Part 1 of the history of sepsis appeared in the November issue.

ED-Centric Treatment

Prior to 2000, there was no universal sense of urgency for treating septic patients. Care was generally fractured, with little collaboration among the pre-hospital service, emergency department, intensive care unit, and wards. Universal use of ultrasound in emergency departments or intensive care units (ICUs) was non-existent during this period, although global myocardial dysfunction from sepsis was an emerging concept.

In 2001, Rivers et al reported results of a new protocolized resuscitation termed early goal-directed therapy (EGDT).1 EGDT was described as a structured treatment protocol that incorporated elements consistent with the 1992 consensus guidelines focusing on preload, afterload, contractility, and oxygen delivery.2 The absolute mortality benefit of 16 percent (46.5 to 30.5 percent) represented one of the most effective modalities to date. Over the ensuing 12 years, multiple observational studies supported a mortality benefit of varying degrees.3 EGDT was included in the first three iterations of the Surviving Sepsis Campaign (SSC) guidelines and was a central component of emergency medicine–specific guidelines.4

Between 2013 and 2015, three international trials found no mortality difference between EGDT and usual care, with usual care including early identification, early lactate measurement, early antibiotic administration (median: 1–3 hours from identification), and early fluid administration (median: 2–3 L).5-7 In pinpointing reasonable causes for the mortality differences between the Rivers trial and these three international trials that showed no dfference, Nguyen et al identified evolving practice over the ensuing 15 years, the baseline central venous oxygen saturation (ScvO2) >70 percent in all three trials, and the potential of a subset of this patient population who could benefit from normalizing an abnormally low ScvO2.8

It is interesting that four randomized, controlled trials encompassing defining points of two decades are scientifically in opposition but philosophically in alignment. They all required the breakdown of long-held barriers and promoting intentional collaboration across levels of care, locations of care, and service lines.

“The reality is that patients presenting with sepsis are admitted to the intensive care unit via the emergency department, general medical or surgical floors, operating rooms, and inter-hospital transport managed by a broad spectrum of specialties and care providers. As patients travel this landscape, current evidence suggests that the diagnostic and therapeutic expertise provided at each venue significantly impacts morbidity and mortality.”
—Emanuel Rivers

Antibiotics

Although the 2018 SSC bundle recommends antibiotics within one hour of emergency department triage, this has not been adopted by the Centers for Medicare and Medicaid Services (CMS), and there are limited supportive data.

A recent study reported an 8 percent increased progression to septic shock from severe sepsis for every hour antibiotics were delayed from triage.9 The potential to mitigate disease progression through early intervention is a core emergency medicine principle. However, prior to operationalization, the difference between retrospective sepsis database evaluations and clinical implementation should be considered. Observational and retrospective evaluation of prospectively collected data support early antibiotic administration impact as life-saving in septic shock patients.

However, benefit is less clear in less acutely ill patients. In the New York study, there was an hourly mortality benefit for treatment after diagnosis for septic shock. However, for severe sepsis, the confidence initiated with one, making the association with an hourly mortality benefit less clear.

In a recent randomized, controlled trial of approximately 2,700 patients, antibiotics were administered by EMS prior to emergency department arrival in 1,548. The difference in median time to antibiotics was approximately 96 minutes, resulting in no mortality difference between early EMS-administered antibiotics and usual care where antibiotics were administered after assessment in the ED.10

Attempts to meet a one-hour timeline in undifferentiated patients will result in antibiotics administration to patients who ultimately did not require them. The unanswered question is, would one or two doses of unnecessary antibiotics be harmful? That risk must be quantified and compared to the risk of antibiotics being potentially delayed in those who do need them while determining bacterial infection.

Current data are imperfect. One retrospective evaluation of gram-negative severe sepsis or septic shock found those who previously received antibiotics within 90 days of admission had an increased length of stay, increased mortality, and increased cost.11

At this time, adherence with the CMS measure of antibiotic administration within three hours from diagnosis of severe sepsis and septic shock is reasonable. An optimal goal of initiating antibiotics within one hour of septic shock diagnosis is also reasonable as the majority of data on time to antibiotics and benefit is are septic shock patients.

Fluid Volume and Type

There is currently an ongoing trial to assess restrictive (at least 2 L IV fluid) compared to liberal fluid therapy. Large-volume infusions with normal saline may cause hyperchloremic acidosis. After 2 L, changing to a more balanced solution such as lactated Ringer’s may be beneficial. Data surrounding albumin are conflicting because the meta-analyses performed often combine heterogeneous patient populations. If the patient is in septic shock, especially if cirrhotic, albumin may be of benefit after the first 2 L of crystalloid.12,13

Vasopressors

Norepinephrine is still the drug of choice in septic shock. However, with global myocardial dysfunction or baseline congestive heart failure, an inotrope may be beneficial.

Hydrocortisone, Thiamine, and Vitamin C

A small before-and-after evaluation of 47 patients reported reduced mortality. However, hypoglycemia case reports have been cited with high-dose vitamin C. Due to anti­oxidizing activity, patients with a normal serum glucose may have a point-of-care glucose reading that is falsely elevated. When treated, patients may become hypoglycemic. Although hypothesis generating, administration of high-dose vitamin C requires more extensive evaluation before general application.

Conclusion

Emergency medicine has impacted sepsis research in multiple areas, including but not limited to early sepsis recognition, treatment, pathogenesis, genetics, biomarkers, microcirculation, immunomodulation, quality improvement, and a new area of compassionomics where compassionate care is linked to better outcomes, lower cost, and less clinician burnout.14 A cursory literature search of ([Title]: septicemia OR septicaemia OR sepsis OR severe sepsis OR septic shock) OR ([Title]: pneumonia AND severe) AND ([All fields] Emergency) resulted in 2,036 total articles, broken down as follows:

• 1960–1989: 48 articles
  1990–1999: 116 articles
  2000–present: 1,872 articles

Emergency medicine has an increasing number of researchers with funding and multi-institutional networks investigating science at an amazing pace.

Emergency medicine initially cares for those for whom everyone else will later provide care. We see those who need us when they need us; we are the safety net. As Dr. Peter Rosen explained, “The equality, appropriateness, and timeliness of the initial care is the biology of and responsibility of our specialty. No one who hasn’t trained for it, or practiced it…is capable of rendering it.”15,16

Providing sepsis care is no different. As we begin our first steps into the next 50 years of ACEP and emergency medicine, we are better positioned than ever to impact the care of the critically ill and injured, especially in the context of sepsis

Dr. Osborn is professor of surgery and emergency medicine at Barnes-Jewish Hospital/Washington University in St. Louis, Missouri.

References

1. Rivers E, Nguyen B, Havstad S, et al; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377.
2. Practice parameters for hemodynamic support of sepsis in adult patients in sepsis. Task Force of the American College of Critical Care Medicine, Society of Critical Care Medicine. Crit Care Med. 1999;27(3):639-660.
3. Otero RM, Nguyen HB, Huang DT, et al. Early goal-directed therapy in severe sepsis and septic shock revisited: concepts, controversies, and contemporary findings. Chest. 2006;130(5):1579-1595.
4. Nguyen HB, Rivers EP, Abrahamian FM, et al. Severe sepsis and septic shock: review of the literature and emergency department management guidelines. Ann Emerg Med. 2006;48(1):28-54.
5. Mouncey PR, Osborn TM, Power GS, et al. Protocolised Management In Sepsis (ProMISe): a multicentre randomised controlled trial of the clinical effectiveness and cost-effectiveness of early, goal-directed, protocolised resuscitation for emerging septic shock. Health Technol Assess. 2015;19(97):i-xxv, 1-150.
6. ProCESS Investigators, Yealy DM, Kellum JA, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683-1693.
7. Peake SL, Bailey M, Bellomo R, et al. Australasian resuscitation of sepsis evaluation (ARISE): a multi-centre, prospective, inception cohort study. Resuscitation. 2009;80(7):811-818.
8. Nguyen HB, Jaehne AK, Jayaprakash N, et al. Early goal-directed therapy in severe sepsis and septic shock: insights and comparisons to ProCESS, ProMISe, and ARISE. Crit Care. 2016;20(1):160.
9. Whiles BB, Deis AS, Simpson SQ. Increased time to initial antimicrobial administration is associated with progression to septic shock in severe sepsis patients. Crit Care Med. 2017;45(4):623-629.
10. Alam N, Oskam E, Stassen PM, et al. Prehospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomised trial. Lancet Respir Med. 2018;6(1):40-50.
11. Micek S, Johnson MT, Reichley R, et al. An institutional perspective on the impact of recent antibiotic exposure on length of stay and hospital costs for patients with gram-negative sepsis. BMC Infect Dis. 2012;12:56.
12. Artigas A, Wernerman J, Arroyo V, et al. Role of albumin in diseases associated with severe systemic inflammation: pathophysiologic and clinical evidence in sepsis and in decompensated cirrhosis. J Crit Care. 2016;33:62-70.
13. Vincent JL, De Backer D, Wiedermann CJ. Fluid management in sepsis: the potential beneficial effects of albumin. J Crit Care. 2016;35:161-167.
14. Trzeciak S, Roberts BW, Mazzarelli AJ. Compassionomics: hypothesis and experimental approach. Med Hypotheses. 2017;107:92-97.
15. Rosen P. The biology of emergency medicine. JACEP. 1979;8(7):280-283.
16. Zink BJ. The biology of emergency medicine: what have 30 years meant for Rosen’s original concepts? Acad Emerg Med. 2011;18(3):301-304.