Authors

  1. Weant, Kyle A. PharmD, BCPS, FCCP
  2. Bailey, Abby M. PharmD, BCPS

Abstract

Sepsis continues to be a devastating, costly, and challenging syndrome to manage in emergency departments (ED) across the nation, and its impact seems to be only increasing. Recently, consensus recommendations have made some profound changes in the way we approach, classify, and treat sepsis. The ED serves as an important initial screening and intervention point for sepsis, and ED care can have a profound impact on overall morbidity and mortality. The provision of early fluid resuscitation, antimicrobial therapy, and vasopressor therapy, if appropriate, is essential in early care. The intent of this review was to compare and contrast changes associated with the management of sepsis in the ED, with particular focus on guideline recommendations for pharmacotherapeutic management.

 

Article Content

SEPSIS affects millions of people per year internationally and is a significant cause of intensive care unit admission (Rhodes et al., 2017). Furthermore, this syndrome has a major impact on the overall health care system, costing more than $20 billion each year in the United States (Singer et al., 2016). The incidence of sepsis also appears to be on the rise, partially attributable to an aging and more vulnerable population (Gaieski, Edwards, Kallan, & Carr, 2013; Iwashyna, Cooke, Wunsch, & Kahn, 2012). The outcomes associated with sepsis are particularly devastating because it is a leading cause of mortality and many survivors are left with long-term disabilities (Iwashyna, Ely, Smith, & Langa, 2010). One of the challenges that has plagued the health care community's approach to sepsis has been the challenge of defining and, subsequently, identifying it. An international panel first attempted to define this syndrome in 1992, calling it a systemic inflammatory response to infection (Bone, Sibbald, & Sprung, 1992). The panel also coined the terms "severe sepsis" and "septic shock" to define sepsis with acute organ dysfunction and sepsis as a patient's blood pressure that is refractory to fluid resuscitation, respectively. Over the years, these definitions and treatment recommendations have been revised and elaborated on but have, overall, remained very similar to their original definitions (Dellinger et al., 2013; Levy et al., 2003). Recently, there have been major changes in the both the definitions of sepsis and the treatment recommendations (Rhodes et al., 2017; Singer et al., 2016). The intent of this review was to compare and contrast the changes associated with the management of sepsis in the emergency department (ED), with a focus on guideline recommendations for pharmacotherapeutic management.

 

DEFINING SEPSIS

Previous definitions of sepsis were largely based on meeting the criteria for systemic inflammatory response syndrome (SIRS; Levy et al., 2003). The SIRS criteria evaluated the patient's temperature, heart rate, respiratory function, and white blood cell count and classified a patient into a spectrum of sepsis that also included "severe sepsis" and "septic shock" based on the existence of organ dysfunction or whether the hypotension was refractory to fluids. Although valid in many respects, the SIRS criteria were less than optimal in aiding providers to screen patients for sepsis. Many of the SIRS criteria are appropriate and adaptive responses to an infection rather than a maladaptive response, which is hypothesized to be at the core of sepsis pathology. In addition, the classification of "severe sepsis" was confusing to many and did not correspond to different modalities of care. The most recent revisions to the definition of sepsis, known as Sepsis-3, define it as follows: "Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection" (Singer et al., 2016, p. 804). However, for those who work with patients at the bedside, the Sepsis-3 definition remains semantics rather than a clinical framework that alters the therapeutic approach. To that end, Sepsis-3 also recommended use of the Sequential Organ Failure Assessment (SOFA) score at the bedside to diagnosis patients who have a suspected sepsis infection (Singer et al., 2016; Vincent et al., 1996). The SOFA score assigns 0-4 points based on the identified organ dysfunction in each of the following systems: pulmonary, coagulation, hepatic, cardiovascular, mentation, and renal. If the SOFA score demonstrates a change from baseline of 2 or more, the patient may be septic. Septic shock is defined as "...persisting hypotension requiring vasopressors to maintain mean arterial pressure (MAP) >= 65 mmHg and having a serum lactate > 2 mmol/L despite adequate volume resuscitation" (Singer et al., 2016, p. 805). The definition of "severe sepsis" has been removed from the Sepsis-3 definitions and is no longer used. Although these revisions represent a refinement in the understanding of sepsis, they are of limited clinical utility in the ED. It is unlikely that practitioners will have the available data or time to calculate SOFA scores on those patients who present emergently to the ED and without a baseline for comparison. Furthermore, the SOFA score provides no clinical utility for ED nursing staff in screening patients upon presentation or during triage. With this in mind, the authors of the Sepsis-3 criteria built an additional screening tool for rapid evaluation of patients for whom calculation of the full SOFA score is impractical. This is the quick Sequential Organ Failure Assessment (qSOFA) score (see Table 1; Singer et al., 2016). Unrelated to the SOFA score, this score is based on a multivariate analysis of factors that were associated with poor outcomes in patients presenting with sepsis. The goal was to help bedside clinicians identify those at highest risk for negative outcomes (Seymour et al., 2016). From these data, the authors identified the three criteria that comprise the qSOFA score to be used as the initial screening criteria for sepsis: respiratory rate, 22 or more breaths per minute; altered mental status; and systolic blood pressure, 100 mmHg or less (see Table 1; Singer et al., 2016). It is important to note that qSOFA is merely a screening tool for sepsis; it was not designed to define sepsis; and if a patient exhibits any of the criteria, it does not necessarily mean that the patient actually has sepsis. Much like the previous SIRS criteria, qSOFA is a surrogate for the dysregulated host response and should be correlated to a source of infection. It should also be stated that the qSOFA screening tool is based on retrospective data and hence needs validation in prospective studies. However, in the interim, qSOFA is a useful tool to assist ED providers and nurses in the identification of patients who may be at the highest risk of significant morbidity and mortality from sepsis.

  
Table 1 - Click to enlarge in new windowTable 1. Sepsis criteria

RECOMMENDATIONS FOR INITIAL MANAGEMENT

The previous versions of the Surviving Sepsis Campaign guidelines recommended a protocolized approach to resuscitation, with multiple specific targets including central venous pressure (CVP), MAP, urine output, and central venous oxygen saturation (Dellinger et al., 2013). These recommendations were based on multiple studies demonstrating improved outcomes with what became known as Early Goal-Directed Therapy (EGDT; Rivers et al., 2001). However, over the years, multiple studies have been conducted around the world demonstrating that such a protocolized approach may not be beneficial (Angus et al., 2015). Most notably, the ARISE, ProCESS, and ProMISe investigators found no difference between routine care and EGDT (ARISE Investigators, Anzics Clinical Trials Group, Peake, et al., 2014; Mouncey et al., 2015; ProCESS Investigators, Yealy, et al., 2014). This is, in part, due to the fact that, over time, many institutions adopted multiple aspects of EGDT as their standard of care and hence the precise implementation of EGDT no longer yields a mortality benefit. For example, in those three studies, all patients received early antibiotics and fluid resuscitation prior to randomization. Nevertheless, the basic tenets of EGDT remain a core component of the bundled response to sepsis: early antibiotics and volume resuscitation.

 

Emergent resuscitation continues to be emphasized in the current guidelines, with recommendations of at least 30 ml/kg of intravenous crystalloid fluid (e.g., 0.9% normal saline or lactated Ringer's) to be given within the first 3 hr (Rhodes et al., 2017). Limited literature is available to support this specific volume of resuscitation fluid; however, it is approximately the average volume provided in the ProCESS and ARISE trails, with the ProMISe trial administering on average 2 L of fluid (ARISE Investigators, Anzics Clinical Trials Group, Peake, et al., 2014; Mouncey, et al., 2015; ProCESS Investigators, Yealy, et al., 2014). Clinicians should of course individualize fluid resuscitation based on patient-specific data. The authors of the guidelines suggest the assessment of dynamic (e.g., passive leg raises) over static variables to assess fluid responsiveness and an MAP target of 65 mmHg in those with shock. Also recommended is resuscitation to a target of the normalization of lactate in those with elevations in lactate levels on initial evaluation. Colloids such as albumin are reserved for those patients who require substantial quantities of crystalloids or are suffering untoward effects from them (e.g., hyperchloremic acidosis). The use of hydroxyethyl starches is not recommended, as these carry significant safety concerns including an increased risk of death and the need for renal replacement therapy (Rochwerg et al., 2014).

 

The current Surviving Sepsis Campaign guidelines recommend the administration of empirical broad-spectrum intravenous antibiotics within 1 hr of the recognition of sepsis (Rhodes et al., 2017). Antimicrobial therapy should ideally be administered after obtaining at least two sets of blood cultures (i.e., aerobic and anaerobic). However, it is acknowledged that if obtaining blood cultures results in a significant delay, then administering antibiotics should be the priority. Available data suggest that for every hour delay in the administration of appropriate antimicrobial therapy, particularly in the setting of septic shock, mortality increases significantly (Beck et al., 2014; Kumar et al., 2006). The selection of the appropriate antimicrobial therapy in the ED is challenging and must account for many factors including local resistance patterns, individual patient risk factors, and the presumed site of infection, to name a few. Hence, it is impossible to recommend a standardized regimen for all patients. The guideline authors recommend that the regimen be broad enough to cover most health care-associated infections and will often require multiple drug therapies (Rhodes et al., 2017). Regardless of the antimicrobials used, it is recommended that these agents be dosed in a manner to optimize their pharmacokinetic and pharmacodynamic profile. In a practical sense, this may mean administering an intravenous loading dose (e.g., vancomycin) or extended infusions of antimicrobials (e.g., piperacillin/tazobactam). The administration of loading doses of antibiotics, followed by extended infusions, optimizes the pharmacokinetic profile of each agent to allow for rapid achievement of target concentrations, followed by sustained ideal concentrations (McKenzie, 2011). They echo previous recommendations that these empirical regimens should be narrowed once the causative pathogens are identified and that these medications be continued for the shortest duration possible, for example, 7-10 days for most infections (Rhodes et al., 2017).

 

RECOMMENDATIONS FOR FURTHER HEMODYNAMIC MANAGEMENT

For patients with hypotension secondary to suspected sepsis, otherwise known as septic shock, the new guidelines recommend a target MAP of 65 mmHg (Rhodes et al., 2017). Several studies have evaluated various target MAPs. Most recently, one study compared a target of 80-85 mmHg versus 65-70 mmHg (Asfar et al., 2014). There was no difference in mortality or adverse effects between the two groups; however, there was a higher incidence of new-onset atrial fibrillation in the high MAP group. This further highlights that although guideline recommendations for blood pressure targets are an important starting point, therapy should still be tailored to the individual patient. If the patient is chronically hypertensive or hypotensive, then perhaps blood pressure targets should be adjusted and continually reassessed so that sufficient, but not excessive, perfusion is occurring to the end organs.

 

For patients with septic shock requiring vasopressor therapy, the guidelines recommend norepinephrine as the vasopressor of choice (see Table 2; Rhodes et al., 2017). If vasopressor therapy, beyond norepinephrine, is required, add either a vasopressin (antidiuretic hormone) infusion (up to 0.03 units/min) or an epinephrine infusion to norepinephrine to raise the MAP. The addition of vasopressin may decrease norepinephrine requirements. The recommendation of norepinephrine as a first-line agent in septic patients has varied through previous guideline revisions wherein dopamine was the recommended vasopressor. In the current guidelines, dopamine is only recommended as an alternative vasopressor in highly selected patients such as those at low risk for tachyarrhythmias and absolute or relative bradycardia. Several studies have demonstrated that there is no difference in mortality or length of stay between patients who receive norepinephrine or dopamine. However, there is a significantly higher incidence of arrhythmias in patients treated with dopamine, most notably new-onset atrial fibrillation (Patel et al., 2010). It has been documented for some time that vasopressin levels are inappropriately lower in those patients with septic shock (Landry et al., 1997). The addition of vasopressin has been demonstrated to provide a sparing effect on norepinephrine dosing but an unclear impact on mortality outcomes (Rhodes et al., 2017). The guidelines continue to recommend limiting the use of phenylephrine because there is inadequate data regarding its impact in this setting. However, this agent may have a role in patients who develop tachyarrhythmias while taking norepinephrine or in the setting of high cardiac output with persistent hypotension.

  
Table 2 - Click to enlarge in new windowTable 2. Vasopressor therapy

Although challenging in an emergent setting such as the ED, the new guidelines recommend the placement of an arterial catheter as soon as possible in patients requiring vasopressor therapy (Rhodes et al., 2017). The authors' general assessment is that the benefits of catheter insertion outweigh the risks and provide an accurate and immediate reflection of blood pressure management. It should be noted that the authors acknowledge that this is a weak recommendation supported by low-quality evidence. What is clear is that traditional cuff measurement of blood pressure is inadequate in this setting, and other modalities of measurement, both invasive and noninvasive, should be explored.

 

For patients who are nonresponsive to vasopressors and fluid resuscitation, the guidelines recommend the addition of dobutamine (Rhodes et al., 2017). Dobutamine is a potent [beta]-agonist and can greatly increase cardiac output. This can be particularly advantageous in the setting of heart failure. However, the increased risk of tachycardia and the potentiation of arrhythmias must be considered. It should be noted that there are no randomized controlled trials assessing the difference between dobutamine and other vasoactive therapies (Annane et al., 2007). For a more thorough review of vasopressor therapy in the ED, the reader is directed to the study by Bockenstedt, Baker, Weant, and Mason (2012).

 

ADJUNCTIVE THERAPIES IN SEPSIS

The use of corticosteroids has long been a point of contention in both the guidelines and the sepsis literature. The current guidelines recommend against the use of hydrocortisone to treat septic shock (Rhodes et al., 2017). However, the authors do concede that in those patients in whom hemodynamic stability is not restored through adequate fluid resuscitation and vasopressor therapy, the use of hydrocortisone 200 mg/day may be an option. Tailoring this to individual patient characteristics may be warranted, especially in patients with a history of steroid use or adrenal dysfunction. This recommendation is consistent with prior guideline revisions (Dellinger et al., 2008).

 

The management of blood glucose has also been highly debated in the setting of sepsis over the years. The current guidelines recommend initiating insulin therapy when two consecutive blood glucose concentrations exceed 180 mg/dl (Rhodes et al., 2017). Providers should target a goal blood glucose level of 180 mg/dl or less by using either intermittent or continuous infusions of insulin. This recommendation is largely based on the results of the NICE-SUGAR trial, is endorsed by multiple associations, and is consistent with prior sepsis guideline recommendations (American Diabetes Association, 2014; Dellinger et al., 2008; NICE-SUGAR Study Investigators, Finfer, et al., 2009; Qaseem, Chou, Humphrey, Shekelle, & Clinical Guidelines Committee of the American College of Physicians, 2014).

 

CONCLUSION

Sepsis continues to be a major contributor to morbidity and mortality around the world. The most recent updates to the definition, screening, and treatment of sepsis demonstrate continued progression in the knowledge of this syndrome and advances in optimizing care. The most important pharmacotherapy aspects continue to be the rapid identification, fluid resuscitation, and provision of broad-spectrum antimicrobial therapy to these patients. Emergent CVP monitoring is no longer recommended; however, the continued aggressive treatment of hemodynamics is recommended with crystalloids and vasopressors as necessary. Although the specific recommendations have greatly evolved over the decades of combating this syndrome, the underlying concept that sepsis is a critical illness requiring rapid identification and emergent treatment remains consistent.

 

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emergency department; pharmacy; sepsis; shock; vasopressors