Recommendations for Sepsis Management

Objective

This chapter will:

1.
Present key evidence pertaining to the treatment of sepsis.

Infection is a common occurrence in the intensive care unit (ICU), as a reason for ICU admission and when acquired in the ICU, and results in significant morbidity and mortality. In the United States the annual incidence of infection-induced organ dysfunction is estimated to be more than 750,000 cases a year, resulting in more than $24 billion in costs, which is more than the gross domestic product of some European countries, such as Estonia, Iceland, or Malta. Despite significant advances in our understanding of infection-induced organ dysfunction, the mortality rates remain unacceptably high, with rates ranging from 10% to 50% based on definition and population used for extraction.

However, first we begin with a discussion of the challenges of defining infection-induced systemic perturbations with a focus on organ dysfunction.

Definitions

The American College of Chest Physicians and the Society of Critical Care Medicine held the first sepsis definitions consensus conference in 1991 with the creation of the term systemic inflammatory response syndrome (SIRS) . The criteria for SIRS were based on heart rate, respiratory rate, temperature, and white blood cell count. Infection associated with abnormalities (specific defined thresholds) of two of these four criteria was called sepsis. SIRS was recognized to occur in noninfectious conditions as well. Severe sepsis was the recommended term to characterize patients with sepsis-induced organ dysfunction or tissue hypoperfusion.

The second sepsis definitions consensus conference was held in 2001 with minor modifications to the 1991 definitions. There was an expansion of clinical and laboratory parameters that would define sepsis, which were additive to the SIRS criteria. The definition of severe sepsis remained unchanged. Septic shock was defined as hypotension characterized by either a systolic blood pressure less than 90 mm Hg or mean arterial pressure (MAP) less than 70 mm Hg despite adequate fluid resuscitation. The third sepsis definitions consensus conference was published in 2015 with major revisions in the sepsis terminology recommended. This committee recommended abandoning the term severe sepsis and using sepsis to describe infection-induced organ dysfunction or tissue hypoperfusion. The previous use of the word sepsis, infection with systemic manifestations, no longer had a specific name, and the word infection was recommended regardless of whether systemic manifestations of infection were present. This most recent document recommended de-emphasizing the SIRS criteria.

Because the 2001 definitions currently are used in the United States for both ICD-10 codes and are the reference standard for the Centers for Medicare and Medicaid Services (CMS) quality metrics, any movement to adopt these definitions likely will be slow and will require planning and coordination with these agencies.

Antibiotics Administration

Antibiotics administration is a cornerstone in the treatment of sepsis. There are three issues pertaining to this important therapy: mode of administration, type of antibiotics, and timing of treatment.

Mode of Administration

In the setting of severe sepsis and septic shock the administration of antibiotics should be done intravenously to ensure adequate bioavailability and prompt delivery of the medication to the blood stream and affected organs of the diseased patient.

Type of Antibiotics

In the absence of a definitive microbe as the cause of severe sepsis, broad-spectrum antimicrobials must be administered to cover a wide range of potential pathogens. This approach is supported by retrospective studies in which inappropriate antibiotic treatment was associated with higher mortality. An additional issue that sometimes arises is whether antifungal agents should be added up front. The decision to cover broadly must be linked to the commitment to de-escalate antibiotics based on culture results. De-escalation therapy is safe and results in improved outcomes.

It would seem reasonable that in a patient with appropriate risk factors (such as cancer on chemotherapy or chronic TPN) that clinicians consider upfront treatment with an antifungal, because if unrecognized, it can be associated with substantial mortality. Another controversial topic is using combination treatment for high index of suspicion of having pseudomonal infection. Recent data suggest that this approach could result in better outcomes.

Timing of Antibiotics Administration

This has been the topic of several studies and one recent meta-analysis. In a large retrospective study of 2731 patients with septic shock in 14 intensive care units (ICUs) from 1998 until 2004 in the United States and Canada, Kumar showed that earlier administration of antibiotics, hour after hour from diagnosis of hypotension improved survival. Delaying the administration beyond the first hour had an exponential impact on mortality. After adjusting for other factors, timing of administration of antibiotics was the most powerful predictor of survival in this patient population. In another study from Europe done in 165 ICUs that included almost 18,000 patients between 2005 and 2010, Ferrer showed similarly that delay in antibiotics administration was associated with a worsening of survival. Not all studies confirm these findings.

In a recent meta-analysis, Sterling et al. combined the results of 11 trials and concluded that there was no definitive evidence to support that early antibiotics treatment was associated with improved outcomes. This study had several notable limitations. As the authors point out, the trials included were heterogeneous. In addition, correctly identifying a time “zero” can be challenging. It has been shown that in the emergency department a significant portion of patients (15% to 23%) with documented severe sepsis are misclassified at triage; thus correctly deciding on an accurate start time for shock is daunting because of the unpredictable and changing clinical course of the disease. Finally, there was little information about appropriateness of the antibiotics (broad vs. narrow spectrum) and results of microbiology testing. Argument for early administration of antibiotics is the earliest possible attempt to limit bacterial growth and spread. In the absence of any possibility of doing a prospective randomized study (because equipoise could not be obtained for the trail that randomized patients to earlier versus later antibiotics) effective antibiotics should be administered as soon as possible and preferably within 1 hour of hypotension or detection of other infection induced organ dysfunction.

Vasopressor Agents

Regarding vasopressor therapy of persistent infection-induced hypotension, important questions to consider are the following: What should the patient's blood pressure goal be? Which vasopressor agent(s) should be used? When should vasopressors be initiated?

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