Osborn_BOOK.
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Early Goal-directed Therapy in the Treatment of
Severe Sepsis and Septic Shock
a report by
Tiffany M Osborn, MD
Former Chair, Section of Critical Care Medicine, American College of Emergency Physicians
As with other critical disease entities, emergency
medicine plays a key role in the chain of survival for
severe sepsis. An estimated 750,000 patients develop
severe sepsis each year in the US,1 with half initially
presenting to the emergency department (ED).2 A similar
increased incidence has been noted in other countries
across the globe posing a significant healthcare challenge
not only in the US, but worldwide.3,4
In light of this increasing prevalence, the Surviving Sepsis
Campaign (SSC) was formed under the administration of
the Society of Critical Care Medicine, the European
Society of Intensive Care Medicine, and the International
Sepsis Forum. The purpose of the group is to achieve a
mortality reduction of 25% in five years and secure
funding for research and improvements in patient care.5
The treatment for sepsis has evolved and transitioned
from a disease that was primarily treated by critical care
physicians in later phases to one that can be impacted
upon dramatically in early phases by astute and
proactive emergency medicine physicians. Clinical trial
data has suggested that early goal-directed therapy
(EGDT), a definitive resuscitation strategy involving
optimizing systemic oxygen delivery to meet oxygen
demand, is associated with significantly improved
outcomes in sepsis.6
Sepsis syndrome is a disease spectrum that ranges
from an inflammatory response, to sepsis, severe
sepsis, and septic shock. Sepsis is defined as an
inflammatory response with a presumed or identified
source of infection. Severe sepsis is defined as sepsis
with one or more organ system dysfunction. Septic
shock is defined as hypotension (mean arterial
pressure (MAP) <65mmHg or systolic blood pressure
(SBP) <90mmHg) after 20–40cc/kg of crystalloid or
colloid equivalent.7
Identifying Candidates for EGDT
Any patient, identified in within the first six hours of
presenting symptoms, who has a presumed or identified
source of infection and hypotension after a 20–40cc/kg
fluid bolus or a presenting lactate ≥4mmol/L is a
EMERGENCY MEDICINE & CRITICAL CARE REVIEW 2006
Critical Care
candidate for EGDT. However, many cases are not so
obvious, as initial presentation of septic shock may be
different than later presentation of the disease process.
The use of lactate as a biomarker for tissue oxygenation
and perfusion has enhanced the early identification of
patients with severe sepsis. Early identification allows for
rapid treatment initiation with significant mortality
benefit. Lactate ≥4mmol/L, independent of blood
pressure, was used as a major entry criteria for the EGDT
study which demonstrated a 16% mortality benefit.6
Tr e a t m e n t I n t e r v e n t i o n s o f E G D T
The SSC and the Institute for Healthcare Improvement
have introduced a new concept called “treatment
bundles” for the management of severe sepsis and septic
shock. A treatment bundle is a group of interventions
that, when administered together create a synergistic
effect generating improved outcomes which exceed any
one component individually.8 The two bundles that
were developed were the six-hour resuscitation bundle
and a 24-hour subacute care bundle. The six-hour
bundle is comprised of three components, early
identification, early antibiotics and cultures, and early
goal-directed therapy. Once any phase of sepsis
syndrome is identified, antibiotics should be initiated as
soon as possible. If the patient has severe sepsis or septic
shock, the SSC recommends starting antibiotics within
three hours of presentation. Provided that antibiotic
treatment will not be delayed, cultures should be
obtained before antibiotics when possible.
Once the patient has been identified, and antibiotics
and cultures have been initiated, then specific measures
of EGDT should be undertaken. EGDT may be
initiated when hypotension is not resolved after
20–40cc/kg IVF administration, or in patients with a
serum lactate elevation (≥4mmol/L) regardless of blood
pressure. EGDT is a three-stage process aimed at
optimizing oxygen delivery.
The first stage is estmating the extent of hypovolemia
and initiating fluid resuscitation. In severe sepsis and
septic shock a 6–10 liter intravascular fluid deficit is
23
Osborn_BOOK.qxp 28/7/06 3:52 pm Page 24
Critical Care
not uncommon.9 The most efficient method to
determine initial fluid requirements is by monitoring
central venous pressure (CVP) trends. Currently, the
most practical and available means for monitoring
remains an internal jugular, subclavian or femoral
central line. Although non-invasive means of assessing
CVP such as ultrasound evaluation of the internal
jugular vein have shown promise, a triple lumen
catheter is preferable in most EDs as it allows for
continuous CVP monitoring while fluids or
medications run uninterrupted in the additional ports.
CVP measurements are not difficult and can be done
by nursing after minimal training. Fluid resuscitation
of a 500cc bolus of crystalloid or colloid equivalent
should be administered every 30 minutes until a CVP
of 8–12mmHg is achieved. If the patient is intubated
resuscitation to a CVP of 12–15 is recommended.The
rate should be modified based upon patient dynamics.
With appropriate volume resuscitation, the cardiac
index may improve by 25–40%10 and up to half of
patients presenting with hypotension may obtain
resolution from fluid replacement alone.11 Although
accurate CVP measurements can be determined from
femoral, internal jugular (IJ) or subclavian (SC) line
placement, central venous oxygen saturation (ScvO2)
measurements require placement of a superior vena
cava, either internal jugular or subclavian, central line.
This value will be critically important in optimizing
therapy later on in the EGDT protocol if initial fluid
boluses are not sufficient.Thus, a subclavian or internal
jugular line is preferable when possible.
If the patient remains hypotensive after fluid boluses, the
second step is to administer vasopressors to optimize the
blood pressure to ≥65mmHg. The MAP may be
transduced off a standard arterial line in either a femoral
or radial location. An arterial line is recommended in
hypotensive patients, especially if vasopressors are
required, as non-invasive BP monitoring in hypotensive
or tachycardic patients may be less accurate.9,12-14 If non-
invasive BP monitoring is the only assessment tool
available, the MAP may be estimated using the equation
MAP = (2DBP+SBP)/3, although this equation has
been shown to be less accurate at higher heart rates.9 In
some clinical situations, the physician may choose to add
vasopressors after the first fluid bolus and titrate down,
keeping the MAP ≥65mmHg, while administering fluid
until CVP goal is attained.
As underscored in two recent opinion papers, much
debate remains regarding the selection of a first line
vasopressor.15,16 One article expressed support for
dopamine rather than norepinephrine as the first-line
vasopressor in sepsis,15 and this remains the vasopressor of
choice in Europe. The other expressed exactly the
24
opposite opinion,16 supporting norepinephrine, the most
utilized vasopressor in the US for septic shock. The
primary difference between the two vasopressors is the
degree to which the different agents affect cardiac index
and systemic vascular resistance to increase MAP.
Dopamine promotes MAP primarily through increased
cardiac index, with little effect on SVR, while
norepinephrine increases MAP primarily through
increased SVR, with a lesser effect on cardiac index.
Dopamine should be avoided in tachycardic patients
(HR>120bpm). Although the SSC has stated that no
definitive data supports the preference of either dopamine
or norepinephrine and either may be considered as a first-
line agent, they indicate vasopressin should be used with
caution as an adjunct until further data are available.
The third phase is evaluating the ScvO2 to assess adequate
tissue oxygenation. ScvO2 is the oxygen saturation of
venous blood in the superior vena cava as it enters the
right atria and provides a direct measurement of tissue
hypoxia.Adequate tissue oxygenation cannot be assumed
until biomarkers reflective of tissue perfusion have been
normalized.Arterial oxygen saturation measured as blood
is ejected from the heart is about 100%.As the oxygenated
blood circulates through the microvasculature, the
peripheral tissues extract an estimated 25% of delivered
oxygen. This is normally measured by evaluating the
oxygen saturation in the pulmonary artery (SVO2)
through a pulmonary artery catheter. However, a practical
alternative is to measure the ScvO2 through a central line,
at the level of the right atria.This is measured by doing a
venous blood gas sampled from the distil (brown) port of
a typical IJ or SC central line, and specifically looking at
oxygen saturation.The goal is a ScvO2 ≥70%. ScvO2 can
be measured by individual blood draws from a typical
super vena cava central line or by using a central line that
allows for continuous monitoring. The benefit of
continuous monitoring is immediate ability to assess the
effect of treatment interventions on oxygen delivery at
the bedside. It provides dynamic, immediate feedback
which enables the emergency physicians to adjust
treatment to realtime physiologic data without
pulmonary artery catheterization or other highly invasive
intensive care unit (ICU)-based techniques that are
impractical in an ED environment. A catheter which
allows for continuous ScvO2 monitoring is inserted in the
same manner as a traditional triple lumen catheter at a
subclavian or internal jugular site. The catheter has an
infared right which allows for oxygen saturation
measurement and an extra port which is attached to a
monitor that displays the ScvO2 after calibration. If the
EP does not have access to this equipment, the ScvO2
may be estimated off of serial venous blood gas analysis
whenever major therapeutic interventions have been
done.This approach, however, is more labor-intensive and
does not provide realtime physiologic monitoring,
EMERGENCY MEDICINE & CRITICAL CARE REVIEW 2006
Eli&Lily_ad.qxp 21/7/06 12:24 pm Page 25
Look
Xigris is indicated for the reduction of mortality in adult patients with
severe sepsis (sepsis associated with acute organ dysfunction) who have
a high risk of death (e.g., as determined by APACHE II†).
Xigris is not indicated in adult patients with severe sepsis and lower risk
of death. Safety and efficacy have not been established in pediatric
patients with severe sepsis.
Bleeding is the most common adverse reaction associated with Xigris
therapy. In the Phase 3 study, serious bleeding events were observed
during the 28-day study period in 3.5% of Xigris-treated and 2.0%
of placebo-treated patients. The difference in serious bleeding
occurred primarily during infusion. Intracranial hemorrhage was
also reported. The risk of ICH may be increased in patients with risk fac-
tors for bleeding such as severe coagulopathy and severe thrombocy-
topenia. Should clinically important bleeding occur, immediately stop the
Xigris infusion.
DR40197 0406 PRINTED IN USA. © 2006, ELI LILLY AND COMPANY. ALL RIGHTS RESERVED. Xigris is a registered trademark of Eli Lilly and Company.
b e n e a t h t h e s ym p t o m s .
While supportive care treats the symptoms
of severe sepsis, Xigris reduces microvascular
dysfunction, an underlying cause *
.
Improve survival in your high-risk patients.
Treat beneath the symptoms.
R e s p o n d w i t h X i g r i s.
SO MORE SURVIVE
Xigris is contraindicated in patients in clinical situations in which bleed-
ing could be associated with a high risk of death or significant morbid-
ity. Certain conditions are likely to increase the risk of bleeding with
Xigris therapy. Additionally, in a subset of patients with single organ dys-
function and recent surgery from two separate placebo-controlled trials,
all-cause mortality was numerically higher in the Xigris groups com-
pared to the placebo group. Patients with single organ dysfunction and
recent surgery may not be at high risk of death irrespective of APACHE
II score, and therefore not among the indicated population.
Please see Brief Summary on adjacent page for Contraindications,
Warnings, and other Important Safety Information, or visit
www.Xigris.com
† APACHE (Acute Physiology And Chronic Health Evaluation). For more information on
using the APACHE II scoring system, please see http://www.sfar.org/scores2/scores2.html
* As defined by an increase in inflammation and coagulation and a decrease in fibrinolysis.
The specific mechanisms by which Xigris exerts its effect on survival in patients with severe
sepsis are not completely understood.
Eli&Lily_ad.qxp 21/7/06 12:25 pm Page 26
XIGRIS姞
Drotrecogin alfa (activated)
BRIEF SUMMARY: Consult the Xigris package insert for complete prescribing information.
CLINICAL STUDIES: The efficacy of Xigris was studied in an international, randomized,
double blind, placebo-controlled trial (PROWESS) of 1690 patients with severe sepsis.
Patients received a 96-hour infusion of Xigris at 24 mcg/kg/hr or placebo starting
within 48 hours after the onset of the first sepsis induced organ dysfunction.
The study was terminated after a planned interim analysis due to significantly lower
mortality in patients on Xigris than in patients on placebo (210/850, 25% vs 259/840,
31% p=0.005).
The observed mortality difference between Xigris and placebo was limited to the half
of patients with higher risk of death, i.e., APACHE II score ≥25, the 3rd and 4th quartile
APACHE II scores. The efficacy of Xigris has not been established in patients with
lower risk of death, e.g., APACHE II score <25.
This is a short summary of the CLINICAL STUDIES section from the complete
prescribing information.
INDICATIONS AND USAGE: Xigris is indicated for the reduction of mortality in adult
patients with severe sepsis (sepsis associated with acute organ dysfunction) who
have a high risk of death (e.g., as determined by APACHE II, see CLINICAL STUDIES
in the full Prescribing Information).
Xigris is not indicated in adult patients with severe sepsis and lower risk of death
(see CLINICAL STUDIES in the full Prescribing Information). Safety and efficacy have
not been established in pediatric patients with severe sepsis.
CONTRAINDICATIONS: Xigris increases the risk of bleeding. Xigris is contraindicated
in patients with the following clinical situations in which bleeding could be associated
with a high risk of death or significant morbidity:
• Active internal bleeding
• Recent (within 3 months) hemorrhagic stroke
• Recent (within 2 months) intracranial or intraspinal surgery, or severe head trauma
• Trauma with an increased risk of life-threatening bleeding
• Presence of an epidural catheter
• Intracranial neoplasm or mass lesion or evidence of cerebral herniation
Xigris is contraindicated in patients with known hypersensitivity to drotrecogin alfa
(activated) or any component of this product.
WARNINGS: Bleeding—Bleeding is the most common serious adverse effect
associated with Xigris therapy. Each patient being considered for therapy with Xigris
should be carefully evaluated and anticipated benefits weighed against potential risks
associated with therapy.
Certain conditions, many of which led to exclusion from the Phase 3 trial, are likely
to increase the risk of bleeding with Xigris therapy. For individuals with one or more
of the following conditions, the increased risk of bleeding should be carefully considered
when deciding whether to use Xigris therapy:
• Concurrent therapeutic dosing of heparin to treat an active thrombotic or embolic
event (see PRECAUTIONS, Drug Interactions)
• Platelet count <30,000 x 106 /L, even if the platelet count is increased after
transfusions
• Prothrombin time-INR >3.0
• Recent (within 6 weeks) gastrointestinal bleeding
• Recent administration (within 3 days) of thrombolytic therapy
• Recent administration (within 7 days) of oral anticoagulants or glycoprotein IIb/IIIa
inhibitors
• Recent administration (within 7 days) of aspirin >650 mg per day or other platelet
inhibitors
• Recent (within 3 months) ischemic stroke (see CONTRAINDICATIONS)
• Intracranial arteriovenous malformation or aneurysm
• Known bleeding diathesis
• Chronic severe hepatic disease
• Any other condition in which bleeding constitutes a significant hazard or would be
particularly difficult to manage because of its location
Should clinically important bleeding occur, immediately stop the infusion of Xigris.
Continued use of other agents affecting the coagulation system should be carefully
assessed. Once adequate hemostasis has been achieved, continued use of Xigris may
be reconsidered.
Xigris should be discontinued 2 hours prior to undergoing an invasive surgical
procedure or procedures with an inherent risk of bleeding. Once adequate hemostasis
has been achieved, initiation of Xigris may be reconsidered 12 hours after major
invasive procedures or surgery or restarted immediately after uncomplicated less invasive
procedures.
Mortality in Patients with Single Organ Dysfunction and Recent Surgery—Among
the small number of patients enrolled in PROWESS with single organ dysfunction and
recent surgery (surgery within 30 days prior to study treatment) all-cause mortality
was numerically higher in the Xigris group (28-day: 10/49; in-hospital: 14/48)
compared to the placebo group (28-day: 8/49; in-hospital: 8/47).
In an analysis of the subset of patients with single organ dysfunction and recent
surgery from a separate, randomized, placebo-controlled study (ADDRESS) of septic
patients not at high risk of death all-cause mortality was also higher in the Xigris group
(28-day: 67/323; in-hospital: 76/325) compared to the placebo group (28-day:
44/313; in-hospital: 62/314). Patients with single organ dysfunction and recent
surgery may not be at high risk of death irrespective of APACHE II score and therefore
not among the indicated population.
PRECAUTIONS: Laboratory Tests—Most patients with severe sepsis have a coagulopathy
that is commonly associated with prolongation of the activated partial thromboplastin
time (APTT) and the prothrombin time (PT). Xigris may variably prolong the APTT.
Therefore, the APTT cannot be reliably used to assess the status of the coagulopathy
during Xigris infusion. Xigris has minimal effect on the PT and the PT can be used to
monitor the status of the coagulopathy in these patients.
Immunogenicity—As with all therapeutic proteins, there is a potential for immuno-
genicity. The incidence of antibody development in patients receiving Xigris has not
been adequately determined, as the assay sensitivity is inadequate to reliably detect all
potential antibody responses. One patient in the Phase 2 trial developed antibodies
to Xigris without clinical sequelae. One patient in the Phase 3 trial who developed
antibodies to Xigris developed superficial and deep vein thrombi during the study, and
died of multi-organ failure on day 36 post-treatment but the relationship of this event
to antibody is not clear.
XIGRIS姞 (drotrecogin alfa [activated]) PV 3427 AMP
Xigris has not been readministered to patients with severe sepsis.
Drug Interactions—Drug interaction studies with Xigris have not been performed in
patients with severe sepsis. However, since there is an increased risk of bleeding with
Xigris, caution should be employed when Xigris is used with other drugs that affect
hemostasis (see CLINICAL PHARMACOLOGY, WARNINGS in the full Prescribing
Information). Approximately 2/3 of the patients in the Phase 3 study received either
prophylactic low dose heparin (unfractionated heparin up to 15,000 units/day) or
prophylactic doses of low molecular weight heparins as indicated in the prescribing
information for the specific products. Concomitant use of prophylactic low dose
heparin did not appear to affect safety, however, its effects on the efficacy of Xigris
have not been evaluated in an adequate and well-controlled clinical trial.
Drug/Laboratory Test Interaction—Because Xigris may affect the APTT assay,
Xigris present in plasma samples may interfere with one-stage coagulation assays
based on the APTT (such as factor VIII, IX, and XI assays). This interference may
result in an apparent factor concentration that is lower than the true concentration.
Xigris present in plasma samples does not interfere with one-stage factor assays
based on the PT (such as factor II, V, VII, and X assays).
Carcinogenesis, Mutagenesis, Impairment of Fertility—Long-term studies in
animals to evaluate potential carcinogenicity of Xigris have not been performed.
Xigris was not mutagenic in an in vivo micronucleus study in mice or in an in vitro
chromosomal aberration study in human peripheral blood lymphocytes with or without
rat liver metabolic activation.
The potential of Xigris to impair fertility has not been evaluated in male or female
animals.
Pregnancy Category C—Animal reproductive studies have not been conducted with
Xigris. It is not known whether Xigris can cause fetal harm when administered to
a pregnant woman or can affect reproduction capacity. Xigris should be given
to pregnant women only if clearly needed.
Nursing Mothers—It is not known whether Xigris is excreted in human milk or
absorbed systemically after ingestion. Because many drugs are excreted in human
milk, and because of the potential for adverse effects on the nursing infant, a decision
should be made whether to discontinue nursing or discontinue the drug, taking into
account the importance of the drug to the mother.
Pediatric Use—The safety and effectiveness of Xigris have not been established in
the age group newborn (38 weeks gestational age) to 18 years. The efficacy of Xigris
in adult patients with severe sepsis and high risk of death cannot be extrapolated to
pediatric patients with severe sepsis.
Geriatric Use—In clinical studies evaluating 1821 patients with severe sepsis,
approximately 50% of the patients were 65 years or older. No overall differences in
safety or effectiveness were observed between these patients and younger patients.
ADVERSE REACTIONS: Bleeding—Bleeding is the most common adverse reaction
associated with Xigris. In the Phase 3 study, serious bleeding events were observed
during the 28-day study period in 3.5% of Xigris-treated and 2.0% of placebo-treated
patients, respectively. The difference in serious bleeding between Xigris and placebo
occurred primarily during the infusion period and is shown in Table 1.1 Serious
bleeding events were defined as any intracranial hemorrhage, any life-threatening
bleed, any bleeding event requiring the administration of ≥3 units of packed red blood
cells per day for 2 consecutive days, or any bleeding event assessed as a serious
adverse event.
Table 1: Number of Patients Experiencing a Serious Bleeding Event by
Site of Hemorrhage During the Study Drug Infusion Perioda In PROWESS1
Xigris Placebo
N=850 N=840
Total 20 (2.4%) 8 (1.0%)
Site of Hemorrhage
Gastrointestinal 5 4
Intra-abdominal 2 3
Intra-thoracic 4 0
Retroperitoneal 3 0
Intracranial 2 0
Genitourinary 2 0
Skin/soft tissue 1 0
Other b
1 1
a
Study drug infusion period is defined as the date of initiation of study drug to the
date of study drug discontinuation plus the next calendar day.
b
Patients requiring the administration of ≥3 units of packed red blood cells per day
for 2 consecutive days without an identified site of bleeding.
In PROWESS, 2 cases of intracranial hemorrhage (ICH) occurred during the infu-
sion period for Xigris-treated patients and no cases were reported in
the placebo patients. The incidence of ICH during the 28-day study period was 0.2%
for Xigris-treated patients and 0.1% for placebo-treated patients. ICH has been report-
ed in patients receiving Xigris in non-placebo controlled trials with an incidence of
approximately 1% during the infusion period. The risk of ICH may be increased in
patients with risk factors for bleeding such as severe coagulopathy and severe throm-
bocytopenia (see WARNINGS).
In PROWESS, 25% of the Xigris-treated patients and 18% of the placebo-treated
patients experienced at least one bleeding event during the 28-day study period. In
both treatment groups, the majority of bleeding events were ecchymoses or gastroin-
testinal tract bleeding.
Other Adverse Reactions—Patients administered Xigris as treatment for severe
sepsis experience many events which are potential sequelae of severe sepsis and may
or may not be attributable to Xigris therapy. In clinical trials, there were no types of
non-bleeding adverse events suggesting a causal association with Xigris.
REFERENCES:
1. Bernard GR, et al. Efficacy and Safety of Recombinant Human Activated Protein C
for Severe Sepsis. N Engl J Med. 2001;344:699-709.
Literature revised June 23, 2005
PV 3427 AMP PRINTED IN USA
Eli Lilly and Company
Indianapolis, IN 46285, USA
www.lilly.com
Copyright © 2001, 2005, Eli Lilly and Company. All rights reserved.
XIGRIS姞 (drotrecogin alfa [activated]) PV 3427 AMP
Osborn_BOOK.qxp 28/7/06 3:53 pm Page 27
Early Goal-directed Therapy in the Treatment of Severe Sepsis and Septic Shock
relatively delaying analysis of therapeutic interventions.
If, despite adequate CVP and MAP, the ScvO2
remains below 70%, a post-resuscitation hematocrit
(Hct) should be evaluated. A post-resuscitation HCT
is used due to potential pseudo-elevation from initial
hypovolemia induced hemoconcentration. If the Hct
<30%, the patient should be transfused to a Hct
≥30% to facilitate oxygen delivery through optimized
hemoglobin concentration.
If goal CVP, MAP and HCT are achieved and the
ScvO2 remains <70%, consider an inotropic agent to
enhance cardiac output and tissue oxygenation. Once
preload, afterload and the concentration of oxygen
carrying units are optimized, the remaining component
of oxygen delivery to be addressed is cardiac output.
Although sepsis is commonly characterized as
hyperdynamic, some patients may present in the early
stages with a decreased preload and myocardial
depression reflecting a hypodynamic state (i.e. low
cardiac output).17 Myocardial depression, thought to
occur as a result of effects of inflammatory mediators,
can be the predominant hemodynamic feature in
15–20% of patients presenting with severe sepsis/septic
shock and may be especially profound in patients with
pre-existing cardiac disease.18 Dobutamine is the most
readily available and most commonly used inotropic
agent, and may be used in patients with a MAP ≥65 and
a heart rate <120bpm. Once the CVP, MAP, and ScvO2
goals have been reached, the EGDT component of the
resuscitation has been completed.
Other Adjuncts
Beyond the EGDT protocol, other therapeutic options
from the 24-hour bundle may be considered such as the
administration of steroids, vasopressin, activated protein
C (drotrecogin alpha or Xigris) and lung protective
strategies for mechanically ventilated patients.
Steroid Administration
As 50–70% of patients in vasopressor dependent shock
may have adrenal insufficiency, corticosteroid
administration should be considered. In one study,
administration of corticosteroids to vasopressor
dependent septic shock patients who failed an
adrenocorticotropic hormone (ACTH) stimulation test
resulted in a 28-day mortality benefit of 10% (63%
placebo vs 53% treatment CI, 0.66–1.04; p=0.04).
Additionally, time on vasopressors was significantly
reduced when inadequate adrenal reserve was treated.The
benefits were achieved without increases in infectious
complications, gastrointestinal bleeding, or mental status
changes. However, there was no improvement in survival
EMERGENCY MEDICINE & CRITICAL CARE REVIEW 2006
when patients with an appropriate cortisol response to
ACTH were treated with steroids.19
Va s o p r e s s i n
Vasopressin is an endogenous stress hormone released
during vasodilatory shock. In the patient with
refractory hypotension, vasopressin deficiency should
be considered. When administered in relatively small,
physiologic doses, vasopressin administration
(0.01–0.04 units/min), corrects the deficiency through
a hypersensitive and synergistic physiologic response
that increases MAP and frequently allows for
catecholamine withdrawal.20,21 However, vasopressin is
not considered a first-line agent, and should be used in
combination with other vasoactive drugs. Dosages
greater than 0.04U/min are not of greater benefit and
may be harmful.10
Activated Protein C
Activated protein C (drotrecoogin alpha, Xigris) has
potent anticoagulant, pro-fibrinolytic, anti-
inflammatory, and anti-apoptotic effects. Drotrecoogin
alpha works to reverse a septic cascade of microvascular
thrombi that cause capillary flow occlusion. Survival
benefit with drotrecogin alfa (activated) is associated
with higher severity of illness, described by either the
number of sepsis-induced organ failures (≥2) or the
Acute Physiology and Chronic Health Evaluation II
(APACHE II) score (>25). Although early studies show
promise, there are significant risks with the most
prevalent being bleeding.22
L o w T i d a l Vo l u m e Ve n t i l a t i o n
The SSC endorsed low tidal volume ventilation
(6cc/kg) and minimal plateau pressure for patients
with acute lung injury or at risk for acute respiratory
distress syndrome (ARDS). Although not specifically a
therapy for severe sepsis/septic shock, a large
multicenter trial from the ARDS Network showed
that the use of low-tidal volume mechanical
ventilation, when acute lung injury is present, reduced
mortality rates from 39.8% to 31%.10,23
Glucose Control
Tight glucose control with blood sugars aggressively
held <110mg/dl during the length of the ICU stay has
been demonstrated to reduce mortality. While tight
glucose control may be less important in the acute
phases of resuscitation, it has been hypothesized that
hyperglycemia exacerbates the inflammatory cascade,
and thus should be considered in the early phases of
treatment when possible.
27
Osborn_BOOK.qxp 1/8/06 12:22 pm Page 28

Critical Care

Prophylaxis Conclusion

Typical prophylactic measures should be undertaken,
including stress ulcer prophylaxis and deep vein thrombosis
(DVT) prophylaxis. Underlying coagulopathies and other
complicating factors may prevent DVT prophylaxis from
beginning in the ED; however stress ulcer prophylaxis with
a H2 blocker can be administered routinely.
Early goal directed therapy produces a reduction
in hospital mortality.The algorithm for the management
of severe sepsis and septic shock revolves around early
diagnosis, early antibiotics, EGDT and adjunctive
therapies in the persistently hypotensive patient, and
generally begins in the ED. ■

References

1. Angus, D C, Linde-Zwirble W T, et al., “Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and
associated costs of care” Crit Care Med (2001);29(7): pp. 1,303–1,310.
2. Rivers E P, Nguyen H B, Huang D T, Donnino M W, “Critical Care and Emergency Medicine”, Curr Opin Crit Care
(2002);8(6): pp. 600–606.
3. Brun-Buisson C, Meshaka P, Pinton P, et al., and the EPISEPSIS Study Group, “EPISEPSIS: a reappraisal of epidemiology
and outcome of severe sepsis in French intenswive care units”, Intensive Care Med (2004);30: pp. 580–588.
4. Finfer S, Bellomo R, Lipman J, et al., “Adult Population incidence of severe spepsis in Australian and New Zealand intensive
care units”, Intensive Care Med (2004);30: pp. 536–555.
5. Osborn T M, Nguyen H B, Rivers E P, “Emergency medicine and the surviving sepsis campaign: an international approach to
managing severe sepsis and septic shock”, Ann of Emerg Med (2005);46(3): pp. 228–231.
6. Rivers E, Nguyen B, Havstad S, et al., “Early goal-directed therapy in the treatment of severe sepsis and septic shock”, N Engl
J Med (2001);345(19): pp. 1,368–1,377.
7. Levy M M, Fink M P, et al., “2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference”,
Intensive Care Med (2003);29 (4): pp. 530–538.
8. Resar R, “Sepsis Bundle History”, Available at http://www.ihi.org
9. Hollenberg S M,Ahrens T S, et al.,“Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update”, Crit
Care Med (2004);32(9): pp. 1,928–1,948.
10. Packman M I, Rackow E C,“Optimum left heart filling pressure during fluid resuscitation of patients with hypovolemic and septic
shock”, Crit Care Med (1983);11(3): pp. 165–169.
11. Sugerman H J, Diaco J F, et al., “Physiologic management of septicemic shock in man”, Surg Forum (1971);22: pp. 3–5.
12. Dellinger R P, “Cardiovascular management of septic shock”, Crit Care Med (2003);31(3): pp. 946–955.
13. Dellinger R P, Carlet JM, Masur H, et al., “Surviving sepsis campaign guidelines for management of severe sepsis and septic
shock”, Crit Care Med (2004);32(3): pp. 858–872.
14. Rogers G G, Oosthuyse T,“A comparison of the indirect estimate of mean arterial pressure calculated by the conventional equation
and calculated to compensate for the heart rate”, Int J Sports Med (2000);21(2): pp. 90–95.
15. Vincent,“The International Sepsis Forum’s controversies in sepsis: my initial vasopressor agent in septic shock is dopamine rather
than norepinephrine”, Crit Care (2003);7(1): pp. 6–8. Epub 2002 Dec 9.
16. Sharma, “The International Sepsis Forum’s controversies in sepsis: my initial vasopressor agent in septic shock is norepinephrine
rather than dopamine”, Crit Care (2003);7(1):3–5. Epub 2002 Nov 1.
17. Astiz M E, Rackow E C, 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 (1988);16: pp. 655–678.
18. Parrillo J E, Burch C, Shelhamer J H, et al.,“A circulating myocardial depressant substance in humans with septic shock. Septic shock
patients with a reduced ejection fraction have a circulating factor that depresses in vitro myocardial cell performance”, J Clin Invest
(1985);76: pp. 1,539–1,553.
19. 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: pp. 862–871.
20. Holmes C L, Patel B M, Russell J A,Walley K R, “Physiology of vasopressin relevant to management of septic shock”, Chest
(2001);120: pp. 989–1002.
21. Malay M B, Ashton R C, Landry D W, et al., “Low-Dose Vasopressin in the Treatment of Vasodilatory Septic Shock”, J of
Trauma (1999);(47) pp. 699–703.
22. Bernard G R,Vincent J-L, Laterre P-F, et al., “Efficacy and safety of recombinant human activated protein C for severe sepsis”,
N Engl J Med (2001);344: pp. 699–709.
23. “Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory
distress syndrome.The Acute Respiratory Distress Syndrome Network”, N Engl J Med (2000);342: pp. 1,301–1,308.

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