The Surviving Sepsis Campaign 2014: An Update on the Management and Performance Improvement For Adults in Severe Sepsis

ABSTRACT: The Surviving Sepsis Campaign includes both guidelines for the management of severe sepsis and septic shock as well as an international performance improvement program centered around the sepsis bundles. In order to logically approach management of severe sepsis, it is important to understand both the definitions of sepsis as well as the burden placed on society by sepsis. This article reviews the key targets for improving outcome in severe sepsis, including early diagnosis, early antibiotics, and early and appropriate fluid resuscitation targeting adequate tissue perfusion.

Born in 2002, the Surviving Sepsis Campaign (SSC) is a global program created by professional societies to (a) reduce mortality rates from severe sepsis through the creation of evidence-based management guidelines and (b) facilitate knowledge transfer and performance improvement at the bedside. Although initially seeded by industry grants, professional organization funding began between 2004 and 2008 and in 2009, the Gordon and Betty Moore Foundation, an independent philanthropic organization, has funded the cause. Figure 1 shows a timeline of The Surviving Sepsis Campaign over the years.

Definitions

In order to understand the management of severe sepsis and associated performance improvement programs, it is first necessary to understand current definitions. 

• Sepsis is defined as a known or suspected infection plus systemic manifestations of infections
(eg, traditional systemic inflammatory response syndrome criteria—tachy-cardia, tachypnea, white blood count changes, and fever/hypothermia as well as other metabolic perturbations or organ dysfunctions). 

• Severe sepsis is defined as sepsis plus infection-induced organ dysfunction or infection-induced acute tissue hypoperfusion. Organ dysfunctions associated with sepsis include acute lung injury, acute kidney injury, coagulopathy, liver dysfunction, and cardiovascular abnormality. Tissue hypoperfusion abnormalities include hypotension, elevated lactate, oliguria, and altered mental status.There is some overlap between tissue hypoperfusion abnormalities and organ dysfunction associated with the cardiovascular system. 

BURDEN OF SEPSIS

Severe sepsis is the leading cause of hospital death.^1,2 An enormous economic burden is attributed to severe sepsis and the general consensus is that early identification and early appropriate evidence-based medical care will impact this burden. 

The Guidelines

The first guidelines were published in 2004³ and sponsored by 14 international scientific organizations with interest and expertise in education and management related to severe sepsis. The 2008 guidelines were sponsored by 16 organizations⁴ and the 2013 guidelines were sponsored by 30 organizations (Figure 2).⁵ 

Since 2008, the SSC has had a strong affiliation with one of the premier evidence-based medicine groups, Grades of Recommendation Assessment, Development and Evaluation (The GRADE Group). Figures 3 and 4 demonstrate the categorization of both a quality of evidence assigned to each SSC recommendation and more importantly, the strength of the recommendation.

Key Recommendations

Key recommendations from the 2013 guidelines publication include: 

• Early quantitative resuscitation of the septic patient during the first 6 hours after recognition

• Blood cultures before antibiotic therapy

• Administration of broad-spectrum antimicrobials therapy within 1 hour of recognition of septic shock and severe sepsis without septic shock as the goal of therapy

• Imaging studies performed promptly to confirm a potential source of infection

• Infection source control with attention to the balance of risks and benefits of the chosen method within 12 hours of diagnosis

• Initial fluid resuscitation with crystalloid and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure as well as the avoidance of hetastarch formulations

• Initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients)

• Fluid challenge technique continued as long as hemodynamic improvement, as based on either dynamic or static variables

• Norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mm Hg

• Epinephrine or vasopressin (0.03 U/min) when an additional agent is needed to maintain adequate blood pressure

• Dopamine is not recommended except in highly selected circumstances

• Dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure

• Avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability 

• Addressing goals of care, including treatment plans and end of life planning, as early as feasible, but within 72 hours of intensive care unit admission

Initial Treatment and Stabilization 

Early diagnosis, early antibiotic administration, and adequate fluid resuscitation are key in decreasing sepsis morbidity and mortality. Sepsis-induced tissue hypoperfusion is defined as either a requirement for vasopressors after adequate fluid challenge or a lactate of ≥4 mg/dL. A myriad of physiological changes drive potential sepsis-induced tissue hypoperfusion in the patient with severe sepsis (Figure 5). This includes increased venous capacitance, decreased arteriolar resistance, decreased ventricular contractility, and capillary leak. Initial fluid therapy is considered paramount in the successful resuscitation of sepsis-induced tissue hypoperfusion. Crystalloids are recommended as the initial fluid of choice. Considerable discussion now exists about the choice of crystalloids between an unbalanced crystalloid (ie, normal saline) and balanced crystalloids (eg, lactated Ringers for Ringer’s acetate). More research is needed in this area but there is some concern as to the decreased pH and hyperchloremia associated with unbalanced crystalloids. This may be associated with untoward renal effects. 

Although randomized trials have failed to demonstrate benefit of albumin versus saline, meta-analysis data supports “potential” benefit of adding albumin to fluid resuscitation regimens in severe sepsis and septic shock when the patient requires substantial amounts of crystalloid.^6,7 Recent data would suggest that there is no advantage of albumin resuscitation targeting normalization of serum albumin over the first week of therapy of severe sepsis.⁸ Hydroxyethyl starches are not recommended for fluid resuscitation for severe sepsis and septic shock due to concern for producing acute kidney injury.^9-11 

Following initial fluid bolus, a patient with sepsis-induced hypotension or tissue hypoperfusion may require vasopressors to maintain blood pressure. Since following adequate intravascular volume repletion, the etiology of persistent hypotension must be related to some combination of decreased inotropy and arterial vasodilation; a combined inotrope vasopressor is recommended. The first choice for vasopressor therapy is norepinephrine.^12,13 A mean arterial pressure (MAP) target of 65 mm Hg is recommended.^14,15 If a MAP target of 65 mm Hg cannot be obtained with norepinephrine, then the 2 alternatives are: the addition of epinephrine to norepinephrine (with the potential for combination therapy or substitution of epinephrine) or low-dose vasopressin (up to .03 U/per minute). 

High dose vasopressin >.04 U/per minute is not recommended. Phenylephrine is also not recommended in the treatment of septic shock except (a) when norepinephrine is associated with serious arrhythmias, (b) cardiac output is known to be high and blood pressure target is difficult to maintain with combined inotrope vasopressors, or (c) as salvage therapy when other drugs are unsuccessful. Dopamine is also not recommended for vasopressor therapy except when the patient has a combination of both bradycardia and hypotension.

Quantitative Resuscitation 

When a patient is characterized as having sepsis-induced tissue hypoperfusion, protocolized care is recommended with attention drawn to achieving specific variables (ie, protocol targets). This would include basic targets such as MAP of 65 mm Hg and urine output of 0.5 ml/kg. Note: Evidence dating back to the early to mid 2000s support MAP target of 60 mm Hg to 65 mm Hg and more recently, comparisons of the use of norepinephrine in septic shock to targets of either 65 mm Hg to 75 mm Hg or 75 mm Hg to 85 mm Hg demonstrate no difference in outcome between the low target and high target group.^14,16 However, there were increased serious arrhythmias associated with the high target group. 

The current recommended bolus strategy for quantitative resuscitation is a minimum of an initial 30 mL/kg of crystalloids (a portion of this may be albumin equivalent) and more rapid administration and greater amounts of fluid may be needed in some patients (grade 1B). 

In 2004, the guidelines recommended traditional early goal-directed therapy targets of a central venous pressure (CVP) of 8 mm Hg to 12 mm Hg and ScvO2 target of ≥70%. However, there has been a significant transition of SSC thought process over the years with a turn toward a more generalized “quantitative resuscitation” approach.¹⁷ The Campaign has recognized and expressed the known limitations of CVP as a target to predict fluid responsiveness and has encouraged alternative methods as additional variables to integrate into decision-making when these are available. These include tracking delta systolic or delta pulse pressure variation with mechanical ventilator induced increases in intrathoracic pressure or stroke volume, tracking changes in these variables with incremental fluid boluses. Tracking flow can be done with a variety of methods to include FloTrac (Edward Lifesciences Corporation), Picco (Phillips Medical), or LiDCO (Lidco LLC), as well as the traditional pulmonary artery catheter. Likewise, the use of ultrasound to judge inferior vena cava size and respiratory variation as well as echocardiography to look at left ventricular chamber size and function may also be useful. Finally, recent data suggest that lactate clearance may offer benefit as part of a quantitative resuscitation protocol.^18,19

Although aggressive fluid resuscitation and associated stabilization of hemodynamics in a patient with septic shock are considered essential for increasing survival and decreasing morbidity from initial cardiovascular instability, this early aggressive fluid resuscitation may be problematic during the later course of the septic patient. With capillary leak that is present with sepsis-induced tissue hypoperfusion, considerable fluid will accumulate outside of the intravascular space and may be associated with lung, brain, and other organ edema. Most patients “autodiurese” as they recover from sepsis. There is now considerable discussion but no evidence-based medicine that mobilization of this fluid from “third spaces” might be facilitated with diuretics once cardiovascular stability is returned with more rapid recovery. However, this is currently speculation.

Steroids

In 2004, the Campaign recommended steroids for the treatment of septic shock. Over the next 2 revisions of the guidelines, the Campaign has since transitioned away for this stance on steroid benefit and is currently recommending against the use of intravenous corticosteroids in adults with septic shock if adequate fluid resuscitation and vasopressor therapy restore hemodynamic stability. When significant hemodynamic stability remains following fluids and vasopressors, corticosteroids are recommend at an IV dose of 200 mg hydrocortisone every 24 hours. 

Performance Improvement Program 

Although considered an important body of knowledge for physician education and a reference source for optimal treatment, guidelines do not have high impact on bedside healthcare practitioner performance. Simply put, guidelines are not enough. In order to change bedside behavior, protocols and performance improvement programs with audit and feedback are needed. Early screening and hospital-based performance improvement programs are now recommended by the Campaign. 

Guidelines are converted to “sepsis bundles,” which are measureable goals ascertained by review of medical records. These quality indicators are to be achieved in this specific disease state over specific time periods. The current sepsis bundles are outlined in Figures 6 and 7. The first set of bundles was created in 2005, followed by an international performance improvement campaign associated with free software and educational materials for voluntary hospital participation. 

Data from 10,000 patients were transmitted into a database housed at the Society of Critical Care Medicine. The results of this sepsis performance improvement program were published in 2010 and showed an association between increasing compliance with the sepsis bundles and decrease in mortality.²⁰ Unpublished data from 30,000 patients continues to show this finding in an even more pronounced fashion. When the database is examined, it is noticed that patients admitted directly to the intensive care unit (ICU) from the emergency department have a much better prognosis than those patients admitted to the ICU from the hospital wards. This is somewhat surprising but may relate to less vigilant monitoring on the hospital floors. 

A recently launched performance improvement program, sponsored by a collaboration between the Society of Critical Care Medicine and the Society of Hospital Medicine (also funded by the Henry and Betty Moore Foundation), is looking at the impact of early recognition and management of severe sepsis on a specifically designated hospital floor performance improvement initiative.

ProCESS Trial

In 2014, the Protocolized Care for Early Septic Shock (ProCESS) trial was published as the first of 3 trials (in progress or completed) that compare alternative resuscitation methodology to the traditional early goal-directed therapy target variables.²¹ The ProCESS trial compared the currently recommended early goal-directed therapy variables for quantitative resuscitation to a special ProCESS trial protocol that did not include central monitoring. 

Surprisingly, there was no difference between any of these approaches—a fact that has been regarded by some as an indictment against the need for quantitative resuscitation. This trial was conducted primarily in large academic centers, well versed with severe sepsis and severe sepsis resuscitation, and most likely all patients received some type of quantitative resuscitation in the mind of the treating team. 

The quality of care delivered to these patients is reflected by the fact that all groups in ProCESS received greater than 2 L average fluid prior to randomization and 75% received antibiotics prior to randomization. In addition, a majority of patients in both the ProCESS and usual care arms had CVP catheters although the trial was not powered to compare patients without CVP catheters with the early goal-directed therapy group. 

The 18% mortality in septic shock in the ProCESS trial does not reflect mortality in typical hospitals in which performance improvement programs, including protocolized care, are still recommended. The ProCESS trial, however, does support the fact that CVP and ScvO2 measurement may not be necessary if the treating physician is knowledgeable of the pathophysiology of severe sepsis and keenly aware of early antibiotic and fluid resuscitation needs. 

Two additional trials—the Australian Resuscitation In Sepsis Evaluation (ARISE) trial and Protocolized Management in Sepsis (ProMISe) trial —are forthcoming. These trials will likely give more important information that will allow an SSC reassessment of current protocolized care and targets used for resuscitation of severe sepsis and septic shock 

The Surviving Sepsis Campaign has been a remarkable journey into international consensus on the management of severe sepsis as well as the linked sepsis performance improvement program. Guideline recommendations and performance improvement quality indicators continue to evolve as new evidence emerges. The performance improvement program continues to expand its scope both geographically and across different hospital areas.

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