Sepsis Bundle for Sepsis

(AIMS Trial)

Overseen By Lori Harmon, RRT, MBA, CPHQ

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Rhode Island Hospital

Disqualifiers: Pregnancy, Hospital transfers, Moribund, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 3 hours

10000 Participants Needed

Trial Summary

What is the purpose of this trial?

Since the introduction of sepsis bundles, there have been multiple published trials that have demonstrated a consistent, strong association between implementation of sepsis "bundles" (3-hour bundle) and improved survival. The current proposal is a Hybrid 2, pragmatic, cluster randomized clinical effectiveness/implementation trial evaluating mortality and respiratory failure-based outcomes, in patients admitted to the emergency department with sepsis, comparing the effectiveness of implementation of the hour-1 bundle to 3-hour bundle, while facilitating adherence to both bundles. In addition, 4 distinct sepsis phenotypes will be derived from routine clinical data to identify specific patient phenotypes that allow for a more precision-based application of sepsis bundles in future studies.

Do I need to stop my current medications for this trial?

The trial information does not specify whether you need to stop taking your current medications.

What data supports the effectiveness of the treatment Sepsis Bundle for sepsis?

Research shows that patients with severe sepsis who received the complete 3-hour bundle had better survival rates in the hospital compared to those who did not. Additionally, adherence to sepsis bundles has been linked to reduced death rates in severe sepsis and septic shock patients. ^{1 2 3 4 5}

Is the Sepsis Bundle safe for humans?

The Sepsis Bundle, including the Hour-1 and 3-Hour Bundles, is used in emergency settings to manage sepsis, but the available research primarily focuses on its effectiveness rather than safety. There is no specific safety data mentioned in the studies, but these bundles are widely implemented in clinical practice, suggesting they are generally considered safe. ^{1 6 7 8 9}

How is the Sepsis Bundle treatment different from other sepsis treatments?

The Sepsis Bundle, including the Hour-1 and 3-Hour Bundles, is unique because it emphasizes rapid, early intervention within the first few hours of sepsis diagnosis, focusing on timely administration of antibiotics, lactate measurement, and blood culture collection. This approach aims to improve survival rates by addressing sepsis aggressively and promptly, which is different from more traditional, less time-sensitive treatments. ^{1 6 10 11 12}

Research Team

Mitchell Levy, MD

Principal Investigator

Rhode Island Hospital

Eligibility Criteria

This trial is for adults over 18 who arrive at the emergency department with sepsis within 6 hours of triage. They must meet specific criteria including infection signs, systemic inflammation response, and organ dysfunction. Pregnant women, patients transferred from other hospitals, those receiving end-of-life care within 6 hours of ED admission or previously admitted for the same condition are excluded.

Inclusion Criteria

I was diagnosed with sepsis within 6 hours of arriving at the emergency department.

Exclusion Criteria

Last admission for patients admitted to same hospital once

All transfers from another hospital

I was placed on comfort care within 6 hours of being admitted to the emergency department.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either the Hour-1 or 3-Hour sepsis bundle interventions

3 hours

Continuous monitoring in the emergency department

Follow-up

Participants are monitored for safety and effectiveness after treatment

28 days

Implementation Evaluation

Evaluation of bundle adherence and effectiveness using the EPIS model

Ongoing throughout the trial

Treatment Details

Interventions

• Sepsis Bundle

Trial Overview The study compares two methods of treating sepsis in an emergency setting: a '1-hour bundle' versus a '3-hour bundle'. It aims to see which method is more effective at reducing mortality and respiratory failure. The trial also seeks to identify patient subtypes that respond best to these treatments using data-driven phenotyping.

Participant Groups

Group I: Hour-1 Bundle Active Control 1 Intervention

If the patient meets 2+ SIRS and chief complaint criteria, a second BPA may be triggered, which displays to the provider. The second alert identifies patients who progress to organ failure based on lab results, or who have a recorded instance of hypotension. When this alert appears, an automatic counter will begin and serve as our Sepsis Time Zero. The provider will receive sepsis order sets and guided to the Sepsis Navigator. The navigator will allow them to review relevant patient data, reference sepsis guidelines, and keep tabs on a live-updating sepsis checklist to ensure they complete each element in order and on time. Following identification in the ED, both study arms will receive the same bundle (see below). The only difference will be the timing: For the Hour-1 bundle, all interventions in the bundle must be initiated within 1 hour.

Group II: 3-Hour Bundle Active Control 1 Intervention

If the patient meets 2+ SIRS and chief complaint criteria, a second BPA may be triggered, which displays to the provider. The second alert identifies patients who progress to organ failure based on lab results, or who have a recorded instance of hypotension. When this alert appears, an automatic counter will begin and serve as our Sepsis Time Zero. The provider will receive sepsis order sets and guided to the Sepsis Navigator. The navigator will allow them to review relevant patient data, reference sepsis guidelines, and keep tabs on a live-updating sepsis checklist to ensure they complete each element in order and on time. Following identification in the ED, both study arms will receive the same bundle (see below). The only difference will be the timing: For the 3-hour bundle, all elements must be completed by 3 hours.

Sepsis Bundle is already approved in United States, European Union for the following indications:

Approved in United States as SEP-1 Bundle for:

• Sepsis
• Septic Shock

Approved in European Union as Sepsis Bundle for:

• Sepsis
• Septic Shock

Who Is Running the Clinical Trial?

Rhode Island Hospital

Lead Sponsor

Trials

275

Recruited

71,400+

Findings from Research

Implementing a 1-hour bundle for sepsis treatment in 67 patients significantly improved the achievement rate of treatment goals, reaching 81% after 12 weeks of training, compared to only 33.3% before training.

Patients treated with the 1-hour bundle experienced shorter durations of mechanical ventilation and ICU stays, and had a significantly lower 28-day mortality rate (10.8% vs. 31.4%) compared to those receiving the traditional 3-hour and 6-hour bundles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Application effect of 1-hour bundle in the treatment of patients with sepsis]. Yang, H., Wang, W., Li, Y., et al.[2020]

Patients with severe sepsis who received the complete 3-hour treatment bundle showed improved in-hospital survival rates compared to those who did not receive the full bundle.

Tracking compliance with the severe sepsis treatment bundle over time highlights its importance in reducing mortality among hospitalized patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe sepsis 3-hour bundle compliance and mortality. Lynn, NB., Gupta, C., Vaaler, M., et al.[2019]

In a study of 1052 patients with septic shock, completing the sepsis bundle components within 3 hours was associated with significantly lower 28-day mortality (17.5%) compared to those who took longer (31.4%).

Completing the sepsis bundle in less than 1 hour did not show a significant mortality advantage over completing it within 1 to 3 hours, suggesting that timely completion within 3 hours is crucial for improving survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Timeline of sepsis bundle component completion and its association with septic shock outcomes. Hu, B., Xiang, H., Dong, Y., et al.[2021]

A national sepsis program in The Netherlands improved adherence to treatment bundles for severe sepsis and septic shock, leading to a significant reduction in in-hospital mortality by 5.8% over 3.5 years among participating ICUs.

The study involved 213,677 ICU patients, with 8,387 severe sepsis patients in participating centers, demonstrating that effective implementation of sepsis screening and treatment bundles directly impacts patient survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Guideline bundles adherence and mortality in severe sepsis and septic shock. van Zanten, AR., Brinkman, S., Arbous, MS., et al.[2022]

The implementation of the Surviving Sepsis Campaign guidelines significantly reduced in-hospital mortality from 57.3% to 37.5% in patients with septic shock, based on a study of 384 patients after the intervention compared to a historical group of 96 patients.

Higher compliance with the 6-hour resuscitation bundle interventions was linked to improved survival rates, with achieving a ScvO2 level of 70% or higher being the only single intervention that significantly impacted mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of the Surviving Sepsis Campaign protocols on hospital length of stay and mortality in septic shock patients: results of a three-year follow-up quasi-experimental study. Castellanos-Ortega, A., Suberviola, B., García-Astudillo, LA., et al.[2022]

In a study of 593 adult patients with sepsis, the use of a complete Hour-1 Sepsis Bundle did not significantly reduce 28-day mortality compared to an incomplete bundle, with mortality rates of 3.6% and 4.2% respectively.

The study found no association between the completeness of the Hour-1 Sepsis Bundle and the occurrence of delayed septic shock, indicating that simply following the complete protocol may not improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The 28-Day Mortality Outcome of the Complete Hour-1 Sepsis Bundle in the Emergency Department. Prachanukool, T., Sanguanwit, P., Thodamrong, F., et al.[2023]

The updated sepsis bundle released by the Surviving Sepsis Campaign in April 2018 combines previous directives but may not align with the best available evidence, raising concerns about its effectiveness.

This narrative review emphasizes that the strength of the recommendations for the one-hour bundle is limited by the quality of the research methods used in the studies supporting it.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Challenging the One-hour Sepsis Bundle. Kalantari, A., Rezaie, SR.[2020]

In a study of 5,072 patients with severe sepsis or septic shock, delays in following the Surviving Sepsis Campaign guidelines were linked to increased mortality, with critical time thresholds identified for each intervention: lactate measurement (20 minutes), blood culture (50 minutes), fluid administration (100 minutes), and antibiotic therapy (125 minutes).

The research indicates that even short delays in administering these interventions can negatively impact patient outcomes, suggesting that timely adherence to sepsis guidelines is crucial for improving survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delay Within the 3-Hour Surviving Sepsis Campaign Guideline on Mortality for Patients With Severe Sepsis and Septic Shock. Pruinelli, L., Westra, BL., Yadav, P., et al.[2022]

This randomized controlled trial aims to determine if initiating the sepsis management 1-hour bundle in the Emergency Department leads to better clinical outcomes compared to the standard 3-hour bundle, with the study conducted across 18 sites.

The trial will also assess how effective a rigorous implementation strategy is in improving compliance with both the 1-hour and 3-hour sepsis bundles, potentially influencing future clinical practices in sepsis management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of implementation methods in sepsis: study protocol for a cluster-randomized hybrid type 2 trial. Frank, HE., Evans, L., Phillips, G., et al.[2023]

In a study of 178 sepsis patients across 17 intensive care units in Japan, completing the hour-1 sepsis care bundle was linked to a lower in-hospital mortality rate (18.0% for adherent care vs. 30.3% for non-adherent care).

Specifically, delays in obtaining blood cultures and administering broad-spectrum antibiotics within the first hour were significantly associated with higher mortality, highlighting the critical importance of these actions in improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hour-1 bundle adherence was associated with reduction of in-hospital mortality among patients with sepsis in Japan. Umemura, Y., Abe, T., Ogura, H., et al.[2022]

In a study of 650 patients with severe sepsis, compliance with the Centers for Medicare and Medicaid Services' 3-hour sepsis management bundle did not significantly affect 28-day in-hospital mortality rates, indicating that simply following the bundle may not improve survival outcomes.

Key predictors of mortality included the Sequential Organ Failure Assessment (SOFA) score and female sex, suggesting that these factors may be more critical in determining patient outcomes than adherence to the 3-hour bundle.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluating the impact of severe sepsis 3-hour bundle compliance on 28-day in-hospital mortality: A propensity adjusted, nested case-control study. August, BA., Griebe, KM., Stine, JJ., et al.[2022]

In a study involving over 14,000 patients with severe sepsis and septic shock, adherence to a 3-hour sepsis treatment bundle significantly reduced in-hospital mortality rates, with adjusted odds ratios indicating a 28% to 40% lower risk of death compared to non-compliance.

Patients who followed the 3-hour bundle also experienced lower treatment costs, with savings ranging from approximately $1,423 to $2,851, highlighting both the efficacy and economic benefits of timely sepsis management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival Benefit and Cost Savings From Compliance With a Simplified 3-Hour Sepsis Bundle in a Series of Prospective, Multisite, Observational Cohorts. Leisman, DE., Doerfler, ME., Ward, MF., et al.[2022]

References

1. China pubmed.ncbi.nlm.nih.gov

[Application effect of 1-hour bundle in the treatment of patients with sepsis]. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Severe sepsis 3-hour bundle compliance and mortality. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Timeline of sepsis bundle component completion and its association with septic shock outcomes. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Guideline bundles adherence and mortality in severe sepsis and septic shock. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Impact of the Surviving Sepsis Campaign protocols on hospital length of stay and mortality in septic shock patients: results of a three-year follow-up quasi-experimental study. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

The 28-Day Mortality Outcome of the Complete Hour-1 Sepsis Bundle in the Emergency Department. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Challenging the One-hour Sepsis Bundle. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Delay Within the 3-Hour Surviving Sepsis Campaign Guideline on Mortality for Patients With Severe Sepsis and Septic Shock. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Assessment of implementation methods in sepsis: study protocol for a cluster-randomized hybrid type 2 trial. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Hour-1 bundle adherence was associated with reduction of in-hospital mortality among patients with sepsis in Japan. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Evaluating the impact of severe sepsis 3-hour bundle compliance on 28-day in-hospital mortality: A propensity adjusted, nested case-control study. [2022]

12. United States pubmed.ncbi.nlm.nih.gov

Survival Benefit and Cost Savings From Compliance With a Simplified 3-Hour Sepsis Bundle in a Series of Prospective, Multisite, Observational Cohorts. [2022]