Did you arrive here by via search engine?
Click here to view the original version of this article

Click to Print This Page
(This section will not print)

Rapid Risk Stratification of Septic Adults in Non-Intensive Care Unit Settings
Jeffrey P. Green, M.D.

Dr. Green is Clinical Research Fellow, Department of Emergency Medicine, University of California, Davis School of Medicine, Sacramento, CA.

Within the past 12 months, Dr. Green reports no commercial conflict of interest.

Albert Einstein College of Medicine, CCME staff, and interMDnet staff have nothing to disclose.

Release Date: 02/20/2012
Termination Date: 02/20/2015

Estimated time to complete: 1 hour(s).

Albert Einstein College of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Albert Einstein College of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
Learning Objectives
Upon completion of this Cyberounds®, you should be able to:
  • Describe severe sepsis and discuss the importance of rapid and accurate risk stratification and apply it to the care of patients
  • Discuss currently available clinical risk stratification tools for rapid risk stratification of severe sepsis in non-intensive care unit settings
  • Describe the physiology of lactate metabolism and its implications for use in sepsis risk stratification
  • Supplement clinical risk stratification of severe sepsis by application of inflammatory biomarkers.


Severe sepsis is a common, deadly condition, usually caused by an infection (highly suspected or confirmed), which provokes a systemic inflammatory response.(1)(2) The inflammatory response is most commonly defined as the presence of two or more Systemic Inflammatory Response Syndrome (SIRS) Criteria (Table 1). The SIRS criteria are intentionally non-specific so that a large proportion of infected patients can be classified as septic. However, this broad inclusion limits the usefulness of a diagnosis of sepsis in distinguishing a high-risk patient population.

Table 1. Systemic Inflammatory Response Criteria.


<36° C or >38° C

Heart Rate

≥90 beats/minute

Respiratory Rate

≥20 breaths per minute or PaCO2 <32 mm Hg

White Blood Cell Count

>12,000 or <4,000 cells/mm3 or >10% bands

Severe sepsis is the leading cause of in-hospital mortality in the U.S.


Not surprisingly, the SIRS criteria do not predict mortality risk in adults with suspected infection.(1) Severe sepsis, which implies sepsis with objective evidence of end-organ dysfunction, carries a significant short-term mortality risk. Each year in the United States there are approximately 750,000 cases of severe sepsis, resulting in 215,000 deaths.(3) Severe sepsis is the leading cause of in-hospital mortality in the U.S., with an estimated in-hospital mortality risk between 25 and 30%.(3) In the U.S. alone, more than 500,000 adult patients present annually to hospitals with evidence of sepsis and organ dysfunction.(4) Additionally, the volume of patients presenting to hospitals with the sepsis syndrome appears to be increasing, placing an ever-growing burden on clinical providers to rapidly identify and risk stratify these patients.(5)

Recently, novel therapies have shown demonstrable efficacy in the treatment of severe sepsis. However, the benefit of these interventions appears to diminish with any delay in time to initiation, making early risk stratification essential. Early Goal Directed Therapy (EGDT) is a resuscitative protocol that reduces mortality in patients with cardiovascular or metabolic organ dysfunction.(6)(7)(8) Studies also demonstrate an apparent association between any delay in the administration of effective antibiotics and increased mortality risk for patients with severe sepsis.(9)

Why Risk Stratification Is Needed

Accurate risk stratification of severe sepsis is essential for efficient allocation of limited healthcare resources. More than 50% of patients with severe sepsis receive some portion of their care in an intensive care unit (ICU) setting, representing the most common cause of non-surgical ICU admissions in the United States.(3) ICU level care would be impossible to provide for all the patients who present annually to U.S. hospitals with severe sepsis. The burden of treating severe sepsis has contributed to the overcrowding of ICUs nationally and added to the more than $16 billion annual cost of caring for this syndrome in the United States.(3) Furthermore, the majority of cases of severe sepsis are initially identified either in the emergency department (ED) or general medical and surgical wards. Efforts to improve risk stratification of sepsis must acknowledge this reality, and develop instruments that can be utilized in these settings.

As the United States population grays, the incidence of severe sepsis will inevitably increase. Accurate risk assessment techniques could focus limited healthcare resources on high-acuity (i.e., seriously ill) patients most likely to benefit and decrease the performance of invasive procedures on low-risk patients. The purpose of this Cyberounds® review is to describe currently available techniques for rapid clinical risk stratification of severe sepsis in non-ICU settings, available biomarkers to supplement clinical risk assessment tools and the underlying physiology of these biomarkers.

Organ Dysfunction

Organ dysfunction can be defined using varying criteria based on objective clinical evidence. Previously developed definitions for organ dysfunction are less efficacious in rapid risk stratification, particularly in non-ICU settings, due to their requirement for extensive and serial testing. Shapiro et al. formulated a system for defining organ dysfunction that can be rapidly calculated and identifies a subset of septic patients at increased short-term mortality risk (Table 2).(1)

Table 2. Organ Failure Definitions From Routinely Available Clinical Variables.


Platelet count <100 k/mm3


Respiratory rate >20, oxygen saturation <90% or <94% with supplemental oxygen or mechanical ventilation


A new finding of altered mental status


Creatinine >2.0 mg/dl without prior chronic renal disease


Anion gap >16 mEq/L or lactate ≥4.0 mmol/L*


Persistent hypotension (SBP< 90 mm Hg) after an isotonic fluid bolus or need for vasopressors to support pressure*

Patients with severe sepsis range from those with multi-system organ failure, including hemodynamic instability, to those with only mild derangements of individual organ systems. Though a portion of patients with severe sepsis have evidence of significant organ dysfunction and hemodynamic compromise on initial presentation, a large percentage of severe sepsis patients initially demonstrate only mild end-organ derangements. Most initially stable patients will have an uncomplicated clinical course with traditional therapies such as appropriate antibiotics, non-optimized fluid administration and source control. However, a portion of these patients will experience clinical worsening and hemodynamic compromise in spite of traditional therapy.(10)

Clinical Risk Stratification Tools

The earliest evidence-based tools for risk stratification of septic patients were developed in the intensive care setting. The Acute Physiology and Chronic Health Evaluation (APACHE), APACHE II, APACHE III, Simplified Acute Physiology Score, Sepsis-Related Organ Failure Assessment, and Mortality Probability Model are all validated for risk assessment of septic patients in the intensive care setting.(11)(12)(13) However, these models are quite comprehensive and rely on variables not typically available early in patient presentation. Furthermore, ICU-developed prognostic tools have generally demonstrated insufficient accuracy when applied to more heterogeneous populations.(14)

The Mortality in Emergency Department Sepsis (MEDS) score is an internally and externally validated clinical decision rule for adult emergency department patients with a suspected infection.(15)(16)(17) This risk stratification tool was specifically developed for rapid risk stratification based on routinely available clinical and laboratory variables, making it useful for early risk assessment in heterogeneous populations (Table 3).

Table 3. Mortality in Emergency Department Sepsis Score.(15)

Clinical Variable Points
Rapidly terminal co-morbid illness


Age >65 years


Bands >5%


Tachypnea or hypoxia




Platelet count <150,000 cells/mm3


Altered mental status


Nursing home resident


Lower respiratory infection


Importantly, the original MEDS cohort was created from patients admitted to the hospital who had a blood culture in the ED.(15) These patients were at relatively low risk of in-hospital mortality (5.3%) compared to the 25-30% in-hospital mortality risk of severe sepsis.(3) Not surprisingly, in validation studies the MEDS score demonstrated poor test characteristics for mortality risk in patients with severe sepsis.(18)(19) At the time of the MEDS score derivation, which was developed from an observational cohort, lactate was not commonly used for risk stratification. However, lactate levels are known to correlate with mortality risk and are an inclusion criterion for EGDT.(6)(20)(21) If MEDS scores were combined with lactate levels or other objective markers of illness severity, we would have a more accurate risk stratification tool for high-risk patients — but this tool has not been developed to date.

REMS and CURB-65
Other risk assessment tools can be rapidly calculated. The Rapid Emergency Medicine (REMS) score, which is a modification of the APACHE II score, correlates with mortality risk in non-surgical ED patients admitted for a suspected infection.(17) The Confusion Urea Nitrogen Respiratory Rate Blood Pressure Age over 65 (CURB-65) scores were developed and validated for risk stratification of patients with community acquired pneumonia. Both the REMS and CURB-65 scoring systems are efficacious for risk stratifying adult patients with a suspected infection.(17) Neither of these scoring systems has been evaluated in a higher risk population of severe sepsis.

The Sequential Organ Failure Assessment (SOFA) score may be useful in adult patients with severe sepsis. The SOFA score quantifies the degree of organ dysfunction in ICU patients and was designed for rapid, serial use. The SOFA score predicts prognosis and response to therapy of critically ill patients. Jones et al. recently demonstrated a moderate to good utility for an initial SOFA score in risk stratifying ED patients who were EGDT candidates.(10) For this study, the SOFA scoring system was slightly modified to use SaO2 (oxygen saturation) when PaO2 was not available (Table 4). These two variables correlate well and the modification did not impact the accuracy of the scoring system. Otherwise, the SOFA score was rapidly and accurately obtainable in potentially septic adult patients.

Table 4. Modified Sequential Organ Failure Assessment Score.(10)

SOFA Score 1 2 3 4
Bilirubin (mg/dL)





PaO2/FiO2 (mm Hg)

< 400

< 300

< 200

< 100





< 67

Platelets x 103/mm3

< 150

< 100

< 50

< 20

Glascow Coma Score





Creatinine (mg/dL)





or urine output (mL/d)




MAP <70

Dopamine ≤5
or dobutamine

Dopamine >5
or norepinephrine

Dopamine >15
or norepinephrine

MAP, mean arterial pressure; CNS, central nervous system; SaO2, peripheral arterial oxygen saturation. Use PaO2 preferentially. Vasoactive medications administered for at least 1 hour (dopamine and norepinephrine μcg/kg/min).

PIRO demonstrates a significant ability to risk stratify sepsis using available clinical variables.

In the Jones study, the initial SOFA score evidenced moderate ability to predict mortality in EGDT candidates [AUC 0.75 (95%CI 0.68-0.83)], but measuring SOFA scores serially over time improved its prognostic accuracy. Though the SOFA score accuracy was only moderate on initial measurement, the relative simplicity of measurement and the value added benefit of serial measurement makes it a valuable tool for risk stratification of severe sepsis. Again, addition of biomarkers known to correlate with illness severity may make the SOFA score more accurate, but assessments of this combination have not been performed. It should be noted that in the Jones study only patients who were EGDT candidates (demonstrated cardiovascular or metabolic dysfunction) were included. Validation of a single measurement of the SOFA score in patients with organ dysfunction of other systems in non-ICU settings has not been performed.

For patients with suspected sepsis, we now have the Predisposition, Infection, Response, Organ (PIRO) Dysfunction Staging System.(22) PIRO attempts to separate the several dimensions of the presentation and inflammatory response of the sepsis syndrome. In both ICU and ED patient populations, this staging system has demonstrated a moderate to good ability to risk stratify sepsis.(23) Though developed as a platform needing further modification with additional validated predictors of patient outcomes, PIRO demonstrates a significant ability to risk stratify sepsis using routinely and rapidly available clinical variables.

Table 5. Predisposition, Infection, Response, Organ dysfunction (PIRO) Staging System.(22)

Predisposition (points) Infection (points) Response (points) Organ Dysfunction (points)
Skin / Soft Tissue Infection


Respiratory Rate >20


BUN >20


No metastasis


Other Infection


Bands >5%


Respiratory Failure / Hypoxemia


With metastasis




Heart Rate >120 bpm


Lactate >4.0 mmol/L




Systolic Blood Pressure
Liver Disease


<70 mm Hg


Nursing Home Residence


70-90 mm Hg


Age (years)
>90 mm Hg




Platelet Count <150,000 / mm3




> 80


COPD - chronic obstructive pulmonary disease; BUN - blood urea nitrogen.

These scoring systems thoughtfully combine predictive factors of patient comorbidities, infectious source, evidence of inflammatory response, and markers of organ dysfunction to determine the overall clinical risk for the patient. Furthermore, the PIRO staging system has demonstrated utility in high-risk septic patients with presenting evidence of organ dysfunction, an area where other rapid risk stratification tools have shown limited benefit.(24) Validation of this finding is warranted, but the PIRO staging system may be clinically valuable for the risk stratification of severe sepsis, particularly in non-ICU settings where clinical variable assessment is limited.

Lactate levels have an established association with mortality in septic patients.

Lactate Levels for Risk Stratification of Severe Sepsis

Lactate levels have an established association with mortality in septic patients, and hyperlactatemia is used as an enrollment criterion in EGDT.(6)(20)(21) The association of lactate levels with mortality risk is independent of dysfunction of other organs.(25) Traditionally, arterial lactate levels were preferred for risk stratification, but multiple studies demonstrated that venous lactate levels correlate with mortality risk.(20)(21) Due to the impracticality and potential complication risk of routine arterial puncture of low-risk patients, current guidelines recommend use of serum lactate levels for mortality risk stratification and enrollment in EGDT.(26)

Reserving measurement of lactate levels for those patients with an abnormal anion gap has also fallen out of favor. Evidence exists that anion gap measurement has only moderate test characteristics for prediction of abnormal lactate levels (anion gap >12 mEq/L: sensitivity 80%, LR+ 2.5 to detect lactate ≥4.0 mmol/L).(27) And, given the significant emphasis on timing for severe sepsis treatment, the implicit delay of waiting for serum chemistry results prior to lactate testing should be avoided. There is evidence that lactate levels have a stronger association with mortality risk when associated with concurrent acidosis, but current guidelines recommend aggressive resuscitation for hyperlactatemic patients regardless of blood pH.(28)

Measurement of serial lactate levels appears to increase the accuracy for mortality risk assessment compared to single lactate testing. Patients presenting with severe sepsis have a ~10% lower mortality risk if a 6-hour repeat lactate level is more than 10% below the initial lactate level. Similarly, patients whose lactate level increases by more than 10% over 6 hours have a ~10% higher mortality risk.(29) For this reason, lactate clearance has been incorporated into an alternative protocol for EGDT that replaces Central Venous Oxygen Saturation (SCVO2) measurement with serial lactate measurement.(30) This non-inferiority study found similar results for patients resuscitated using a lactate clearance approach. The same investigators also demonstrated that patients with poor lactate clearance had increased mortality risk even if they had a normal SCVO2, suggesting that the risk associated with poor lactate clearance in sepsis may not be related to decreased oxygen perfusion.(31)

Hyperlactatemia of sepsis may be caused...by increased circulating catecholamine levels.

Hyperlactatemia in sepsis is classically believed to be caused by end-organ hypoperfusion, which leads to anaerobic glycolysis and lactate accumulation.(32) However, recent evidence demonstrates that lactate accumulation associated with systemic infection may not be related to tissue hypoxia.(33)(34) Instead, the hyperlactatemia of sepsis may be caused, at least partially, by increased circulating catecholamine levels. The inflammatory response to a systemic infection results in increased serum levels of epinephrine and other catecholamines, with a subsequent increase in activity of the sodium-potassium ATPase pump (Figure 1).(33)(35) This increased energy requirement overwhelms the ability of mitochondrial oxidative metabolism to produce ATP.(36) Aerobic glycolysis in the cytosol provides the required ATP for the sodium-potassium pump, but leads to increased lactate levels.(36)(37)

Figure 1. Epinephrine Stimulates Lactate Production By Increasing Na+/K+-ATPase Activity With ATP Provided By Aerobic Glycolysis.

Click image for larger view.

The lactate resulting from this process may be useful as a serum energy transporter during the hypermetabolic state of severe sepsis and may be a component of the compensatory response to systemic inflammation, rather than a byproduct of end-organ hypoperfusion.(38)(39)

Lactate accumulation secondary to elevated catecholamine levels appears to be associated with a significant mortality risk. Levy et al. recently demonstrated, in a cohort of non-shock, non-hyperlactatemic ICU patients with presumed sepsis, that plasma catecholamine levels have a significant association with the development of septic shock and mortality risk (AUC 0.94 ± 0.05).(40) Additionally, patients in this study had intramuscular dialysis catheters placed to measure muscle lactate levels. There is evidence that lactate production in sepsis predominantly originates in muscle tissue.(41)

The Levy study demonstrated that patients with elevated catecholamine levels also had an increased gradient of intramuscular-to-plasma lactate and elevated lactate gradients had a significant correlation with mortality (AUC 0.96 ± 0.03). Apparently, these patients were producing sub-clinical levels of lactate, presumably secondary to increased catecholamine levels, causing hyperlactatemia, septic shock and a high mortality rate.

Prolonged catecholamine elevation has been associated with an increased mortality risk in sepsis in other studies.(42)(43)(44) Catecholamine elevation leads to cardiac, hepatic and metabolic dysfunction and is believed to effect the immunomodulatory response to sepsis. Studies of experimental sepsis have demonstrated that direct inhibitors of sympathetic activity, and thus catecholamine production, decrease mortality risk.(45)(46) Catecholamine levels also strongly correlate with lactate levels in sepsis.(47) Given these findings, one may hypothesize that in some cases the association of lactate levels with mortality in sepsis may simply be a result of lactate’s strong association with catecholamine levels. Hyperlactatemia secondary to systemic inflammation should be accompanied by a concomitant elevation of inflammatory biomarkers.

In certain cases, patients with hyperlactatemia have concurrent evidence of poor perfusion. For these patients, lactate levels and mortality risk seem to decrease significantly with rapid, goal-directed resuscitation.(30) In studies of lactate clearance, however, a significant proportion of patients with initial hyperlactatemia did not have improved outcomes or decreases in lactate levels with aggressive volumetric expansion. If non-fluid responsive lactate accumulation in sepsis is a result of increased catecholamine levels, and the catecholamine surge is caused by the inflammatory response to infection, then inflammatory biomarkers should also be elevated in these patients. This group of patients would likely not respond to fluid resuscitation and have a significant short-term mortality risk.

The overall accuracy of lactate levels for mortality in sepsis is only moderate, and patients with severe sepsis and normal lactate levels may continue to have significant mortality risk. This may reflect the potential of multiple physiologic processes contributing to lactate formation in sepsis. If additional inflammatory biomarkers could be measured to distinguish lactate production in a hypermetabolic state from lactate produced due to lack of perfusion, perhaps the association of lactate with mortality risk could be better distinguished. Several inflammatory biomarkers have been investigated for rapid risk stratification in sepsis with varying degrees of established utility.

Interleukin 6
Interleukin-6 (IL-6) is a pleiotropic cytokine produced by both lymphoid and nonlymphoid cells and helps regulate the acute-phase inflammatory response. IL-6 is rapidly induced during acute inflammatory reactions, reaching peak activity levels within two hours of endotoxin injection.(48) Plasma IL-6 levels are strongly correlated with mortality risk in abdominal sepsis and to a lesser extent in generalized sepsis.(49)(50) Persistent IL-6 elevations over time, however, appear to be more predictive of mortality risk than initial measurements, somewhat limiting IL-6’s utility in rapid risk stratification. IL-6 levels are not routinely assayable in most clinical laboratories, such that practical applicability is limited at this time. Future studies demonstrating that IL-6 can distinguish high and low-risk sepsis, as well as the underlying etiologic pathogen, may lead to more widespread use.

Procalcitonin is a 116–amino acid prohormone of calcitonin. Under normal conditions, this prohormone is produced by C cells of the thyroid gland, cleaved by proteolytic enzymes into calcitonin and secreted into the circulation. During periods of systemic inflammation, such as sepsis, procalcitonin is produced and secreted by extra-thyroidal tissue. Procalcitonin is believed to have a biological role as a mediator of the inflammatory cascade of sepsis and may directly influence the negative effects of the inflammatory cascade.(51) Procalcitonin levels have been demonstrated to correlate with the presence of infection.(52)(53)(54) A recent meta-analysis demonstrated that procalcitonin levels have a global odds ratio of 15.4 for distinguishing infection with abnormal SIRS criteria from non-infected abnormal SIRS (AUC 0.78).(55) The correlation between procalcitonin and infection is so accurate that procalcitonin is considered to be efficacious for antibiotic stewardship (PRORATA trial).(56) In this randomized controlled trial, providers appropriately stopped antibiotics earlier when they had knowledge of the procalcitonin levels as opposed to when they did not know these levels.

Procalcitonin levels are also known to be more elevated in septic patients when they have concurrent evidence of organ dysfunction.(57) Furthermore, severity of illness scores seem to correlate with procalcitonin levels, though the degree of correlation has varied in different trials.(58)(59)(60)(61) Procalcitonin generally outperforms other inflammatory biomarkers, including C-reactive protein, in predicting the presence and severity of infection.(62)(63)

Though the majority of these studies were performed in ICU populations, evidence exists that procalcitonin levels correlate with the presence and severity of infection in heterogeneous adult patient populations.(62)(64)(65)(66)(67) Procalcitonin levels have been shown to be useful for mortality risk stratification of septic patients both in the ICU and ED.(68)(69)(70) Procalcitonin levels predict mortality risk in septic shock.(70)(71) Further research is needed to determine which populations would benefit from routine procalcitonin testing and the specific associated mortality risk, but clearly procalcitonin demonstrates promise as an adjunct to clinical risk stratification tools.

Combining Inflammatory Biomarkers With Lactate Levels for Mortality Risk Stratification

There is evidence that using inflammatory biomarkers for mortality risk stratification in conjunction with lactate levels increases their accuracy. Viallon et al. found that combining procalcitonin and lactate levels allowed for improved mortality risk stratification of septic adult patients than either biomarker used independently.(72) Phua et al. demonstrated that for patients in septic shock in the ICU, when procalcitonin and lactate levels both increased over time patient prognosis was poor, but when either biomarker increased in isolation, short-term mortality risk was no greater than for patients with no biomarker increase.(25)

Green et al. demonstrated that among adult ED patients admitted for a suspected infection and a serum lactate ≥4.0 mmol/L, patients were five times more likely to die if they also had an elevated C-Reactive Protein (CRP) level.(73) In this study, patients with a lactate ≥4.0 mmol/L and a normal CRP were no more likely to die within 28 days than patients with a normal lactate (Figure 2). Studies have demonstrated that CRP has only moderate ability to predict mortality risk in sepsis when measured in isolation.(74)(75) When combined with lactate levels the two biomarkers appear to have significantly greater predictive capacity.

Figure 2. Twenty-eight-day Mortality of Adult Septic Patients Stratified By Serum Lactate and CRP Level (mg/dL). Bars=95% C.I.(73)

Click image for larger view.

These findings suggest that lactate’s association with mortality may be dependent on simultaneous abnormalities of the inflammatory cascade. When perfusion-induced lactate abnormalities are rapidly corrected with volumetric resuscitation and serial lactate measurements decrease, mortality risk drops substantially. However, in non-fluid responsive hyperlactatemia mortality is substantial (>60%).(31) These patients may have lactate accumulation due to the catecholamine surge of sepsis and require interventions focused on mitigating this response.


Severe sepsis is a common, deadly condition, but recent studies have demonstrated that rapid identification and treatment can decrease mortality risk for these patients. Several clinical risk stratification instruments have been developed that take advantage of commonly used clinical variables to rapidly risk assess patients. While the MEDS score has been validated for clinical risk stratification in septic patients with minimal immediate evidence of organ dysfunction, it is less efficacious in patients with objective evidence of organ dysfunction. The SOFA score has utility for rapid risk stratification in sepsis, and even greater efficacy with serial measurement to assess the response to therapy and need for further interventions. The PIRO staging system has utility for risk stratification in sepsis and has potential as a rapid risk stratification tool in high-risk patients.

Serum lactate levels have a demonstrated association with mortality risk in sepsis, even when measured as a serum sample. Serial lactate measurement increases the accuracy of lactate measurement for mortality risk and has been used as marker of adequate resuscitation. Lactate accumulation in sepsis may be caused by end-organ hypoperfusion, but increasing evidence exists that lactate accumulation in sepsis is related largely to the hypermetabolic state of sepsis. IL-6 and procalcitonin have a significant association with mortality risk in sepsis, even early in the clinical presentation. Inflammatory biomarkers, including procalcitonin and CRP, may be more predictive of mortality risk when assessed in combination with lactate levels, possibly due to the underlying physiology of lactate in sepsis.


1Shapiro N, Howell MD, Bates DW, et al. The association of sepsis syndrome and organ dysfunction with mortality in emergency department patients with suspected infection. Ann Emerg Med 2006; 48:583-590
2Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31:1250-1256
3Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29:1303-1310
4Wang HE, Shapiro NI, Angus DC, et al. National estimates of severe sepsis in United States emergency departments. Crit Care Med 2007; 35:1928-1936
5Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003; 348:1546-1554
6Rivers 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; 345:1368-1377
7Trzeciak S, Dellinger RP, Abate NL, et al. Translating research to clinical practice: a 1-year experience with implementing early goal-directed therapy for septic shock in the emergency department. Chest 2006; 129:225-232
8Jones AE, Focht A, Horton JM, et al. Prospective external validation of the clinical effectiveness of an emergency department-based early goal-directed therapy protocol for severe sepsis and septic shock. Chest 2007; 132:425-432
9Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med 2010; 38:1045-1053
10Jones AE, Trzeciak S, Kline JA. The Sequential Organ Failure Assessment score for predicting outcome in patients with severe sepsis and evidence of hypoperfusion at the time of emergency department presentation. Crit Care Med 2009; 37:1649-1654
11Castella X, Gilabert J, Torner F, et al. Mortality prediction models in intensive care: acute physiology and chronic health evaluation II and mortality prediction model compared. Crit Care Med 1991; 19:191-197
12Beck DH, Smith GB, Pappachan JV, et al. External validation of the SAPS II, APACHE II and APACHE III prognostic models in South England: a multicentre study. Intensive Care Med 2003; 29:249-256
13Ferreira FL, Bota DP, Bross A, et al. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA 2001; 286:1754-1758
14Jones AE, Fitch MT, Kline JA. Operational performance of validated physiologic scoring systems for predicting in-hospital mortality among critically ill emergency department patients. Crit Care Med 2005; 33:974-978
15Shapiro NI, Wolfe RE, Moore RB, et al. Mortality in Emergency Department Sepsis (MEDS) score: a prospectively derived and validated clinical prediction rule. Crit Care Med 2003; 31:670-675
16Sankoff JD, Goyal M, Gaieski DF, et al. Validation of the Mortality in Emergency Department Sepsis (MEDS) score in patients with the systemic inflammatory response syndrome (SIRS). Crit Care Med 2008; 36:421-426
17Howell MD, Donnino MW, Talmor D, et al. Performance of severity of illness scoring systems in emergency department patients with infection. Acad Emerg Med 2007; 14:709-714
18Nguyen HB, Banta JE, Cho TW, et al. Mortality predictions using current physiologic scoring systems in patients meeting criteria for early goal-directed therapy and the severe sepsis resuscitation bundle. Shock 2008; 30:23-28
19Jones AE, Saak K, Kline JA. Performance of the Mortality in Emergency Department Sepsis score for predicting hospital mortality among patients with severe sepsis and septic shock. Am J Emerg Med 2008; 26:689-692
20Howell MD, Donnino M, Clardy P, et al. Occult hypoperfusion and mortality in patients with suspected infection. Intensive Care Med 2007; 33:1892-1899
21Trzeciak S, Dellinger RP, Chansky ME, et al. Serum lactate as a predictor of mortality in patients with infection. Intensive Care Med 2007; 33:970-977
22Howell MD, Talmor D, Schuetz P, et al. Proof of principle: the predisposition, infection, response, organ failure sepsis staging system. Crit Care Med 2011; 39:322-327
23Rubulotta F, Marshall JC, Ramsay G, et al. Predisposition, insult/infection, response, and organ dysfunction: A new model for staging severe sepsis. Crit Care Med 2009; 37:1329-1335
24Nguyen HB, Van Ginkel C, Batech M, et al. Comparison of Predisposition, Insult/Infection, Response, and Organ dysfunction, Acute Physiology And Chronic Health Evaluation II, and Mortality in Emergency Department Sepsis in patients meeting criteria for early goal-directed therapy and the severe sepsis resuscitation bundle. J Crit Care 2011
25Mikkelsen ME, Miltiades AN, Gaieski DF, et al. Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock. Crit Care Med 2009; 37:1670-1677
26Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36:296-327
27Berkman M, Ufberg J, Nathanson LA, et al. Anion gap as a screening tool for elevated lactate in patients with an increased risk of developing sepsis in the Emergency Department. J Emerg Med 2009; 36:391-394
28Lee SW, Hong YS, Park DW, et al. Lactic acidosis not hyperlactatemia as a predictor of in hospital mortality in septic emergency patients. Emerg Med J 2008; 25:659-665
29Nguyen HB, Rivers EP, Knoblich BP, et al. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med 2004; 32:1637-1642
30Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 2010; 303:739-746
31Arnold RC, Shapiro NI, Jones AE, et al. Multicenter study of early lactate clearance as a determinant of survival in patients with presumed sepsis. Shock 2009; 32:35-39
32Kruse JA, Carlson RW. Lactate metabolism. Crit Care Clin 1987; 3:725-746
33James JH, Luchette FA, McCarter FD, et al. Lactate is an unreliable indicator of tissue hypoxia in injury or sepsis. Lancet 1999; 354:505-508
34Levy B. Lactate and shock state: the metabolic view. Curr Opin Crit Care 2006; 12:315-321
35Bundgaard H, Kjeldsen K, Suarez Krabbe K, et al. Endotoxemia stimulates skeletal muscle Na+-K+-ATPase and raises blood lactate under aerobic conditions in humans. Am J Physiol Heart Circ Physiol 2003; 284:H1028-1034
36Levy B, Gibot S, Franck P, et al. Relation between muscle Na+K+ ATPase activity and raised lactate concentrations in septic shock: a prospective study. Lancet 2005; 365:871-875
37Levy B, Sadoune LO, Gelot AM, et al. Evolution of lactate/pyruvate and arterial ketone body ratios in the early course of catecholamine-treated septic shock. Crit Care Med 2000; 28:114-119
38Leverve XM. Lactate in the intensive care unit: pyromaniac, sentinel or fireman? Crit Care 2005; 9:622-623
39Gladden LB. Lactate metabolism: a new paradigm for the third millennium. J Physiol 2004; 558:5-30
40Levy B, Perez P, Gibot S, et al. Increased muscle-to-serum lactate gradient predicts progression towards septic shock in septic patients. Intensive Care Med; 36:1703-1709
41Daniel AM, Shizgal HM, MacLean LD. The anatomic and metabolic source of lactate in shock. Surg Gynecol Obstet 1978; 147:697-700
42Jones SB, Romano FD. Dose- and time-dependent changes in plasma catecholamines in response to endotoxin in conscious rats. Circ Shock 1989; 28:59-68
43Hall RC, Hodge RL. Vasoactive hormones in endotoxin shock: a comparative study in cats and dogs. J Physiol 1971; 213:69-84
44Boldt J, Menges T, Kuhn D, et al. Alterations in circulating vasoactive substances in the critically ill--a comparison between survivors and non-survivors. Intensive Care Med 1995; 21:218-225
45Ackland GL, Yao ST, Rudiger A, et al. Cardioprotection, attenuated systemic inflammation, and survival benefit of beta1-adrenoceptor blockade in severe sepsis in rats. Crit Care Med 2010; 38:388-394
46Hofer S, Eisenbach C, Lukic IK, et al. Pharmacologic cholinesterase inhibition improves survival in experimental sepsis. Crit Care Med 2008; 36:404-408
47Levy B, Desebbe O, Montemont C, et al. Increased aerobic glycolysis through beta2 stimulation is a common mechanism involved in lactate formation during shock states. Shock 2008; 30:417-421
48Song M, Kellum JA. Interleukin-6. Crit Care Med 2005; 33:S463-465
49Patel RT, Deen KI, Youngs D, et al. Interleukin 6 is a prognostic indicator of outcome in severe intra-abdominal sepsis. Br J Surg 1994; 81:1306-1308
50Casey LC, Balk RA, Bone RC. Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med 1993; 119:771-778
51Becker KL, Snider R, Nylen ES. Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations. Crit Care Med 2008; 36:941-952
52Castelli GP, Pognani C, Meisner M, et al. Procalcitonin and C-reactive protein during systemic inflammatory response syndrome, sepsis and organ dysfunction. Crit Care 2004; 8:R234-242
53Wanner GA, Keel M, Steckholzer U, et al. Relationship between procalcitonin plasma levels and severity of injury, sepsis, organ failure, and mortality in injured patients. Crit Care Med 2000; 28:950-957
54Brunkhorst FM, Wegscheider K, Forycki ZF, et al. Procalcitonin for early diagnosis and differentiation of SIRS, sepsis, severe sepsis, and septic shock. Intensive Care Med 2000; 26 Suppl 2:S148-152
55Uzzan B, Cohen R, Nicolas P, et al. Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis. Crit Care Med 2006; 34:1996-2003
56Bouadma L, Luyt CE, Tubach F, et al. Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet 2010; 375:463-474
57Endo S, Aikawa N, Fujishima S, et al. Usefulness of procalcitonin serum level for the discrimination of severe sepsis from sepsis: a multicenter prospective study. J Infect Chemother 2008; 14:244-249
58Whang KT, Steinwald PM, White JC, et al. Serum calcitonin precursors in sepsis and systemic inflammation. J Clin Endocrinol Metab 1998; 83:3296-3301
59Hensler T, Sauerland S, Lefering R, et al. The clinical value of procalcitonin and neopterin in predicting sepsis and organ failure after major trauma. Shock 2003; 20:420-426
60Balc IC, Sungurtekin H, Gurses E, et al. Usefulness of procalcitonin for diagnosis of sepsis in the intensive care unit. Crit Care 2003; 7:85-90
61Luzzani A, Polati E, Dorizzi R, et al. Comparison of procalcitonin and C-reactive protein as markers of sepsis. Crit Care Med 2003; 31:1737-1741
62Lee CC, Chen SY, Tsai CL, et al. Prognostic value of mortality in emergency department sepsis score, procalcitonin, and C-reactive protein in patients with sepsis at the emergency department. Shock 2008; 29:322-327
63Meisner M, Adina H, Schmidt J. Correlation of procalcitonin and C-reactive protein to inflammation, complications, and outcome during the intensive care unit course of multiple-trauma patients. Crit Care 2006; 10:R1-10
64Caterino JM, Scheatzle MD, Forbes ML, et al. Bacteremic elder emergency department patients: procalcitonin and white count. Acad Emerg Med 2004; 11:393-396
65Hausfater P, Garric S, Ayed SB, et al. Usefulness of procalcitonin as a marker of systemic infection in emergency department patients: a prospective study. Clin Infect Dis 2002; 34:895-901
66Hausfater P, Juillien G, Madonna-Py B, et al. Serum procalcitonin measurement as diagnostic and prognostic marker in febrile adult patients presenting to the emergency department. Crit Care 2007; 11:R60
67Chan YL, Tseng CP, Tsay PK, et al. Procalcitonin as a marker of bacterial infection in the emergency department: an observational study. Crit Care 2004; 8:R12-20
68Bossink AW, Groeneveld AB, Thijs LG. Prediction of microbial infection and mortality in medical patients with fever: plasma procalcitonin, neutrophilic elastase-alpha1-antitrypsin, and lactoferrin compared with clinical variables. Clin Infect Dis 1999; 29:398-407
69Jensen JU, Heslet L, Jensen TH, et al. Procalcitonin increase in early identification of critically ill patients at high risk of mortality. Crit Care Med 2006; 34:2596-2602
70Clec'h C, Ferriere F, Karoubi P, et al. Diagnostic and prognostic value of procalcitonin in patients with septic shock. Crit Care Med 2004; 32:1166-1169
71Phua J, Koay ES, Lee KH. Lactate, procalcitonin, and amino-terminal pro-B-type natriuretic peptide versus cytokine measurements and clinical severity scores for prognostication in septic shock. Shock 2008; 29:328-333
72Viallon A, Guyomarc'h S, Marjollet O, et al. Can emergency physicians identify a high mortality subgroup of patients with sepsis: role of procalcitonin. Eur J Emerg Med 2008; 15:26-33
73Green JP, Berger T, Garg N, et al. Serum lactate is a better predictor of short-term mortality when stratified by C-reactive protein in adult emergency department patients hospitalized for a suspected infection. Ann Emerg Med 2011; 57:291-295
74Lobo SM, Lobo FR, Bota DP, et al. C-reactive protein levels correlate with mortality and organ failure in critically ill patients. Chest 2003; 123:2043-2049
75Silvestre J, Povoa P, Coelho L, et al. Is C-reactive protein a good prognostic marker in septic patients? Intensive Care Med 2009; 35:909-913