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Pharmacist Continuing Education - The changes in sepsis guidelines

25 May 2018 2:36 PM | Anonymous

The changes in sepsis guidelines: How do they shape our current practice?

Authors: Paige Hagen, PharmD: PGY-1 Resident SSM Health St. Clare Hospital and Christopher K. Carter, PharmD, BCCCP: SSM Health St. Clare Hospital

Program Number: 2018-04-09
Approval Dates: 6/6/18 - 9/6/18
Approved Contact Hours: One (1) CE(s) per LIVE session.

Learning Objectives

  1. Recognize where early goal directed therapy came from and when it was incorporated into the Surviving Sepsis Campaign guidelines.
  2. Identify the trio of trials that largely impacted the 6-hour resuscitation bundle from the 2012 to 2016 guidelines.
  3. Apply the findings from the trio of trials to current medical practice.

Sepsis’ Impact and Importance
Even with advances in medicine, sepsis remains difficult to define and is associated with high mortality rates. Sepsis accounts for roughly 31.5 million cases annually, resulting in 5.3 million deaths. Patients who survive are at higher risk for long-term physical, cognitive, and psychosocial morbidity, and have an increased mortality rate for up to two years after an event.1   

In addition to high mortality rates, sepsis poses a significant burden to our healthcare system due to the cost of treatment. In the United States, sepsis is the number one highest cost of hospitalizations, averaging roughly $24 billion dollars for treatment annually. The average hospital stay costs about $18,400, but depends on when sepsis was detected. If detected early on in the emergency department, it costs about $3,000. If not detected until after admission, the cost of treatment can be as much as $32,000. Additionally, patients with sepsis experience a length of stay that is 75% longer than patients with other disease states. Furthermore, sepsis is the number one cost of readmissions with roughly 62% of patients re-admitted within 30 days. 2 

With the high mortality rates and the significant cost burden to our healthcare system, it is important to constantly re-evaluate and re-define the approach to the treatment of sepsis and septic shock. 

Timeline of Trials for Early Goal Directed Therapy (EGDT)
In 2001, Rivers et al. published striking evidence from their trial looking at early goal directed therapy (EGDT) for the treatment of severe sepsis and septic shock. EGDT involves the measurement of central venous oxygen saturation, central venous pressure, and mean arterial pressure through central venous and arterial catheterization. According to the protocol, patients are administered crystalloid or colloid fluids, vasoactive agents, red blood cell transfusions, and/or inotropic agents in order to meet each monitoring parameter and achieve an optimal balance between oxygen demand and oxygen delivery. This trial was the first attempt at showing benefit from EGDT with the purpose of determining whether EGDT before admission to the intensive care unit (ICU) effectively reduced the incidence of multi-organ dysfunction, mortality, and the use of health care resources among patients with severe sepsis or septic shock.  When looking at in-hospital mortality rates, the study found benefit in the EGDT group versus the usual care group (30.5 % vs. 46.5%). Additionally, it found that those who received EGDT at the earliest stages of sepsis and septic shock experience significant short-term and long-term benefits, such as early identification and treatment of patients at high risk for cardiovascular collapse and for early intervention to help restore the balance between oxygen delivery and oxygen demand to the vital organs.3

In 2004, EGDT was incorporated into the Surviving Sepsis Campaign guidelines’ three and six hour treatment bundles.

Since 2014, there has been a rapid influx of sepsis literature, with the publication of three large trials and updated definitions. The trio of trials was aimed at reproducing the findings by Rivers et al. and to better determine the generalizability of these results.

Protocolized Care for Early Septic Shock (ProCESS)4 was published in May of 2014. It was conducted across the United States and randomly assigned patients with septic shock to one of three groups for six hours of resuscitation: protocol based EGDT, which mimicked the protocol from Rivers et al.; protocol based standard therapy that did not require the placement of a central venous catheter (CVC), administration of inotropes, or blood transfusions; and usual care. The primary endpoint looked at 60-day in-hospital mortality. As a result when comparing EGDT to protocolized standard therapy to usual care, no significant difference was found in mortality rates (21% vs 18.2 % vs 18.9%). However, the protocol-based care groups resulted in increased use of central venous catheterization, IV fluids, vasoactive agents, and blood transfusions.

The Australasian Resuscitation in Sepsis Evaluation (ARISE)5 was published in October 2014 as the second trial aiming to determine if EGDT, as compared with usual care, would decrease 90-day all-cause mortality among patients presenting to the emergency department (ED) with early septic shock in diverse health care settings. This trial was conducted in 51 tertiary care and non-tertiary care metropolitan and rural hospitals across Australia and New Zealand, with several sites in Finland, Hong Kong, and the Republic of Ireland. Patients presenting to the ED with early septic shock were randomly assigned to EGDT or usual care. For the studied primary endpoint of all-cause mortality within 90 days after randomization, no significant difference between the EGDT and usual care groups was found (18.6% vs 18.8%).  There were also no differences in 28 day or in-hospital mortality, duration of organ support, or length of hospital stay.

Protocolized Management in Sepsis (ProMISe)6 rounded out the trio of trials with its publication in April of 2015. Its aim was to determine if the 6-hour EGDT resuscitation protocol was superior, in terms of clinical and cost-effectiveness measures, to usual care in patient presenting with early septic shock to National Health Service emergency departments in England. When studying the primary endpoint of all-cause mortality at 90-days, there was no significant difference among those receiving 6 hours of EGDT compared to usual care (29.5 % vs 29.2%). The EGDT group had increased used of central venous catheters, IV fluids, vasoactive drugs, and red-cell transfusion as a result of the treatment protocol. Additionally, ProMISe found that continuous monitoring with ScvO2 and strict protocolization did not show an improvement in overall outcomes.

Finally, in May of 2015, a meta-analysis was published comparing the results of the trio of trials in addition to past trials that used EGDT.7 Eleven trials were reviewed to address the question of whether EGDT, compared with other resuscitation strategies, was associated with a survival benefit. The study’s primary outcome was mortality in patients presenting to the ED with septic shock at 28 days, 90 days, and hospital discharge.  The results found no difference between EGDT and usual care (23.2% vs 22.4%). Additionally, EGDT was associated with an increased rate of admission to the ICU and increased the utilization of resources.

It is important to take a step back and analyze these results as a whole. Some may ask, “why is it that Rivers et al. found ground breaking evidence with EGDT in lowering mortality rates, yet the trio of trials and meta-analysis found no difference in mortality outcomes and no benefit of this specific protocol?” One explanation for these results may stem from the improvement of “usual care” from 2001 to 2014. Detection and treatment of sepsis and septic shock has improved dramatically over the years. To this day, usual care is centered on the fundamentals of the Rivers et al. protocol which includes fluid resuscitation, blood cultures, and early initiation of broad-spectrum antibiotics. The only difference is that “usual care” today is not using the parts of EGDT that are extraneous in most patients like inotropes, blood transfusions, and central lines.

Updated Sepsis Definition
In February of 2016, there was an update to the definitions of sepsis and septic shock titled “The Third International Consensus Definitions of Sepsis and Septic Shock (Sepsis-3).”8 The definitions had last been revised in 2001 and the aim of the authoring task group was to provide practitioners with more robust criteria to diagnose patients with sepsis and identify patients with a suspected infection that would likely progress to a life-threatening state. From the review and updates, Sepsis-3 found four key findings.

First, the previous definition focused excessively on the inflammatory process, which portrayed a misleading model that sepsis follows a continuum from sepsis to severe sepsis to septic shock. Additionally, Sepsis-3 determined that the systemic inflammatory response syndrome (SIRS) criteria lacked specificity and sensitivity and are present in many hospitalized patients. This likely has then led to an over-diagnosis of sepsis. It was also thought that SIRS criteria do not indicate a dysregulated, life-threatening response as was intended by the 2001 definition. The taskforce therefore defined sepsis as a “life- threatening organ dysfunction caused by a dysregulated host response to infection.” This new definition helps to emphasize the importance of urgent recognition and the severity of mortality with a septic presentation.

Secondly, Sepsis-3 found that there were multiple definitions in use for sepsis, septic shock, and organ dysfunction, which lead to discrepancies in reported incidence and observed mortality. As a result, organ dysfunction was redefined as an increase in the SOFA score of ≥ two points.  This assumes that patient’s baseline SOFA score should be zero, unless the patient has pre-existing organ dysfunction. Of note, an increase in SOFA score ≥ two points is associated with in-hospital mortality of greater than 10%.

Furthermore, Sepsis-3 determined that the term “severe sepsis” is redundant since sepsis is now further defined as life-threatening organ dysfunction and eliminated this distinction  Septic shock was also further defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. It is clinically identified by a vasopressor requirement to maintain a mean arterial pressure (MAP) ≥65 mmHg and a serum lactate > two mmol/L (>18 mg/dL) in the absence of hypovolemia. Patients with septic shock are associated with in-hospital mortality rates of > 40%.

Finally, Sepsis-3 introduced the QuickSOFA (qSOFA) score that provides simple criteria to identify patients with suspected infection who are likely to have poor outcomes. It can be performed quicker than the SOFA score, as it does not require invasive testing and can be reassessed repeatedly. It is advised that the qSOFA be used to prompt physicians to further investigate for organ dysfunction, initiate therapy as appropriate, and to increase patient monitoring. With the updated definitions and clinical criteria, Sepsis-3 can facilitate earlier recognition and timely management for patients with sepsis or those at risk of developing sepsis.

Surviving Sepsis Campaign’s Response to Sepsis-3
In response to the updated Sepsis-3 definitions and the new evidence from the aforementioned trials, the Surviving Sepsis Campaign published new guidelines in 2016. 9,10 These guidelines specifically updated the six-hour sepsis treatment bundle by removing the requirement of a CVC to monitor central venous pressure (CVP) and central venous oxygen saturation (ScvO2) in all patients with septic shock who received timely antibiotics and fluid resuscitation.

SEP-1 Core Measure
In response to the updated definition and sepsis guidelines, it is important to take into account CMS’ introduction of SEP-1, the sepsis core measure. SEP-1 was implemented October 1, 2015 and uses the 2001 sepsis definition that uses SIRS criteria for sepsis, severe sepsis, and septic shock recognition. The core measure does support bundle compliance as stated in the most recent Surviving Sepsis Campaign guidelines (2016). In order to receive reimbursement from CMS, all measures outlined by SEP-1 must be met. It is important to note that over-diagnosis of sepsis may occur under this core measure due to the use of the 2001 definition instead of the updated definition.  This should be considered at an entity level when determining what resources will be required to ensure CMS compliance.

Effect on Current Medical Practice
Rivers et al. originally found striking evidence in lowering sepsis mortality rates using EGDT. From there, EGDT was incorporated into the Surviving Sepsis Campaign Guidelines in 2004. When a trio of trials attempted to recreate the finding by Rivers et. al., EGDT was not substantiated or associated with a lower rate of mortality. They also discovered that strict monitoring and measurement of CVP and ScvO2 did not improve mortality outcomes.

Following the publication of ProCESS, ARISE, and ProMISe, the 2001 definition of sepsis was updated with the publication of Sepsis-3. The aim of Sepsis-3 was to update the definition of sepsis and provide greater consistency and clarity for diagnosing sepsis. Additionally Sepsis-3 introduced the QuickSOFA score, allowing for quick recognition of patients with a suspected infection that would likely result in poor outcomes.

From the trial results and the publication of Sepsis-3, the Surviving Sepsis Campaign Guidelines updated the six-hour bundle, removing the requirement for CVP and ScvO2.. Eliminating these requirement will help to decrease the healthcare resource utilization costs and lower rates of ICU admissions.

Even with the rapid influx of sepsis literature, CMS’ SEP-1 core measure still uses the 2001 definition that uses SIRS criteria for sepsis, severe sepsis, and septic shock recognition. With this, over-diagnosis of sepsis may occur across entities to ensure CMS compliance.

In summary, there has been great advancements in sepsis literature since 2001, reshaping our current practices. Even with all of the new discoveries, I believe that the EGDT fundamentals outlined by Rivers et al. for early resuscitation in sepsis and septic shock remain unchanged. The fundamentals are as important today as they were in 2001 which include fluid resuscitation, blood cultures, and early initiation of broad-spectrum antibiotics.

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  1. Raith EP, Udy AA, Bailey M, McGloughlin S, MacIsaac C, Bellomo R, Pilcher DV, for the Australian and New Zealand Intensive Care Society (ANZICS) Centre for Outcomes and Resource Evaluation (CORE). Prognostic Accuracy of the SOFA Score, SIRS Criteria, and qSOFA Score for In-Hospital Mortality Among Adults With Suspected Infection Admitted to the Intensive Care Unit. JAMA. 2017; 317(3):290–300.
  2. Sepsis Alliance. (2016). Sepsis fact sheet. Retrieved from http://www.sepsis.org/downloads/2016_sepsis_facts_media.pdf.
  3. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M, Early Goal-Directed Therapy Collaborative Group (2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368–1377.
  4. The ProCESS Investigators (2014) A randomised trial of protocol-based care for early septic shock. N Engl J Med 370:1683–1693.
  5. The ARISE Investigators and the ANZICS Clinical Trials Group (2014) Goal-directed resuscitation for patients with early septic shock. N Engl J Med 371:1496–1506.
  6. Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RG, Jahan R, Harvey SE, Bell D, Bion JF, Coats TJ, Singer M, Young JD, Rowan KM, ProMISe Trial Investigators (2015) Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 372(14):1301–1311.
  7. Angus DC, Barnato AE, Bell D, et al. A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive Care Med 2015; 41: 1549–1560.
  8. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315(8):801-810.
  9. Dellinger RP, Schorr CA, Levy MM. A users’ guide to the 2016 Surviving Sepsis Guidelines. Intensive Care Medicine. 2017; 43(3):299-303.
  10. Rhodes A, Evans LE, Alhazzani W, et al: Surviving Sepsis Campaign: International Guidelines for the Management of Sepsis and Septic Shock: 2016. Intensive Care Med 2017 Jan 18.

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