Sepsis, an extreme response to infection that can cause tissue damage and organ failure if not treated promptly and appropriately,1 is a leading cause of death worldwide.2 Projections based on hospital data alone suggest that, globally, there are more than 31 million sepsis cases and 5 million deaths from sepsis each year.2 However, disease burden and death rates may be higher than reported since, in less developed countries where there is a higher prevalence of infectious disease, sepsis epidemiological data are lacking.2 Each year in the United States, sepsis affects more than 1.5 million people and kills roughly 250,000.3 According to the Agency for Healthcare Research and Quality, sepsis accounts for more hospital expenditures than acute myocardial infarction and acute cerebrovascular disease combined, and septicemia was the most expensive condition treated in the United States in 2013, consuming a staggering $23.7 billion.4
The reported incidence of sepsis continues to rise.5 Possible explanations include the increase in antibiotic-resistant infections, the growing use of immunosuppressive medications, improved coding of sepsis as a result of automatic calculations of clinical variables in electronic health records (EHRs), improved diagnosis of sepsis because of greater awareness, and the aging of the U.S. population with the subsequent accompanying surge in chronic disease.6, 7 In countries with advanced health care delivery systems, people over age 65 account for 60% of sepsis cases and 75% of sepsis-related deaths.8 According to the Centers for Disease Control and Prevention, seven in 10 patients with sepsis recently received health care services or had chronic diseases that required frequent medical care.3
Prompt recognition and treatment of sepsis are essential to saving lives. Early goal-directed therapy has been shown to improve patient outcomes and decrease mortality by more than 15% compared with standard care.9, 10 In response to the landmark study by Rivers and colleagues, in which in-hospital mortality rates were lower in patients receiving early goal-directed therapy compared with those receiving usual care (30.5% versus 46.5%),10, 11 the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM) recommended early goal-directed therapy for sepsis and, in 2002, launched the Surviving Sepsis Campaign (SSC) to improve sepsis care. The SSC guidelines were first published in 2004 and have undergone three revisions, most recently in 2016.12 (See Table 1 for a summary of the 2016 guidelines.12) As the 2016 SSC guidelines were being developed, the SCCM and ESICM also convened a task force to evaluate and update sepsis definitions and clinical criteria based on advances in the understanding of sepsis pathobiology and epidemiology.5 In February 2016, this task force published the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3),5 which introduced new screening, assessment, and management strategies.
Nurses play a critical role in the early detection of sepsis, as they are often first to recognize signs and symptoms of infection. As such, nurses can ensure that patients are screened promptly and treated appropriately. This article reviews the revised definitions of sepsis and septic shock; reviews screening and assessment tools used to identify sepsis in the ICU, in the ED, on the medical–surgical unit, and outside the hospital; describes sepsis diagnostic criteria, as well as the care bundles at the center of the SSC treatment guidelines; and discusses the nursing implications associated with sepsis and its management.
EVOLUTION OF SEPSIS DEFINITIONS AND SCREENING TOOLS
The first definitions developed to guide sepsis management were introduced in 1991 and based on the idea that sepsis was a systemic inflammatory response syndrome (SIRS) characterized by two or more of the following13:
- temperature above 38°C or below 36°C
- heart rate above 90 beats per minute
- respiratory rate above 20 breaths per minute or partial pressure of arterial carbon dioxide below 32 mmHg
- white blood cell count greater than 12,000/mm3 or less than 4,000/mm3, or the presence of immature neutrophils (“bands”) exceeding 10%
In the presence of infection, SIRS was identified as sepsis, and in the presence of multiple organ dysfunction syndrome, hypoperfusion, or hypotension, the syndrome was described as severe sepsis.13 The SIRS criteria met early opposition, as these same physiologic criteria are often observed in such noninfectious conditions as pancreatitis, burns, ischemia, trauma, and hemorrhagic shock.13
Sepsis-3. Over the past 27 years, as more was discovered about sepsis-induced biological changes, sepsis diagnostic criteria were expanded; however, sepsis definitions remained largely unchanged until Sepsis-3.5 In 2016, the Sepsis-3 task force determined that the term sepsis should be defined as “life-threatening organ dysfunction” brought on by a “dysregulated” response to infection, and that the term septic shock should be used to describe “a subset of sepsis” in which “circulatory, cellular, and metabolic abnormalities” substantially increase the risk of death over that associated with sepsis alone. Septic shock can be identified in patients who require vasopressor therapy to maintain a mean arterial pressure (MAP) of at least 65 mmHg, or have a serum lactate level greater than 2 mmol/L (18 mg/dL), despite adequate fluid resuscitation.5 The task force deemed the term severe sepsis redundant, as it was often used interchangeably with the term sepsis, and they unanimously agreed that SIRS screening criteria were unhelpful, being nonspecific and overly sensitive.5 In earlier studies, SIRS criteria had identified 87% of ICU patients and 50% of medical patients as having sepsis.14, 15 Sepsis-3 thus no longer supports use of the term severe sepsis or use of the SIRS criteria as a screening tool for sepsis.
New screening tools. For ICU sepsis screening, the Sepsis-3 task force recommended use of the Sequential Organ Failure Assessment (SOFA) score, which had been developed to elucidate the progression of multisystem organ failure and evaluate the effects of various therapies on organ dysfunction and failure.16 For sepsis screening in non-ICU settings, they recommended use of the quick SOFA (qSOFA), an abbreviated version developed in 2016 by Seymour and colleagues.5 In contrast to the SOFA score, the qSOFA requires no laboratory tests and can be repeated frequently, prompting further assessment of organ function, initiation or escalation of treatment, or transfer to intensive care.5 (See The Sequential Organ Failure Assessment (SOFA) Score16, 17 and The Quick Sequential Organ Failure Assessment (qSOFA) Score.5, 17)
When Seymour and colleagues retrospectively reviewed data from 148,907 hospital patients with suspected infection (15,768 ICU patients and 133,139 non-ICU patients), they found that the predictive validity for in-hospital mortality of SOFA criteria was significantly greater than both the SIRS and qSOFA criteria when applied to ICU patients. Outside of the ICU, however, qSOFA had significantly greater predictive validity for in-hospital mortality than either the SIRS or SOFA criteria.18 Likewise, an international prospective cohort study performed in 30 EDs within four European countries found that the qSOFA score was better at predicting in-hospital mortality than the SIRS criteria, supporting Sepsis-3 recommendations.19
Nursing assessments for sepsis should consider patients’ history, risk factors, and SOFA or qSOFA criteria before determining next steps (see Nursing Assessment for Sepsis).
CLINICAL DECISION SUPPORT TOOLS
Clinical decision support (CDS) encompasses a variety of tools that can be integrated into the EHR to assist health care providers in making timely evidence-based decisions. Because of the need for prompt recognition and treatment of sepsis to prevent life-threatening complications, the integration of sepsis CDS into EHRs is invaluable. When coupled with protocol-driven staff response, the implementation of electronic screening tools has been shown to reduce door-to-bolus and door-to-antibiotics times by 31 and 59 minutes, respectively, in ED patients with suspected sepsis.20 EHR sepsis screening tools have a sensitivity of 93%, a specificity of 98%, and a negative predictive value of up to 100%.21, 22 Like that of other sepsis screening methods, however, the positive predictive value of EHR sepsis screening tools is low, ranging from 21% to 45%, highlighting the importance of clinical judgment in identifying patients with sepsis.21, 22
EARLY GOAL-DIRECTED THERAPY: THE SEPSIS BUNDLES
Bundles are a structured set of interventions that have consistently been shown to improve patient outcomes when performed collectively.23 In 2004, the SSC introduced a six-hour resuscitation bundle and a 24-hour management bundle.24 Data collected on 29,470 patients in 218 hospitals in the United States, South America, and Europe between January 2005 and June 2012 indicated that adherence to the 2004 bundles was associated with a 25% relative risk reduction in sepsis mortality rates.25 In 2012, the SSC revised the 2004 sepsis care bundles, dropping the management bundle and dividing the resuscitation bundle into three- and six-hour time periods to improve adherence to the SSC guidelines.9, 24 In 2015, the SSC revised the bundles again in accordance with new evidence.26 This year, in order to treat sepsis as a medical emergency with the same degree of urgency as trauma and stroke, the SSC combined the three- and six-hour bundles into a one-hour bundle.27 Developed “with the explicit intention of beginning resuscitation and management immediately,” the one-hour bundle comprises the following27:
- Measure lactate level. Remeasure if initial lactate is > 2 mmol/L.
- Obtain blood cultures prior to administration of antibiotics.
- Administer broad-spectrum antibiotics.
- Begin rapid administration of 30 mL/kg crystalloid for hypotension or lactate ≥ 4 mmol/L.
- Apply vasopressors if patient is hypotensive during or after fluid resuscitation to maintain MAP ≥ 65 mmHg.
THE ONE-HOUR SEPSIS BUNDLE
Serum lactate is measured to assess for tissue hypoperfusion in patients who are not yet hypotensive but who are at risk for septic shock (those with tachypnea and altered mentation in the presence of suspected infection, for example). Lactate levels of 4 mmol/L or higher are associated with a mortality rate of 30%.9 Either arterial or venous lactate samples may be used.
Blood cultures. To increase the probability of identifying the causative organism and the specific site of infection, two or more blood cultures, one drawn percutaneously and another through the current vascular access device, and any other indicated cultures (such as urine, cerebrospinal fluid, wound, or sputum) should be collected before broad-spectrum antibiotics are administered, provided it does not delay antibiotic administration by more than 45 minutes.9 It should be noted that cultures are negative in more than half of patients with sepsis who are receiving empiric antimicrobial therapy when blood is drawn.9
Broad-spectrum antimicrobials. Appropriate broad-spectrum antimicrobial therapy has been shown to reduce mortality in patients with gram-positive and gram-negative bacteremia, as well as in those with fungal and viral infections.9
When the causative organism is identified, antimicrobial therapy should be narrowed to reduce the risk of resistant pathogens, toxicity, and costs.9 The Infectious Diseases Society of America (IDSA) recommends that facilities develop clinical practice guidelines that standardize antimicrobial prescribing practices based on local epidemiology.28 Procalcitonin levels can also be used to guide the duration of antibiotic therapy to avoid antimicrobial resistance, reduce length of stay, and lower costs.29
Crystalloid administration. A 30 mL/kg bolus of crystalloid IV fluids should be administered for hypotension (a systolic blood pressure below 90 mmHg) or for a lactate level of 4 mmol/L or higher.9 Patients with sepsis may have ineffective arterial circulation due to vasodilation, resulting in poor tissue perfusion and tissue hypoxia. Administering 30 mL/kg of IV fluids will expand circulating volume and promote adequate perfusion pressure.
Controversy over volume resuscitation. Some have raised concerns that following SSC resuscitation recommendations may result in volume overload, especially in patients with congestive heart failure, end-stage renal disease, or acute respiratory distress syndrome. In one study of more than 400 adult ICU patients receiving treatment for sepsis or septic shock, 67% showed evidence of volume overload on day 1 following initial fluid resuscitation and 48% had persistent fluid overload into day 3.30 The importance of fluid administration, however, is underscored by the fact that the mortality rate of patients with sepsis and hypotension is nearly 37% and increases to more than 46% if combined with a lactate level of 4 mmol/L or higher.31
Vasopressors should be administered to patients with persistent hypotension that does not respond to fluid resuscitation (those who are unable to maintain a MAP of at least 65 mmHg after receiving 30 mL/kg of crystalloid iv fluids).9 If the patient has life-threatening hypotension, vasopressor therapy should not be withheld until delivery of the 30 mL/kg bolus is completed. Norepinephrine is the first-line vasopressor for septic shock. Epinephrine is the second-choice vasopressor and may be used in addition to or instead of norepinephrine at the discretion of the provider.9 Phenylephrine has been found to reduce splanchnic blood flow,32 and therefore is not recommended in the treatment of septic shock unless norepinephrine is triggering serious arrhythmias, cardiac output is elevated, and blood pressure is persistently low, or inotropes or vasopressors and low-dose vasopressin fail to raise MAP sufficiently.9 Vasopressin and dopamine are not considered first-line agents, but may be used as salvage therapy.9 An experimental angiotensin II medication has shown promise in a recent trial after improving blood pressure and reducing doses of concomitant vasopressors within three hours in patients with vasodilatory shock.33
Ongoing critical care assessments.Noninvasive hemodynamic monitoring. The 2012 SSC guidelines called for invasive hemodynamic monitoring to reassess volume status and tissue perfusion. This recommendation was revised in 2015 to include noninvasive measures, such as a repeated focused examination (after initial fluid resuscitation) incorporating vital sign assessment; cardiopulmonary, capillary refill, pulse, and skin findings; or bedside cardiovascular ultrasound and dynamic assessment of fluid responsiveness with passive leg raise or fluid challenge. These changes were made after three trials did not demonstrate the superiority of a central venous catheter to other noninvasive means.26, 34-36
Invasive hemodynamic monitoring. Based on provider discretion, in the presence of persistent hypotension that does not respond to crystalloid iv fluid resuscitation, a central venous catheter may be inserted to monitor both central venous pressure and central venous oxygen saturation. Although invasive hemodynamic monitoring was recommended for patients with a lactate level above 4 mmol/L in earlier SSC guidelines, the 2016 guidelines suggest using dynamic measures instead, which have demonstrated greater accuracy.12 These include passive leg raises, stroke volume measurement, and variations in systolic pressure or pulse pressure on ventilators.
Remeasure lactate. To evaluate peripheral tissue perfusion, serum lactate should be remeasured after delivery of the 30 mL/kg bolus of crystalloid iv fluids. A serum lactate level > 2 mmol/L despite adequate volume resuscitation, combined with vasopressor requirements to maintain a MAP of at least 65 mmHg, is associated with a hospital mortality rate above 40% and should prompt further diagnostic evaluation and therapeutic intervention to improve tissue perfusion.5
GOVERNMENTAL MEASURES TO PREVENT SEPSIS
Health care providers and hospitals are held accountable for patient outcomes. The Centers for Medicare and Medicaid Services (CMS) provide greater reimbursement for better performers, assessing a 1% payment reduction to hospitals ranking in the lowest quartile with respect to preventable hospital-acquired infections, including sepsis.37 In October 2015, sepsis became a Joint Commission core measure; hospital reimbursement is now tied to adherence to the SSC sepsis bundles.38 All of the SSC bundle elements must be met to ensure adherence and improve patient outcomes. The Institutes of Medicine (IOM)—now known as the Health and Medicine Division of the National Academies of Sciences, Engineering, and Medicine—Joint Commission, CMS, and Institute for Healthcare Improvement have called for increased transparency regarding practice outcomes.39 The New York State Department of Health has mandated public reporting of sepsis survival and bundle compliance since 2013, and the subsequent reductions in in-hospital mortality40 should lead other states to follow suit. By implementing evidence-based practice guidelines and standards to improve patient safety and clinical outcomes, hospitals can provide clinically effective care, thereby minimizing the incidence of sepsis and readmissions, while increasing reimbursement.
LEADING THROUGH EVIDENCE-BASED PRACTICE
The IOM has called for 90% of clinical decisions and interventions to be evidence based by the year 2020.41 Achieving this goal will require health care providers to identify gaps in translating research to clinical practice and to implement proven decision-making tools, protocols, and policies. Integrating sepsis CDS tools into EHRs promotes prompt recognition and treatment of sepsis.
The Modified Early Warning Score (MEWS) was developed in 2001 to identify hospitalized patients at risk for clinical deterioration. The MEWS takes into account all components of the qSOFA (systolic blood pressure, respiratory rate, and mental status), as well as heart rate and temperature.42 Points are assigned based on values for each physiologic parameter. Scores of 5 or higher are associated with an increased risk of death and ICU admission.42 The MEWS has been adapted at many facilities to help nurses evaluate subtle signs of deterioration, increase use of rapid response teams, and increase nurses’ confidence in their patient assessments.43 The score can be calculated by the EHR system or manually on every shift by nursing staff. A rising MEWS should prompt nurses to consider possible sources of infection. When used appropriately in the hospital setting, the MEWS has been shown to reduce the number of code blues by as much as 50%.43
Customized sepsis screening tools can be incorporated into EHRs, using best practice advisories or components of the SOFA, qSOFA, and SIRS criteria, based on facility preferences. As nurses are at the forefront of patient care, it is important to couple such screening tools with nurse-initiated provider notification (see Putting It All Together: When Sepsis Is Suspected). The Society for Healthcare Epidemiology of America, in association with the IDSA, American Hospital Association, and Joint Commission, has compiled a Compendium of Strategies to Prevent Healthcare-Associated Infections in Acute Care Hospitals. All sections are available for download at www.shea-online.org/index.php/practice-resources/priority-topics/compendium-of-strategies-to-prevent-hais.
The quest to determine best practices in the areas of fluid resuscitation, screening tools, and early goal-directed therapy continues to provide numerous research opportunities in the areas of fluid resuscitation, screening tool validation, and efficacy of early goal-directed therapy on mortality and adverse events.
Although more conservative fluid resuscitation than that recommended by the SSC has been shown to increase the number of ventilator-free days and to decrease ICU days, there have been no significant findings regarding reduced mortality rates.44 Large randomized trials are needed to determine the fluid resuscitation measures that optimally affect mortality rates.
The validation of the screening tools used to identify sepsis provides another opportunity for future research. When Churpek and colleagues compared the qSOFA, SIRS criteria, MEWS, and National Early Warning Score (NEWS) in predicting in-hospital mortality and critical care transfer in non-ICU patients, they found that the qSOFA was more accurate than the SIRS criteria but less accurate than the MEWS or NEWS.45 As this study was performed in only one academic institution, further investigation and validation is needed to increase the external validity of these screening tools.
Finally, what is the effect of early goal-directed therapy on mortality and adverse events? The Australasian Resuscitation in Sepsis Evaluation trial, as well as a meta-analysis by Rusconi and colleagues, found that early goal-directed therapy did not decrease mortality but caused no significant adverse events.34, 46 Additionally, Rusconi and colleagues found no difference in hospital mortality rates, length of required organ support, or length of hospital stay. A limitation of this meta-analysis is that the therapies administered, especially IV fluid volume, varied widely across the studies evaluated, and early antibiotic administration, which is both common practice and part of bundled early goal-directed therapy, was noted in all trials.46
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