By Kathryn Radigan, MD, MSCI

Attending Physician, Division of Pulmonary and Critical Care, Stroger Hospital of Cook County, Chicago

Dr. Radigan reports no financial relationships relevant to this field of study.

Sepsis remains the leading cause of death in U.S. hospitals.1 Similar to acute stroke and myocardial infarction, immediate identification and optimal management in the early hours of sepsis improve outcomes. Although we have made strides in the right direction with decreasing mortality rates, the incidence continues to increase.2 In addition to compliance with the sepsis bundles (now mandated by the United States Centers for Medicare and Medicaid Services), how can critical care providers revolutionize and individualize sepsis care for optimal results?

History

Early recognition and appropriate, aggressive treatment have improved sepsis mortality. Early goal-directed therapy (EGDT), as presented by Rivers in 2001, was one of the first studies to bring attention to these issues.3 Despite some controversy, Rivers was the first to identify high-risk patients, mobilize resources for intervention, and execute a protocol to reverse initial hemodynamic abnormalities associated with sepsis with a subsequent decrease in mortality. After Rivers and his colleagues gained attention, the Surviving Sepsis Campaign (SSC) was launched in 2002 through collaboration between the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine with the goal to reduce sepsis-related mortality. These efforts were advanced further in 2004 when the SSC drafted guidelines for the management of severe sepsis and septic shock, which were updated and optimized in 2008, 2012, and 2016.

Surviving Sepsis Campaign Guidelines

Although there were a number of adaptations to the 2016 guidelines, initial resuscitation and antibiotics were the focus.4,5 Strict EGDT targets are no longer emphasized, and dynamic measurements rather than static variables to predict fluid responsiveness are favored. The idea is to use these dynamic variables before and after fluid administration, assessing for both fluid responsiveness and clinical improvement. Unfortunately, fluids often are not stopped even when no clinical benefit has been shown.6 The goal is to transition from a protocolized, quantitative strategy of resuscitation to one that is a more patient-centered approach, guided by hemodynamic assessment, including dynamic variables for responsiveness to fluids and ongoing reevaluation of the patient’s response to treatment.

Antibiotics were the other focus, with an emphasis on source control and early, appropriate antibiotics.4 Although substantial controversy remains, the new guidelines recommend antibiotics targeting the specific source of infection within one hour, with an assessment of whether the patient is at increased risk for resistance and ensuring the antibiotics are dosed optimally. Empiric broad-spectrum therapy with one or more antimicrobials to cover all likely pathogens (bacterial and potentially fungal or viral coverage) for patients presenting with sepsis or septic shock also has been recommended.

Improving Sepsis Care

A multipronged, evidence-based strategy to improve care is recommended. The strategy may include education, sepsis coordinators, early interventions (i.e., antibiotics, fluids, source control), and quality improvement initiatives. Sepsis coordinators and the establishment of a pilot program may be a first step in optimal care. Sepsis coordinators, who act as expert leaders in the field of nursing with critical care experience, are crucial in optimizing sepsis care, identifying barriers, and providing feedback and education in addition to collecting data to institute change in areas that need further development. SCCM guidelines recommend piloting programs on a particular unit, which allows for changes on a small scale, promotes an environment where frontline staff can provide feedback, and ensures that modifications are effective and optimized before a broader initiative to other units.7

Education

It is vital to develop a system-wide, comprehensive approach to educate all nurses, rapid response teams, physicians, and pharmacists about sepsis. Institutions may start by instituting treatment algorithms and management bundles in accordance with SSC guidelines. Sepsis preference lists and antibiotic algorithms with infusion rates may help to facilitate care and should be available easily or within an order set. Mandatory electronic learning sepsis modules, which include pre-testing, clinical vignettes, and post-testing, have been effective. It is recommended that key information be available online, printed on pocket cards to facilitate wide distribution, and/or posted in all clinical care units and work areas. Educational programs alone have been promising, with one pilot study revealing in-hospital mortality decreased from 79% to 32%, largely as a result of educational efforts by their sepsis program.8-10

Early Intervention and Care

Earlier identification is achieved more often through a multifaceted approach with nursing as the driving force for the earliest intervention. Usually it starts with the adoption of an institutional surveillance system, screening tool, and/or protocol designed to facilitate early recognition and treatment of sepsis.

Surveillance systems have been widely used for sepsis and often are successful since they are designed to be more proactive rather than reactive in their response to sepsis. These may be manual or automated systemic inflammatory response syndrome (SIRS)-based or non-SIRS-based systems. Although numerous screening tools and protocols are available for use, Thiel and colleagues were some of the first to develop a simple algorithm, the Recursive Partitioning And Regression Tree (RPART) analysis, to generate a prediction model that could be used in an automated fashion to screen hospitalized patients for impending septic shock.11 Their work revealed a positive predictive value (PPV) of 21.4% and a negative predictive value (NPV) of 96.1% for the diagnosis of septic shock in one of their validation cohorts.12

Since that time, multiple electronic algorithms have been developed and improved on these standards. More recently, Churpek and colleagues compared multiple systems for predicting outcomes across different suspicion of infection criteria in hospitalized patients outside the intensive care unit (ICU). The group found electronic Cardiac Arrest Risk Triage (eCART) to be the most accurate, followed by Modified Early Warning Score (MEWS), the National Early Warning Score (NEWS) system, quick Sequential Organ Failure Assessment (qSOFA), and then SIRS criteria, with SOFA scores found to be the least accurate among both sepsis-specific and general early warning scores.13 Green and colleagues also revealed the eCART system had superior accuracy in predicting adverse outcomes, including in-hospital cardiac arrest, ICU transfer, and death within 24 hours of observation.14

Although standard operating procedures and protocols may appear helpful in optimizing sepsis care delivery, three government-funded, multicenter, randomized, controlled trials from the United States (Protocolized Care for Early Septic Shock [ProCESS]), Australasia (Australasian Resuscitation in Sepsis Evaluation [ARISE]), and the United Kingdom (Protocolised Management in Sepsis [ProMISe]) failed to show lower mortality with EGDT than with usual care.15-17 Even though protocols have been less successful, compliance with the bundles continues to demonstrate improved outcomes. Levy and colleagues demonstrated that increased compliance with sepsis performance bundles was associated with a 25% relative risk reduction in the mortality rate.18 Compliance with bundles at 3 and 6 hours and even up to 18 hours have demonstrated a significant mortality benefit.19,20 Although multiple bundle components of the Sepsis Center for Medicare and Medicaid Services (CMS) Core Measure (SEP-1) were associated with reduced mortality or decreased days of vasopressor therapy for patients who presented with sepsis in the emergency department, only broad-spectrum intravenous antibiotic treatment was associated with reduced mortality when time 0 occurred in an inpatient unit.21 The most recent severe sepsis bundle recommendations include serum lactate, blood cultures, and antibiotics within three hours, along with 30 mL/kg of crystalloid fluids if evidence of hypotension or elevated lactic acid is present. Repeat lactic acid within six hours is recommended if initial lactic acid is elevated. For septic shock, recommendations are similar but also include a repeat volume status and tissue perfusion assessment, along with vasopressors if indicated, within six hours.

The unfortunate aspect of electronic tools for the identification and treatment of sepsis is that they often are only as good as they are used. Semler and colleagues were involved in a randomized controlled trial that included an electronic tool for the evaluation and treatment of sepsis in the ICU.22 This electronic tool was built to receive information on patients who met modified SIRS criteria, notify providers of the finding, and solicit an assessment to determine if the patient clinically met criteria for sepsis. Unfortunately, there was no difference between use of the electronic tool and usual care regarding the primary outcome of completion of all indicated SSC six-hour bundle elements or time to completion of each arm individually. There was no difference in ICU mortality, ICU days, and ventilator-free days between the intervention and control groups. This was predominantly because clinicians only used the tool for 28% of available cases. This study emphasizes that the success of future electronic tools to optimize sepsis care depends on clinicians actually using the resources available.

Early Antimicrobial and Fluid Administration

As previously mentioned, a recent study showed that broad-spectrum intravenous antibiotic treatment was the only intervention associated with reduced mortality when time 0 occurred in an inpatient unit.21 Inadequately dosed or delayed antibiotics led to an increased mortality of almost 8% per hour over the first six hours after sepsis diagnosis, supporting the idea that there may be a “golden hour” of antibiotic administration.23,24 In a multicenter observational study of the timing of antimicrobial administration in septic shock, Amaral and colleagues revealed that patients who were at the highest risk for delays were those admitted to the ICU from the hospital wards, patients in academic institutions, patients with nosocomial infections or pneumonia, and those with longer hospitalizations before the onset of septic shock.25 Patients who were older, with a higher Acute Physiology Score, more comorbidities, and the absence of fever at presentation also were more likely to have administration of antimicrobials delayed.

For most institutions, it is vital to retrospectively evaluate their own timing of antibiotic delivery and scrutinize for areas of improvement. There may be unacceptably high rates of failure to recognize sepsis or inappropriate empiric antimicrobial initiation (e.g., failure to evaluate previous culture data, evaluate risk factors for resistant organisms, and/or acknowledge previous antibiotic administration).26 In addition, there may be failure to identify administrative or logistic factors to timely administration. Possible solutions to delays include using “stat” orders, using order sets, addressing delays in obtaining blood and site cultures pending antimicrobial administration, providing optimal sequencing of antimicrobial delivery or using simultaneous delivery of key antimicrobials, as well as improving supply chain deficiencies. Focusing on improved communication among medical, pharmacy, and nursing staff often is most valuable.

Other antibiotic issues also may be due to preparation. If mixing and delivering antimicrobial agents promptly from the pharmacy is not possible, establishing a supply of premixed drugs for urgent situations is a suitable plan of care.26 If the antimicrobials will not remain stable as a premixed solution, this issue must be taken into consideration with more troubleshooting. In choosing antibiotics, clinicians should rely on antibiotics safely administered as a bolus or rapid infusion, while others may require an extended infusion. Ensuring prompt IV infusion of antimicrobial agents should be a priority.

The literature on the amount of fluid to administer to patients in septic shock is evolving. While current guidelines recommend a 30 mL/kg crystalloid bolus, this may not apply to patients who have been resuscitated previously. A randomized clinical trial, the Crystalloid Liberal Or Vasopressor Early Resuscitation in Sepsis (CLOVERS) trial, is currently underway and will compare a liberal vs. restrictive approach to intravenous fluid (IVF) resuscitation and earlier use of vasopressors.27

Sepsis Quality Improvement Initiatives

Armin and colleagues tested a quality improvement initiative that included earlier identification of sepsis, prompt antimicrobial administration, and an educational program. They found a significant improvement in sepsis mortality with an observed sepsis mortality reduction of 4.6%, along with a 1.1-day shorter ICU duration of stay and a 2.2-day shorter overall hospital stay.28 Although not statistically significant, hospital costs were reduced by $1,949 on average per patient with sepsis.

Levy and colleagues conducted the largest prospective series of severe sepsis patients in more than 30 countries that included a multifaceted, collaborative intervention designed to facilitate adoption of the SSC resuscitation and management bundles. This initiative included physician and nurse champions, introduction of sepsis bundles, education, distribution of a secure database application that allowed for data collection and transfer, as well as audit and feedback.29 They demonstrated that an increase in compliance with the intervention bundle was associated with a 25% relative risk reduction in mortality. They also observed reductions in ICU and hospital length-of-stay in high-compliance institutions relative to low-compliance institutions.

Summary

Optimal evidence-based sepsis management includes a multidisciplinary approach with educational interventions, systems for earlier identification, prompt antimicrobial administration, and constant feedback to care teams. It is vital that nurse- and physician-specific barriers to sepsis care are identified and modified. Piloting identified solutions in targeted areas before rolling them out system-wide can provide valuable feedback and other opportunities for optimization. Once these initiatives have been optimized, an institution-specific plan for sustainability of interventions that includes monitoring and feedback is critical.

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