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doi:10.1016/j.ccc.2008.04.002 criticalcare.theclinics.com
S2 RIVERS & AHRENS
Understanding
6-Hour Quality and
Epidemiology the Care Teams
Bundle Costs
Pathogenesis
Early
Recognizing Timely Definitive Realizing
Staging of
One Has a Interventions Care: Improved
Illness
Problem? Upon Arrival ED or ICU? Outcomes
Severity
a
Diagnostic criteria for sepsis in the pediatric population are signs and symp-
toms of inflammation plus infection with hyper- or hypothermia (rectal tempera-
ture >38.5 or <35 C), tachycardia (may be absent in hypothermic patients), and
at least one of the following indications of altered organ dysfunction: altered
mental status, hypoxemia, increased serum lactate level, bounding pulses.
Data from Refs. [5], [16].
Antibiotic therapy
Infection source control
Fluid therapy
Vasopressors
Inotropic therapy
Corticosteroids
Recombinant human activated protein C (rhAPC)
Blood product administration
Supportive therapy topics include [6]:
Mechanical ventilation of sepsis-induced acute lung injury (ALI)/acute
respiratory distress syndrome (ARDS)
Sedation, analgesia, and neuromuscular blockade in sepsis
Glucose control
Renal replacement
Bicarbonate therapy
Deep vein thrombosis prophylaxis
Stress ulcer prophylaxis
Selective digestive tract decontamination
Consideration for limitation of support
From Townsend S, Dellinger RP, Levy MM, et al, editors. Implementing the
Surviving Sepsis Campaign. Des Plaines, Brussels, and Land O Lakes: Society
of Critical Care Medicine, European Society of Intensive Care, and International
Sepsis Forum; 2005; with permission.
Fig. 2. Components of EGDT. Abbreviations: EGDT, early goal-directed therapy; CVP, cen-
tral venous pressure; MAP, mean arterial pressure; ScvO2, central venous oxygen saturation.
(From 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;345:1368–77; with permission.)
Fig. 3. Delayed initiation of antimicrobial therapy increases mortality. Bars represent 95% CI.
(From 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):1589–96; with permission.)
S12 RIVERS & AHRENS
Predisposition
A list of risk factors for the development of sepsis is included in Box 4
[12]. Epidemiologic data have provided some insight regarding patients
who are more likely to develop sepsis. An analysis of NHDS data from
1995 to 2000 indicated that the average patient with sepsis is elderly (60.8
plus or minus 13.7 years old) [3]. NHDS data from 1979 to 2000 revealed
From Picard KM, O’Donoghue SC, Young-Kershaw DA, et al. Development and
implementation of a multidisciplinary sepsis protocol. Crit Care Nurse 2006;
26(3):43–54; with permission.
SEPSIS RECOGNITION AND TREATMENT PROTOCOLS S13
that men are more likely than women to develop sepsis and that sepsis
development is more likely for blacks and other nonwhite patients than
for white patients [3].
Several comorbid conditions are also associated with poorer outcomes
for patients with sepsis. Cancer, cirrhosis, congestive heart failure, and
HIV infection have been associated with increased risk of sepsis progression
and/or death [17,29]. The risk of death is twice as great for sepsis patients
with cancer as for those without and is comparable to the risk observed
in sepsis patients who have HIV infection [29]. Awareness of risk factors
can aid clinicians in identifying patients at higher risk for progressing to se-
vere sepsis.
Response
Physiologic indicators of sepsis, severe sepsis, and septic shock (see
Box 2) reflect a patient’s reaction to infection and a systemic inflammatory
response. An international study of data from Europe, Canada, and Israel
confirmed increased risk of progression from sepsis to severe sepsis or septic
S14 RIVERS & AHRENS
Organ dysfunction
Signs. Severe sepsis is defined as sepsis accompanied by organ dysfunction,
hypoperfusion, or hypotension (see Box 2) [15]. As noted at the beginning of
this resource, epidemiologic data indicate that the percentage of sepsis
patients who have organ dysfunction is increasing [3]. As new support tech-
nologies have become available to sustain critically ill patients, progressive
organ failure, rather than underlying illness, has emerged as a major threat
to survival [15]. It is important to recognize that [15]:
Organ dysfunction occurs on a progressive continuum.
Recognition of early organ abnormalities can facilitate treatment at
earlier stages of MODS.
SEPSIS RECOGNITION AND TREATMENT PROTOCOLS S15
Cardiovascular
Tachycardia
Hypotension
Altered central venous pressure (CVP)
Altered pulmonary artery occlusive pressure (PAOP)
Abnormal cardiac index
Renal
Oliguria
Anuria
Increased creatinine
Hepatic/gastrointestinal (GI)
Hyperbilirubinemia
Increased enzymes
Decreased albumin
Increased prothrombin time (PT)
Ileus
Hematologic
Thrombocytopenia
Coagulation abnormalities
Hypoperfusion
Increased serum lactate levels
Decreased capillary refill
Skin mottling
Table 1
Common scoring systems for patients with severe sepsis or septic shock
Scoring System Description
ICU scoring systems
Acute Physiology and Chronic Developed as mortality prediction tool
Health Evaluation (APACHE) II Consists of variables including
Online calculators: temperature, MAP, heart rate,
http://www.icumedicus.com/icu_scores/apache.php respiratory rate, oxygenation, arterial pH,
http://www.sfar.org/scores2/apache22.html serum sodium, serum potassium, serum
creatinine, hematocrit, white blood
count, GCS, age, chronic health
APACHE IV is recommended except
for sepsis patients, in whom
APACHE II is more appropriate
APACHE II score R25 indicates
rhAPC administration is appropriate
Simplified Acute Physiology Score (SAPS) II Introduced in 1994
Online calculators: Includes variables similar to APACHE
http://www.icumedicus.com/icu_scores/saps.php
http://www.sfar.org/scores2/saps2.html
Sequential Organ Failure Assessment (SOFA) Developed to describe severity
Online calculators: of organ dysfunction
http://www.icumedicus.com/icu_scores/sofa.php Includes questions regarding
http://www.sfar.org/scores2/sofa2.html cardiovascular, neurologic, renal, liver,
respiratory, and coagulation function
Multiple Organ Dysfunction Score (MODS) Developed to describe severity
Online calculators: of organ dysfunction
http://www.icumedicus.com/icu_scores/mods.php Includes questions regarding
http://www.sfar.org/scores2/mods2.html cardiovascular, neurologic, renal, liver,
respiratory, and coagulation function
ED scoring systems
Mortality in Emergency Department Identifies ED patients at risk for infection
Sepsis Score (MEDS) One of first systems to examine course
of sepsis beginning in the ED
Rapid Acute Physiology Score (RAPS) Abbreviated APACHE II system
Predicts mortality before, during,
and after critical care transport
Rapid Emergency Medicine Score (REMS) RAPS plus age and peripheral oxygen
saturation data
Predictive value better that RAPS,
similar to APACHE II
Abbreviations: ED, emergency department; GCS, Glasgow Coma Score; MAP, mean
arterial pressure; rhAPC, recombinant human activated protein C. (Data from Refs. [26],
[36], [42], [105–107].)
Several methods are available to assess blood flow and tissue oxygena-
tion. They are summarized in Tables 2 and 3 [27,47]. Blood flow measure-
ments often have been neglected because of difficulties associated with the
use of available technologies [48]. Newer, less-invasive techniques, such as
external and esophageal Doppler and thoracic bioimpedance, increasingly
are employed by clinicians [30,48]. Acceptance in particular clinical settings
likely will depend on ease and speed of use, expense, and accuracy [30]. For
example, Doppler techniques are minimally invasive, inexpensive, rapid, and
accurate, but their use requires highly experienced operators in the ED
[30,49]. Thoracic bioimpedance is a technology that is less operator-depen-
dent and may be appropriate in an ED setting, but it is subject to patient
physical limitations [49]. Given the ultimate goal of adequate tissue oxygen-
ation, blood flow measurements should be coupled with measurements of
tissue oxygenation [30].
Measurements that are in common use to assess tissue oxygenation are
SvO2, ScvO2, and lactate [30]. All three are global, indirect measures of tis-
sue oxygenation that require venous access [30,47]. Decreased SvO2 and
ScvO2 values reflect increased oxygen extraction by tissues experiencing
oxygen deficit in early sepsis [30]. Increased lactate levels signal increased
anaerobic metabolism in the face of insufficient oxygen to meet tissue needs
[30]. For all three indices (SvO2, ScvO2, and lactate), trends provide a more
complete picture of tissue oxygenation status than single measurements [30].
SvO2 and ScvO2 are measured by means of pulmonary artery catheters
(PACs) and right-atrial central venous catheters (CVCs), respectively, pro-
viding indications of global oxygenation rather than local tissue-level
Table 2
Techniques for measuring blood flow
Arterial/venous Cost !$25 Suitable for
Technique access required? per patient? all patients?
External Doppler No Yes Yes
Esophageal Doppler No No No, the patient
must be sedated.
Thoracic No Yes No, the patient must have
bioimpedance normal anatomy and
access to the neck.
Exhaled CO2 No No No, the patient must be
Fick method on a ventilator.
Pulse contour Yes No No, the patient must have
at least an arterial line
in place.
Pulmonary Yes No No, the patient must have
artery catheter a central line in place.
From Ahrens T. Hemodynamics in sepsis. AACN Adv Crit Care 2006;17(4):435–45; with
permission.
S20
Table 3
Techniques for measuring tissue oxygenation
Measure Method Variables Global/regional Invasive/noninvasive
Established techniques
Systemic oxygenation PAC VO2/DO2/ERO2 Global Invasive
Mixed venous O2 saturation PAC–blood gas analyses SvO2 Global Invasive
Antimicrobial therapy
The importance of timely antimicrobial treatment has been mentioned
(see Fig. 3) [24,25]. Delaying empiric antibiotic treatment to await culture
results has negative consequences [6,25]. Clinicians should be aware that
blood cultures will be negative in more than 50% of severe sepsis/septic
shock cases [6]. Furthermore, restricting use of antibiotics to limit develop-
ment of resistance or reduce cost is not appropriate in this patient popula-
tion. Broad-spectrum therapy is warranted until information (causative
agent, antibiotic susceptibilities) is available for therapeutic adjustment [6].
Selection of an appropriate antimicrobial agent, often in the absence of
microbiologic confirmation, requires consideration of patient-related char-
acteristics such as drug intolerances, recently used antibiotics, previous
infections, underlying disease, and clinical syndrome [6]. Awareness of the
prevalence of infections caused by specific organisms can provide clinicians
with insight into appropriate empiric antimicrobial therapy. Pathogen resis-
tance patterns in the hospital and community, along with hospital protocols
to limit antibiotic resistance, also should be considered [6]. The SSC guide-
lines recommend that clinicians consider the setting-specific prevalence of
oxacillin (methicillin)-resistant Staphylococcus aureus (ORSA or MRSA)
and the possibility of candidemia when selecting an initial antibiotic therapy
[6]. Clinicians also should be cognizant of general microbial trends. Based
on epidemiologic data from 1979 to 2000, gram-positive bacteria have
become the most common cause of infection in patients who have sepsis
(52%), followed by gram-negative bacteria (38%), polymicrobial infections
(5%), and fungal infections (5%) [3]. Gram-positive bacteria replaced gram-
negative as the most common causative organism in 1988, and sepsis caused
by fungal infections increased 207% from 1979 to 2000 [3]. Furthermore,
S22 RIVERS & AHRENS
Biomarkers
Studies have been performed to identify biomarkers for use in the early
identification of patients at risk of developing severe sepsis and septic shock.
Kinasewitz and colleagues [51] identified 13 biomarkers that correlated with
initial sepsis severity: d-dimer, interleukin (IL)-6, protein C, antithrombin
(AT), activated partial thromboplastin time (APTT), prothrombin time
(PT), protein S, plasminogen activator inhibitor (PAI), thrombin-activat-
able fibrinolysis inhibitor (TAFI), soluble thrombomodulin (sTM), IL-10,
IL-8, and tumor necrosis factor (TNF)-a. None of these factors, however,
were predictive of outcome. The authors speculated that this null finding
was because of the large variability in levels between patients.
Contrary to the observation of Kinasewitz, other studies have identified
a relationship between protein C levels and sepsis or therapeutic outcome
[52,53]. At this time, a predictive correlation between protein C levels and
sepsis outcome has been demonstrated [54,55]. Procalcitonin (PCT) also
has been identified as a biomarker for progression to severe sepsis and septic
shock. As with protein C, data have not demonstrated consistently that PCT
is a sensitive and specific indicator of sepsis. Results of recent meta-analyses
indicate that PCT may be a poor, moderate, or good diagnostic marker for
sepsis [56–58]. Many recent studies, however, have documented the benefits
of PCT measurements for sepsis evaluation in critically ill patients and in
guiding antimicrobial therapy [59–65]. US Food and Drug Administration
(FDA)-approved PCT assays are commercially available [66].
Despite identification of correlations between some biomarkers and sep-
sis outcome, commentary from the 2001 SCCM/ESICM/ACCP/ATS/SIS
International Sepsis Definitions Conference suggests that further investiga-
tion is required before biomarkers can be used for staging sepsis [16]. Epide-
miologic studies of biomarkers were deemed to be essential, as was the need
to assess the specific roles of biomarkers in different aspects of sepsis (eg,
coagulopathy and adrenal dysfunction) [16]. The current SSC guidelines
do not include information regarding the use of biomarkers, aside from
a comment indicating that they are not useful for diagnosing infection [6].
Currently, information suggests that biomarkers may be useful in identify-
ing patients at risk for developing severe sepsis or septic shock, but guide-
lines for clinical application are not available.
SEPSIS RECOGNITION AND TREATMENT PROTOCOLS S23
Genetic predisposition
A recent editorial illuminated the current status of research to identify
genetic polymorphisms predisposing individuals to poor or good outcomes fol-
lowing severe sepsis or septic shock. The author cited a list of studies exploring
the association between gene polymorphisms and sepsis outcome or suscepti-
bility. Overall, the studies yielded contradictory results, negative results, or re-
sults that have not been confirmed in experiments demonstrating causality [67].
Genes considered in these studies included TNF-a, TNF-b, IL-10, IL-8, and
CXCR2 [67]. In addition, a recent article by Jessen and colleagues [68] revealed
no association between commonly described single nucleotide polymorphisms
of TNF-a, IL-1b, plasminogen activator-1, urokinase plasminogen activator,
CD14, and toll-like receptor 4. These publications indicate that the develop-
ment of genetic screens to determine sepsis predisposition is at an early stage.
Scoring systems
Alternative scoring systems have been proposed to better predict the risk of
sepsis progression and potential response to therapy [16,17]. The PIRO system
for staging sepsis stratifies patients according to predisposing conditions, nature
and extent of infection, nature and magnitude of host response, and degree of
organ dysfunction [16]. The system remains in the early stages of development.
In contrast, Alberti and colleagues [17] have performed multivariate anal-
ysis of sepsis progression risk factors, developed a weighted grading tool
based on the relative risk contributions of the components, and chara-
cterized the tool’s performance in a set of 1531 patients. The risk factors
included in the model are [17]:
Bilirubin greater than 30 mmol/L
Heart rate greater than 120 beats/min
Sodium greater than 145 mmol/L
Platelets less than 150 109/L
SBP less than 110 mm Hg
Temperature greater than 38.2 C
Mechanical ventilation
Pneumonia
Peritonitis
Gram-positive cocci
Aerobic gram-negative bacilli
Primary bacteremia
This scoring system is unique in its consideration of progression risk as an
endpoint.
Fig. 4. Sepsis protocol implementation reduces mortality risk. (Data from Refs. [10,23,81–92].)
Among the studies included in Fig. 4, several assessed protocols that were
developed based on the SSC care bundles. The reported outcome improve-
ments were similar to those reported for all of the protocol implementation
studies. Nguyen and colleagues [88] observed hospital mortality rates of
21% for patients who received all treatments specified in the bundles and
40% for those who did not (P%.01). Gao and colleagues [83] also identified
increased hospital mortality in patients who did not receive all sepsis bundle
treatments. The SSC recommends that the sepsis care bundles form the basis
for institution-specific sepsis protocols [5]. These studies reinforce this rec-
ommendation and demonstrate the care bundles’ value in clinical settings.
Fig. 5. Example: Surviving Sepsis Campaign and Institute for Healthcare Improvement evalua-
tion for severe sepsis screening tool. (Courtesy of the Surviving Sepsis Campaign and the Institute
for Healthcare Improvement; with permission. Available at: http://www.survivingsepsis.org/files/
Tools/evaluationforseveresepsisscreeningtool.pdf.)
SEPSIS RECOGNITION AND TREATMENT PROTOCOLS S31
Fig. 6. Example: Surviving Sepsis Campaign sepsis care bundle badge cards. (Courtesy of the
Surviving Sepsis Campaign; with permission.)
The SSC and IHI also provide means to overcome barriers by facilitating
information exchange between institutions and providing a venue for shar-
ing personal experiences regarding severe sepsis quality improvement
efforts. A newsletter (Campaign Update) and update sessions at partner
society congresses provide information regarding SSC progress, including
successes and approaches of participating institutions. Information regard-
ing educational opportunities such as symposia and other presentations is
S32 RIVERS & AHRENS
Fig. 7. Example: severe sepsis protocol for admission and antibiotic therapy.
Summary
Because sepsis-related mortality is unacceptably high, the SSC has set
a quality improvement goal to reduce mortality caused by severe sepsis
and septic shock by 25% by 2009. Clearer definitions of sepsis, severe sep-
sis, and septic shock will help in achieving this goal, as will recently
updated evidence-based management guidelines for severe sepsis and septic
shock. To be effective, these definitions and guidelines need to be applied
to the early identification and aggressive treatment of patients who have
severe sepsis or septic shock. Early goal-directed therapy to achieve hemo-
dynamic stabilization has been demonstrated to decrease mortality in
patients who have septic shock. Currently, clinicians must rely on clues
to sepsis progression in the patient’s medical history, vital signs, hemody-
namic monitoring, lactate levels, and indications of organ dysfunctiondall
in the context of infectiondto identify patients who have severe sepsis.
Of these, hemodynamic monitoring, lactate levels, and indications of organ
dysfunction may be most useful in indicating the patient’s stage of sepsis.
In the future, less-invasive measures of hemodynamics and blood flow,
molecular techniques for identifying infectious agents, refined scoring sys-
tems, biomarkers, and genetic screening may aid clinicians in identifying
patients who have severe sepsis. Once a patient who has severe sepsis
has been identified, timely implementation of guideline recommendations
should follow. Resources and tools are available through the SSC and
IHI to facilitate the efficient translation of the SSC guideline recommenda-
tions into clinical practice.
SEPSIS RECOGNITION AND TREATMENT PROTOCOLS S35
The intensivist arrives 2 hours after the request for consultation (4 hours
after presentation). The patient’s temperature and respiratory rate have in-
creased. His heart rate also has increased, although it is still within normal
limits. BP is also in normal range but has decreased from presentation.
S36 RIVERS & AHRENS
The intensivist confirms that the patient is severely septic. The patient is
admitted to the ICU, but transfer takes 3 hours because of bed and resource
limitations.
Discussion
In a setting with a protocol for the management of severe sepsis and
septic shock, including education regarding early recognition, the triage
clinician in the ED ideally would have recognized that the presence of an in-
fected wound, systemic inflammatory response (ie, elevated respiratory rate,
fever), and organ dysfunction (ie, sluggishness indicating altered mental
status) as signs that the patient likely had severe sepsis at presentation in
SEPSIS RECOGNITION AND TREATMENT PROTOCOLS S37
the ED. These findings would trigger immediate actions that could affect the
course of this case positively, including lactate measurement, appropriate
cultures, initial fluid bolus, and EGDT. In addition, a surgical consultation
should have been requested to determine appropriate source control mea-
sures. In this case, amputation of the foot may have been appropriate. Sebat
and colleagues [10] demonstrated that protocol implementation can decrease
the time to reach treatment goals. Times were decreased significantly pre-
versus postprotocol for intensivist arrival (2:00 versus 0:50), ICU/operating
room admission (2:47 versus 1:30), fluid administration (3:52 versus 1:45),
and PAC placement (3:50 versus 2:10). A significant decrease in mortality
caused by septic shock also was achieved following protocol adoption;
mortality rates were 40.7% before and 28.2% after protocol implementation
(P ¼ .035) [10].
Given improvements similar to those described by Sebat and colleagues,
the course of the case might evolve as follows in a setting where protocols
for managing severe sepsis and septic shock have been implemented.
Staff designated for management of severe sepsis and septic shock are
alerted and arrive in the ED.
Blood and wound cultures are collected before initiation of antibiotic
therapy.
CVC with ScvO2 monitoring capability is placed.
Serum lactate level is determined.
IV antibiotic appropriate for diabetic foot wound (ampicillin plus
sulbactam) is initiated.
IV fluid resuscitation is started and guided by CVP monitoring.
S38 RIVERS & AHRENS
Case study 2
Elderly postoperative patient
A 70-year-old woman is hospitalized, recovering following bowel resec-
tion for colon cancer. She also receives medication for hypertension and
hypercholesterolemia. Initially, the patient was doing well and was friendly
and talkative with the postoperative staff. Approximately 48 hours after sur-
gery, her mental status changed, and she began to alternate between agitated
and listless states. Vital signs at that time indicate decreased BP and elevated
heart rate, respiratory rate, and temperature.
After 3 hours, the patient’s MAP and ScvO2 remain depressed, and her
respiratory rate and lactate levels remain elevated. After resuscitation to
achieve CVP of 8 to 12 mm Hg, the patient receives 5 mg/min norepineph-
rine in addition to fluid therapy, is transferred to a dedicated sepsis bed in
the ICU, and is placed on mechanical ventilation for ALI. At this point,
the patient’s APACHE II score is determined to be 23.
Discussion
The patient’s condition continued to deteriorate even with good adher-
ence to a protocol for the management of septic shock. At 24 hours after
ICU admission, multiple organ dysfunction and an APACHE II score of
at least 25 indicate a high risk of death. An appropriate action in continuing
aggressive treatment and after addressing the surgical issues for this patient
would be rhAPC administration.
Case study 3
Female college student presents to emergency department with suspected
urinary tract infection and fatigue
A 20-year-old female college student presents in the ED with severe pain
on urination and marked sluggishness since the previous day. She thinks she
has a urinary tract infection (UTI) that started developing a few days earlier.
She says she feels much more tired than usual and is having trouble waking
up and concentrating on anything, but that may be because she has been
staying up late to study for examinations. She takes a daily vitamin. Tylenol,
aspirin, and over-the-counter antihistamines and decongestants are used as
needed.
The patient fulfills several criteria for sepsis: suspected infection, fever,
elevated heart rate, change in mental status (ie, lethargy). Based on this as-
sessment, the ED clinician feels that activation of a sepsis alert is warranted.
Consistent with the sepsis management protocol, he obtains cultures for se-
rum lactate and microbiology.
All cultures are obtained and sent for testing (if appropriate) within
30 minutes. The patient’s lactate level is 4.2 mmol/L. The ED clinician
orders appropriate empirical antibiotics and EGDT. An appropriate antibi-
otic is administered. The patient’s vital signs are essentially unchanged from
presentation, however. A CT scan of the abdomen is ordered.
Members of the sepsis team arrive 1 hour after presentation and confirm
a diagnosis of severe sepsis, probably secondary to the UTI. The patient is
transferred to the ICU, and the transfer is completed within 1 hour (3 hours
after presentation).
SEPSIS RECOGNITION AND TREATMENT PROTOCOLS S41
The patient’s temperature, heart rate, and BP remain the same, but her
MAP, CVP, and ScvO2 are low. Fluid therapy is initiated.
One hour after fluid therapy initiation, MAP and CVP are at target resus-
citation levels, but the patient’s heart rate remains elevated, and her ScvO2
has not reached target level (70%). Fluid resuscitation is continued, and
inotropic therapy is started.
out a surgical cause of the UTI such as a stone. Following observation, the
patient is discharged with an antibiotic prescription.
Discussion
Despite the patient’s insistence that she had a UTI and was just tired be-
cause of schoolwork, the attending ED clinician did not overlook the signs
suggesting severe sepsis (ie, infection, fever, potential organ dysfunction
[elevated heart rate, recent onset of severe fatigue]) and performed a serum
lactate screen. This confirmed the suspicion that the patient should be
entered into the severe sepsis protocol. Following EGDT initiation, the
patient’s condition improved quickly.
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