The Surviving Sepsis Campaign: Where have we been and where are we going?

Sepsis is familiar to most physicians in clinical practice, but guidance from the medical literature on how best to manage it has traditionally been confusing.

Starting in 2002, the Surviving Sepsis Campaign has worked to reduce worldwide mortality from severe sepsis and septic shock by developing and publicizing guidelines of best practices based on evidence from the literature. The campaign published its first management guidelines in 2004.

In this article, I review the most recent guidelines^1,2 (published in 2013) and discuss the campaign’s ongoing performance-improvement program.

DEFINING SEPSIS

Sepsis is a known or suspected infection plus systemic manifestations of infection. This includes the sepsis inflammatory response syndrome. Criteria include:

• Tachycardia (heart rate > 90 beats per minute)
• Tachypnea (> 20 breaths/minute or Paco₂ < 32 mm Hg)
• Fever (temperature > 38.3°C [100.9°F]) or hypothermia (core temperature < 36°C [96.8°F])
• High or low white blood cell count (> 12.0 × 10⁹/L or < 4.0 × 10⁹/L), or a normal count with more than 10% immature cells.

The definition of sepsis was broadened in 2002 to include other systemic manifestations of infection, such as changes in blood glucose level and organ dysfunction.

Severe sepsis is defined as sepsis plus either acute organ dysfunction or tissue hypoperfusion due to infection, with tissue hypoperfusion defined as:

• Hypotension (systolic blood pressure < 90 mm Hg, or a drop in systolic blood pressure of > 40 mm Hg)
• Elevated lactate
• Low urine output
• Altered mental status.

In severe sepsis, organ dysfunction is caused by blood-borne toxins and involves acute lung and kidney injury, coagulopathy (thrombocytopenia and increased international normalized ratio), and liver dysfunction.

Septic shock is present when a patient requires vasopressors after adequate intravascular volume repletion.

SEPSIS IS DEADLY AND COSTLY

Severe sepsis is the leading cause of hospital death. Patients admitted with severe sepsis are eight times more likely to die than those admitted with other conditions.³ The economic burden is enormous: it is the most expensive condition treated in US hospitals, costing an estimated $20.3 billion in 2011, of which $12.7 billion came from Medicare.

THE SURVIVING SEPSIS CAMPAIGN

The Surviving Sepsis Campaign is a global effort to reduce the rate of death from severe sepsis. The campaign’s methods include:

Patients with severe sepsis are eight times more likely to die than those with other conditions

• Educating physicians, the public, the media, and government about the high rates of morbidity and death in severe sepsis
• Creating evidence-based guidelines for managing sepsis and establishing global best-practice standards
• Facilitating the transfer of knowledge by developing performance-improvement programs to change bedside practice.

The campaign is funded with a grant from the Gordon and Betty Moore Foundation. The campaign’s guidelines are not associated with any direct or indirect industry support. The 2013 guidelines were backed by 30 international organizations.^1,2

All recommendations are ranked with numerical and letter scores, according to the GRADE system: 1 indicates a strong recommendation and 2 a weak one. The letters A through D reflect the quality of evidence, ranging from high (A) to very low (D).

GIVING ANTIBIOTICS EARLY IMPROVES OUTCOMES

A number of studies have suggested that starting appropriate antibiotics early improves outcomes in severe sepsis and septic shock. The death rate increases with each hour of delay.⁴

Recommendation. Intravenous antibiotic therapy should be started as soon as possible, and within the first hour after recognition of septic shock (grade 1B) and severe sepsis without septic shock (grade 1C).

The feasibility of achieving this goal has not been scientifically validated, and the recommendation should not be misinterpreted as the current standard of care. Even hospitals that participate in performance-improvement programs often struggle to start antibiotics, even within 6 hours of recognition. Nevertheless, the goal is a good one.

Some have questioned the early antibiotic recommendation because of concerns about antibiotic overuse and resistance. For a patient with some manifestation of systemic inflammation, such as organ dysfunction or hypotension with no clear cause, the campaign’s position is to provide empiric antibiotics early and then, if a noninfectious cause is found, to stop the antibiotics. Moreover, as soon as a causative pathogen has been identified, the regimen should be switched to the most appropriate antimicrobial that covers the pathogen and is safe and cost-effective. Collaboration with an antimicrobial stewardship program, if available, is encouraged.

FIND THE INFECTION SOURCE PROMPTLY: SOURCE CONTROL MAY BE REQUIRED

Recommendation. A specific anatomic diagnosis of infection (eg, necrotizing soft-tissue infection, peritonitis complicated by intra-abdominal infection, cholangitis, intestinal infarction) requiring consideration of emergency source control should be confirmed or excluded as soon as possible. If needed, surgical drainage should be undertaken for source control within the first 12 hours after a diagnosis is made (grade 1C).

FLUID THERAPY: CRYSTALLOIDS FIRST

Recommendation. In fluid resuscitation of severe sepsis, use crystalloids first (grade 1B).

Mortality risk increases with each hour of delay in starting antibiotics

No head-to-head trial has shown albumin to be superior to crystalloids, and crystalloids are less expensive. However, normal saline has a higher chloride content than plasma, which leads to non-anion-gap metabolic acidosis. It is called an unbalanced crystalloid, having a high chloride content and no buffer. There is concern that this reduces renal blood flow and the glomerular filtration rate, creating the potential for acute kidney injury. Although no high-level evidence supports this concern, some animal studies and historical control studies suggest that a balanced crystalloid such as Ringer’s lactate, Ringer’s acetate, or PlasmaLyte (having a chloride content close to that of plasma and the buffers acetate or lactate) may be associated with better outcome in resuscitation of severe sepsis.

Use albumin solution if necessary

Recommendation. Albumin should be used in the fluid resuscitation of severe sepsis and septic shock for patients who require substantial amounts of crystalloids (grade 2C).

Finfer et al⁵ compared the effect of fluid resuscitation with either an albumin or saline solution in nearly 7,000 patients in intensive care and found that death rates over 28 days were nearly identical between the two groups. Although this study was not designed to measure an effect in subsets of patients, the subgroup with severe sepsis had a lower mortality rate with albumin (relative risk 0.87, 95% confidence interval 0.74–1.02). In a meta-analysis of 17 studies of albumin vs crystalloids or albumin vs saline, Delaney et al⁶ found a significant survival advantage with an albumin solution in patients with sepsis and severe septic shock.

Sometimes, in patients admitted to intensive care with septic shock and receiving two or three vasopressors and large amounts of a crystalloid solution, vasopressors can be reduced when fluid is being given, but as soon as the fluid infusion rate is decreased, the need for increasing vasopressors returns. This scenario is an indication for changing to an albumin solution.

Recommendation. Initial fluid challenge in sepsis-induced tissue hypoperfusion (as evidenced by hypotension or elevated lactate) with suspicion of hypovolemia should be a minimum of 30 mL/kg of crystalloids, a portion of which can be an albumin equivalent. Some patients require more rapid administration and greater amounts of fluid (grade 1B).

Other fluid resuscitation considerations

Recommendation. Hydroxyethyl starch (hetastarch) should not be used for fluid resuscitation of severe sepsis and septic shock (grade 1B).

Five large clinical trials^7–11 compared hetastarch with crystalloids in the resuscitation of severe sepsis or septic shock. None found an advantage to using hetastarch, and three found it to be associated with higher rates of acute kidney injury and renal-replacement therapy.

Blood is not considered a resuscitation fluid.

Full fluid replacement is still needed in heart or kidney disease

Often, doctors hesitate to administer full fluid resuscitation to patients with septic shock or sepsis-induced hypotension who have baseline cardiomyopathy with a low ejection fraction or who have end-stage renal disease and are anuric. However, these patients’ baseline intravascular volume status has changed because of venodilation and capillary leak leading to reduced blood return to the heart. They require the same amount of fluids as other patients to return to their baseline state.

To avoid fluid overload in these patients, however, we recommend providing fluid in smaller boluses. For a young, previously healthy patient, 2 L of crystalloid should be provided as quickly as possible. Patients with heart or kidney disease should receive smaller (250- or 500-mL) boluses, with oxygen saturation checked after each dose, as hypoxemia is one of only two potential downsides of aggressive fluid resuscitation (the other being the further raising of intra-abdominal pressure in the intra-abdominal compartment syndrome).