Home Educatione-Learning Rapid Treatment of Severe Sepsis
  • Date
  • September 27, 2012
  • Specialties
  • Pulmonary, Critical Care
  • Learning Categories
  • Learning Category 2: Self-Directed Learning
  • CME Credit
  • Credit not available as of July 1, 2013

Rapid Treatment of Severe Sepsis

PCCSU Volume 25, Lesson 26


The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.


  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

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Credit no longer available as of July 1, 2013.

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The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

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PCCSU Volume 25 Editorial Board

Steven A. Sahn, MD, FCCP

Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor
Richard A. Matthay, MD, FCCP

Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison

By Steven Q. Simpson, MD, FCCP; and Lucas R. Pitts, MD

Dr. Simpson is Associate Professor of Medicine and Director of Fellowship Training, and Dr. Pitts is Assistant Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of Kansas Medical Center, Kansas City, Kansas.

Dr. Simpson has disclosed that he is the Third Eli Lilly and Company Distinguished Scholar in Critical Care Medicine of the American College of Chest Physicians and The CHEST Foundation.

Dr. Pitts has nothing to disclose.


  1. List reasons why the incidence of severe sepsis is rising.
  2. Recognize the criteria for systemic inflammatory response syndrome.
  3. Provide the criteria for organ failure in severe sepsis.
  4. Relate three controversial areas of early goal-directed therapy.
  5. State the definition of a treatment goal.

Key words: antibacterial agents; multiple organ failure; sepsis syndrome; septic shock; systemic inflammatory response syndrome

Abbreviations: CVP = central venous pressure; EGDT = early goal-directed therapy; MAP = mean arterial pressure; PCT = procalcitonin; PPV = pulse pressure variation; PRBC = packed red blood cell; SBP = systolic blood pressure; Scvo2 = central venous oxygen saturation; SIRS = systemic inflammatory response syndrome; SSC = Surviving Sepsis Campaign; Svo2 = mixed venous oxygen saturation; SVV = stroke volume variation


Severe sepsis is underrecognized and is frequently not treated as aggressively as it should be, owing to changes in the treatment paradigm during the last decade that are sometimes misunderstood and attacked in the literature for nonscientific reasons.1-3 Severe sepsis is a complex illness, and it has been difficult to achieve consensus among experts regarding a unified approach to treating patients with severe sepsis and septic shock. Nevertheless, certain principles may help guide the care of these patients. In this lesson, we underscore the need for rapid, organized, and aggressive care for patients with severe sepsis.


Severe sepsis exists along a progressive continuum of physiologic responses to infection that share a foundation in the systemic inflammatory response syndrome (SIRS). SIRS is common to many noninfectious maladies, as well as to the spectrum of infectious conditions related to sepsis. For example, SIRS has been well documented in many noninfectious conditions such as acute pancreatitis, polytrauma, massive hemorrhage, autoimmune disorders, burns, and exogenous administration of inflammatory mediators such as tumor necrosis factor.

SIRS was initially defined in 1992 by the American College of Chest Physicians and the Society of Critical Care Medicine Consensus Conference Committee, and it is characterized by discrete physiologic criteria.4 The hallmark of SIRS consists of the presence of two of more of the following:

  1. Body temperature < 98.6° F or > 100.4° F
  2. Heart rate > 90/min
  3. Respiratory rate > 20/min
  4. Hyperventilation, indicated by a Paco2 of < 32 mm Hg
  5. White blood cell count < 4,000/µL, > 12,000//µL, or the presence of > 10% immature neutrophils.

By definition, the physiologic changes associated with SIRS represent acute changes from a patient’s baseline in the absence of other known causes. The SIRS response is a systemic inflammatory response to a specific insult, either infectious in nature or otherwise.

Sepsis represents the occurrence of SIRS arising from a known or suspected infection. The presence of SIRS in the setting of sepsis represents a dysregulated systemic inflammatory response to such an infection, but it does not lead to remote organ dysfunction. Severe sepsis refers to the presence of sepsis as well as signs of organ dysfunction or hypoperfusion at sites remote to that of the infection itself. Hallmarks of such organ dysfunction include5,6:

  1. Hypotension (systolic blood pressure SBP < 90 mm Hg; mean arterial pressure MAP < 70 mm Hg; SBP decrease > 40 mm Hg)
  2. Renal failure that manifests as a creatinine value increase > 0.5 mg/dL, poor urine output (defined as < 0.5 mL/kg for ≥ 1 h), or the need for renal replacement therapy
  3. Altered mental status (from individual patient baseline)
  4. Thrombocytopenia (< 100,000 platelets/mL)
  5. Respiratory failure that manifests by arterial hypoxemia (Pao2/Fio2 < 300)
  6. Coagulation abnormalities (international normalized ratio > 1.5 or activated partial thromboplastin time > 60 s)
  7. Ileus
  8. Hyperbilirubinemia (plasma total bilirubin level > 4 mg/dL)
  9. Hyperlactatemia (> upper limit of normal)
  10. Septic shock refers to a state of acute circulatory collapse that arises out of response to the dysregulated inflammatory response of sepsis. It is defined by persistent hypotension (in the absence of other known causes) that is refractory to volume resuscitation.


Severe sepsis is a public health issue in the United States and throughout the world. By one estimate, the condition affected more than 750,000 Americans in 1995, and the condition was shown by two separate epidemiologic studies to be steadily rising in incidence.7-9 A recent estimate placed the number of cases per year in the United States at 1.14 million. Other studies made more conservative estimates of case numbers, but the methodologic limitation of nearly all of these epidemiologic studies is that they primarily rely on providers to make a diagnosis of sepsis, which results in an outcome that may be best characterized as the treated incidence of sepsis, rather than the actual incidence of the condition.10 Based on available data, the incidence of severe sepsis appears to be somewhere between 95 and 300 cases per 100,000 per year in the United States.

Even the most conservative estimates of severe sepsis incidence demonstrate that it is dramatically rising. Two separate studies using similar—but not identical—techniques have demonstrated an annual rise in incidence of 8.4% and 8.7%.8,9 At this growth rate, the incidence would be expected to double approximately every 8.5 years. The incidence of severe sepsis is dramatically higher among the elderly, apparently rising exponentially each year after age 65, and this rise in severe sepsis incidence coincides with the rising number of individuals in that age group. Beginning in 2011, more than 10,000 Americans per day—members of the baby boom generation—are turning 65 years of age, and this phenomenon will continue for approximately 19 years.11 Therefore, it is unlikely that the incidence of severe sepsis will diminish any time in the near future.


Severe sepsis is a deadly condition. The original description of the sepsis syndrome, which became the basis for our current definition of severe sepsis, showed a mortality of 13% among those patients who never developed shock, 27.5% among patients who subsequently developed shock, and 43.2% among patients who had shock on presentation.12 In a score of therapeutic trials during the 1990s and early 2000s that used current definitions of severe sepsis and septic shock to enroll patients, the mortality in the placebo arm was between 30% and 40%.13 The mortality rate of septic shock appears to have declined over time, having been estimated at approximately 80% in the 1950s and 1960s, but the rate was in the low 50% range during the 1990s. In a French multicenter study, Annane and colleagues14 found that septic shock was present in 8.2% of hospital admissions and resulted in a crude mortality of 60.1% over the 1990s; however, this study also showed a mortality decline from 62.1% to 55.9% over the course of the decade, which the authors attributed to improvements in ICU care during that time. Clearly, severe sepsis and septic shock must be taken seriously and aggressively treated.

The focus of this lesson is rapid, aggressive treatment of severe sepsis; however, there would be no need to pursue an aggressive treatment course unless one could clearly alter the lethality of severe sepsis, septic shock, or both by doing so. Fortunately, improved sepsis survival via organized, rapid, and aggressive treatment has been demonstrated in numerous studies. The landmark study of this nature outlined a treatment approach termed early goal-directed therapy (EGDT) by Rivers and colleagues.15 In this approach, specific treatments were applied and specific clinical features were monitored to achieve specified clinical objectives within 6 h. The authors purposefully selected for study the sickest of patients, those with septic shock, or those with serum lactate levels above 36 mg/dL. They found that mortality was reduced by approximately one-third (from 46.5% to 30.5%) when compared with “usual” care. Although some of the chosen specific treatments and objectives have been assailed in the sepsis literature, the fact remains that this study demonstrated the largest reduction in severe sepsis mortality of any controlled study to date.16 Some of the controversial elements of EGDT are discussed below. However, the paper was landmark in nature and the technique was likely successful not only because of the specific clinical parameters that it followed or because of the specific treatments applied, many of which will change with time as more studies are performed and the science progresses; instead, its landmark nature and likely its success derive from actually having specific goals or objectives met during treatment. In most studies of therapies for severe sepsis, the overall outcome or mission—improved survival—is specified, but many of the steps to achieve that outcome are left unspecified by the protocol and are frequently termed “usual care.” A number of published studies have now demonstrated that use of the EGDT treatment strategy, alone or in combination with a rapid response team, a shock team, or other approaches to early recognition and rapid, aggressive treatment can reduce the lethality of severe sepsis.16-19

The Surviving Sepsis Campaign (SSC), initially launched in 2004 with the publication of its surviving sepsis guidelines, demonstrated in its first data analysis an absolute reduction in mortality of 5.4%, in part by using a bundle of care measures and objectives to be met within the first 6 h of care.2 The campaign first developed guidelines for sepsis treatment that were culled from a comprehensive literature review and ranked according to quality of evidence and strength of recommendation.20 The guidelines also used a concept known as “bundling of care” or “care bundles.” The principle behind this concept is that, when multiple treatments are known to be effective in their own right, the combination of those treatments in a “bundle,” with the goal of completing the entire bundle for each patient, may be additive, or even synergistic, in achieving positive outcome. The SSC guidelines made use of two separate bundles: one, called the “resuscitation bundle,” outlined care measures to be taken in the first 6 h of care, and the other, the “management bundle,” outlined care measures to be taken within the first 24 h of care. The resuscitation bundle was based on, although not identical to, EGDT. Patient survival was positively associated with the duration of hospital participation in the campaign and with the proportion of patients who received the treatment bundles in their entirety. These trends continue with the 2011-2012 analysis of more than 30,000 patients in the SSC database (unpublished data).


One of the most important advancements in the care of patients with severe sepsis and septic shock came in the form of EGDT.15 EGDT simultaneously introduced a novel method for measuring tissue oxygenation/perfusion in severe sepsis and septic shock, applied several common therapies in a systematic, goal-oriented fashion, and effected a significant mortality benefit in patients presenting to the ED with severe sepsis and septic shock. Although some elements of EGDT remain controversial, the process has resulted in a paradigm shift away from a piecemeal approach to the care of septic patients to that of goal-directed, systematic, timely care. EGDT has been further refined since its initial publication by the SSC, which has released consensus recommendations in 2004 and, most recently, in 2008 regarding the treatment of severe sepsis and septic shock.6,20

EGDT is founded upon the measurement of central venous oxygen saturation (Scvo2) as the indicator of tissue oxygenation and guide to successful therapy for severe sepsis. All therapies administered for EGDT ultimately aim to normalize Scvo2 (≥ 70%) and, in doing so, to normalize tissue perfusion and provide the necessary conditions for the reversal of organ dysfunction in severe sepsis and septic shock.

A principal EGDT intervention in the treatment of severe sepsis and septic shock is the initiation of an aggressive fluid resuscitation. Following (ideally, concurrent with) antibiotic administration, a central venous catheter is placed to permit the measurement of central venous pressure (CVP), which is intended to provide a measure of intravascular volume status during aggressive volume resuscitation, in patients with septic shock or a serum lactate level above 36 mg/dL. A central venous catheter also permits the measurement of Scvo2, the ultimate measure of end-organ perfusion in EGDT. After placement of a central venous catheter, IV fluids should be administered in the form of either colloid or crystalloid, with the goal of raising CVP to 8 mm Hg or greater (12-15 mm Hg in patients on ventilators). Additional goals consist of normalizing MAP of patients who are hypotensive (≥ 65 mm Hg) and the reversal of oliguria (urine output ≥ 0.5 mL/kg/h). IV fluid boluses were administered by Rivers and colleagues15 in 500-mL increments every 30 min, but the SSC guidelines also suggest administering fluid boluses of 20 mL/kg over 5-10 min each, titrating to improvement in hemodynamics and CVP.6

It is important to note that IV fluids should be administered even in the setting of normotension if patients have serum lactate value above 36 mg/dL, targeting improvements in CVP. If a patient is hypotensive, either while receiving IV fluids or despite appropriate volume resuscitation, vasopressors should be administered to raise MAP to 65 mm Hg or higher. Norepinephrine and dopamine were recommended with equal weight by the SSC in 2008, but recent data indicate that the use of norepinephrine is associated with fewer adverse events.21 Notably, Rivers and colleagues also utilized vasodilators to lower arterial blood pressure if SBP was 90 mm Hg or above, targeted to an SBP lower than 90 mm Hg with a concurrent MAP of 60 mm Hg or above. The SSC does not address vasodilator use. As with other therapies used in EGDT, the ultimate goal of administering IV fluids and vasoactive agents is normalization of Scvo2.

In EGDT, if Scvo2 remains below 70% despite an appropriate volume resuscitation and normalization of blood pressure, red blood cells are transfused to achieve a hematocrit of 30% or more. If, following the administration of red blood cells, Scvo2 remains below 70%, inotropic agents (dobutamine) should be administered to increase cardiac output with the goal of improving tissue oxygenation. Dobutamine should be started at a dose of 2.5 µg/kg/min and increased in 30-min intervals by 2.5 µg/kg/min until Scvo2 is at goal (≥ 70%). It is not recommended to titrate a dobutamine infusion higher than 20 µg/kg/min. In addition, it is not recommended to improve cardiac output to supranormal levels.

The algorithm is repeated until the goal Scvo2 is reached. Not only does EGDT have a specific goal (the Scvo2) by which to measure the effectiveness of therapy, but, importantly, it also contains a timeframe for that goal to be achieved, specifying that the target Scvo2 be reached utilizing the aforementioned therapies within the first 6 h of presentation.

Although EGDT and approaches to sepsis that use EGDT have been effective at saving lives, there are issues with the technique that have given some authors pause and have limited its use in a number of institutions. When they are taken individually, the components of EGDT have weaknesses or limitations in their usefulness that leave these authors skeptical that combining them will produce a positive outcome. Often foremost among these concerns is the reliance of EGDT on CVP of 8-12 mm Hg as a goal for volume administration. For decades it has been known that CVP is, at best, a proxy for the desired information—left ventricular end-diastolic volume and, because of the Frank-Starling mechanism, left ventricular stroke volume.22 Marik and colleagues22 systematically reviewed the literature examining the ability of CVP to estimate intravascular volume, and they showed that the relationship of CVP to intravascular volume is unreliable or nonexistent in a broad variety of patients. In addition, CVP is not predictive of right ventricular end-diastolic volume or stroke volume even in normal individuals, nor do changes in CVP predict the magnitude or direction of changes in these two parameters.23

Tissue hypoxia is a hallmark of severe sepsis and septic shock, and it is mediated through numerous mechanisms, including vasodilation, capillary shunting, volume depletion, microvascular occlusion, reduction in cardiac contractility, and impaired oxygen utilization.24-26 EGDT uses two markers of tissue hypoxia, serum lactate and Scvo2, to identify septic patients at high risk of death and to track their clinical progress, respectively. Both of these markers have been criticized as being insensitive for the detection of tissue hypoxia; that is, tissue hypoxia can be present without increases in overall serum lactate levels or reductions in Scvo2, owing both to shunting at the microvascular level and to impaired cellular oxygen uptake. Scvo2 is itself a surrogate for mixed venous oxygen saturation (Svo2), and some data suggest that it is less reliable in the setting of sepsis or of shock—where intensivists are likely to use it—than in normal individuals.27,28 There is lack of agreement as to whether normalization of serum lactate levels or normalization of Scvo2 is the more appropriate treatment goal for patients with severe sepsis.29,30 The most recent controlled trial suggests that survival is significantly increased in patients with severe sepsis in whom lactate levels are normalized but Scvo2 is not compared with patients in whom Scvo2 is normalized but lactate levels are not.31 However, the patient numbers in that trial are small, and further research will be important if the question is to be resolved.

One of the more controversial aspects of EGDT is its use of packed red blood cell (PRBC) transfusion to achieve a hemoglobin goal of 10 g/dL in patients with severe sepsis who have not achieved the target Scvo2 even after CVP and MAP goals have been met. Current guidelines for PRBC transfusion recommend a more restrictive approach to PRBC transfusion in trauma and general critical care patients, with a target of 7 g/dL.32 The most important evidence supporting that transfusion trigger comes from a multicenter Canadian study demonstrating an actual mortality benefit when the lower hemoglobin target is used.33 The Canadian study was published at a time when the EGDT trial was in midcourse; therefore, the new transfusion trigger could not have been taken into account during the trial. EGDT transfusion targets are based on knowledge and practices extant at the inception of the original trial. However, it is worth noting that patients in the EGDT arm of the trial did, in fact, receive more PRBC than patients in the control group while also demonstrating an improved survival.15 It is impossible to determine whether and to what extent PRBC transfusion contributed to or detracted from the observed survival benefit of EGDT in the study conducted by Rivers and colleagues.15

The least controversial aspect of EGDT, particularly as it is implemented by the SSC, is the rapid administration of broad-spectrum antibiotics. The SSC guidelines recommend antibiotic administration within 1 h of presentation with severe sepsis. In a certain sense, it is ironic that aggressive antibiotic administration is universally accepted as appropriate therapy because there are no placebo-controlled trials of antibiotics in severe sepsis to be found, nor are there likely ever to be any. Nevertheless, there is good evidence of the importance of early, broad-spectrum antibiotics in septic shock. Kumar and colleagues34 used a retrospective design to determine the effect of time delays in administering the correct antibiotic to patients with septic shock in ICUs across North America. They demonstrated that mortality in septic shock proportionally rises with time delay in the administration of antibiotic therapy. Patients who received appropriate antibiotics within 30 min of presentation with septic shock had a mortality of 17.3%, while delays of 4 h resulted in mortality of 58%; moreover, the delays were at least 6 h in 50% of patients.34 Because patients who received antibiotics to which their organisms were not susceptible did just as poorly as patients who did not receive any timely antibiotics, the studies underscore the need for broad-spectrum antibiotics at the inception of care. Antibiotics should be treated as emergency therapy for patients with severe sepsis.

Emerging Issues in Resuscitation

One of the most challenging issues in the resuscitation of severe sepsis has been the inability to accurately measure intravascular volume status during the initial phase of volume resuscitation. EGDT and the SSC guidelines have relied on CVP as a measure of intravascular volume status, denoting a CVP of 8 mm Hg or higher as a target in a spontaneously breathing patient and 12-15 mm Hg as a target in a patient supported by a ventilator. As reviewed above, there is considerable controversy regarding whether CVP should be used in treatment given that it is an unreliable indicator of intravascular volume status.

In the recent past, other dynamic methods for determining intravascular volume status have been investigated. Among them are pulse pressure variation (PPV) and stroke volume variation (SVV), aortic flow Doppler echocardiography, stroke volume assessed by echocardiography, and positive-pressure, ventilation-induced changes in the diameter of the vena caval. PPV and SVV are based on simple physiologic principles. Positive pressure variation induces cyclic changes in the preload of both the right and left ventricles. When conditions of intravascular volume depletion are present, the magnitude of these changes is great because the ventricles are operating on the steep portion of the Frank-Starling curve. In situations of adequate volume status, preload is greater, and the PPV/SVV is much smaller since the left ventricle has adequate preload conditions throughout the respiratory cycle. A meta-analysis of 29 individual studies suggested that PPV and SVV measured during volume-controlled mechanical ventilation accurately predicted volume responsiveness with very high sensitivity and specificity. The sensitivity and specificity were retained even in conditions of poor left ventricle function.

The threshold value of volume responsiveness was shown across all studies to be consistently between 12% and 13%.35 Pulse oximeter plethysmography waveform variation has also been shown to correlate very well with PPV and SVV in predicting volume responsiveness and is another similar alternative to noninvasively predicting volume responsiveness in the ICU setting when a patient does not have an arterial line in place.36,37 Each of the techniques listed above relies not on a static measure of a pressure that is a surrogate for ventricular filling, but on the direct result of that ventricular filling, stroke volume. These techniques, which are still being perfected but are gaining wider use, more closely assess the issue in which intensivists are interested—the stroke volume and cardiac output—compared with CVP or other pressures. Each of them is a better guide for volume administration in severe sepsis than the currently used CVP. One or even a few of them are likely to emerge as the most cost-effective, time-effective, or simply the easiest to use choice(s) for resuscitation.

Measures of tissue perfusion and oxygenation hold some promise as monitoring tools in severe sepsis. Sublingual orthogonal polarization spectroscopy is a promising technique that has demonstrated utility in patients with severe sepsis. Sublingual microcirculatory evaluation using this technique was shown in relevant animal models of sepsis to reflect gut microcirculation.38 Sublingual microcirculatory alterations are present in patients with severe sepsis and are persistent in those who die from severe sepsis.39,40 In addition, these microcirculatory alterations can be improved by fluid administration or dobutamine in patients with severe sepsis.41-43 The technique has not yet caught on in routine practice, possibly because of the expense of the tool and possibly because it was only semiquantitative in nature; however, a recent publication demonstrated a quantitative use of the technique that may make it more accessible for routine use in sepsis resuscitation.44,45

Procalcitonin (PCT) has garnered attention as a possible diagnostic test for sepsis by aiding to differentiate sepsis from other causes of SIRS. Among more than 150 biomarkers that have been tested as potential diagnostic markers for sepsis,46,47 PCT has shown the most promise, but it has failed to demonstrate a degree of reliability that warrants full support for its use in this role.48 At present, the test provides no better diagnostic information than the clinical definitions of sepsis given above for diagnosis. However, PCT has recently been investigated as a biomarker that can be used to tailor ongoing antibiotic therapy, ie, indicate when antibiotics can be discontinued, with some success. The use of PCT in this way reduced antibiotic duration in the treatment of lower respiratory tract infections in outpatients in both the primary care setting and the ED.49-51 Recently, it has been shown to reduce antibiotic exposure in patients who are critically ill without compromising clinical outcomes.52,53

Perhaps the single most effective new treatment tool for severe sepsis is not a specific pharmaceutical agent or piece of technology; rather, it is the growth of a principle—the principle of setting and achieving goals as we treat patients who are critically ill, including those with severe sepsis. A goal is best defined as a specific, measurable outcome that is relevant and achievable and that is accomplished in a more or less specific amount of time. Goals are distinguished from the overall mission of safely returning patients to their lives and activities by their specificity and their time limits. (Readers should be aware that literature about setting and achieving goals seems to use two different, but equivalent, terminologies. Some authors use the terms “goal” and “mission” as we have done. Others use the term “goal” as we have used the term “mission” and call the specific, timely, and measurable steps the “objectives.” In goal-setting theory, this is referred to as translating general goals into specific goals. The principles involved are the same; it is only the terminology that is different.)

The original trial conducted by Rivers and colleagues15 was the first to demonstrate the effectiveness of this approach in severe sepsis, and the SSC clearly showed that the principle can be effective in a broad variety of nonresearch settings, across numerous disciplines, and with an international scope.

Goal-setting theory was developed in the 1960s, and, by 1990, the positive impact of goal setting on human performance had been demonstrated in 88 different areas of performance.54,55 As a field of endeavor, medicine has come late to the party in terms of enhancing patient outcomes by setting and achieving specific goals. Setting and achieving therapeutic goals is compatible with—in fact demanded by—evidence-based practice; evidence cannot logically be linked to action unless a goal is given.56,57 The literature of goal setting establishes that feedback is key to the successful completion of any task.58 In the ICU, that feedback is immediate and readily available as long as providers use it to their own and their patients’ advantage. CVP and MAP are instantaneously obtained. Scvo2 and lactate values can be instantaneous or only briefly delayed. Moreover, by collecting and maintaining the feedback data, providers can improve their performance with individual patients as well as with the collection of patients in their practice. Goal setting with feedback is the basis for long-term performance improvement.

One may question whether the goals of EGDT are the correct ones. Is tissue oxygenation the right goal? Is Scvo2 the correct marker of tissue oxygenation? Is CVP or MAP the correct stepping stone to adequate tissue oxygenation? Are the current goals timely enough, or should they be achieved faster? In fact, there are currently three separate clinical trials in North America, Europe, and Australia–Asia aimed at addressing those questions. Each trial seeks to determine whether goal-directed care with less complex goals is as effective as EGDT, or more so, in reducing severe sepsis mortality. It is clear that EGDT, which was designed in the 1990s using treatment and monitoring modalities that were logical at the time, will evolve as clinical science replaces its weaker components and improves on its stronger ones. However, the component of EGDT that is its linchpin, the establishing and achieving of physiologic goals or objectives and meeting them in a timely fashion, should not—and likely will not—change.



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