Paramedic Initiated Treatment of Sepsis Targeting Out-of-hospital Patients (PITSTOP)

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
The ultimate goal of this research program is to evaluate a fundamental change in the delivery of sepsis care. Currently, patients with severe sepsis do not receive key evidence-based therapies until they have been assessed in emergency departments - often introducing considerable delays. This research tests whether integrating paramedics directly into a chain-of-survival for sepsis will improve outcomes for these critically ill patients. In essence, this research seeks to break down silos of care, delivering sepsis treatments based on when they are needed, rather than on where the patient is physically located. If the trial is positive, the results will have broad implications for other health systems by showing that prehospital identification and treatment of sepsis increases the number of patients that survive this life-threatening condition. If the trial fails to demonstrate effectiveness of prehospital sepsis treatments, it will ensure that resources are not needlessly invested in large-scale implementations of paramedic sepsis protocols, as has been done in several other jurisdictions. A lack of benefit would also cast doubt on the observational data suggesting that early antibiotics are important, and suggest a more restrained approach to empiric antibiotic therapy.

Official Title
-----------------
Paramedic Initiated Treatment of Sepsis Targeting Out-of-hospital Patients (PITSTOP)

Conditions
-----------------
Severe Sepsis or Septic Shock

Intervention / Treatment
-----------------
* Drug: Comparison 1: Prehospital Ceftriaxone
* Drug: Comparison 1: Placebo
* Drug: Comparison 2: Liberal fluids
* Drug: Comparison 2: Conservative fluids


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with Sepsis, defined as (all 3 must be present): i) Paramedic suspects possible infection: e.g. suspected pneumonia, urinary tract infection, skin infection, bone and joint infection, intra-abdominal infection, meningitis ii) Presence of fever: Temperature ≥ 38.0°C measured by paramedic or history of fever during previous 24 hours iii) Presence of hypotension: Systolic blood pressure < 100mmHg Age ≥ 18 years Exclusion Criteria: Post cardiac arrest Suspected ST-segment elevation myocardial infarction (STEMI) Suspected acute cerebrovascular accident (CVA) Acute severe trauma Obvious severe non-traumatic bleeding Signs of fluid overload Suspected acute congestive heart failure (CHF) Known Clostridium difficile infection within the last 6 weeks Known pregnancy or breastfeeding Known allergy or sensitivity to penicillin or cephalosporin Receiving oral or subcutaneous anticoagulants or low molecular weight heparin Paramedic is unable to identify patient by first and last name and/or health card number

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: This is a 2x2 factorial RCT, with simultaneous randomization of individual patients into 2 randomized controlled trials. The first RCT compares administration of 1g of intramuscular ceftriaxone versus placebo. In this RCT, participants, care providers, investigators, and outcome assessors will all be masked to the treatment allocation. The second RCT compares a liberal fluid resuscitation (up to 2litres of intravenous 0.9% saline) versus conventional resuscitation (administration of intravenous 0.9% saline, started only when systolic blood pressure is <90mmHg and only continued until systolic blood pressure is >= 100mmHg). In this RCT, only participants and outcome assessors will be masked.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Comparison 1: Prehospital Ceftriaxone<br>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 | Drug: Comparison 1: Prehospital Ceftriaxone<br>* Paramedics will administer 1g of intramuscular ceftriaxone.<br>* Other names: Ceftriaxone;|
| Placebo Comparator: Comparison 1: Placebo<br>The placebo is provided in a sterile and completely covered vial. | Drug: Comparison 1: Placebo<br>* Paramedics will administer an identical volume of reconstituted intramuscular placebo.<br>* Other names: 0.9% saline for injection;|
| Experimental: Comparison 2: Liberal fluids<br>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. | Drug: Comparison 2: Liberal fluids<br>* Paramedics will administer up to 2 litres of intravenous saline (0.9%) to all patients regardless of systolic blood pressure, and reassessing this infusion after each 250ml are infused.<br>* Other names: intravenous saline (0.9%) for injection;|
| Active Comparator: Comparison 2: Conservative fluids<br>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. | Drug: Comparison 2: Conservative fluids<br>* Paramedics will administer intravenous saline (0.9%) according to the Medical Directive, which allows for infusion of fluids if systolic blood pressure is <90mmHg and continued until systolic blood pressure is >=100mmHg.<br>* Other names: intravenous saline (0.9%) for injection;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary outcome: mortality prior to hospital discharge to day 90. | Dichotomous outcome reported as percentage | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Organ dysfunction during first 24 hours (mechanical ventilation, vasopressor therapy (any), dialysis | Dichotomous outcome reported as percentage | 24 hours | 
| Organ dysfunction during hospitalization (mechanical ventilation) | Dichotomous outcome reported as percentage | until hospital discharge, measured up to maximum of day 90 | 
| duration of hospital admission (if any) | Measured in days from time of randomization | until hospital discharge, measured up to maximum of day 90 | 
| duration of first ICU admission (if any) | Measured in days from time of randomization | until ICU discharge, measured up to maximum of day 90 | 
| Proportion of patients with positive blood cultures obtained in hospital | Dichotomous outcome reported as percentage | 24 hours | 
| Microbiology results (if any) | Descriptive outcome, reported as frequency distribution of positive culture results | 24 hours | 
| Proportion of patients receiving antibiotics within first 24 hours of hospitalization | Dichotomous outcome reported as percentage | 24 hours | 
| Frequency distribution and mean time to first dose of antibiotics (if any) within first 24 hours of hospitalization | Measured in hours from time of randomization | 24 hours | 
| Proportion of patients receiving IV fluids (>250mL) within first 24 hours of hospitalization | measured in milliliters | 24 hours | 
| Total amount of IV fluids administered during transport and first 24 hours of hospitalization (if any) | measured in milliliters | 24 hours | 
| Proportion of patients with pulmonary edema identified during transport to hospital and on initial chest x-ray | Dichotomous outcome reported as percentage | during transport and on initial chest x-ray (if completed) | 
| Proportion of patients with blood, urine, sputum cultures that grow organisms resistant to ceftriaxone | Dichotomous outcome reported as percentage | 24 hours | 
| Proportion of patients diagnosed with sepsis or infection by emergency department physician | Dichotomous outcome reported as percentage | during admission | 
| Proportion of hospitalized patients who grow any antibiotic-resistant organism (methicilin resistant S. aureus, Clostridium difficile, extended beta-lactamase resistant organisms) | Dichotomous outcome reported as percentage | during admission | 
| Proportion of patients with anaphylaxis or suspected allergic reactions to study medication | Dichotomous outcome reported as percentage | during admission |