tissue hypoxia.6‑9
The hypodynamic phase in particular
is associated with the generation of
inflammatory mediators with increased
morbidity and mortality if unrecognized
or left untreated. This phase also can be
present with normal vital signs.10-12 Thus,
the hemodynamic derangements of sepsis
can be hypovolemia, vasodilatation,
myocardial depression and impairment of
oxygen utilization. These derangements
Over 500,000
patients present
each year to the ED
with severe sepsis
and septic shock,
having a resulting
mortality ranging
from 20%-60%.
Cardiovascular, Neurovascular and Infectious Emergencies
may exist alone or in combination beginning
upon hospital presentation (Table 1 and
Figure 2).
Previous Hemodynamic Optimization
Figure 1. An implementation model of early goal-directed therapy (EGDT)
Early work by Shoemaker et al.13 observed
that survivors of critical illness had supranormal levels of oxygen delivery compared
to non-survivors. This prompted some
clinicians to target supra-normal levels in
all critically-ill patients without outcome
benefit.14, 15 The relatively later timing of
the intervention in the intensive care unit
(ICU) setting, and absence of a deliverydependent phase of systemic consumption
with decreased SvO2 and increased lactate,
differentiates these studies from EGDT. A
meta-analysis of hemodynamic optimization
trials by Kern suggested early, but not
late, hemodynamic optimization reduced
mortality.16 It has since become increasingly
evident from multiple subsequent studies the
six hour time interval used in the EGDT trial
was not only important from a diagnostic
perspective, but had outcome implications
based on adequacy of care.17-21 EGDT was
performed for these patients in the pre-ICU
or ED phase of the disease, within hours of
patient presentation.
Table 1. The hemodynamic stages of sepsis
Treatment of Sepsis: How to Make Goal Directed
Therapy a Consistent Approach in Your ED
The use of
lactate ≥ 4 mmol/L
as a marker for
severe tissue
hypoperfusion and as
Figure 2. The study design of early goal-directed therapy (EGDT)
a predictor of
mortality is supported
Early Recognition of the High Risk Patient
The use of lactate ≥ 4 mmol/L as a marker for severe tissue hypoperfusion and as a
predictor of mortality is supported by a number of studies.22-26 Although there is some
controversy regarding other potential mechanisms underlying lactate accumulation
in severe sepsis, serial lactate levels can assess lactate clearance or changes in lactate
over time.27 Nguyen et al. has also reconfirmed work by others showing increased
lactate clearance rates during the first 6 hours of sepsis presentation are significantly
associated with preserved organ function and improved survival.20, 28 Lactate levels
can be performed by venipuncture.
by a number of studies.
Lactate levels can
be performed by
The Components of EGDT
EGDT allows emergency physicians to diagnose and treat each of the hemodynamic
perturbations urgently (Figure 2) using recommendations and endpoints supported
by consensus statements from both critical care and emergency medicine.2932
The titration of intravenous fluid to a central venous pressure (CVP) of 8-12
mmHg provides an objective endpoint for preload optimization while preventing
volume overload. As a result, more fluid administration can be given initially
and safely, leading to a 14% reduction in vasopressor, steroid use and mechanical
Cardiovascular, Neurovascular and Infectious Emergencies
While there is debate regarding whether
ScvO2 is a numeric equivalent to
SvO2,36‑41 it has clinical utility and reflects
outcome.21,42,43 The Surviving Sepsis
Campaign recommends an SvO2 of 65%
and an ScvO2 of 70% as resuscitation
endpoints.31, 38 Given the challenges of
using a pulmonary artery catheter (PAC)
in an early setting such as the ED, the
ScvO2 represents a convenient surrogate,
but not a replacement, for SvO2. While
continuous monitoring allows for a
more rapid adjustment of hemodynamic
intermittent values will suffice.
While there is debate
Acute anemia and global tissue hypoxia
provide potent stimuli for erythropoietin
regarding whether
production to increase marrow production
ScvO2 is a numeric
of red blood cells (RBCs).44 Severe
sepsis and septic shock patients who
equivalent to SvO2, it
have both an impaired marrow response
has clinical utility and
and variable erythropoietin levels
reflects outcome.
may lack this compensatory ability to
increase hemoglobin concentrations.45, 46
The combination of anemia and presence
of global tissue hypoxia represent the
physiologic rationale to transfuse RBCs
in these patients. Volume resuscitation
results in hemodilution. The threshold
for transfusion is based on consideration
of a physiologic rationale such as low ScvO2 and increased lactate
or global tissue hypoxia, a high-risk patient population, and expert
consensus. These are important considerations when comparing EGDT
patients to those enrolled in ICU transfusion studies. Hebert et al., Marik
et al. and others have shown a restrictive strategy of red-cell transfusion
(7-9 mg/dl) was “at least as effective and possibly superior to a liberal
transfusion strategy in critically ill patients.”47, 48 However, these studies
did not specifically address patients with severe sepsis and septic shock.
Patients with co-morbidities including atherosclerotic heart disease,
congestive heart failure, and renal failure are substantially represented
in the EGDT study. Excluding such patients limits the generalizability
of prior transfusion studies for patients with severe sepsis and septic
In previous studies, dobutamine therapy
has been associated with increased
Not only did the
resuscitation endpoints of these studies
delivery, but also some patients received
doses of dobutamine as high as 200
mcg/kg/min. The selection of patients
in a delivery dependent state, lower
dose, timing of therapy, and endpoints of
resuscitation were different between the
EGDT study and previous studies.51 In
the EGDT study, patients were treated
using a lower dobutamine dose (average
dose 10.3 mcg/kg/min to maximum 20
mcg/kg/min), which was titrated upward
to achieve ScvO2 ≥ 70%.9
Cerra et al. and Spronk et al. noted
hemodynamic improvement in the
microcirculation for septic patients with
the use of nitroglycerin.52,53 Vasodilator
therapy was used in 9% of EGDT patients
who met protocol criteria. These patients
had median baseline ScvO2 of 46 % and
a previous history of hypertension and
congestive heart failure. It is becoming
microcirculatory flow is associated with
systemic inflammation, acute organ
dysfunction, and increased mortality.
Using new technologies to directly
image microcirculatory blood flow may
help define the role of microcirculatory
dysfunction in oxygen transport and
circulatory support.54
egdt Effects on Systemic Inflammation and Organ Dysfunction
There is a pathologic link between
the clinical presence of global tissue
hypoxia, generation of inflammation,
and the mitochondrial impairment
of oxygen utilization seen in septic
Treatment of Sepsis: How to Make Goal Directed
Therapy a Consistent Approach in Your ED
The Effect of EGDT on Mortality
The baseline mortality of 51% prior to the
study was reduced to 46.5% with standard
care and 30.5% after the introduction of
EGDT at the Henry Ford Health Center.
Published programs of EGDT to date
represent a cumulative total of over 3,000
patients. In these confirmatory studies, a
mean mortality prior to implementation
was 45.6 ± 7.9% (range 59.0 to 29.3%) and
25.8 ± 5.7% (range 29.0 to 18.0%) after
implementation of EGDT for an average
reduction of 19.6%, which is greater than the
original study of 16%.9, 61-72 In these studies
which were performed in both academic and
community hospital settings enrolled patients
with similar age and APACHE II scores
to the original trial. These studies provide
external validity EGDT is generalizable and
reproducible. While these implementation
programs may include additional therapies
such as aggressive hemodialysis, glucose
control, recombinant activated protein C,
corticosteroids and protective lung strategies,
multivariate analyses reveal the EGDT
contributes statistically significant mortality
benefit when compared to these other
Figure 3. Algorithm of early goal-directed therapy (EGDT)
patients.55-57 Furthermore, early fluid therapy has been shown
to decrease the release of inflammatory mediators.58 There
is a significant reduction in proinflammatory response that
accompanies EGDT therapy.59 The reduction in interleukin
8 in particular is accompanied by increased PaO2/FIO2 ratios
including improved lung function and decreased need for
mechanical ventilation. Similar findings in D-dimer activity
are noted in the coagulation cascade which is similar to that
seen with recombinant activated protein C.60 This may be one
of the plausible explanations for the decreased need for organ
support therapy such as mechanical ventilation, vasopressor
therapy, and hemodialysis in patients who received EGDT
versus standard care.
Table 2. Early goal-directed therapy (EGDT)
decreases these components of care:
1. Mortality by 16-20%
2. Components of the inflammatory response
3. Morbidity of organ dysfunction
4. Need for vasopressor therapy
5. Need for mechanical ventilation
6. Sudden cardiopulmonary complications in
the first 24 hours
7. Length of hospital stay
8. Health care resource consumption
Cardiovascular, Neurovascular and Infectious Emergencies
Implementation Strategies of EGDT
EGDT represents one of the first ED based therapies shown
to improve outcome, however, it remains incompletely
practiced. The reasons range from ED overcrowding,
variation in skill levels among clinicians in the ED
setting, and the lack of understanding of the continuum
of care required to implement this therapy. A coordinated
patient care model similar to the treatment of AMI, stroke
and trauma is required. To achieve a consistent level of
quality at various locations within the hospital, multiple
models of care may be required. The first model of sepsis
management is ED based. A second and increasingly
popular model incorporates a multidisciplinary rapid
response team which utilizes mobile resources to care for
the patient irrespective of location.73 The third concept is
an ICU based model which rapidly transfers the patient
to the ICU where EGDT is performed in the ICU.63 Each
of these unique models must be tailored to the institution
(Figure 2).
A Cost Analysis of EGDT
EGDT can provide up to a 23.4% reduction in hospital
costs related to severe sepsis and septic shock.72 EGDT
is most cost-effective if patient volumes exceed sixteen
patients per year and irrespective of whether the care is
primarily provided by the ED, rapid response team, or the
ICU. This volume of patients is easily seen in a 200-bed
hospital. A mean reduction of 4 days per admission, or a
32.6% reduction in hospital length of stay, for survivors
and 13.9% reduction in PAC use (both p<0.03) were seen
in the EGDT study. Similar findings have been noted by
other investigators.64, 65
EGDT results in significant reductions in morbidity,
mortality, vasopressor use, and health care resource
consumption. EGDT modulates some components of
inflammation, which is reflected by improved organ
function. The end-points used in the EGDT protocol,
outcome results and cost effectiveness have subsequently
been externally validated, revealing similar or even better
findings than the original trial. Adherence to the principles
of early recognition, early mobilization of resources,
and multidisciplinary collaboration is imperative if
improvements in the morbidity and mortality associated
with sepsis are to parallel those seen with other severe
disease states such as AMI, trauma and stroke.
Hollenberg S. Top Ten List in Myocardial Infarction. Chest.
Mullins R, Mann, NC. Population based research assessing the
effectiveness of Trauma Systems. J Trauma. 1999;47(3 Suppl):S59-66.
Yang Q, Botto, LD, Erickson,D. Improvement in stroke mortality
in Canada and the United States, 1999 to 2002. Circulation.
Wang HE, Shapiro NI, Angus DC, et al. National estimates of severe
sepsis in United States emergency departments. Crit Care Med. 2007;
Parrillo JE, Parker MM, Natanson C, et al. Septic shock in humans.
Advances in the understanding of pathogenesis, cardiovascular
dysfunction, and therapy. Ann Intern Med. 1990;113(3):227-242.
Astiz ME, Rackow EC, Kaufman B, et al. Relationship of oxygen
delivery and mixed venous oxygenation to lactic acidosis in patients
with sepsis and acute myocardial infarction. Crit Care Med. Jul
Silance PG, Vincent JL. Oxygen extraction in patients with sepsis
and heart failure: another look at clinical studies. Clin Intensive Care.
Astiz ME, Rackow EC, Weil MH. Oxygen delivery and utilization
during rapidly fatal septic shock in rats. Circ Shock. 1986;20(4):281290.
Rivers EP, Nguyen B, Havstad S, et al. Early goal-directed therapy
in the treatment of severe sepsis and septic shock. N Engl J Med
10. Rady MY, Rivers EP, Nowak RM. Resuscitation of the critically ill in the
ED: responses of blood pressure, heart rate, shock index, central venous
oxygen saturation, and lactate. Am J Emerg Med. 1996;14(2):218-225.
Treatment of Sepsis: How to Make Goal Directed
Therapy a Consistent Approach in Your ED
11. Brun-Buisson C, Doyon F, Carlet J, et al. Incidence, risk factors, and
outcome of severe sepsis and septic shock in adults. A multicenter
prospective study in intensive care units. French ICU Group for Severe
Sepsis. JAMA. 1995;274(12):968-974.
31. Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign
guidelines for management of severe sepsis and septic shock. Intensive
Care Med. 2004;30(4):536-555.
12. Vincent JL, De Backer D. Oxygen uptake/oxygen supply dependency:
fact or fiction? Acta Anaesthesiol Scand Suppl. 1995;107:229-237.
32. Hollenberg SM, Ahrens TS, Annane D, et al. Practice parameters for
hemodynamic support of sepsis in adult patients: 2004 update. Crit Care
Med. 2004;32(9):1928-1948.
13. Shoemaker WC, Appel PL, Kram HB, et al. Prospective trial of
supranormal values of survivors as therapeutic goals in high-risk surgical
patients. Chest. 1988;94(6):1176-1186.
33. Levy MM, Macias WL, Vincent JL, et al. Early changes in organ
function predict eventual survival in severe sepsis. Crit Care Med.
14. Hayes MA, Timmins AC, Yau EH, et al. Elevation of systemic oxygen
delivery in the treatment of critically ill patients. N Engl J Med.
34. 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. JAMA. 2002;288(7):862-871.
15. Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented
hemodynamic therapy in critically ill patients. SvO2 Collaborative
Group. N Engl J Med. 1995;333(16):1025-1032.
35. Estenssoro E, Gonzalez F, Laffaire E, et al. Shock on admission day is
the best predictor of prolonged mechanical ventilation in the ICU. Chest.
Feb 2005;127(2):598-603.
16. Kern JW, Shoemaker WC. Meta-analysis of hemodynamic optimization
in high-risk patients. Crit Care Med. 2002;30(8):1686-1692.
36. Reinhart K, Kuhn HJ, Hartog C, et al. Continuous central venous and
pulmonary artery oxygen saturation monitoring in the critically ill.
Intensive Care Med. Aug 2004;30(8):1572-1578.
17. Engoren M. The effect of prompt physician visits on intensive care unit
mortality and cost. Crit Care Med. 2005;33(4):727-732.
18. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before
initiation of effective antimicrobial therapy is the critical determinant of
survival in human septic shock. Crit Care Med. 2006;34(6):1589-1596.
19. Lundberg JS, Perl TM, Wiblin T, et al. Septic shock: an analysis of
outcomes for patients with onset on hospital wards versus intensive care
units. Crit Care Med. 1998;26(6):1020-1024.
20. Nguyen HB, Rivers EP, Knoblich BP, et al. Early lactate clearance is
associated with improved outcome in severe sepsis and septic shock.
Crit Care Med. 2004;32(8):1637-1642.
21. Varpula M, Tallgren M, Saukkonen K, et al. Hemodynamic variables
related to outcome in septic shock. Intensive Care Med. 2005;31:10661071.
22. Aduen J, Bernstein WK, Khastgir T, et al. The use and clinical
importance of a substrate-specific electrode for rapid determination of
blood lactate concentrations. JAMA. 1994;272(21):1678-1685.
23. Broder G, Weil MH. Excess lactate: An index of reversibility of shock in
human patients. Science. 1964;143:1457-1459.
24. Cady LD, Jr., Weil MH, Afifi AA, et al. Quantitation of severity of
critical illness with special reference to blood lactate. Crit Care Med.
25. Shapiro NI, Howell MD, Talmor D, et al. Serum lactate as a predictor of
mortality in emergency department patients with infection. Ann Emerg
Med. 2005;45(5):524-528.
26. Grzybowski M. Systemic inflammatory response syndrome criteria
and lactic acidosis in the detection of critical illness among patients
presenting to the emergency department. Chest. 1996;110(4):145S.
27. James JH, Luchette FA, McCarter FD, et al. Lactate is an
unreliable indicator of tissue hypoxia in injury or sepsis. Lancet.
28. De Backer D. Lactic acidosis. Minerva Anestesiol. 2003;69(4):281-284.
29. Practice parameters for hemodynamic support of sepsis in adult patients.
Task Force of the American College of Critical Care Medicine, Society
of Critical Care Medicine. Crit Care Med. 1999;27(3):639-660.
30. Nguyen HB, Rivers EP, Abrahamian FM, et al. Severe sepsis and septic
shock: review of the literature and emergency department management
guidelines. Ann Emerg Med. 2006;48(1):28-54.
37. Ladakis C, Myrianthefs P, Karabinis A, et al. Central venous and
mixed venous oxygen saturation in critically ill patients. Respiration.
38. Chawla LS, Zia H, Gutierrez G, et al. Lack of equivalence between
central and mixed venous oxygen saturation. Chest. 2004;126(6):18911896.
39. Edwards JD, Mayall RM. Importance of the sampling site for
measurement of mixed venous oxygen saturation in shock. Crit Care
Med. 1998;26(8):1356-1360.
40. Reinhart K, Rudolph T, Bredle DL, et al. Comparison of central-venous
to mixed-venous oxygen saturation during changes in oxygen supply/
demand. Chest. 1989;95(6):1216-1221.
41. Varpula M, Karlsson S, Ruokonen E, et al. Mixed venous oxygen
saturation cannot be estimated by central venous oxygen saturation in
septic shock. Intensive Care Med. Sep 2006;32(9):1336-1343.
42. Rivers E. Mixed vs central venous oxygen saturation may be
not numerically equal, but both are still clinically useful. Chest.
43. Krafft P, Steltzer H, Hiesmayr M, et al. Mixed venous oxygen saturation
in critically ill septic shock patients. The role of defined events. Chest.
44. Fisher JW. Erythropoietin: physiology and pharmacology update. Exp
Biol Med (Maywood). 2003;228(1):1-14.
45. Nielsen OJ, Thaysen JH. Erythropoietin deficiency in acute tubular
necrosis. J Intern Med. Jun 1990;227(6):373-380.
46. Abel J, Spannbrucker N, Fandrey J, et al. Serum erythropoietin levels in
patients with sepsis and septic shock. Eur J Haematol. 1996;57(5):359363.
47. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized,
controlled clinical trial of transfusion requirements in critical care.
Transfusion Requirements in Critical Care Investigators, Canadian
Critical Care Trials Group. N Engl J Med. 1999;340(6):409-417.
48. Marik PE, Sibbald WJ. Effect of stored-blood transfusion on oxygen
delivery in patients with sepsis. JAMA. 1993;269(23):3024-3029.
49. Hebert PC, Tinmouth A, Corwin HL. Controversies in RBC transfusion
in the critically ill. Chest. 2007;131(5):1583-1590.
Cardiovascular, Neurovascular and Infectious Emergencies
50. Hayes JK, Luo X, Wong KC, et al. Effects of dobutamine,
norepinephrine and epinephrine on intramucosal pH and hemodynamics
of dogs during endotoxic shock. Acta Anaesthesiol Sin. 1998;36(3):113126.
51. Vincent JL, Roman A, Kahn RJ. Dobutamine administration in septic
shock: addition to a standard protocol. Crit Care Med. 1990;18(7):689693.
52. Cerra FB, Hassett J, Siegel JH. Vasodilator therapy in clinical sepsis
with low output syndrome. J Surg Res. 1978;25(2):180-183.
53. Spronk PE, Ince C, Gardien MJ, et al. Nitroglycerin in septic shock after
intravascular volume resuscitation. Lancet. 2002;360(9343):1395-1396.
54. Trzeciak S, Rivers EP. Clinical manifestations of disordered
microcirculatory perfusion in severe sepsis. Crit Care. 2005;9(Suppl 4):
55. Boulos M, Astiz ME, Barua RS, et al. Impaired mitochondrial function
induced by serum from septic shock patients is attenuated by inhibition
of nitric oxide synthase and poly(ADP-ribose) synthase. Crit Care Med.
56. Karimova A, Pinsky DJ. The endothelial response to oxygen deprivation:
biology and clinical implications. Intensive Care Med. 2001;27(1):1931.
57. Benjamin E, Leibowitz AB, Oropello J, et al. Systemic hypoxic
and inflammatory syndrome:an alternative designation for «sepsis
syndrome». Crit Care Med. 1992;20(5):680-682.
67. Micek ST, Roubinian N, Heuring T, et al. Before-after study of a
standardized hospital order set for the management of septic shock. Crit
Care Med. 2006;34(11):2707-2713.
68. Qu HP, Qin S, Min D, et al. [The effects of earlier resuscitation on
following therapeutic response in sepsis with hypoperfusion.]. Zhonghua
Wai Ke Za Zhi. 2006;44(17):1193-1196.
69. Stenstrom RJ, Hollohan K, Nebre R, et al. Impact of a sepsis protocol
for the management of patients with severe sepsis and septic shock in
the emergency department. JCMU. 2006 2006;8(3):S16.
70. Jones A, Focht A, Horton J, et al. Clinical effectiveness of implementing
early goal directed therapy in the emergency department care of severe
sepsis and septic shock: a prospective study. Acad Emerg Med. May
2007;14(5 Suppl 1):S186-187.
71. Nguyen HB, Corbett SW, Steele R, et al. Implementation of a bundle
of quality indicators for the early management of severe sepsis and
septic shock is associated with decreased mortality. Crit Care Med. Apr
72. Shorr AF, Micek ST, Jackson WL, Jr., et al. Economic implications of
an evidence-based sepsis protocol: can we improve outcomes and lower
costs? Crit Care Med. 2007;35(5):1257-1262.
73. Frank ED. A shock team in a general hospital. Anesth Analg.
58. Dorresteijn MJ, van Eijk LT, Netea MG, et al. Iso-osmolar prehydration
shifts the cytokine response towards a more anti-inflammatory balance
in human endotoxemia. J Endotoxin Res. 2005;11(5):287-293.
59. Rivers EP, Kruse JA, Jacobsen G, et al. The influence of early
hemodynamic optimization on biomarker patterns of severe sepsis and
septic shock. Crit Care Med. 2007;35(9):2016-2024.
60. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of
recombinant human activated protein C for severe sepsis. N Engl J Med.
61. Gao F, Melody T, Daniels DF, et al. The impact of compliance with
6-hour and 24-hour sepsis bundles on hospital mortality in patients with
severe sepsis: a prospective observational study. Crit Care. 2005;9(6):
62. Kortgen A, Niederprum P, Bauer M. Implementation of an evidencebased «standard operating procedure» and outcome in septic shock. Crit
Care Med. 2006;34(4):943-949.
63. Sebat F, Johnson D, Musthafa AA, et al. A multidisciplinary community
hospital program for early and rapid resuscitation of shock in nontrauma
patients. Chest. 2005;127(5):1729-1743.
64. Shapiro NI, Howell MD, Talmor D, et al. Implementation and outcomes
of the Multiple Urgent Sepsis Therapies (MUST) protocol. Crit Care
Med. 2006;34(4):1025-1032.
65. Trzeciak S, Dellinger RP, Abate NL, et al. Translating research to
clinical practice: a 1-year experience with implementing early goaldirected therapy for septic shock in the emergency department. Chest.
66. Lin SM, Huang CD, Lin HC, et al. A modified goal-directed protocol
improves clinical outcomes in intensive care unit patients with septic
shock: a randomized controlled trial. Shock. 2006;26(6):551-557.