By Dean L. Winslow, MD, FACP, FIDSA

Professor of Medicine, Division of General Medical Disciplines, Division of Infectious Diseases and Geographic Medicine, Stanford University

Dr. Winslow reports no financial relationships relevant to this field of study.

SYNOPSIS: In the Protocolized Resuscitation in Sepsis Meta-Analysis (PRISM), 3,723 patients’ outcomes from the ProCESS, ARISE, and ProMISe randomized, controlled trials of early goal-directed therapy (EGDT) were evaluated. EGDT did not result in better outcomes than usual care and was associated with higher costs. The authors of a second study looked at outcomes of 49,331 patients with sepsis treated in New York from April 2014 to June 2016. More rapid completion of the three-hour sepsis bundle and antibiotic administration (but not rapid bolus administration of IV fluids) was associated with reduced in-hospital mortality.

SOURCES: The PRISM Investigators, Rowan KM, Angus DC, et al. Early, goal-directed therapy for septic shock — A patient-level meta-analysis. N Engl J Med 2017;376:2223-2234.

Seymour CW, Gesten F, Prescott HC, et al. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med 2017;376:2235-2244.

In the PRISM meta-analysis, data were pooled across the three large prospective randomized, controlled trials (ProCESS, ARISE, and ProMISe) of early goal-directed therapy (EGDT) vs. usual care. The primary outcome was 90-day mortality. Secondary outcomes included one-year survival, organ support, and hospitalization costs. Included in the analysis were 3,723 patients from 138 hospitals in seven countries. Mortality at 90 days was 24.9% in the EGDT arm and 25.4% in the usual care arm. The EGDT arm was associated with greater use of intensive care unit (ICU) and cardiovascular support and higher costs, but resulted in no benefit in any of the secondary outcomes. Subgroup analysis showed no benefit of EGDT even in patients with more severe septic shock (higher lactate levels and other factors predicting higher risk of death).

In the large 49,331 patient analysis of New York sepsis data from 149 hospitals, 82.5% of patients had the three-hour sepsis bundle (consisting of blood cultures, administration of antibiotics, and lactate measurements) completed within three hours. Among patients who had the three-hour bundle completed within 12 hours, a longer time to the completion of the bundle was associated with higher risk-adjusted in-hospital mortality, as was a longer time to the administration of antibiotics, but not a longer time to the completion of a bolus of intravenous fluids.

COMMENTARY

The famous Rivers trial,1 in which the term “early goal-directed therapy” of sepsis was coined, has influenced the management of sepsis positively throughout the world. The small, single-center Rivers trial emphasized, and the results of subsequent larger and better-quality randomized, controlled trials made clear, that patients who have sepsis recognized earlier and receive appropriate antibiotics and appropriate fluid resuscitation in a timely fashion experience better outcomes than patients who have diagnosis and appropriate treatment delayed.

Unfortunately, since the Rivers trial was published in the New England Journal of Medicine in 2001, many of the specific interventions in the EGDT arm (including measurement of CVP, central venous O2 saturation, use of serum lactate to guide fluid resuscitation, the mandated “one-size-fits-all” 30 mL/kg IV saline bolus) have not been shown to be helpful in subsequent trials. Despite this, many of these interventions now have been codified into “sepsis bundles” mandated by the Centers for Medicare & Medicaid Services (CMS). Compliance with these bundles is tracked by hospitals’ QI committees, is publicly reportable, and soon reimbursement will be tied to adherence to these bundles, with little room given for thoughtful deviation.

Another unwanted side effect is that the wide net that is cast to define sepsis ends up catching many patients who are not really septic. An extreme example I saw recently was a patient with a bad asthma attack, who, despite being normotensive, was labeled as having “sepsis” since the patient had HR > 90, high respiratory rate, and leukocytosis (from stress or glucocorticoid administration). This then triggered the drawing of a serum lactate (which is often elevated due to the inhaled β-agonists patients with wheezing are generally receiving in the ED). This then triggers the 30 mL/kg fluid challenge. In a young, healthy person, this generally is tolerated but could easily put an older patient with diastolic dysfunction into pulmonary edema. I also recently saw a 90-year-old lady from a skilled nursing facility receive 2.1 liters of IV saline because she was tachycardic, had leukocytosis, and had a minimally elevated lactate in the setting of PCR+ influenza (and no evidence of sepsis, but had received an albuterol treatment) despite a blood pressure of 150/100. She ended up in the ICU and needed BiPAP as well as 40 mg of IV furosemide as a result of the pulmonary edema that developed.

Similarly, I have seen residents order IV saline boluses in patients with atrial flutter with 2:1 conduction, multifocal atrial tachycardia, and supraventricular tachycardia (rather than treating the underlying arrhythmia). Just recently Kalil et al2 also published a wonderful meta-analysis of 19,998 patients from 31 observational studies and six randomized trials. As in the two studies discussed above, he also showed that survival was not correlated with sepsis bundle compliance but rather that survival was associated with more rapid administration of appropriate antibiotics that occurred in the EGDT arms of the studies he examined.

As I was writing this piece, it occurred to me that the effect of EGDT on survival in sepsis may be analogous to the improvement that we saw in survival of acute myocardial infarction and unstable angina after critical care units (CCUs) became common beginning in the 1960s. When I did my Medicine residency in the 1970s, the “CCU bundle” (although we didn’t call it that) consisted of: admission to a dedicated CCU where the patient had continuous cardiac monitoring; care generally provided by internists or cardiologists rather than general practitioners; nursing care from experienced nurses trained in ACLS who could defibrillate patients rapidly if necessary; O2 administered by nasal cannula at 2 L/min; prophylactic heparin SQ; and at the sight of the first VPC, the patient was given a lidocaine bolus and drip. Over the years, it was shown that supplemental O2 wasn’t helpful unless the O2 saturation was low, and prophylactic lidocaine was actually harmful, but the survival advantages afforded by CCU-level care were real, and we eventually eliminated the interventions that were found to be unhelpful or harmful.

I am hoping that some of our professional societies and both ID and critical care experts will be able to persuade CMS to allow thoughtful deviation from these mandated sepsis bundles and also to modify them by eliminating some elements (like serum lactate levels and “one-size-fits-all” 30 mL/kg fluid bolus) that actually drive inappropriate care.

REFERENCES

  1. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-1377.
  2. Kalil AC, Johnson DW, Lisco SJ, Sun J. Early goal-directed therapy for sepsis: A novel solution for discordant survival outcomes in clinical trials. Crit Care Med 2017;45:607-614.