Practice Guidelines: Sepsis Rachel Garvin, MD, FNCS Neuroscience Grand Rounds August 24, 2018

Quick Overview Sepsis and the Stats Pathophysiology History Current recommendations

Sepsis Greek word for decay

Sepsis 2016 CDC data Old and young, immune compromised 70% of patients had recently used a healthcare facility or had a chronic illness Lung, urine, gut and skin Staph ecoli and some forms of strep are most common organisms 1/3 patients who die in the hospital have sepsis

1.5 million cases per year in the US with >250,000 deaths Survivors have shorter life span and often poorer quality of life with increased risk of suicde #1 cost of hospitalization Most expensive condition treated in the hospital ICU patients with sepsis cost 6x more than regular ICU patients High mortality – up to 62% of patient who develop septic shock High readmission rates – 60% Sepsis Alliance reports that up to 80% of deaths could be prevented with rapid diagnosis and treatment

MAP >/= 65

Type A: Decreased tissue oxygenation (e.g., from decreased blood flow) Type B B1: Underlying diseases (sometimes causing type A) B2: Medication or intoxication B3: Inborn error of metabolism

1992:Sepsis 1: SIRS (signs but infection source not necessary), Sepsis and septic shock initially defined. Sepsis-1 was defined as infection or suspected infection leading to the onset of SIRS

SIRS Criteria

2001: Sepsis 2: 2 SIRS + infection 2001: Sepsis 2: 2 SIRS + infection.. Expanded list of diagnostic criteria. Use of EWS (APACHE, SOFA, MEWS) to predict 30 day mortality 2016: Sepsis 3: Definition: Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Severe sepsis was removed from definitions in sepsis 3 Despite many endorsements from various societies (SCCM, American Thoracic Society, and the American Association of Critical Care Nurses), it has NOT been endorsed by ACEP, SAEM, ACCP, or IDSA due to extensive concerns. A primary concern for non-ICU providers is that these definitions have not been prospectively validated in a generalizable population, nor has it been validated or studied in the Emergency Department, pre-hospital or non-ICU, inpatient setting. IN ICU setting, SOFA and SIRS perform the same in predicting mortality  As the authors state, this update was needed for many reasons, these include the fact that SIRS is non-specific (Kaukonen et al. NEJM 2015), there is now a much improved understanding of pathobiology, and most felt that SIRS is an expected inflammatory response to infection and other physiologic insults (burns, pancreatitis, etc.) As an aside, we need to also consider anti-inflammatory, hormonal, metabolic, coagulation, bio-energetic, neuronal and autonomic factors. Lastly, they felt that the existing terminology to describe sepsis could be confusing e.g. Severe Sepsis vs. Sepsis (septicemia, sepsis syndrome).

Definition

1992:Sepsis 1: SIRS (signs but infection source not necessary), Sepsis and septic shock initially defined. 2001: Sepsis 2: revisited the SIRS definition to be several as opposed to more than 1. Expanded list of diagnostic criteria. Use of EWS (APACHE, SOFA, MEWS) to predict 30 day mortality 2016: Sepsis 3: Definition: Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Severe sepsis was removed from definitions in sepsis 3 Despite many endorsements from various societies (SCCM, American Thoracic Society, and the American Association of Critical Care Nurses), it has NOT been endorsed by ACEP, SAEM, ACCP, or IDSA due to extensive concerns. A primary concern for non-ICU providers is that these definitions have not been prospectively validated in a generalizable population, nor has it been validated or studied in the Emergency Department, pre-hospital or non-ICU, inpatient setting. IN ICU setting, SOFA and SIRS perform the same in predicting mortality  As the authors state, this update was needed for many reasons, these include the fact that SIRS is non-specific (Kaukonen et al. NEJM 2015), there is now a much improved understanding of pathobiology, and most felt that SIRS is an expected inflammatory response to infection and other physiologic insults (burns, pancreatitis, etc.) As an aside, we need to also consider anti-inflammatory, hormonal, metabolic, coagulation, bio-energetic, neuronal and autonomic factors. Lastly, they felt that the existing terminology to describe sepsis could be confusing e.g. Severe Sepsis vs. Sepsis (septicemia, sepsis syndrome).

We randomly assigned patients who arrived at an urban emergency department with severe sepsis or septic shock to receive either six hours of early goal-directed therapy or standard therapy (as a control) before admission to the intensive care unit. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment. In-hospital mortality (the primary efficacy outcome), end points with respect to resuscitation, and Acute Physiology and Chronic Health Evaluation (APACHE II) scores were obtained serially for 72 hours and compared between the study groups. 263 patients Mortality 30.5% vs 46.5%

The protocol was as follows. A 500-ml bolus of crystalloid was given every 30 minutes to achieve a central venous pressure of 8 to 12 mm Hg. If the mean arterial pressure was less than 65 mm Hg, vasopressors were given to maintain a mean arterial pressure of at least 65 mm Hg. If the mean arterial pressure was greater than 90 mm Hg, vasodilators were given until it was 90 mm Hg or below. If the central venous oxygen saturation was less than 70 percent, red cells were transfused to achieve a hematocrit of at least 30 percent. After the central venous pressure, mean arterial pressure, and hematocrit were thus optimized, if the central venous oxygen saturation was less than 70 percent, dobutamine administration was started at a dose of 2.5 μg per kilogram of body weight per minute, a dose that was increased by 2.5 μg per kilogram per minute every 30 minutes until the central venous oxygen saturation was 70 percent or higher or until a maximal dose of 20 μg per kilogram per minute was given. Dobutamine was decreased in dose or discontinued if the mean arterial pressure was less than 65 mm Hg or if the heart rate was above 120 beats per minute. To decrease oxygen consumption, patients in whom hemodynamic optimization could not be achieved received mechanical ventilation and sedatives.

Transfusion for Hgb <7 vs Hgb <9 ICU patients with septic shock Primary outcome death after 90 days of randomization Patients with ACS were excluded About 1000 pts

We analyzed data from 998 of 1005 patients (99 We analyzed data from 998 of 1005 patients (99.3%) who underwent randomiza- tion. The two intervention groups had similar baseline characteristics. In the ICU, the lower-threshold group received a median of 1 unit of blood (interquartile range, 0 to 3) and the higher-threshold group received a median of 4 units (interquartile range, 2 to 7). At 90 days after randomization, 216 of 502 patients (43.0%) assigned to the lower-threshold group, as compared with 223 of 496 (45.0%) assigned to the higher-threshold group, had died (relative risk, 0.94; 95% confidence interval, 0.78 to 1.09; P=0.44). The results were similar in analyses adjusted for risk factors at baseline and in analyses of the per-protocol populations. The numbers of patients who had ischemic events, who had severe adverse reactions, and who required life support were similar in the two intervention groups. CONCLUSIONS Among patients with septic shock, mortality at 90 days and rates of ischemic events and use of life support were similar among those assigned to blood transfusion at a higher hemoglobin threshold and those assigned to blood transfusion at a lower threshold; the latter group received fewer transfusions.

Do We Need EGDT? PRoCESS 2014 ARISE 2014 ProMISe 2015 Questions relating to external validity of EGDT PRoCESS: 31 emergency departments in the United States, we randomly assigned patients with septic shock to one of three groups for 6 hours of resuscitation: protocol-based EGDT; protocol based standard therapy vs standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions; or usual care. The primary end point was 60-day in-hospital mortality. We tested sequentially whether protocol-based care (EGDT and standard-therapy groups combined) was superior to usual care and whether protocol-based EGDT was superior to protocol-based standard therapy. Secondary outcomes included longer-term mortality and the need for organ support. ARISE: EGDT or usually care. Antibiotics administered before randomization.. The primary outcome was all-cause mortality within 90 days after randomization. PROMISE:Patients were randomly assigned to receive either EGDT (a 6-hour resuscitation protocol) or usual care. The primary clinical outcome was all-cause mortality at 90 days. Also looked at cost effectiveness – found that EGDT increased costs Both Trials: increased use of central venous catheters, intravenous f luids, vasoactive drugs, and red-cell transfusions.

2016: Sepsis 3: Definition: Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. SIRS and Severe sepsis was removed from definitions in sepsis 3 Septic Shock: : ‘sepsis with persistent hypotension requiring vasopressors to maintain MAP ≥65 mm Hg and having a serum lactate >2 mmol/L (18 mg/ dL) despite adequate volume resuscitation’ Despite many endorsements from various societies (SCCM, American Thoracic Society, and the American Association of Critical Care Nurses), it has NOT been endorsed by ACEP, SAEM, ACCP, or IDSA due to extensive concerns. A primary concern for non-ICU providers is that these definitions have not been prospectively validated in a generalizable population, nor has it been validated or studied in the Emergency Department, pre-hospital or non-ICU, inpatient setting. IN ICU setting, SOFA and SIRS perform the same in predicting mortality  As the authors state, this update was needed for many reasons, these include the fact that SIRS is non-specific (Kaukonen et al. NEJM 2015), there is now a much improved understanding of pathobiology, and most felt that SIRS is an expected inflammatory response to infection and other physiologic insults (burns, pancreatitis, etc.)

Increase in SOFA >/+ 2 = life threatening organ dysfunction Patients with an increase of 2 or more in the SOFA score have an esti- mated in hospital mortality of 10% due to sepsis and a 2-fold to 25-fold increased risk of death compared with patients with a SOFA score of <2. The Sepsis-3 definitions requiring the presence of organ dysfunction to define sepsis may hinder the awareness of the importance of early recognition and treatment of infections before organ dysfunction appears, de-emphasizing intervention at earlier stages when it is most treatable. Outside the ICU, SOFA was found only as good as the previous SIRS criteria

Screening tool for patients outside of the ICU for risk of sepsis qSOFA with low sensitivity. Not intended to define sepsis, but rather, who is at risk and likely to have poor outcomes High number of false negatives and subsequent delayed dx

The Guidelines The 2012 sepsis guidelines defined sepsis as ‘the presence (probable or documented) of infection together with systemic manifestations of infec-tion’. In the 2016 guidelines, sepsis is redefined by the taskforce as ‘a life-threatening organ dysfunc- tion caused by a dysregulated host response to infection'.

For quality of evidence

Strong vs Weak recommendations A number of best practice statements (BPSs) appear throughout the document; these statements represent ungraded strong recommendations and are used under strict criteria. A BPS would be appropriate, for example, when the bene t or harm is unequivocal, but the evidence is hard to summarize or assess using GRADE method- ology.

Strength of recommendation

Overview YOU Sepsis Fast Fight the bugs Fluids Frequent Reassessment

30cc/kg in the first 3 hours MAP >/= 65 Screen patients 30cc/kg in the first 3 hours MAP >/= 65 Use lactic acid level to guide resuscitation Cx before antibiotics; abx within 1 hour Procalcitonin Source control Screen: BPS Fluids: Strong recommendation – low quality of evidence MAP: strong rec – mod QOE Lactic – weak rec – low QOE Cx – BPS Abx: strong rec; mod QOE Procalcintonin can be used to look at shortening duration of abx: weak rec – Low QOE

Norepi is first line vasopressor Can add vaso or epi Arterial line for pressors IV steroids (HCT 200mg/day) PRBCs only if hgb <7 No Bicarb infusions Norepi: strong rec – mod QOE Vaso or epi: to help increase MAP or decrease norepi requirement Aline: weak rec – very low QOE Steroids: if still hypotensive: weak rec – low QOE PRBCS: strong rec – high QOE Bicarb: not needed if pH >7.15

3 and 6 hour bundles For patients identified with organ dysfunction Plevin R, Callcut R. Trauma Surg Acute Care Open 2017

New 1 hour sepsis bundle Previous 3 and 6 hour bundles combined now into 1 hour bundles. No new evidence to support 1 hour time frame

Wrapping it up Be suspicious Treat early: Don’t need the SOFA MAP and Antibiotics Don’t need the SOFA

Questions?