Early Paramedic Treatment for Sepsis

(PITSTOP Trial)

Recruiting at 3 trial locations

Overseen By Damon Scales, MD PhD FRCPC

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Dr. Damon Scales

Must not be taking: Anticoagulants, Heparin

Disqualifiers: Cardiac arrest, STEMI, CVA, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

2040 Participants Needed

Trial Summary

What is the purpose of this trial?

Sepsis occurs when a serious infection - most commonly infection of the lungs, urinary system, or blood - leads to acute organ failure. It is a common, expensive, and frequently lethal condition. A growing body of evidence suggests that early recognition and treatment of sepsis can improve survival. Unfortunately, many patients with sepsis do not receive key therapies until physicians working in Emergency Departments have assessed them - often introducing marked delays. It is estimated that one-half of patients with sepsis are treated and transported to hospital by paramedics. This allows paramedics a unique opportunity to provide early treatment at the initial point of patient contact, thereby decreasing the time to treatment for these critically ill patients. This randomized controlled trial will evaluate whether prompt recognition followed by early antibiotics and/or intravenous fluids delivered by paramedics in the field leads to improved survival, compared to usual care, for patients who are transported to the hospital with sepsis.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but if you are taking anticoagulants (blood thinners), you cannot participate.

What data supports the effectiveness of the drug ceftriaxone (Rocephin) in treating sepsis?

Research shows that ceftriaxone (Rocephin) is effective in treating various bacterial infections, including sepsis, with good results in most cases. In a study, 90% of cirrhotic patients with bacterial infections responded well to ceftriaxone, and another study found that a 2 g daily dose reduced treatment failure in ICU patients. ^{1 2 3 4 5}

Is ceftriaxone generally safe for humans?

Ceftriaxone, used in various infections, is generally well-tolerated, but it can cause neutropenia (a low level of a type of white blood cell) and may have risks when used with intravenous calcium. In patients with acute renal failure, its elimination is impaired, requiring dosage adjustments. ^{1 2 3 6 7}

How is the treatment for sepsis using Ceftriaxone and fluid management different from other treatments?

This treatment is unique because it combines the antibiotic Ceftriaxone with a specific approach to fluid management, using either conservative (restricted) or liberal (more generous) fluid therapy, which is still debated in the medical community. The focus on early paramedic intervention and the balance of fluid volumes makes it distinct from standard sepsis treatments that may not emphasize these aspects. ^{8 9 10 11 12}

Research Team

Damon Scales, MD

Principal Investigator

Sunnybrook Health Sciences Centre

Eligibility Criteria

Adults over 18 with suspected sepsis, indicated by possible infection, fever (≥38.0°C), and low blood pressure (systolic <100mmHg) can join. Excluded are those with stroke, heart failure, penicillin/cephalosporin allergy, severe trauma or bleeding, recent cardiac arrest or myocardial infarction, fluid overload signs, C. difficile infection in the past 6 weeks, pregnancy/breastfeeding or on certain anticoagulants.

Inclusion Criteria

I am 18 years old or older.

I have sepsis with suspected infection, fever over 38.0°C, and low blood pressure.

Exclusion Criteria

I am taking blood thinners.

I am suspected to have sudden heart failure.

I have had a Clostridium difficile infection in the past 6 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Prehospital Treatment

Paramedics administer early antibiotics and/or intravenous fluids to patients with suspected sepsis in the field

Immediate intervention

1 visit (in-person)

Hospitalization

Patients are transported to the hospital and receive further treatment and monitoring for sepsis

Up to 90 days

Follow-up

Participants are monitored for mortality and organ dysfunction after treatment

90 days

Treatment Details

Interventions

• Ceftriaxone
• Conservative fluids
• Liberal fluids
• Placebo

Trial Overview The PITSTOP trial is testing if early treatment for sepsis by paramedics improves survival rates. It compares two approaches: one group receives an antibiotic called Ceftriaxone and either liberal or conservative fluids before hospital arrival; the other gets a placebo instead of antibiotics.

Participant Groups

Group I: Comparison 2: Liberal fluids Experimental Treatment 1 Intervention

Paramedics will administer up to 2 litres of intravenous 0.9% saline solution to all participants in this arm regardless of blood pressure, reassessing for signs of volume overload after each 250ml.

Group II: Comparison 1: Prehospital Ceftriaxone Active Control 1 Intervention

1g of Ceftriaxone will be administered by immediate intramuscular (IM) injection. The drug is provided in a sterile and completely covered vial as a white, odourless powder

Group III: Comparison 2: Conservative fluids Active Control 1 Intervention

Paramedics will administer 0.9% saline solution to participants who have systolic blood pressure \<90mmHg, and will only continue the infusion until the systolic blood pressure is \>=100mmHg.

Group IV: Comparison 1: Placebo Placebo Group 1 Intervention

The placebo is provided in a sterile and completely covered vial.

Ceftriaxone is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Rocephin for:

• Sepsis
• Bacterial infections
• Meningitis
• Gonorrhea
• Pelvic inflammatory disease

Approved in United States as Rocephin for:

• Sepsis
• Bacterial infections
• Meningitis
• Gonorrhea
• Pelvic inflammatory disease
• Lower respiratory tract infections
• Skin and skin structure infections
• Urinary tract infections

Approved in Canada as Rocephin for:

• Sepsis
• Bacterial infections
• Meningitis
• Gonorrhea
• Pelvic inflammatory disease
• Lower respiratory tract infections
• Skin and skin structure infections
• Urinary tract infections

Who Is Running the Clinical Trial?

Dr. Damon Scales

Lead Sponsor

Trials

1

Recruited

2,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Sunnybrook Research Institute

Collaborator

Trials

33

Recruited

216,000+

Findings from Research

Rocephin (ceftriaxone) demonstrated high efficacy in treating septicaemia, with a successful cure in 21 out of 23 cases when administered intravenously at a dosage of 2 x 1 g/day.

The drug showed excellent clinical and biological tolerance, making it easy to administer, although one case required additional treatment with ampicillin and one case was ineffective against resistant enterococci.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical study of Rocephin, a 3d generation cephalosporin, in various septicaemias. Ghosen, V., Chamali, R., Bar-Moshe, O., et al.[2018]

In a study involving 51 cirrhotic patients with 62 episodes of bacterial infection, intravenous ceftriaxone was administered once daily for 7-10 days, showing a good response rate in 90% of cases.

Ceftriaxone was effective in treating various types of infections, including pneumonia and spontaneous bacterial peritonitis, indicating its potential as a reliable treatment option for bacterial infections in cirrhotic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of ceftriaxone in the treatment of bacterial infections in cirrhotic patients. Mercader, J., Gomez, J., Ruiz, J., et al.[2018]

In a study of 12 patients (5 with acute renal failure and 7 without), ceftriaxone clearance was found to be significantly impaired in those with renal issues, indicating that dosage adjustments are necessary based on kidney function.

The research showed that renal clearance of ceftriaxone is closely linked to creatinine clearance, and that non-renal clearance is also reduced, suggesting that patients with acute renal failure may not effectively eliminate the drug, necessitating careful monitoring and dosage modifications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clearance of ceftriaxone in critical care patients with acute renal failure. Heinemeyer, G., Link, J., Weber, W., et al.[2019]

In a pilot study of 57 critically ill patients with sepsis, continuous infusion of ceftriaxone showed a trend towards better clinical outcomes compared to once-daily bolus dosing, particularly in patients who received treatment for 4 or more days.

Logistic regression analysis indicated that continuous infusion was associated with significantly improved clinical outcomes, especially in patients with lower APACHE II scores, suggesting that this method of administration may enhance the efficacy of ceftriaxone in severe cases of sepsis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is continuous infusion ceftriaxone better than once-a-day dosing in intensive care? A randomized controlled pilot study. Roberts, JA., Boots, R., Rickard, CM., et al.[2015]

In a study of 212 ICU patients receiving ceftriaxone for non-CNS infections, those treated with 2 g daily had a significantly lower treatment failure rate (5.7%) compared to those receiving 1 g daily (17.0%), indicating that higher dosing may improve clinical outcomes.

Ceftriaxone 2 g dosing was associated with a reduced likelihood of treatment failure, with an adjusted odds ratio of 0.190, suggesting that higher doses could be beneficial for ICU patients at lower risk of mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Clinical Outcomes among Intensive Care Unit Patients Receiving One or Two Grams of Ceftriaxone Daily. Ackerman, A., Zook, NR., Siegrist, JF., et al.[2021]

In a matched-cohort study of 142 critically ill adults, the combination of ceftriaxone and high-dose intravenous calcium did not show a significant increase in hospital mortality or severe adverse outcomes compared to patients not receiving this combination.

The study provides reassurance regarding the safety of using ceftriaxone and calcium together in critically ill adults, although it acknowledges that rare adverse effects cannot be completely ruled out.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concomitant ceftriaxone and high-concentration intravenous calcium therapy in adult critical care patients: a matched cohort study. Dalton, BR., Zuege, DJ., Shahpori, R., et al.[2015]

Intravenous treatment with ceftriaxone significantly reduces neutrophil counts in patients, with a mean drop from 3.93 to 3.15 × 10^9 L-1, indicating a potential risk of neutropenia.

The extent of neutrophil reduction can be predicted using a multifactor linear regression model based on routine baseline blood indices, allowing for better monitoring and management of patients receiving ceftriaxone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biochemical and Haematological Predictors of Reduced Neutrophil Granulocyte Count associated with Intravenous Ceftriaxone Treatment. Puri, BK., Derham, A., Monro, JA.[2020]

Starch solutions should be avoided in sepsis patients due to lack of benefit and potential harm, including kidney issues and increased mortality, as highlighted by recent large clinical trials.

Norepinephrine is recommended as the first-line vasopressor for sepsis treatment, while early antibiotic therapy is crucial, and etomidate should not be used in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative treatment of patients with sepsis. Ibsen, M., Perner, A.[2013]

The CLASSIC trial, involving 1554 adult ICU patients with septic shock, aims to compare the effects of restricted versus standard intravenous fluid therapy on 90-day all-cause mortality.

The study will use advanced Bayesian analyses to assess the probabilities of benefits and harms from different fluid therapy approaches, providing clearer insights for clinicians on treatment effectiveness and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conservative vs. liberal fluid therapy in septic shock - Protocol for secondary Bayesian analyses of the CLASSIC trial. Sivapalan, P., Meyhoff, TS., Hjortrup, PB., et al.[2022]

In a study involving 123 adult patients with sepsis but no shock, a 24-hour protocol that restricted intravenous fluid administration significantly reduced the total IV crystalloid fluid volumes compared to standard care (562 ml vs. 1370 ml).

Despite the reduction in fluid volumes, there were no significant differences in adverse events, mechanical ventilation, acute kidney failure, or mortality between the restrictive and standard care groups, suggesting that the fluid restriction protocol is safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Restrictive fluids versus standard care in adults with sepsis in the emergency department (REFACED): A multicenter, randomized feasibility trial. Jessen, MK., Andersen, LW., Thomsen, MH., et al.[2023]

The REFRESH trial is a multicenter, open-label study designed to compare the effects of standard care (a second 1000-ml fluid bolus) versus restricted fluid maintenance in patients with sepsis and hypotension, aiming to determine the optimal fluid resuscitation strategy.

This trial will not only measure the total fluid volume administered in the first 6 hours but also assess secondary outcomes like organ support days and 90-day mortality, while exploring biomarkers to understand the impact of fluid volume on inflammation and vascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

REstricted Fluid REsuscitation in Sepsis-associated Hypotension (REFRESH): study protocol for a pilot randomised controlled trial. Macdonald, SPJ., Taylor, DM., Keijzers, G., et al.[2018]

A systematic review of 7002 articles on fluid therapy in sepsis identified only 20 relevant randomized controlled trials, highlighting a significant lack of detailed information on the characteristics of fluids used, such as chloride content and buffering substances.

The study emphasizes the importance of providing clear descriptions of fluid compositions in clinical trials, as this information is crucial for both researchers and clinicians to make informed decisions about fluid resuscitation in sepsis management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluid resuscitation in severe sepsis and septic shock: systematic description of fluids used in randomized trials. Rochwerg, B., Włudarczyk, A., Szczeklik, W., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical study of Rocephin, a 3d generation cephalosporin, in various septicaemias. [2018]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Use of ceftriaxone in the treatment of bacterial infections in cirrhotic patients. [2018]

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

Clearance of ceftriaxone in critical care patients with acute renal failure. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Is continuous infusion ceftriaxone better than once-a-day dosing in intensive care? A randomized controlled pilot study. [2015]

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

Comparison of Clinical Outcomes among Intensive Care Unit Patients Receiving One or Two Grams of Ceftriaxone Daily. [2021]

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

Concomitant ceftriaxone and high-concentration intravenous calcium therapy in adult critical care patients: a matched cohort study. [2015]

7. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Biochemical and Haematological Predictors of Reduced Neutrophil Granulocyte Count associated with Intravenous Ceftriaxone Treatment. [2020]

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

Perioperative treatment of patients with sepsis. [2013]

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

Conservative vs. liberal fluid therapy in septic shock - Protocol for secondary Bayesian analyses of the CLASSIC trial. [2022]

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

Restrictive fluids versus standard care in adults with sepsis in the emergency department (REFACED): A multicenter, randomized feasibility trial. [2023]

11. England pubmed.ncbi.nlm.nih.gov

REstricted Fluid REsuscitation in Sepsis-associated Hypotension (REFRESH): study protocol for a pilot randomised controlled trial. [2018]

12. Poland pubmed.ncbi.nlm.nih.gov

Fluid resuscitation in severe sepsis and septic shock: systematic description of fluids used in randomized trials. [2022]