The Journal of Emergency Medicine, Vol. 31, No. 2, pp.

185199, 2006
Copyright 2006 Elsevier Inc.
Printed in the USA. All rights reserved
0736-4679/06 $see front matter

doi:10.1016/j.jemermed.2006.05.008

Selected Topics:
Critical Care Medicine

MANAGEMENT OF SEPSIS DURING THE EARLY GOLDEN HOURS

Murugan Raghavan,

MD, MRCP (UK),*

and Paul E. Marik,

MD, FCCP, FCCM

*Department of Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania and Division of Pulmonary
and Critical Care Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
Reprint Address: Paul Marik, md, fccp, Chief, Pulmonary and Critical Care Medicine, Thomas Jefferson University, 1015 Chestnut Street,
Suite M 100, Philadelphia, PA 19107

e AbstractSevere sepsis and septic shock are common

causes of morbidity and mortality. Interventions directed at
specific endpoints, when initiated early in the golden
hours of patient arrival at the hospital, seem to be promising. Early hemodynamic optimization, administration of
appropriate antimicrobial therapy, and effective source
control of infection are the cornerstones of successful management. In patients with vasopressor-dependent septic
shock, provision of physiologic doses of replacement steroids may result in improved survival. Administration of
drotrecogin alfa (activated), (activated protein C) has been
shown to improve survival in patients with severe sepsis
and septic shock who have a high risk of mortality. In this
article we review the multi-modality approach to early
diagnosis and intervention in the therapy of patients with
severe sepsis and septic shock. 2006 Elsevier Inc.

of sepsis occur each year, at least 225,000 of which are

fatal (2). Sepsis is now the 10th leading cause of death in
the United States (2,5). Despite the use of antimicrobial
agents and advanced life-support care, the case fatality
rate for patients with sepsis has remained between 30%
and 50% over the past three decades (3,6). Survivors of
sepsis and septic shock are observed to have a higher 6and 12-month mortality rate and a significantly lower
health-related quality of life (7,8). Recent advances in
understanding the pathophysiology of sepsis have led to
the evolution of newer therapies that have demonstrated
surprising efficacy (9 15). The current systematic review closely focuses on evidence-based recommendations, made by the Society of Critical Care Medicines
Surviving Sepsis Campaign 2004 guidelines (16). In
addition, we also performed literature search using terms
such as severe sepsis, septic shock, sepsis syndrome,
critical illness, and early resuscitation using the Medline database from 1960 to the present, and have attempted to include major clinical trials and other systematic reviews published in this field.

e Keywordssevere sepsis; septic shock; sepsis syndrome; critical illness; early resuscitation; golden hour

INTRODUCTION
In recent decades the reported incidence of sepsis has
increased dramatically, largely due to the advancing age
of the population, an increased number of invasive procedures performed, and immunosuppressive therapy (1
3). Sepsis is among the most common reasons for admission to intensive care units throughout the world (4).
In the United States alone, approximately 750,000 cases

SEPSIS PATHOPHYSIOLOGY
When the body is challenged by foreign microbial
agents, homeostatic mechanisms come into play that
attempt to rid the body of the foreign agent without

Selected Topics: Critical Care Medicine is coordinated by Joseph Varon, MD, of Baylor College of Medicine, Houston,
Texas

RECEIVED: 17 November 2004;

ACCEPTED: 30 March 2005
185

186

M. Raghavan and P. E. Marik

damaging the host. This involves the activation of proand anti-inflammatory pathways, which are tightly controlled and regulated (17). In most individuals, the body
is able to achieve a balance between pro-inflammatory
and anti-inflammatory mediators and homeostasis is restored. In some patients, however, this balance is upset
with an excessive pro-inflammatory response resulting in
systemic inflammatory response syndrome (SIRS),
multi-system organ dysfunction, septic shock and, ultimately, death (1720).
The constellation of abnormalities that characterize
severe sepsis and septic shock includes circulatory dysfunction with intravascular volume depletion, peripheral
vasodilatation, myocardial depression, and a diffuse microcapillary injury leading to hypoperfusion of vital organ vascular beds (2124). This occurs in the setting of
a hypermetabolic state resulting in an imbalance between
oxygen delivery and demand leading to tissue hypoxia.
This may be further complicated by cytopathic hypoxia
due to sepsis-induced mitochondrial dysfunction (25,26).
Tissue hypoxia is assumed to be the key factor leading to
multi-organ failure and death (17,27). Thus, early aggressive resuscitation of the septic patient may limit or
reverse tissue hypoxia and the progression to organ failure. This transition to organ failure occurs during the
critical golden hours, when time is survival, and the
definitive recognition and treatment of sepsis provides
maximal benefit in terms of outcome (9). These golden
hours may elapse in the Emergency Department (ED),
hospital ward, or the intensive care unit (ICU) (28 30).
Lundberg and coworkers demonstrated that for patients
with septic shock on the hospital wards, there were
clinically important delays in the transfer of patients to
the ICU, reception of intravenous fluid boluses, and
reception of inotropic agents, which had implications for
increased mortality (29).
Current management of sepsis includes early hemodynamic optimization with other physiologic organ supportive measures, timely and appropriate usage of antimicrobial agents, and treating or eliminating the source
of infection. Attempts at down-regulating the pro-inflammatory response with novel agents directed at specific
pro-inflammatory mediators has uniformly met with failure (17,3134). Recently several modalities including
activated protein C and stress doses of glucocorticoids
have been demonstrated to decrease mortality in critically ill septic patients (9 11,20,3537).

DIAGNOSIS OF SEVERE SEPSIS AND

SEPTIC SHOCK
Sepsis is a systemic process with a myriad of clinical
manifestations. The initial symptoms of sepsis are non-

specific and include malaise, tachycardia, tachypnea, fever, and sometimes hypothermia. Although most patients
with sepsis have an elevated white cell count, some
patients present with a low white cell count, which in
general is a poor prognostic sign. Other clinical manifestations include altered mental status, hypotension, respiratory alkalosis, metabolic acidosis, hypoxemia with
acute lung injury, thrombocytopenia, consumptive coagulopathy, proteinuria, acute tubular necrosis, intrahepatic cholestasis, elevated transaminases, hyperglycemia,
and hypoglycemia (see Table 1).
Patients may present with clinical features of a localized site of infection, such as cough, tachypnea, and
sputum production due to pneumonia; flank pain and
dysuria with complicated urinary tract infection; and
abdominal pain with intra-abdominal infection. The
manifestations of sepsis sometimes can be quite subtle,
particularly in the very young, the elderly, and those with
chronic debilitating or immunosuppressing conditions.
These patients may present with normothermia or hypothermia. The failure to generate a temperature greater
than 37.5C (99.6F) in the first 24 h of clinical illness
has been associated with an increased mortality rate
(38,39). An altered mental state or an otherwise unexplained respiratory alkalosis may be the presenting feature of sepsis.
The signs and symptoms of systemic inflammation are
not useful in distinguishing infectious from noninfectious causes of SIRS. Furthermore, a bacterial pathogen
is not isolated in all patients with sepsis. Consequently, a
number of markers have been evaluated as more specific
indicators of infection (40,41). Tools such as procalcitonin (PCT) may be useful and have been shown to be
superior to other inflammatory markers such as TNF-,
IL-6, IL-1, and C-reactive protein (CRP) in outcome

Table 1. Criteria for Organ Systems Dysfunction during

Severe Sepsis and Septic Shock
Cardiovascular
SBP 90 mm Hg or MAP 70 mm Hg for at
least 1 h despite adequate fluid resuscitation
Vasopressor use
Renal
Urine output 0.5 ml/kg /h for 1 h, despite
adequate fluid resuscitation
Respiratory O2
PaO2/FiO2 250 in the presence of other organs
or systems failure or
200 if the lung is the only dysfunctional organ
Hematologic
Platelet count 80,000/mm3 or 2 by 50% in the
preceding 3 days
Unexplained metabolic acidosis
pH 7.30 or base deficit 5.0 mmol/L
Lactate level 1.5 times normal
SBP systolic blood pressure; MAP mean arterial pressure.

Management of Sepsis

prediction among critically ill patients (42,43). Nevertheless, various noninfectious insults such as major surgery, tissue trauma, and prolonged circulatory failure
may induce these markers, thereby decreasing the specificity in differentiating sepsis from other inflammatory
states (17). Consequently, an aggressive search and early
consideration of sepsis is required in distinguishing severe sepsis from other causes of hypotension and organ
dysfunction on the patients arrival at the hospital.
Numerous studies have evaluated the use of lactate as
a diagnostic, therapeutic, and prognostic marker of
global tissue hypoxia in patients with circulatory shock
(44 46). An elevated serum lactate concentration, although lacking in precision, may identify tissue hypoperfusion in non-hypotensive patients. Lactate concentrations 4 mmol/L in the presence of the systemic
inflammatory response syndrome (SIRS) have been
shown to significantly increase intensive care unit (ICU)
admission rates and mortality rate in normotensive patients (47). Although the sensitivity and specificity of
single lactate concentrations as markers of tissue hypoperfusion have been debated, serial measurements or
lactate clearance over time have been shown to be better
prognosticators of organ failure and mortality (48,49).
Persistent elevations in lactate 24 h are associated with
a mortality rate as high as 89% (50).
Nguyen et al. evaluated the clinical utility of the
lactate clearance as an indicator of outcome in severe
sepsis and septic shock in a prospective observational
study (44). Septic shock therapy was initiated in the ED
and continued in the ICU. Lactate clearance was defined
as the percent decrease in lactate from ED presentation to
hour 6. A total of 111 patients were enrolled, with an ED
length of stay 6.3 3.2 h, and an overall in-hospital
mortality rate of 42.3%. Survivors compared with nonsurvivors had a lactate clearance of 38.1 34.6 vs. 12.0
51.6%, respectively (p 0.005). Multivariate logistic
regression analysis showed that lactate clearance had a
significant inverse relationship with mortality (p 0.04).
There was an approximately 11% decrease in likelihood
of mortality for each 10% increase in lactate clearance.
Therefore, patients with higher lactate clearance after 6 h
of ED intervention have improved outcomes compared
with those with lower lactate clearance.

EARLY GOAL-DIRECTED THERAPY OF

SEPTIC SHOCK
Rivers et al. showed that early goal-directed hemodynamic optimization starting in the ED for severe sepsis
and septic shock patients significantly decreases morbidity and mortality (9). A key to this success is the early
recognition of sepsis and the mobilization of frontline

187

health care providers analogous to patients with acute

myocardial infarction, stroke, and trauma (51). The study
showed that early aggressive therapy that optimized cardiac preload, afterload, and contractility in patients with
severe sepsis and septic shock improved survival. The
authors employed infusions of colloid or crystalloid,
vasoactive agents, and transfusions of red cells to increase oxygen delivery. Resuscitation endpoints chosen
for assessment of the adequacy of oxygen delivery were
the normalization of values for mixed venous oxygen
saturation (ScvO2), lactate concentration, base deficit,
and pH. Patients in the group that received early goaldirected therapy received more fluid, inotropic support,
and blood transfusions during the first 6 h than did
control patients, who received standard resuscitation
therapy. During the interval from 7 to 72 h, patients in
the group receiving early goal-directed treatment had a
higher mean central venous oxygen concentration, a
lower mean lactate concentration, a lower mean base
deficit, and a higher mean pH than the control group.
Mortality was 30.5% in the group receiving early goaldirected treatment, as compared with 46.5% in the control group (p 0.009). The patients in the early-therapy
group received, on average, approximately 1500 mL
more in total fluids in the first 6 h of treatment than did
the standard-therapy group and had a significantly higher
mean arterial pressure (mean [ SD], 95 19 vs. 81
18 mm Hg, respectively; p 0.001). Although the
benefit of red cell transfusions and optimization of mixed
venous saturation are of questionable benefit in patients
with severe sepsis, early aggressive resuscitation with
fluids and vasopressor agents to restore the balance between oxygen delivery and oxygen demand may largely
explain the improved survival among those patients who
received early goal-directed therapy (52).
Similarly, Levy et al. analyzed the Sequential Organ
Failure Assessment (SOFA) scores during the first 48 h
in 1036 severely septic patients (53). They hypothesized
that if early resuscitation is associated with improved
outcome in severe sepsis, then a dynamic risk prediction
model based on changes in clinical parameters from
baseline to Day 1 should be predictive of outcome. In
their study, mortality rates correlated with baseline cardiovascular (p 0.0022), renal (p 0.0001), hematologic (p 0.0044), and respiratory (p 0.0013) SOFA
scores. From baseline to day 1, the direction of change in
cardiovascular, renal, respiratory, hematologic, and hepatic functions independently predicted 28-day mortality. The implications of this study are that if organ
dysfunction is not improving during the first day of
severe sepsis, the mortality risk is significantly increased,
underscoring the importance of early recognition and
therapeutic intervention to prevent sequential organ dysfunction.

188

M. Raghavan and P. E. Marik

Recognize severe sepsis and septic shock on arrival to ED

Maintain airway and establish i.v. access

Pre-ICU Management

Aggressive volume resuscitation with

crystalloids and colloids (see Table 2)

If MAP < 70 mm Hg, after at least 2000

mL of fluids

Start Norepinephrine (0.01 g/kg/min)

Continue i..v. fluids
Monitor MAP
Monitor urine output

If MAP < 70 mm Hg despite

norepinephrine of 0.5 g/kg/min with poor
tissue perfusion
(Catecholamine- resistant shock)

Early empiric broad spectrum

antimicrobial therapy and source control

Fluid responsive
Draw random Cortisol
and administer Hydrocortisone
100 mg i.v. q 8 h*

Consider Recombinant Activated

Protein C (24 g/kg/h) i.v. for 96
h if new 2 or organ systems
failure @ (see Table 1)

Echocardiogram or PAC assessment of

LV function

ICU Management

Low CI

Start Dobutamine

High CI with low SVR

Start Vasopressin 0.01U/min

Persistent shock

Shock resolution

Observe

Monitor
MAP
pH
Lactic acid
Oxygenation
Urine output
Sublingual Co2

Intensive Glycemic control with i.v. Insulin (Target glucose 80-110 mg/dL)
Low Tidal volume ventilation for lung injury (VT 6 mL/kg; Ppl < 30 cms H20)
Narrow antimicrobials based on culture results
Early CVVH for sepsis-induced acute renal failure
Semi-recumbent head positioning to 45
Early enteral nutrition
Sedation goal with intermittent awakening
Deep vein thrombosis prophylaxis
Stress ulcer prophylaxis

Figure 1. Suggested algorithm for management of patients

presenting with severe sepsis and septic shock during the
initial golden hours. MAP mean arterial pressure; CVVH
continuous veno-venous hemofiltration; VT tidal volume;
CI cardiac index; PAC pulmonary artery catheter. *See
Figure 2 for further evaluation of adrenocortical function and
treatment. @If no contraindications present such as active
internal bleeding, recent (< 3 months) hemorrhagic stroke,
recent (< 2 months) intracranial or intraspinal surgery, or
severe head trauma, trauma with an increased risk of lifethreatening bleeding, presence of an epidural catheter, intracranial neoplasm or mass lesion or evidence of cerebral
herniation.

Therefore, it is imperative that a clinical decision to

stratify at-risk patients with sepsis and to identify those
with an increased risk of dying begins as soon as the
patient arrives in the hospital. Use of scoring systems
such as the Mortality in Emergency Department Sepsis
Score (MEDS) may prove helpful with triage decisions,
ICU placement, selection and activation of various therapeutic interventions (54).

VOLUME RESUSCITATION
The resuscitation of a patient with severe sepsis or sepsis-induced tissue hypoperfusion (hypotension or lactic

acidosis) should begin as soon as the syndrome is recognized, and should not be delayed pending hospital or
ICU admission (Figure 1). The hallmarks of severe sepsis and septic shock include intravascular volume depletion, peripheral vasodilatation with hypotension, myocardial depression, and abnormal blood flow distribution
(17,55). Several studies have demonstrated that indices
of inadequate tissue perfusion and oxygenation are
strong predictors of multi-organ dysfunction and death in
patients with sepsis (56 59).
Aggressive volume resuscitation is considered the
best initial approach to therapy for the cardiovascular
instability of sepsis (16,60,61). Hypotension often can be
reversed with fluid administration alone. Volume repletion alone in patients with septic shock has been shown
to produce significant improvement in cardiac function
and systemic oxygen delivery, thereby enhancing tissue
perfusion (60,62 64). Fluid requirements for the initial
resuscitation of patients with septic shock are commonly
large, with up to 10 L of crystalloids or 4 L of colloids
required in the first 24 h (9,60,62,63,65). Rapid infusion
of fluids is best initiated with boluses of 500 to 1000 mL
titrated to endpoints, such as a mean arterial pressure
70 mm Hg, heart rate 100 beats/min, and urine output
0.5 mL/kg/h during the initial 6 h (Figure 1, Table 1)
(9,16,66). After the initial volume resuscitation with
approximately 5 L of fluids in the first 6 h, maintenance
fluids should be administered at a rate of 150 200 mL/h,
with 500-cc boluses as required (17,66). In approximately 50% of patients with sepsis who initially present
with hypotension, fluids alone will reverse hypotension
and restore hemodynamic stability.
The choice of crystalloid or colloid (or both) for
resuscitation of patients with sepsis remains a controversial issue (6770). Crystalloids have generally been recommended as the volume expander of first choice (60).
However, in sepsis, the interstitial volume is increased
due to the marked increase in capillary permeability.

Table 2. Suggested Fluid Resuscitation Algorithm for

Hemodynamic Instability of Severe Sepsis and
Septic Shock
1 L N/S 1520 min
1 L Ringers 30 min
Start Norepinephrine if MAP 70 mm Hg
1 L Hextend 3040 min
1 L Ringers 3040 min
1 L Hextend 3040 min
Ringers lactate 200 cc/h
Bolus 500 cc Hextend as required
Monitor
MAP, Urine Output
Oxygenation
LV functionbedside ECHO
Sublingual CO2

Management of Sepsis

Therefore, crystalloids will further increase the interstitial fluid volume with less than a quarter of the volume
remaining intravascularly (71). It has been suggested,
therefore, that in patients with sepsis, colloids such as
albumin may limit the degree of third space loss and
prevent tissue and pulmonary edema by enhancing
plasma oncotic pressure (56,62,70,72). However, in the
critically ill patient, there is a very poor relationship
between the serum albumin and colloid osmotic pressure
(73,74). Furthermore, sepsis is characterized by a generalized capillary leak, reducing the importance of the
colloid osmotic pressure in influencing fluid flux.
Currently, 0.9% NaCl (normal saline) is the most
commonly used resuscitation fluid, in patients with sepsis (75). However, large volumes of saline infusion have
been shown to cause hyperchloremic metabolic acidosis
(76 78). Although the clinical consequences of this metabolic acidosis are not well understood, it has been
shown to have lower mortality when compared to metabolic acidosis of other etiologies in humans (79). The
hyperchloremia associated with saline-based solutions
has been shown to decrease splanchnic mucosal perfusion, glomerular filtration, and cause coagulopathy (80
83). Balanced salt solutions such as Lactated Ringers and
colloids have therefore been proposed as alternatives.
Although resuscitation with Lactated Ringers solution
results in improved arterial pH, it fails to improve survival time in animal models of septic shock (75). As the
volume of distribution is much larger for crystalloids
than for colloids, resuscitation with crystalloids requires
more fluid to achieve the same endpoints and results in
more edema (16).
Finfer et al., in a recent multicenter, randomized,
double-blind trial, compared the effect of fluid resuscitation with 4% albumin or saline on mortality in
6997 heterogeneous ICU patients (65). There were no
significant differences between the groups in the mean
number of days spent in the ICU, days spent in the
hospital, days of mechanical ventilation, days of renalreplacement therapy, or mortality between the two
groups. However, in the subgroup analysis of patients
with severe sepsis, the relative risk of death during the
28-day study period among those randomly assigned
to receive albumin as opposed to saline was 0.87, as
compared with a corresponding relative risk of 1.05
among patients without severe sepsis (p 0.06 by the
test for a common relative risk). In contradistinction to
an earlier meta-analysis that suggested that albumin
administration increases mortality in critically ill patients, this study provides evidence that volume resuscitation that includes a colloid (in this case albumin)
may be preferable to saline alone for intravascular
volume resuscitation of patients with severe sepsis
(69). However, given the concerns regarding the cost

189

and risks associated with human blood products, routine administration of human albumin to septic patients cannot be recommended (65).
Similarly, the use of packed cells as first-line therapy to increase the ScvO2 and thereby oxygen delivery
cannot be recommended. Currently, there is good evidence that packed red cells do not increase oxygen
consumption (at least in the first 24 h) in patients with
sepsis (84,85). Paradoxically, old units of packed
red cells may cause tissue dysoxia in patients with
sepsis (84,85). Furthermore, transfusions of packed
red cells have been shown to increase mortality in
critically ill patients with sepsis (84,86,87).

VASOPRESSOR THERAPY
When an appropriate fluid challenge (at least 2 L) fails to
restore adequate blood pressure (mean arterial pressure
[MAP] 70 mm Hg) and organ perfusion, therapy with
a vasopressor agent should be started (Figure 1). Vasopressor therapy also may be required to maintain perfusion in the face of life-threatening hypotension, even
when fluid resuscitation is in progress and hypovolemia
has not yet been corrected (16). Patients with sepsis have
a markedly abnormal ventricular response to volume
infusion, with a significantly smaller increase in left
ventricular stroke work index than controls in response
to fluid challenges (61). Moreover, due to the massively
reduced systemic vascular resistance, patients may remain hypotensive despite adequate fluid resuscitation
(38).
Currently, norepinephrine remains the first-choice vasopressor agent in patients with septic shock (16). Although there is no high quality evidence, human and
animal studies suggest many advantages of norepinephrine over other vasopressor agents (88 92). Norepinephrine increases mean arterial pressure due to its vasoconstrictive effects, with little change in heart rate and less
increase in myocardial oxygen consumption compared
with dopamine (16,93). Norepinephrine has been shown
to improve hemodynamic parameters including splanchnic perfusion and tissue oxygen utilization in most patients with sepsis (9395). Despite many practitioners
concerns, there are no data to indicate that this agent has
a deleterious renal effect (93,96,97).
Dopamine has traditionally been the vasoactive drug
of choice in patients with sepsis (16,60,98,99). However,
dopamine may not be the ideal vasopressor for a number
of reasons (9395,99). During sepsis, dopamine has been
shown to cause more tachycardia and potentiate dysrhythmias as chronotropic sensitivity to -adrenergic
stimulation by dopamine is increased (95,100 102). In
addition, the positive chronotropic and inotropic effects

190

of dopamine elevate myocardial oxygen requirements,

which may not be adequately met by increased coronary
flow (102). In critically ill septic patients, low-dose dopamine has been shown to cause precapillary vasoconstriction with diversion of blood flow away from the gut,
hastening gut ischemia (103105). Furthermore, dopamine potentiates immune suppression during sepsis by
inhibiting stimulated lymphocyte proliferation, immunoglobulin synthesis, cytokine production; and promotes
lymphocyte apoptosis (106 110). Dopamine also decreases growth hormone secretion and thyrotropin release (111). Growth hormone deficiency may also contribute to a negative nitrogen balance during critical
illness (17).
The widespread use of low-dose dopamine to improve
renal function in critically ill patients has been refuted by
a large randomized trial and two meta-analyses comparing low-dose dopamine to placebo (112114). In the
Australian and New Zealand Trials Group randomized
controlled study, there was no difference in either primary outcomes (peak serum creatinine, need for renal
replacement therapy, urine output, time to recovery of
normal renal function) or secondary outcomes (survival
to either ICU or hospital discharge, ICU stay, hospital
stay, dysrhythmias) between low-dose dopamine and
placebo (112). Thus, the available data do not support
administration of low doses of dopamine to maintain or
improve renal function (112,113).
Hypotensive patients with severe sepsis may have a
low, normal, or increased cardiac output. In hemodynamically unstable patients who have signs of inadequate
tissue perfusion after adequate volume resuscitation, require assessment of left ventricular (LV) function
(115,116). This may be best achieved by bedside transthoracic echocardiography. Portable hand-carried ultrasound machines are now available that allow for repeated
assessment of global left ventricular function by the
emergency physician or intensivist (116 121). In addition to an accurate assessment of left and right ventricular function during septic shock, either trans-thoracic or
trans-esophageal echocardiography may be used to assess vena cava collapsibility as a gauge of preload responsiveness in mechanically ventilated patients
(119,121123). Furthermore, various other methods of
measuring cardiac output such as esophageal Doppler
probes and electrical bio-impedance techniques have
been successfully used by emergency physicians
(124,125).
Patients with poor left ventricular contractility (or low
to normal cardiac output) despite adequate fluid resuscitation should be started on dobutamine, in conjunction
with vasopressor therapy, to augment cardiac output.
Dobutamine has been demonstrated to increase oxygen
delivery and reverse both systemic and local indices of

M. Raghavan and P. E. Marik

tissue hypoxia in patients with sepsis (104,126 128).

Nevertheless, the use of dobutamine in isolation may
cause or potentiate hypotension due to 2-mediated vasodilatation. The coexistence of a decreased ejection
fraction and widespread vasodilatation implies that it
may be advantageous to use two drugs with different
receptor profiles to attain the desired effect (55,126). The
combination of dobutamine and norepinephrine has been
demonstrated to increase both the cardiac output and
peripheral vascular resistance and to improve indices of
tissue oxygenation in patients with severe sepsis (126).
There are concerns about the use of epinephrine in
patients with sepsis because this agent has been shown to
cause a significant increase in the serum lactate concentration with an associated decrease in the serum pH
(129,130). This rise in lactate has not been demonstrated
with the use of the other commonly used inotropic
agents. The increased lactate production may be due to
increased glycogenolysis or a maldistribution of blood
flow (131). There are limited data on the hemodynamic
effect of phenylephrine in patients with sepsis (63,132).
Although this agent increases blood pressure and systemic vascular resistance, it usually lowers cardiac output.
Low-dose vasopressin (0.01 0.04 units/min) may be
considered in patients with refractory shock despite adequate fluid resuscitation and high-dose conventional
vasopressors (16,133,134). During early septic shock,
vasopressin concentrations are elevated; however, with
continued shock, concentrations decrease to normal
range in the majority of patients between 24 and 48 h
resulting in relative vasopressin deficiency (135). Because vasopressin also has been shown to increase serum
cortisol levels via stimulation of ACTH release, a relative vasopressin deficiency state during septic shock
may predispose to a relative adrenal insufficiency and
increased mortality (136 138). Therefore, it is conceivable that supplementation of a physiologic dose of steroids and vasopressin improves survival. Pending the
outcome of ongoing trials, vasopressin is not recommended as a replacement for norepinephrine as a firstline agent. Vasopressin is a direct vasoconstrictor without inotropic or chronotropic effects and may result in
decreased cardiac output and hepatosplanchnic flow
(139). Doses of vasopressin 0.04 units/min have been
associated with myocardial ischemia, significant decreases in cardiac output, and cardiac arrest (137).

GOALS OF HEMODYNAMIC SUPPORT

The primary goal of sepsis resuscitation is to expedite
the correction of tissue hypoxia and oxygen debt to
prevent sequential organ dysfunction (9). Various end-

Management of Sepsis

points have been proposed to confirm the adequacy of

resuscitation, including normalization of values for
mixed venous oxygen saturation ( 70%), central
venous pressure ( 8 12 mm Hg), arterial lactate
concentration, base deficit, urine output and pH (9,16).
However, these global markers may fail to detect
tissue hypoxia in vital vascular beds. For instance,
central venous pressure and pulmonary artery occlusion pressure (PAOP) have been shown to be poor
indicators of intravascular volume status and preload
responsiveness (52). In addition, alterations in central
venous pressure and PAOP associated with changes in
circulating volumes do not correlate significantly with
changes in end diastolic volume and stroke volume
(140 142). This lack of correlation between pressure
and volume indexes of preload has been ascribed to
several causes, including, most prominently, variations in ventricular compliance specific to the patient
groups studied (143). During sepsis, mixed venous
oxygen saturation (SmvO2) and, by inference, central
venous oxygen saturation (ScvO2), have been postulated to be a surrogate marker for the adequacy of
oxygen delivery and an endpoint of resuscitation
(9,16). However, during sepsis, mixed venous oxygen
saturation has been shown to poorly correlate with
cardiac output and indices of tissue oxygenation due to
microcirculatory flow maldistribution and shunting
(22,56,144,145). When patients present with hypovolemia and normal or low cardiac output, mixed venous
oxygen saturation is frequently low and is likely to
increase with resuscitation. However, although a low
SmvO2 indicates inadequate oxygen delivery, a normal SmvO2 does not exclude a tissue oxygen debt,
especially in sepsis, possibly due to shunting (56,144).
The endpoint of the initial phase of resuscitation is
to achieve a mean arterial pressure of 70 to 80 mm Hg
as rapidly as possible. A decrease in the mean arterial
pressure to less than the renal autoregulatory range
(mean arterial pressure, 70 mm Hg) leads to an
abrupt decrease in glomerular filtration rate (GFR)
(146). Serial measurements of other indices of perfusion such as urine output and lactate levels may help
to identify patients with occult persistent shock. In
patients receiving vasopressor agents, sublingual capnography provides useful information as to the adequacy of splanchnic oxygen utilization and to assess
the adequacy of volume and pressor resuscitation
(21,144,145). Currently, there is insufficient evidence
for routine consideration of invasive hemodynamic
monitoring (pulmonary artery catheters and oximetric
central venous catheters) in patients with septic shock
(142,147150).

191

ANTI-INFECTIVE THERAPY
The importance of the early and accurate diagnosis of
suspected infection, to select initial empirical anti-microbial therapy and to achieve source control, cannot be
overemphasized (Figure 1). Sepsis remains the primary
diagnosis in over 50% of patients who die in the ICU
(4,151). Recent studies have clearly demonstrated that
delays in initiating appropriate anti-infective therapy for
bactremia and other serious infections is associated with
increased mortality rates (15,37,152156).
Most patients presenting with severe sepsis have a
pulmonary, genitourinary, primary blood stream, intraabdominal, or intravenous catheter as a source of infection, and two-thirds of patients with severe bacterial
sepsis have negative blood cultures (157159). To optimize identification of causative organisms, at least two
blood cultures (at least 20 mL) should be obtained with
at least one drawn percutaneously and one drawn
through each vascular access device, unless the device
was recently ( 48 h) inserted (152,160). Cultures of
other sites such as urine, cerebrospinal fluid, wounds,
respiratory secretions, or other body fluids should be
obtained before antibiotic therapy is initiated, as the
clinical situation dictates. For patients presenting with
severe sepsis and septic shock secondary to communityacquired pneumonia, who are mechanically ventilated,
ED-based bronchoalveolar lavage technique allows for
early identification of pathogens, which leads to changes
in antibiotic therapy (161). Non-bronchoscopic protected
bronchoalveolar lavage, when successfully done by the
emergency physician, offers the potential advantage of
evaluating patients who are antibiotic nave without negatively affecting their care.

ANTIMICROBIAL THERAPY
Antimicrobial therapy remains the cornerstone of treatment in patients with sepsis. Empiric intravenous antibiotic therapy should be started within the first hour of
recognition of severe sepsis, after appropriate cultures
have been obtained. Selection of antimicrobial therapy
for patients presenting with severe sepsis and septic
shock depends on a number of factors including the
source or focus of infection, whether the infection is
community- or hospital-acquired, knowledge of local
antimicrobial resistance patterns, presence of indwelling
catheters, and immunologic status of the patient. Initial
empirical anti-infective therapy should include one or
more drugs that have activity against the likely pathogens (bacterial or fungal) and that penetrate into the
presumed source of sepsis.

192

In recent years there has been a tremendous increase

in infections caused by Gram-positive organisms such as
methicillin-resistant Staphylococcus aureus (MRSA)
(162166). Methicillin resistance has an important impact on antimicrobial options due to the lost efficacy of
anti-staphylococcal penicillin and early generation cephalosporins (167). Increasingly, MRSA infections have
their origin in the general outpatient community, a trend
that is, in part, the result of prior antimicrobial exposure
(168 170). Vancomycin is generally the first-line antimicrobial therapy in these patients.
The initial selection of an empirical antimicrobial
regimen should be broad enough, covering all likely
pathogens because there is little margin for error in
critically ill patients. There is currently ample evidence
that failure to initiate appropriate therapy promptly (i.e.,
therapy that is active against the causative pathogen) has
adverse consequences on outcome (15,37). Patients with
severe sepsis or septic shock warrant broad-spectrum
therapy until the causative organism and its antibiotic
susceptibilities are defined.
Once a pathogen is isolated, monotherapy is adequate for most infections (171). Indications for double-antimicrobial therapy include suspected or proven
Pseudomonas aeruginosa infections, enterococcal infections, the treatment of febrile-neutropenic patients,
and severe intra-abdominal infections (172,173). In
patients with culture-negative sepsis, continuation of
the initial empiric combination is warranted. Additional antibiotics or a change in antibiotics may be
required in patients with culture-negative sepsis who
do not seem to be responding to the initial empiric
regimen. Dosing regimens should take into account
whether the antibiotic kills by time-dependent kinetics (e.g., -lactam antibiotics, vancomycin) or concentration-dependent kinetics (e.g., aminoglycoside)
(174,175). Recent data suggest that the clinical effectiveness of -lactam antibiotics and vancomycin is
optimal when the concentration of the antimicrobial
agent at the site of infection exceeds the minimum
inhibitory concentration of the infecting organism for
a prolonged period (176,177). In addition, antibiotic
dosing should also take into account the patients
hepatic and renal function. The antimicrobial regimen
should be reassessed after 48 72 h on the basis of
microbiological and clinical data with the aim of using
a narrow spectrum antibiotic to prevent the development of resistance, to reduce toxicity, and to reduce
costs. Once a causative pathogen is identified, there is
no evidence that combination therapy is more effective than monotherapy. The duration of therapy should
typically be 710 days and guided by clinical response
(16).

M. Raghavan and P. E. Marik

SOURCE CONTROL OF SEPSIS

Every patient presenting with severe sepsis should be
evaluated for the presence of a focus on infection amenable to source control measures. Specifically, this includes the drainage of an abscess or local focus on
infection, debridement of infected necrotic tissue, removal of a potentially infected device, or the definitive
control of a source of ongoing microbial contamination.
When a focus of infection amenable to source control
measures such as an intra-abdominal abscess, a gastrointestinal perforation, cholangitis, or intestinal ischemia
has been identified as the cause of severe sepsis or septic
shock, source control measures should be instituted as
soon as possible after initial resuscitation (16). If intravascular access devices are potentially the source of
severe sepsis or septic shock, they should be promptly
removed after establishing other vascular access. When
patients develop sepsis of unknown source, it may be
reasonable to leave vascular access devices in place until
the source of infection can be determined. However,
when patients have severe sepsis or septic shock of
unknown source, clinicians should consider removal and
replacement of vascular access devices to be a priority,
even if the device is tunneled or surgically implanted
(178).

CORTICOSTEROIDS
In patients with vasopressor-dependent septic shock,
there has been a great deal of interest regarding the
assessment of adrenal function and the indications for
adrenal replacement therapy (12,13,138,179,180). Although the exact incidence of adrenal insufficiency varies with the diagnostic test and cortisol level used to
diagnose the disorder, in one series approximately 61%
of critically ill septic shock patients had adrenal insufficiency when a baseline cortisol concentration of 25
g/dL was used as the diagnostic threshold (13). Therefore, any patient who presents with septic shock should
be considered for treatment with stress doses of corticosteroids (hydrocortisone, 100 mg i.v. q. 8 hourly) pending the results of diagnostic testing (random cortisol
level) (Figure 2). During septic shock, treatment with
stress-level doses of hydrocortisone has been demonstrated to improve hemodynamic status, down-regulate
the proinflammatory response, and improve mortality;
however, what currently remains controversial is the
diagnosis of this disorder (12,181186). In a highly
stressed patient with severe sepsis and septic shock, a
random cortisol level assesses the integrity of the entire
HPA axis (187). Dysfunction at the hypothalamic, pituitary, or adrenal level will result in low circulating cor-

Management of Sepsis

Figure 2. Strategy for evaluation of adrenocortical function

and treatment of patients with vasopressor-dependent severe sepsis and septic shock.

tisol levels ( 25 g/dL), and therefore a stress random

cortisol level of 25 g/dL in a patient with refractory
hypotension warrants a trial of low-dose glucocorticoids
(179).
Marik and Zaloga studied whether a baseline (random) cortisol concentration 25 g/dL was a better
discriminator of adrenal insufficiency than the standard
(250 g) and the low-dose (1 g) corticotropin stimulation tests, in 59 patients with septic shock (13). Following baseline cortisol level, patients were given 1 g of
corticotrophin (low dose), followed 60 min later by an
injection of 249 g of corticotropin (high-dose test).
Cortisol concentrations were obtained 30 and 60 min
after administration of low- and high-dose corticotropin.
All patients were administered hydrocortisone (100 mg
every 8 h) for the first 24 h while awaiting results of
cortisol assessment. Patients were considered steroid responsive if the pressor agent could be discontinued
within 24 h of the first dose of hydrocortisone. Sixty-one
percent of patients met the criteria of adrenal insufficiency when a baseline cortisol concentration of 25
g/dL was used. Ninety-five steroid-responsive patients
had a baseline cortisol concentration 25 g/dL. Receiver operating characteristic curve analysis revealed
that a stress cortisol concentration of 23.7 g/dL was the
most accurate diagnostic threshold for determination of
the hemodynamic response to glucocorticoid therapy.
The sensitivity of a baseline cortisol 25 g/dL in
predicting steroid responsiveness was 96%, compared
with 54% for the low-dose test and 22% for the high-

193

dose test. Therefore, a random cortisol concentration of

25 g/dL in a highly stressed patient is a very useful
diagnostic threshold for the diagnosis of adrenal insufficiency (13).
Annane and colleagues, in a placebo-controlled, randomized, double-blind, multicenter study, enrolled 300
adult patients with septic shock after undergoing a short
high-dose (250g) corticotropin test (138). Patients were
randomly assigned to receive either hydrocortisone (50
mg i.v. every 6 h) and fludrocortisone (50 g tablet once
daily) (n 151) or matching placebos (n 149) for 7
days. The mortality was 53% in the corticosteroid group
and 63% in the placebo group. Vasopressor therapy was
withdrawn in 40% of patients who received placebo and
in 57% in the corticosteroid group (hazard ratio, 1.91;
95% confidence interval [CI] 1.29 2.84; p 0.001). The
number of patients needed to treat to safe one additional
life at day 28 was 8.
From a practical point of view it is reasonable to
initiate treatment with low dose steroids in the ED or
ICU in any patient presenting with septic shock and
refractory hypotension pending the results of random
cortisol (Figures 1, 2) (16). Due to poor sensitivity of
low-dose and high-dose corticotrophin stimulation testing, these tests are not recommended in the severely
stressed vasopressor-dependant septic shock patient
(13,188 190). Glucocorticoids should be continued in
those patients with a stress cortisol level of 25 g/dL
and in those patients with a level 25 g/dL who have
demonstrated a hemodynamic response (lesser vasopressor requirement) to glucocorticoid replacement (13,188).
We believe this to be a useful (although not the only)
approach to the diagnosis of adrenal failure in the critically ill septic patient until more specific diagnostic tests
become available that can quantitate glucocorticoid activity at the cellular or nuclear level.

ACTIVATED PROTEIN C
Recombinant Human Activated Protein C (rhAPC) is the
first novel agent that has proved effective in the treatment of sepsis (11,191,192). Protein C is a vitamin
K-dependent blood factor that is synthesized in the liver
and secreted as a zymogen (193). Conversion of protein
C to its active form (APC) occurs when it complexes
with thrombin and endothelial cell thrombomodulin. Activated protein C is an endogenous anticoagulant that
inactivates factors Va and VIIIa, thereby preventing the
generation of thrombin and microvascular thrombi formation (11,194). While the anti-thrombotic and profibrinolytic activity of APC preserves and restores microcirculatory blood flow, the anti-inflammatory
property prevents tissue injury and organ dysfunction

194

(195,196). Other anti-inflammatory effects of APC include inhibition of TNF-, macrophage migration inhibitory factor, leukocyte adhesion to Selectins, limiting the
inflammatory response induced by thrombin within the
microvasculature, and decreasing nuclear factor B activation in target cells (197201).
Bernard et al., in a randomized multicenter, doubleblind trial (PROWESS), studied the efficacy of APC on
28-day all-cause mortality rate in patients with severe
sepsis (11). Patients were randomly assigned to receive a
continuous infusion of APC at 24 g/kg/h or placebo
intravenously for 96 h. Subjects were randomized within
24 h of onset of sepsis-related organ failure, such that the
maximum time window for receipt of study drug was
48 h. A total of 1690 randomized patients were treated
(840 in the placebo group and 850 in the APC group).
The mortality rate was 30.8% in the placebo group and
24.7% in the APC group. APC was associated with a
19.4% (95% CI 6.6 30.5) relative risk reduction and
6.1% absolute reduction in the risk of death (p 0.005).
The number of patients needed to treat to save one
additional life was 16. The incidence of serious bleeding
was higher in the APC group than in the placebo group
(3.5% vs. 2.0%, respectively, p 0.06). A post hoc
analysis revealed that the benefit was observed among
subjects who had APACHE II scores of 25 or more (a
13% absolute reduction), whereas the subjects with
lower risk showed no benefit from activated protein C.
Other subgroups in which APC was beneficial included
patients older than 50 years of age, patients with more
than one organ system dysfunction, and in patients who
had shock at the time of the infusion.
In a separate preliminary analysis of the subset of
patients with single organ dysfunction and recent surgery
from a separate, randomized, placebo-controlled study
(ADDRESS) of septic patients at lower risk of death
(APACHE II score 25 or single sepsis-induced organ
failure at any APACHE II score), all-cause mortality was
found to be higher in the APC group (28-day: 67/323;
in-hospital: 76/325) compared with the placebo group
(28-day: 44/313; in-hospital: 62/314). Therefore, APC
may be harmful in less ill patients with single organ
dysfunction alone (APACHE score 25) and cannot be
recommended.
Based on the PROWESS study, recombinant APC is
currently recommended in patients at high risk of death
(APACHE II 25, sepsis-induced multiple organ failure, septic shock, or sepsis-induced acute respiratory
distress syndrome [ARDS]) if there are no absolute contraindications related to bleeding risk or relative contraindication that outweigh the potential benefit of rhAPC
(Figure 1) (16). Based on the PROWESS study, some
authors have advocated the use of APACHE- II scores to
risk stratify patients for whom administration of APC

M. Raghavan and P. E. Marik

would be beneficial (202). However, this approach is

flawed for several reasons. First, APACHE score was
developed for use to include patients with homogenous
severity of illness in clinical trials, and not for decisions
in individual patients (203). Second, APACHE II as
obtained in the PROWESS trial was based on data obtained within the 24 h immediately before study randomization, not the first 24 h in the intensive care unit
(11,193). Third, the inter-observer and intra-observer
variability in the determination of APACHE II scores
among experienced intensive care physicians may be as
high as 10% to 20% (204,205). Fourth, it is unclear
whether or not patients should receive APC if their
APACHE II score falls from, say, 26 to 23 as they are
resuscitated with fluids and vasopressors, before the infusion of the drug has begun, and finally, the use of
APACHE II scores in this new manneras a screening
test to determine which patients should receive a new
therapy and which patients should not has not been
validated.
Currently, it is reasonable that a risk assessment is
best determined by bedside clinical evaluation and judgment. Given the uncertainty of risk assessment and the
potential for rapid deterioration of patients with severe
sepsis and septic shock, the decision to give APC to a
high-risk patient must be made early in the initial golden
hours of onset of sepsis, based on the number of failing
organs rather than scores (Figure 1, Table 1).

MULTIDISCIPLINARY SEPSIS TEAMS

Early recognition and treatment of severe sepsis poses a
considerable problem in the ED (29,51). As early recognition and aggressive resuscitation have been shown to
decrease mortality from septic shock, it would be optimal
to recognize the syndrome as soon as a patient presents
to the ED. Because this is often difficult for practical
purposes, several hospitals, like the University of Pittsburgh Medical Center in Pittsburgh, and Thomas Jefferson University Hospital in Philadelphia, Pennsylvania,
have implemented a multidisciplinary sepsis team for
screening and providing continuous early goal-directed therapy from the ED to the ICU for patients
presenting with sepsis. The team has a specific written
protocol for sepsis management. The team is also responsible for monitoring and improving physician and nurse
compliance with the protocol, as well as continuous
quality assessment, and follow-up of all patients receiving sepsis therapy. These teams currently perform several important tasks such as: (1) to quantify the number
of patients meeting entry criteria for early goal-directed
therapy; (2) to identify barriers to care, such as logistics,
communication, equipment, and disposition from the

Management of Sepsis

ED; (3) to provide a consistent level of response from the

team to the ED, 24 h a day, 7 days a week, including a
critical care medicine physician and extra nursing support; and (4) to facilitate prompt and quick physical
transfer of septic shock patients to the intensive care unit
from the ED, thereby decreasing waiting times.
CONCLUSION
Significant advances have been made in our understanding of sepsis in the last decade, with newer promising
therapies that decrease mortality. Nevertheless, early recognition of severe sepsis in the initial golden hours,
with intervention directed towards physiologic optimization, continues to be a problem in practice. Implementing
measures such as hospital-based sepsis teams, specific
written sepsis protocols, early stabilization and aggressive resuscitation in the emergency department with
early transfer to the ICU may aid in improved outcome
of these patients. In addition, future investigations should
consider timing of intervention and quality of life as a
consequence of delays in institution of antisepsis as an
important endpoint variable. T2
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