Out-Of-Hospital Cardiac Arrest, Pneumonia
Conditions
Keywords
out-of-hospital cardiac arrest, cardiac arrest, pneumonia, randomized clinical trial, infection, ceftriaxone, microbiome, inflammation, prophylaxis
Brief summary
Randomized-controlled trial and microbiome assessment to understand the risk-to-benefit ratio of prophylactic antibiotics (Ceftriaxone) vs placebo in patients with pneumonia and inflammation after cardiac arrest outside the hospital.
Detailed description
Pneumonia is an infection of the lungs resulting in alveolar inflammation and fluid or purulent material accumulation. It is the most common infection after cardiac arrest occurring in up to 65% of patients treated with targeted temperature management. Pneumonia may result from aspiration during cardiopulmonary resuscitation (CPR), or by introduction of oropharyngeal flora into the lungs during airway management. Preventing infection after OHCA may: 1) reduce exposure to broad-spectrum antibiotics and subsequent collateral damage, 2) prevent hemodynamic derangements due to local and systemic inflammation, and 3) prevent an association between infection and morbidity and mortality. These benefits must be balanced with the risk for altering bacterial resistomes in the absence clinical infection. Accordingly, further study is warranted to understand the risk-to-benefit ratio of prophylactic antibiotics.
Interventions
DRUGStandard of care without prophylaxis
Administer antibiotics in response to infection
DRUGAntibiotic prophylaxis
Ceftriaxone 2 gm IV q12h for 3 days
Sponsors
MaineHealth
National Institute of General Medical Sciences (NIGMS)
University of New England
David J. Gagnon
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The clinical team responsible for the participant (physicians, nurses and others) and involved with direct patient care will be blinded. Investigators will be blinded and the placebo will match the study drug. Outcomes Assessors will be blinded to treatment assignment during assessments of pneumonia and functional outcome.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* ≥18 years of age * Comatose (do not follow simple verbal commands) * Have any initial heart rhythm (shockable or non-shockable) * OHCA including the emergency department
Exclusion criteria
* Name on opt-out list * In-hospital cardiac arrest * Interval \>6 hours from ICU admission to study drug receipt * Preexisting terminal disease making 180-day survival unlikely * Refused informed consent * Emergent coronary artery bypass grafting * Anaphylaxis or angioedema to beta-lactam antibiotics (i.e., cephalosporins or penicillins) * Under legal guardianship or prisoner * Known colonization with methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococcus (VRE) * Clinical bacterial infection prior to hospital admission defined as any one of the following: * Infectious prodrome preceding OHCA * Active course of antibiotics for infection prior to admission * Active infection documented in the electronic medical record * Family or surrogate endorsement of an active infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinically-diagnosed Early-onset Pneumonia | 4 days | Percentage of Participants with Clinically-diagnosed Early-onset Pneumonia occurring \<4 days after initiation of mechanical ventilation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Microbiologically-confirmed Late-onset Pneumonia | ≥ 4 days | Percentage of Participants with Microbiologically-confirmed late-onset pneumonia occurring ≥4 days after initiation of mechanical ventilation |
| Clinically-diagnosed Late-onset Pneumonia | ≥ 4 days | Percentage of Participants with Clinically-diagnosed late-onset pneumonia occurring ≥4 days after initiation of mechanical ventilation |
| Non-pulmonary Infections | During the intervention and immediately after the intervention until hospital discharge, up to 6 months | Percentage of Participants with non-pulmonary infections |
| ICU-free Days During Admission | 28 days | ICU-free days in the first 28 days of admission |
| Mechanical Ventilator-free Days During Admission | 28 days | Mechanical ventilator-free days in the first 28 days of admission |
| Microbiologically-confirmed Early-onset Pneumonia | 4 days | Percentage of Participants with Microbiologically-confirmed Early-onset Pneumonia occurring \<4 days after initiation of mechanical ventilation |
| Functional Outcome at 6 Months Post-hospital Discharge | 6 months post-hospital discharge | Median mRS (0 as no residual symptoms and 6 as death) at 6 Months Post-hospital Discharge |
| Clostridioides Difficile-associated Diarrhea | During the intervention and immediately after the intervention until death or hospital discharge | Percentage of Participants with Clostridioides difficile-associated Diarrhea |
| Type One Hypersensitivity Reactions | Three days | Percentage of Participants with Type One (immediate-type) hypersensitivity reactions |
| Participants With Gallbladder Disease | During the intervention and immediately after the intervention until death or hospital discharge | Percentage of Participants with Gallbladder disease |
| Death in the Hospital | During the intervention (3 days) and immediately after the intervention until subject death or hospital discharge, an average of 30 days | Percentage of Participants who Die in the Hospital during admission |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| No Prophylaxis (Placebo) Standard care without antibiotic prophylaxis and treatment of infection if clinically warranted.
Administer antibiotics in response to infection.
Standard of care without prophylaxis: Administer antibiotics in response to infection | 26 |
| Prophylaxis Antibiotic prophylaxis for 3 days. Antibiotic prophylaxis with Ceftriaxone 2 gm IV q12h for 3 days.
Antibiotic prophylaxis: Ceftriaxone 2 gm IV q12h for 3 days | 26 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Prophylaxis | Total | No Prophylaxis (Placebo) |
|---|---|---|---|
| Age, Continuous | 60 years | 60 years | 59 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 51 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 25 Participants | 50 Participants | 25 Participants |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 4 Participants |
| Sex: Female, Male Male | 24 Participants | 46 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 19 / 26 | 11 / 26 |
| other Total, other adverse events | 0 / 26 | 0 / 26 |
| serious Total, serious adverse events | 0 / 26 | 0 / 26 |
Outcome results
Primary
Clinically-diagnosed Early-onset Pneumonia
Percentage of Participants with Clinically-diagnosed Early-onset Pneumonia occurring \<4 days after initiation of mechanical ventilation
Time frame: 4 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| No Prophylaxis (Placebo) | Clinically-diagnosed Early-onset Pneumonia | 18 Participants |
| Prophylaxis | Clinically-diagnosed Early-onset Pneumonia | 10 Participants |
Secondary
Clinically-diagnosed Late-onset Pneumonia
Percentage of Participants with Clinically-diagnosed late-onset pneumonia occurring ≥4 days after initiation of mechanical ventilation
Time frame: ≥ 4 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| No Prophylaxis (Placebo) | Clinically-diagnosed Late-onset Pneumonia | 6 Participants |
| Prophylaxis | Clinically-diagnosed Late-onset Pneumonia | 3 Participants |
Secondary
Clostridioides Difficile-associated Diarrhea
Percentage of Participants with Clostridioides difficile-associated Diarrhea
Time frame: During the intervention and immediately after the intervention until death or hospital discharge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| No Prophylaxis (Placebo) | Clostridioides Difficile-associated Diarrhea | 0 Participants |
| Prophylaxis | Clostridioides Difficile-associated Diarrhea | 0 Participants |
Secondary
Death in the Hospital
Percentage of Participants who Die in the Hospital during admission
Time frame: During the intervention (3 days) and immediately after the intervention until subject death or hospital discharge, an average of 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| No Prophylaxis (Placebo) | Death in the Hospital | 19 Participants |
| Prophylaxis | Death in the Hospital | 11 Participants |
Secondary
Functional Outcome at 6 Months Post-hospital Discharge
Median mRS (0 as no residual symptoms and 6 as death) at 6 Months Post-hospital Discharge
Time frame: 6 months post-hospital discharge
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| No Prophylaxis (Placebo) | Functional Outcome at 6 Months Post-hospital Discharge | 6 units on a scale |
| Prophylaxis | Functional Outcome at 6 Months Post-hospital Discharge | 6 units on a scale |
Secondary
ICU-free Days During Admission
ICU-free days in the first 28 days of admission
Time frame: 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| No Prophylaxis (Placebo) | ICU-free Days During Admission | 0 days |
| Prophylaxis | ICU-free Days During Admission | 16 days |
Secondary
Mechanical Ventilator-free Days During Admission
Mechanical ventilator-free days in the first 28 days of admission
Time frame: 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| No Prophylaxis (Placebo) | Mechanical Ventilator-free Days During Admission | 0 days |
| Prophylaxis | Mechanical Ventilator-free Days During Admission | 25 days |
Secondary
Microbiologically-confirmed Early-onset Pneumonia
Percentage of Participants with Microbiologically-confirmed Early-onset Pneumonia occurring \<4 days after initiation of mechanical ventilation
Time frame: 4 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| No Prophylaxis (Placebo) | Microbiologically-confirmed Early-onset Pneumonia | 13 Participants |
| Prophylaxis | Microbiologically-confirmed Early-onset Pneumonia | 6 Participants |
Secondary
Microbiologically-confirmed Late-onset Pneumonia
Percentage of Participants with Microbiologically-confirmed late-onset pneumonia occurring ≥4 days after initiation of mechanical ventilation
Time frame: ≥ 4 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| No Prophylaxis (Placebo) | Microbiologically-confirmed Late-onset Pneumonia | 4 Participants |
| Prophylaxis | Microbiologically-confirmed Late-onset Pneumonia | 1 Participants |
Secondary
Non-pulmonary Infections
Percentage of Participants with non-pulmonary infections
Time frame: During the intervention and immediately after the intervention until hospital discharge, up to 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| No Prophylaxis (Placebo) | Non-pulmonary Infections | 0 Participants |
| Prophylaxis | Non-pulmonary Infections | 0 Participants |
Secondary
Participants With Gallbladder Disease
Percentage of Participants with Gallbladder disease
Time frame: During the intervention and immediately after the intervention until death or hospital discharge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| No Prophylaxis (Placebo) | Participants With Gallbladder Disease | 0 Participants |
| Prophylaxis | Participants With Gallbladder Disease | 0 Participants |
Secondary
Type One Hypersensitivity Reactions
Percentage of Participants with Type One (immediate-type) hypersensitivity reactions
Time frame: Three days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| No Prophylaxis (Placebo) | Type One Hypersensitivity Reactions | 0 Participants |
| Prophylaxis | Type One Hypersensitivity Reactions | 0 Participants |