Mahtab Foroozesh, M.D., Program Director

Reviewed by Brijesh Patel

Sepsis remains a deadly and costly syndrome worldwide. The Surviving Sepsis Campaign has incorporated early goal-directed therapy (EGDT) in their guidelines, largely on the basis of a 2001 single-center, proof-of-concept study by Rivers and colleagues, which indicated that a protocolized approach to management of sepsis reduced hospital mortality (2). However, adaptation of EGDT into general practice has been limited because of concerns over cost, protocol complexity, and generalizability (3).

The ProMISe (Protocolized Management in Sepsis) trial was an open, multicenter, parallel-group, randomized controlled trial of the clinical and cost effectiveness of protocolized resuscitation with EGDT compared with usual care (1).

The ProMISe trial analyzed data on 1,243 patients with severe sepsis/septic shock across 56 emergency departments in the UK. Included patients had at least two of four systemic inflammatory response syndrome criteria as well as either a lactate level greater than 4 mmol/L or systolic blood pressure less than 90 mm Hg after fluid challenge. Patients with pulmonary edema, stroke, major gastrointestinal bleeding, pregnancy, advanced HIV, or imminent death were excluded. Patients were then randomized to “usual” vs. algorithm-driven care that largely relied on endpoints defined in the trial by Rivers and colleagues. Of note, all patients received antibiotics before randomization.

The study showed significantly higher use of central venous catheters, arterial lines, transfusions, and dobutamine in the EGDT arm. Furthermore, patients in the EGDT arm had more intensive care unit (ICU) admissions, worse Sequential Organ Failure Assessment scores at 6 hours, longer use of advanced cardiovascular support, and longer ICU length of stay. Despite these findings, there was no significant difference in 90-day mortality between groups (29.5% EGDT vs. 29.2% in usual care group, P = 0.90) and no meaningful difference in secondary outcomes, including health-related quality of life or adverse events. There was a trend to higher 90-day hospital costs in the EGDT group.

The ProMISe trial, along with ProCESS (PROtocol-based Care for Early Septic Shock) and ARISE (Australasian Resuscitation in Sepsis Evaluation) trials, demonstrates that beyond early identification, fluid resuscitation, and antibiotics, a protocolized approach to sepsis using parameters such as central venous oxygen saturation would not improve outcomes. In fact, the ProMISe trial implies that such criteria may even lead to overutilization of resources. On the other hand, all three studies highlighted the importance of early administration of fluids and antibiotics as noted by the better-than-expected mortality in the usual care groups. Inconsistencies in achieving these simple goals may be the reason for the differences in mortality among the three studies.

Reviewed by Daniel Smith

Treatment of sepsis has remained largely supportive, with early care dominated by antibiotics and intravenous fluids. Lactoferrin is a glycoprotein with a number of favorable antimicrobial and immunomodulatory properties that may provide a novel approach to improve sepsis outcomes (5). A recombinant form of lactoferrin, talactoferrin, had been shown in a 2013 phase II trial to decrease mortality in severe sepsis. However, this study had unspecified “drug allocation issues” that may have affected results. Therefore, a repeat phase II trial followed by a phase III component was designed to confirm the effect of talactoferrin on sepsis mortality.

The OASIS (Oral Talactoferrin in Severe Sepsis) trial was a multicenter, randomized, placebo-controlled, double-blinded phase II/III trial to determine the effect of thrice-daily oral talactoferrin administration on 28-day all-cause mortality in patients admitted to the ICU with severe sepsis. Included patients had at least three of four systemic inflammatory response syndrome criteria and evidence of end-organ dysfunction. Patients were excluded if they met any of the following criteria: on immunosuppression medications, New York Heart Association class IV heart failure, severe liver disease, severe burns, poorly controlled HIV/AIDS, or imminent death. To limit the number of patients required for enrollment and minimize confounders, patients were randomized using permuted block method stratification by presence of septic shock, urinary source of infection, and geographic distribution. Owing to this block randomization, all-cause mortality endpoints were analyzed using a Cochran-Mantel-Haenszel test across the three stratifications.

The trial was stopped early on recommendations of the drug monitoring safety board for futility and potential hazard of the trial drug after 305 (153 talactoferrin, 152 placebo) patients were enrolled. All-cause mortality was higher in the talactoferrin group versus placebo at 28 days (25 vs. 18%, P = 0.11), in-hospital (28 vs. 18%, P < 0.05), and 3 months (30 vs. 20%, P < 0.05).

To explain the disparity of results between talactoferrin studies, the authors drew multiple parallels to a phenomenon found by the PROWESS (Protein C Worldwide Evaluation in Severe Sepsis) group evaluating drotrecogin: the newer studies show lower placebo mortality and concomitant negative study drug effect, perhaps driven by improving baseline sepsis care (6). However, although lower mortality rates could increase the requisite sample sizes to show a significant improvement, such an argument is substantially weakened in this case by the higher mortality in the talactoferrin group, which reached statistical significance for the in-hospital and 3-month values. Regardless, the OASIS study adds another drug to the long list of ineffective pharmaceutical augmentation strategies for treating sepsis.

Reviewed by Faisal Siddiqui

More than 1 million patients are admitted with sepsis each year in the United States; of these, nearly a quarter die, exceeding the combined mortality from breast, lung, and prostate cancer (8). Consequently, increasing resources are being spent toward identifying sepsis and mitigating its deadly toll. Many institutions have implemented sepsis recognition protocols to identify patients early because previous work showed that this strategy improves outcomes (9).

This SWAT (Sepsis Workup and Treatment) trial was undertaken at the emergency department (ED) of the Medical University of South Carolina. They evaluated the efficacy of early identification, triage, and mobilization of resources for patients with sepsis. Sepsis was identified on clinical suspicion of infection with either hypotension (SWAT A) or presence of two systemic inflammatory response syndrome criteria (SWAT B) in triage. Patients meeting either category triggered a “sepsis alert,” leading to rapid administration of antibiotics and intravenous fluids.

This was a retrospective study of the adult ED patients and consisted of preintervention (pre-SWAT) and post-intervention (post-SWAT) cohorts, further subdivided into whether they met the aforementioned SWAT A or SWAT B criteria. A total of 238 patient medical records were abstracted for the study (108 in pre-SWAT and 130 for post-SWAT group). There were no demographic differences between cohorts; however, patients in the post-SWAT group had a statistically significant higher number of systemic inflammatory response syndrome criteria and lower systolic blood pressure. The average times to intravenous fluids and antibiotic administration were 31 minutes and 59 minutes quicker, respectively, in the postimplementation group. However, these changes did not translate into a mortality benefit.

The study’s main limitations were its retrospective design, differences in severity of illness between groups, and an element of selection bias (physicians called sepsis alert for “sicker” patients). Another confounder is poor adherence to the protocol, as a significant portion of post-SWAT patients did not receive antibiotics within the first hour.

Time and again, the only consistent management principle that has shown to improve outcomes in patients with sepsis is early identification and treatment with intravenous fluids and antibiotics. The sepsis alert system helps expedite this process, as shown in this study and several others. Although the decreased door to antibiotics time is an important finding, the lack of demonstrated mortality benefit could be due to above-mentioned confounders, including the fact that more than half of the patients still did not get antibiotics in a timely manner.