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E X PE RT O P I N I O N

Early interventions in severe sepsis and septic shock:
a review of the evidence one decade later
E. P. RIVERS 1, M. KATRANJI 2, K. A. JAEHNE 1, S. BROWN
G. ABOU DAGHER 1, C. CANNON 3, V. COBA 1

1

1Department

of Emergency Medicine and Surgery, Henry Ford Hospital, Wayne State University, Detroit, MI, USA;
of Medicine, Pulmonary and Critical Care Medicine, Pontiac Osteopathic Hospital, Pontiac, MI, USA;
3Department of Emergency Medicine, University of Kansas, Medical Center, Kansas City, KS, USA
2Department

ABSTRACT
The outcomes of acute myocardial infarction, trauma, and stroke have improved by implementing processes that
provide early diagnosis and aggressive interventions at the most proximal point of disease presentation. A common
feature in these conditions is the implementation of early intervention strategies. One decade ago, a similar approach
to sepsis began when a prospective randomized trial compared early goal-directed therapy (EGDT) to standard care
using specific criteria for the early identification of high risk patients with infection. The components of EGDT were
derived from expert consensus opinion to produce a protocol to reverse the hemodynamic perturbations of hypovolemia, vasodysregulation, myocardial suppression and increased metabolic demands for patients with severe sepsis in
the intensive care unit (ICU). However, EGDT was provided at the most proximal phase of disease presentation in the
Emergency Department (ED). With EGDT, a reduction in mortality of over 16% was shown over standard care. Since
the EGDT study was published a decade ago, significant emphasis worldwide has been placed on a comprehensive
approach to the first 6 hours of sepsis management which is commonly referred to as the resuscitation bundle (RB).
The RB consists of early diagnosis, risk stratification using lactate levels, hemodynamic response after a fluid challenge,
antibiotics, source control and hemodynamic optimization or EGDT. This review will examine one decade of evidence
for the components of the RB examining its impact on systemic inflammation, the progression of organ failure, health
care resource consumption and mortality in severe sepsis and septic shock. (Minerva Anestesiol 2012;78:712-24)
Key words: Sepsis - Shock, septic - Lactatic acid - Resuscitation.

S

epsis represents a continuum beginning with
a host-pathogen interaction that triggers a
complex interplay between pro-inflammatory,
anti-inflammatory and apoptotic mediators.1
As the disease progresses, organ dysfunction can
result from circulatory insufficiency from hypovolemia, myocardial depression, increased metabolic demands and vasoregulatory perfusion abnormalities. These hemodynamic perturbations
lead to an imbalance between systemic oxygen
supply and demand, leading to global tissue hypoxia and shock. These pathogenic events significantly contribute to the morbidity and mortality in early sepsis.2, 3

712

A critical decrease in systemic oxygen delivery
(DO2) is followed by an increase in the systemic
oxygen extraction ratio (O2ER) and a decrease
in central venous oxygen saturation (ScvO2) or
mixed venous oxygen saturation (SvO2). This increase in OER is a compensatory mechanism to
match systemic oxygen demands. When the limit of this compensatory mechanism (OER>50 to
60%) is reached, anaerobic metabolism ensures
leading to lactate production.4 In this critical delivery dependent or hypodynamic phase, lactate
concentrations are inversely related to DO2 and
ScvO2/SvO2 (Figure 1).5 This phase can occur
with normal vital signs and is commonly referred

MINERVA ANESTESIOLOGICA

June 2012

appropriate cultures. multiple studies have confirmed the risk stratification of this level for illness severity and mortality in both the prehospital and in-hospital setting. block.2. overlay. a hypotensive episode is associated with an increase risk for sudden and unexpected death. the animal and retrospective human literature MINERVA ANESTESIOLOGICA 713 . It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems. It is not permitted to frame or use framing techniques to enclose any trademark. No additional reproduction is authorized. Vol.12 The failure to increase OER and thus increase systemic oxygen consymption (VO2) may be secondary to impairment of microvascular oxygen perfusion or mitochondrial dysfunction. In regards to the success of the EGDT group. COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA Early interventions in severe sepsis and septic shock Figure 1. vasopressors). cover.14 This approach called early good-directed therapy (EGDT) was tested against standard care in a randomized control trial resulting in a mortality benefit of over 16%. 6.18 After Aduen et al. 6 RIVERS arterial oxygen content (packed red blood cells.13 These recommendations included the following: early identification of high risk patients. or other proprietary information of the Publisher. This was not a standard of care in emergency department (ED) throughout the United States at the time where baseline mortality was estimated to be over 50%. It is not permitted to make additional copies (either sporadically or systematically.8-11 After adequate resuscitation.—Oxygen delivery and consumption. This was followed by strategies aimed at early hemodynamic optimization of oxygen delivery guided by preload (central venous pressure or surrogate. Compensated sepsis is characterized by an elevated ScvO2/SvO2 and normal lactate. where the patient outwardly appears less ill.This document is protected by international copyright laws. to as “occult shock”. Wilson et al. 7 This state predominantly characterizes the early sepsis presentation (Figure 2) and is an important distinction from previous unsuccessful sepsis resuscitation trials performed in the ICU setting. and appropriate antibiotic administration. The use of all or any part of the Article for any Commercial Use is not permitted. a hyperdynamic phase follows the hypodynamic phase. or change any copyright notices or terms of use which the Publisher may post on the Article.19-23 Antibiotic therapy Once patients are identified.15 Over the last decade the various components of EGDT or the resuscitation bundle have been examined. fluids). afterload (mean arterial pressure. Later an elevated lactate and elevated ScvO2/SvO2 denote pathologic delivery dependence or delivery independence and is associated with increased mortality. either printed or electronic) of the Article for any purpose.5%) compared to the historical care mortality which was over 50%. oxygen). established the general prognostic value of a lactate of 4 mM/L on hospital admission. In the 2001 publication. As a result organ dysfunction and sudden cardiopulmonary collapse are complications associated with this phase if unrecognized or left untreated. electronic mailing or any other means which may allow access to the Article. It is not permitted to remove. Although it is intuitive. the control or standard care arm also received continuous central venous pressure (CVP).16. stroke and acute myocardial infarction. these components which were also recommended by a consensus of expert opinion 14 were applied at the most proximal site of hospital presentation mirroring the approach to trauma. In order to avoid the ethical issues (withholding life saving therapy). The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. wrote a series of expert opinions beginning in 1976 that comprised the tenets of early sepsis management (Figure 2). It is permitted for personal use to download and save only one file and print only one copy of this Article. Origin of the resuscitation bundle (RB) components The RB and its components are not novel strategies. 17 Early risk stratification using blood pressure and lactate levels EGDT begins with early identification of high risk patients based on hypotension (systolic blood pressure <90 mmHg) and a lactate level >4 mmol/L (Figure 2).24 While there are no prospective outcome trials to support early administration of antibiotics. arterial blood pressure and urine output monitoring. logo. validated and incorporated into evidence based guidelines. it must be emphasized that control group therapy also reduced mortality (46. source control and appropriate cultures should be obtained. obscure.No. source control. and contractility (inotropes) if ScvO2 remained low (Figure 2). 78 .

logo. cover.This document is protected by international copyright laws. No additional reproduction is authorized. The production of reprints for personal or commercial use is not permitted. It is not permitted to make additional copies (either sporadically or systematically. electronic mailing or any other means which may allow access to the Article. either printed or electronic) of the Article for any purpose. or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to remove. showed that early antibiotic MINERVA ANESTESIOLOGICA June 2012 . regarding the benefits of early and appropriate antibiotic administration is present in both animal and multiple human studies of sepsis. block.—The early goal directed therapy algorithm. The use of all or any part of the Article for any Commercial Use is not permitted.26. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems. or other proprietary information of the Publisher. The creation of derivative works from the Article is not permitted. COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA RIVERS 714 Early interventions in severe sepsis and septic shock Figure 2. obscure. 29 Hutchinson et al.25-28 The time period for the combination of antibi- otics and early hemodynamic optimization has been shown to be approximately 3-6 hours to archive the best outcomes in human studies. overlay. It is not permitted to frame or use framing techniques to enclose any trademark. It is permitted for personal use to download and save only one file and print only one copy of this Article.

the use of albumin is associated with lower mortality. but over 72 hours there were no differences in the amount of fluid between the two groups. block. However. electronic mailing or any other means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted.48 In a multicenter study.30 Central venous pressure and fluid therapy While some question the accuracy of CVP in assessing volume status. In the absence of diminished early volume therapy. The production of reprints for personal or commercial use is not permitted. These observations reveal that hypotension is more refractory to fluid administration at the Vol.33.37 Mean arterial pressure and vasopressor use The mean arterial blood pressure target in EGDT is supported by Varpula and Dunser et al. It is not permitted to remove. examined all of the sepsis bundle elements at 6 and 24 hours of sepsis and found that the attainment of an ScvO2 >70% had the statistically most significant impact on survival than all other bundle elements.14. It is not permitted to make additional copies (either sporadically or systematically. cover. 48 While there is a difference. COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA Early interventions in severe sepsis and septic shock administration was associated with a significantly reduced hospital length of stay and hospital costs. equivalent outcomes have been shown when compared to the pulmonary artery catheter for assessment of fluid status in acute lung injury. It is permitted for personal use to download and save only one file and print only one copy of this Article. and mechanical ventilation (increased oxygen demands). aggressive fluid therapy which is associated with improved outcomes must be distinguished from late aggressive fluid therapy. ScvO2 becomes a trigger for increasing inspired oxygen concentration (arterial hypoxia). Pope et al. inotrope therapy (myocardial suppression). it was shown that patients reaching this MINERVA ANESTESIOLOGICA 715 . therapeutic maneuvers to increase DO2 or decrease VO2 are required to normalize this number. 39-41 De Backer et al.31 CVP measurement is indicative of fluid responsiveness in the lower ranges and a CVP >10 is the upper limit for algorithms of fluid challenges.47. 38 They examined hemodynamic variables in septic shock patients during the first 24-48 h of treatment and found a MAP below 60-65 mmHg to be most predictive of 28-30-day mortality and organ function.3 One of the attributes of early volume therapy is a significant reduction in vasopressor therapy which further reduced need for vasopressin and corticosteroid therapy. Early.33 Ferrer et al.12 Castellanos-Ortega et al. logo. concluded a negative impact on survival when CVP was used as a guide to fluid management. 6 RIVERS later stage of disease presentation. there was an increase in the incidence of sudden hemodynamic deterioration and vasopressor use. either printed or electronic) of the Article for any purpose.43-46 Multiple studies have compared ScvO2 with SvO2 showing that there is an absolute difference (5%) between the two sites. In a meta-analysis.42 Central venous and tissue oxygen saturation Many of the salutary effects of ScvO2 monitoring are based on its ability to detect imbalances of DO2 to VO2 in the delivery dependent phase even with normal vitals signs.3.32 CVP has been shown to have a significant association with 30day mortality. It may be because of this that administration and duration of vasopressors also correlates with worse outcome. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems. showed that there was no significant difference in the rate of death between patients treated with dopamine as the first-line vasopressor agent and those who were treated with norepinephrine.49 In a meta-analysis examining five studies comprising over 11000 patients. an equal amount of fluid is used over the first 72 hours of hospitalization. 78 .No. No additional reproduction is authorized.This document is protected by international copyright laws. or change any copyright notices or terms of use which the Publisher may post on the Article. The creation of derivative works from the Article is not permitted.36 The administered volume in the EGDT group within the first 6 hours was significantly greater compared to standard therapy group. has shown that the delayed use of vasopressor therapy for cardiovascular support is incrementally associated with a significantly higher mortality than any other organ failure beyond the first 24 hours of sepsis. Levy et al.6 In the presence of a low value. found that the failure to reach a ScvO2 greater than 70% within the first six hours is associated with significantly increased (14%) mortality. the use of dopamine was associated with a greater number of adverse events.34 and Boyd et al. the clinical utility of both sites is comparable and validated by outcome studies. Thus.35 The use of CVP appears to be time sensitive. or other proprietary information of the Publisher. however. EGDT is associated with greater volume administration and diminished vasopressor use over first 6 hours of resuscitation. obscure. It is not permitted to frame or use framing techniques to enclose any trademark. red blood cell transfusion (decreased arterial oxygen content). overlay. It is preferable that this endpoint be met with fluid versus vasopressor therapy.

findings suggest that the sublingual microcirculation is globally unaltered by RBC transfusion in septic patients yet can improve in patients 716 with altered capillary perfusion at baseline. The use of all or any part of the Article for any Commercial Use is not permitted.51 Afessa et al. block. When this compensatory response is inadequate.5% is used as a trigger for transfusion.57 While there are many publications that incriminate RBC transfusions with worse outcome. COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA RIVERS Early interventions in severe sepsis and septic shock endpoint were twice as likely to survive than patients without reaching this endpoint. altered mental status and “the look of impending demise”. electronic mailing or any other means which may allow access to the Article.55 Hemoglobin threshold and red blood cell transfusion Anemia in early severe sepsis and septic shock results from a combination of pre-existing disease. It is permitted for personal use to download and save only one file and print only one copy of this Article. Colin et al. the work of breathing can be eliminated which consumes 20-40% of systemic oxygen delivery. 51 Further evidence exists showing that continuous ScvO2 monitoring is superior to intermittent monitoring.67%. StO2 appears to systematically overestimate lower ScvO2 values and underestimate at higher ScvO2 values.54 Thus. The creation of derivative works from the Article is not permitted.43 Because hemoglobin concentrations may vary in the central.45. It is not permitted to frame or use framing techniques to enclose any trademark. acute volume resuscitation. It is not permitted to remove. who found that mortality is optimized when an ScvO2 of 69.66 The outcome benefit may be related MINERVA ANESTESIOLOGICA June 2012 .This document is protected by international copyright laws.3% and in the 48 patients who met EGDT adherence requirements.53 Mesquida et al. or change any copyright notices or terms of use which the Publisher may post on the Article. the mortality rate was 16. In the 135 patients who did not meet EGDT adherence requirements.52 Tissue oxygenation (StO2) can be obtained using near-infrared spectroscopy using a probe applied to the thenar portion of the hand. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems. For instance. established that physical examination findings of inadequate circulation are not useful for predicting low cardiac index or ScvO2. logo. peripheral and microvascular circulations. or other proprietary information of the Publisher. before ScvO2 is available. performed a retrospective review of 183 sepsis episodes in patients with pre-existing echocardiograms (prior to the sepsis event) documenting systolic dysfunction.61 Shah et al.60 Grissom et al.9% greater frequency in the EGDT versus the control group in the original EGDT study and this incidence is consistent with previous findings by Parrillo et al. the physiologic rationale for transfusion of red blood cells (RBCs) during this delivery dependent physiology (increased lactate and low ScvO2) is warranted. Napoli showed that while a statistically significant relationship existed between StO2 and ScvO2. the oxygen carrying capacity and rheological characteristics of a specific region is unpredictable.44 Decreasing systemic oxygen consumption The indications for ventilatory support include hypoxia. impaired bone marrow response and a proposed decrease in the sensitivity of erythropoietin receptors. but this predictive value did not hold for StO2 values above 75%. This concept has been supported by Vallet et al.33. obscure. 62 Furthermore. a recent large observational study found that RBC transfusion was associated with decreased mortality rates. found masseter tissue oxygen saturation predictive of 28-day mortality.58 Further studies are needed to support the current recommendation for a hemoglobin of 10 mg/dL during septic shock. early administration of a neuromuscular blocking agent improves outcome and decreases duration of mechanical ventilation. A persistently low ScvO2 may signal cardiopulmonary decompensation and the need for ventilator support. It is not permitted to make additional copies (either sporadically or systematically. StO2 might be useful very early in resuscitation. the mortality rate was 36. P<0. cover.05.59 Myocardial dysfunction and inotrope therapy The early recognition of myocardial dysfunction requiring inotropic use was found to be at a 12. severe metabolic acidosis.50 ScvO2 remains significantly predictive of outcome 47 hours after the onset of acute lung injury and up to 48 hours in the ICU phase of sepsis. No additional reproduction is authorized. either printed or electronic) of the Article for any purpose.56 Anemia leads to a compensatory increase in systemic oxygen extraction to systemic oxygen needs. examined 962 patients using a propensity score for each bundle element and found that compliance with lactate measurement and inotrope administration was independently associated with decreased risk of mortality. In examining this variable in early resuscitation.63-65 In patients with severe adult respiratory distress syndrome. found that StO2 values below 75% predicted low ScvO2 values with high specificity. hypercarbia. overlay. The production of reprints for personal or commercial use is not permitted.

SvO2 is more sensitive at detecting impending tissue hypoxia than lactate. and ScvO2 of 70% while patients in the lactate clearance group were resuscitated to normalize central venous pressure. More importantly. MINERVA ANESTESIOLOGICA 717 . logo.5% in the control group versus 33. Hospital mortality was significantly reduced from 43. Targeting CVP.This document is protected by international copyright laws. It is permitted for personal use to download and save only one file and print only one copy of this Article. In the control group. mean arterial pressure. there were no significant differences in lactate clearance between treatment groups.9% in the lactate group. the treatment team had no knowledge of lactate levels (except for the admission value). employed a modified EGDT protocol in a medical ICU without the use of ScvO2 compared to a control group. The creation of derivative works from the Article is not permitted. 78 . randomly allocated patients with an elevated lactate (>3 mm/L) to decrease lactate by 20% or more per two hours for the initial eight hours in the lactate group. It is not permitted to frame or use framing techniques to enclose any trademark. the mortality reduction was further enhanced when retrospectively grouped by improving levels of lactate clearance. cover. Nguyen et al. there was a decrease in organ failure. Jansen et al. an issue not addressed by Jones et al. this study could not exclude the possibility that this had an impact on the observed outcome difference. showed that when patients received EGDT.72-74 These observations indicate that using lactate and ScvO2 are complimentary endpoints and not mutually exclusive. more frequently in vasodilatory shock (vasopressor dependent) and less mechanically ventilated. It is not permitted to make additional copies (either sporadically or systematically.4 Therefore. The production of reprints for personal or commercial use is not permitted. mechanical ventilation from 7-72 hours and ICU length of stay. inotropes and mechanical ventilation which are physiologically triggered by ScvO2. No additional reproduction is authorized. patients assigned to the ScvO2 group were resuscitated to normalize central venous pressure. This might actually argue against lactate as a target of hemodynamic therapy. 6 RIVERS ScvO2) where the production of lactate exceeds its clearance and the serum lactate levels begin to rise. and achieve a lactate clearance of at least 10%. The study protocol was continued until all goals were achieved or for up to six hours. in a more supply independent phase at baseline (ScvO2 and lower lactate levels at study baseline). or other proprietary information of the Publisher. It is not permitted to remove.69 In this study. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems. The disturbances of lactate metabolism that occur during sepsis are probably more complex than an isolated defect of cellular oxygenation. obscure. Compared to the EGDT study. or change any copyright notices or terms of use which the Publisher may post on the Article.47.No. only 30 interventions were made in only 10% of the patient population. Twenty to 50% of septic shock patients will never elevate lactate levels at presentation or during the clinical course and frequently develop multi-system organ failure. However. COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA Early interventions in severe sepsis and septic shock to early restoration of the balance between DO2 and VO2. found that the clearance of lactate over the first six hours after presentation was associated with a significant decrease in pro. were of a lower illness severity. Modified versions of the resuscitation bundle Lin et al.42. The use of all or any part of the Article for any Commercial Use is not permitted. Continuous ScvO2 monitoring provides a real time assessment. electronic mailing or any other means which may allow access to the Article. They concluded that lactate clearance guided resuscitation was non-inferior or equivalent to a ScvO2 guided resuscitation based on no difference in mortality. overlay. the patients enrolled by Jones et al. Figure 1. The lactate group received more fluids and vasodilators. packed red blood cells. It is these patients (delivery dependent or hypodynamic phase) that require additional interventions such as supplemental oxygen.70 The lactate group treatment did not result in faster reduction of lactate when compared with control group therapy.71 Further a normal lactate in isolation does not exclude the presence of tissue hypoperfusion. mean arterial pressure.68 Jones et al.67 In a recent prospective multicenter trial of EGDT implementation. either printed or electronic) of the Article for any purpose. 52 In an ICU based study. These events signal reaching the critical OER (low Vol. block.and anti-inflammatory biomarkers. Lactate clearance Nguyen et al. However. 43 This was based on previous investigations using lactate clearance over 24 and 72 hours in the ICU setting. These interventions reduce sudden cardiopulmonary complications by 50%. duration of inotrope therapy. improved organ function and reduced mortality. In the lactate group. more efficient attainment of resuscitation endpoints and greater mortality benefit than intermittent sampling. declared that lactate clearance is equivalent to ScvO2 using the EGDT algorithm in a noninferiority study. given that ScvO2 monitoring was mandatory in the lactate group and facultative in the control group.

—Comparison of sepsis intervention studies using the resuscitation bundle compared to the original EGDT study. Impact on inflammation. hemoglobin and urine output. COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA RIVERS Early interventions in severe sepsis and septic shock Table I. overlay.75 In a further analysis of EGDT patients. the external validity and generalizability of the RB containing varying versions of EGDT has been established in multiple studies.76 The observation of a 15% reduction in mechanical ventilation over 72 hours is an example of preventing this second hit. the microcirculation and organ failure The association between global tissue hypoxia and inflammation has been well described in vivo models. 49.0% 6. The creation of derivative works from the Article is not permitted. There was more rapid reversal of shock and less delayed vasopressor administration.5% 0.77 Therapeutic efforts targeting the microcirculation are in progress but to date having not shown outcome benefit. The production of reprints for personal or commercial use is not permitted. 41. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems. alteration of the inflammatory cascade is evidenced by significantly lower IL-8 levels. 80-128 Summary of implementation study Number of patients APACHE II score Sex.2 57.45 0.4% greater creatinine level rise per hour (P=0.37 18.8 67. ventilator support duration.4 64. and tissue hypoperfusion associated major organ dysfunction. Rivers also showed that the persistence of global tissue hypoxia (increased lactate and low ScvO2) correlates significantly with the activity of inflammatory mediators. 41.03) in patients admitted from the hospital ward. duration of mechanical ventilator support and duration of antibiotic administration.1 (12)% 133 20. It is not permitted to remove. In patients treated with EGDT. No additional reproduction is authorized. ICU stay.84 46.5% 130 21. When untreated. or change any copyright notices or terms of use which the Publisher may post on the Article. or other proprietary information of the Publisher. block.34 16.51 These findings support the observations of a decreased need for mechanical ventilation over the first 72 hours of presentation in the original EGDT trial. Outcome evidence in adult patients Over the last decade.4 50.79 In a subanalysis of patients enrolled in the Fluid and Catheter Treatment Trial (FACTT) of the National Institutes of Health. an improved SvO2 was significantly associated with improved mortality and decrease in duration of mechanical ventilation.3% 5. obscure. but also to shortening the length of ICU stay. It is not permitted to make additional copies (either sporadically or systematically. These studies comprise over 50 publications containing over 18000 adult patients (Table I).4 46.4 50. found that a delay in achieving hemodynamic goals of EGDT was significantly associated with the development of acute kidney injury (P=0. The authors added that with ScvO2 measurement there was a chance of improving clinical outcomes further.15 63.02) and resulted in a 3. cover. Before or control After Control EGDT 9527 24. 49.9 29. this modified therapeutic protocol provides an alternative that reduces mortality.73 Adjunctive therapies to further modulate the inflammatory response when used early may enhance the beneficial effects of EGDT.25 *Includes before and after and concurrent implementation studies. NNT=number needed to treat.24 58.This document is protected by international copyright laws. 80-128 The outcome benefit of these studies combined equal or exceed the reduction in mortality found in the original MINERVA ANESTESIOLOGICA June 2012 .1 30. logo. either printed or electronic) of the Article for any purpose. this pathogenic mechanism of inflammation can lead to a “second hit” phenomenon of multi-organ failure and worsening 718 inflammation. It is permitted for personal use to download and save only one file and print only one copy of this Article. **The average mortality of each study.8.8. MAP. It is not permitted to frame or use framing techniques to enclose any trademark.78 Kiers et al. 68.3 62. % Males Age (years) Mortality before (SD)** Relative risk reduction Absolute risk reduction NNT Rivers et al. Acute Respiratory Distress Syndrome Network. Boulos et al. not only led to a significant decrease of the mortality rate.8 (26)% 9884 24. 68. For medical ICUs without facility to monitor ScvO2. have shown that SvO2 is significantly associated with mitochondrial function and that inflammatory mediators in septic patients can significantly alter mitochondrial function. The use of all or any part of the Article for any Commercial Use is not permitted. electronic mailing or any other means which may allow access to the Article.

Peer reviewed evidence based guidelines currently exist for the management of sepsis in the pediatric patient. medical and surgical patients. 132 A recent study in children showed that fluid boluses significantly increased 48-hour mortality in critically ill children with impaired perfusion in these resource-limited settings in Africa. However. either printed or electronic) of the Article for any purpose.129-131 These outcomes results have been observed in community and tertiary care hospitals.136 It is important to note that therapies confirmed in adults are not necessarily translated to pediatric patients.No.141 Importance of timing Does the effectiveness of the RB attenuate over time? Coba et al. The compliers at 18 h had an absolute 10. even these compliance rates will not improve and will decrease over time. Decreases mortality (16-18%) Decreases the progression of organ failure –– Decreases the progression of acute kidney injury –– Decreases need for mechanical ventilation Modulates the early inflammatory response Decreases health care costs (20%) –– Decreased duration of mechanical ventilation –– Decreased hospital length of stay Is effective up to 18 hours after disease onset (in the ED and ICU) Decreases sudden cardiopulmonary complications Is effective in community and tertiary care hospitals Diagnostic components (associated with increased mortality): –– Lactate > 4 mm/L –– Systolic blood pressure <90 mmHg Components (associated with improved outcomes): –– Antibiotics within 1 to 3 hours –– CVP >8 mmHg –– MAP >65 mmHg –– Hematocrit >30% –– ScvO2 >70% –– Threshold for red blood cell transfusion –– Need for inotropic therapy –– Indication for and response to mechanical ventilation –– Is not equivalent to lactate clearance MINERVA ANESTESIOLOGICA 719 . 135 The difference between these studies may be multifactorial including the etiology of the infection which was primarily malaria not bacterial. It is not permitted to make additional copies (either sporadically or systematically.138 EGDT has been shown to decrease hospital related costs consistently by 20%. The production of reprints for personal or commercial use is not permitted. 6 RIVERS plying with the goals of EGDT on patient outcomes when completed beyond the six-hour recommendation period. Compliance was assessed at 6. It has been stated that the original EGDT study enrolled patients of higher illness severity than that observed in other studies. cover.142 Multiple studies have shown that standardized order sets. logo.87 Without a continuous quality initiative (CQI). 78 . baseline APACHE II scores and mortality rate of these previous adult studies are similar to the original EGDT study. obscure. Table II.137 Health care resource consumption The associated cost for sepsis in the United States approaches over $ 50 billion per year or 2.98 Studies that are in the process of examining the components of EGDT can be found at www. or change any copyright notices or terms of use which the Publisher may post on the Article. ED and ICU settings.01). overlay. the mortality reduction remains significant. COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA Early interventions in severe sepsis and septic shock trial. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems.134.5% of the health care expenditure. The creation of derivative works from the Article is not permitted.133 These findings are a departure from previous trials finding that aggressive fluid therapy and EGDT improves mortality in pediatric sepsis.8% versus 9. 47. block.gov. This study uniquely shows that when bundle completion is extended to 18 hours.1% vs.139. No additional reproduction is authorized.129. enhanced bedside monitor display. It is permitted for personal use to download and save only one file and print only one copy of this Article. the compliers at 18 h had a greater reduction in predicted mortality of 26. 18 and 24 hours after diagnosis of severe sepsis or septic shock.2% significantly lower in-hospital mortality compared to the non-compliers at 18 h (37. the mean age. electronic mailing or any other means which may allow access to the Article. 140 The cost savings are largely driven by a significant decrease in hospital length of stay by five days per patient. examined the impact of com- Vol. Similar findings were noted by Castellanos-Ortega et al. Outcome evidence in pediatric patients EGDT has shown to be beneficial in a prospective randomized pediatric trial.This document is protected by international copyright laws. It is not permitted to remove.4% (P<0. or other proprietary information of the Publisher. The use of all or any part of the Article for any Commercial Use is not permitted. It is not permitted to frame or use framing techniques to enclose any trademark.clinicaltrials. making it the most expensive disease treated in hospital since 1997.3%).—Early goal directed therapy.119 Challenges of implementation Significant reductions in mortality have been shown even with suboptimal compliance rates approaching 51%. When adjusted for differences in baseline illness severity.

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Practice parameters for hemodynamic support of sepsis in adult patients in sepsis. Dellinger RP. Improving severe sepsis outcomes: cost and time to first antibiotic dose. It is not permitted to frame or use framing techniques to enclose any trademark.37:1670-7. or change any copyright notices or terms of use which the Publisher may post on the Article. Simmons DH. Jaeschke R et al. Society of Critical Care Medicine. Association between timing of antibiotic administration and mortality from septic shock in patients treated with a quantitative resuscitation protocol. Intensive Care Med 1998.   26.345:1368-77. Rackow EC. Gaieski DF. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock.136:1237-48. Early changes in organ function predict eventual survival in severe sepsis. Dellamonica P. De Backer D. Crit Care Med 1999. Massone R. Resuscitation of the critically ill in the ED: responses of blood pressure. Trzaskoma B et al. 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Kumar A. Estenssoro E. Vice Chairman and Research Director. MPH. Conflicts of interest. The costs and cost-effectiveness of an integrated sepsis treatment protocol. 144. It is not permitted to frame or use framing techniques to enclose any trademark. Dr. stock or research support associated with the EGDT study.Accepted for publication on March 21. obscure. JAMA 2008. 270-Clara Ford Pavilion. Novack V. Astra Zeneca. Esai Pharmaceuticals Idaho Technologies. Shock on admission day is the best predictor of prolonged mechanical ventilation in the ICU.34:187-99. 2011 . 145. Aggennix and Alere Corporation. he has been a onetime consultant for Aggennix. electronic mailing or any other means which may allow access to the Article. Shapiro N. Massimo and Sangard. Light B. Corresponding author: E. overlay.37:21736. 2799 West Grand Boulevard. Bracht H. COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA RIVERS Early interventions in severe sepsis and septic shock 140. Georgieff M. Parrillo JE et al. Talmor D. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. Canales H. 146. E-mail: erivers1@hfhs. Dr. either printed or electronic) of the Article for any purpose. It is not permitted to make additional copies (either sporadically or systematically. The use of all or any part of the Article for any Commercial Use is not permitted. Clinical Professor. 2012. Stahl W. Henry Ford Hospital. Howell MD.299:2294-303. Radermacher P. Laffaire E. It is not permitted to remove. USA. Chest 2005. Loyola S. Rivers. block. Crit Care Med 2008.This document is protected by international copyright laws. Cannon has received consulting fees from Eisai Pharmaceuticals. Crit Care Nurs Q 2011. An innovative approach to meeting early goal-directed therapy using telemedicine. P. Improving outcome in severe sepsis and septic shock: results of a prospective multicenter collaborative.127:598-603. Wayne State University. Central venous oxygen saturation and emergency intubation--another piece in the puzzle? Crit Care 2009. et al. et al. MD. Greenberg D. J Emerg Med 2009. 141.minervamedica. No additional reproduction is authorized. Reina R et al. Department of Emergency Medicine. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems. Lisbon A. Ferrer RMD. Levy MMMDF. In the past four years.it 724 MINERVA ANESTESIOLOGICA June 2012 . 142. Detroit. Chest 2009.org This article is freely available at www. Rivers E.13:172. Senior Staff Attending in Surgical Critical Care and Emergency Medicine. Ellis P. Roberts D. The creation of derivative works from the Article is not permitted. Fornos J. logo. Cannon C. 143. Wilhelm J. Holthaus C. Gonzalez F. Received on May 3. Rivers receives research support from the National Institute of Health. Rivers has never personally owned any patents or Early Interventions in Severe Sepsis and Septic Shock: The Evidence One Decade Later received royalties. Initiation of inappropriate antimicrobial therapy results in a 5-fold reduction of survival in human septic shock.—None related to this publication. MI 48202. or other proprietary information of the Publisher. Artigas AMDP.136:1237-48. Arabi Y. cover. Dr.36:1168-74. Sáenz G. The production of reprints for personal or commercial use is not permitted. or change any copyright notices or terms of use which the Publisher may post on the Article.