Aspiration, Aspiration Pneumonia
Conditions
Keywords
ventilator associated pneumonia
Brief summary
The purpose of this study is to evaluate the use of early antibiotics in ICU patients who appear to have aspirated, to help determine whether this improves outcomes by reducing the later incidence of pneumonia and other negative consequences.
Detailed description
ICU patients with signs of aspiration on imaging and a clinical history supportive of aspiration, but with no clear signs of infectious pneumonia, will be randomized to receive either 5 days of empiric antibiotics or supportive care only. They will be followed for 30 days with a primary outcome of ICU length-of-stay and various secondary outcomes including mortality, ventilator days, and antibiotic days.
Interventions
DRUGCeftriaxone
If there is low risk for P. aeruginosa and/or methicillin-resistant staphylococcus aureus (MRSA), as deemed by the treating team: Ceftriaxone 2 g IV, every 24 hours for 5 days
At any point after 24 hours, clinicians may (but are not required to) transition stable patients on ceftriaxone to the oral agent Amoxicillin + clavulanate (Augmentin) 875 mg PO or per feeding tube, twice daily for the remainder of 5 days
DRUGCefepime
If there is significant risk of P. aeruginosa and/or MRSA as deemed by the treating team: Cefepime 2 g IV, every 8 hours for 5 days, plus vancomycin
DRUGVancomycin
If there is significant risk of P. aeruginosa and/or MRSA as deemed by the treating team: Vancomycin IV, dosed by trough or AUC/MIC (area under the curve/minimum inhibitory concentration) monitoring for 5 days, plus cefepime. Order nasal MRSA swab and consider discontinuing vancomycin if MRSA swab is negative.
DRUGLevofloxacin
At any point after 24 hours, clinicians may (but are not required to) transition stable patients on cefepime to levofloxacin PO or per feeding tube, 750 mg every 24 hours for the remainder of 5 days
Sponsors
UConn Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Admitted to the ICU within the last 24 hours, or with a witnessed aspiration event in the last 24 hours while in the ICU * Radiographic findings on chest x-ray or CT deemed by the treating ICU team to be consistent with aspiration (e.g. dependent infiltrates or intraluminal airway debris) * Clinical history consistent with possible aspiration (e.g. cardiac arrest, found unconscious, or with a witnessed aspiration event).
Exclusion criteria
* Already received 3 or more doses of any antibiotic since hospital presentation, unless the last dose was greater than 1 week before enrollment * Requires antibiotic therapy for the treatment of other infections * Patient comfort measures only at time of screening * Currently participating in other trials using investigational drugs or interventions * Currently pregnant * Currently a prisoner * The consenting party (patient or their legally authorized representative) is unable to understand or read English at a fifth-grade level. * 2 or more of the following are present at the time of screening: * White blood cell count: ≥ 11.0 * Temperature ≥ 38.0C (100.4F) * Purulent secretions * S/F (pulse oximetry saturation to FiO2) ratio ≤ 215
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ICU-free Days | From admission to 30 days, death, or hospital discharge, whichever occurs first | Number of days not spent in the ICU, between date of admission and 30 days afterwards. Death or discharge can both reduce this measure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hospital-free Days | From admission to 30 days, death, or hospital discharge, whichever occurs first | Number of days not spent in the hospital, between date of admission and 30 days afterwards. Death or discharge can both reduce this measure. |
| Antibiotic-free Days | Days with no antibiotics from admission to 30 days, death, or hospital discharge, whichever occurs first | Number of days without any antibiotics administered, between date of admission and 30 days afterwards. Death, discharge, or antibiotic use can all reduce this measure. |
| Number of Participants Intubated After Enrollment | Between admission to 30 days, death, or hospital discharge, whichever occurs first | Yes/no |
| Number of Participants Who Underwent Tracheostomy After Enrollment | Between admission to 30 days, death, or hospital discharge, whichever occurs first | Yes/no |
| Number of Participants Who Developed Pneumonia After Enrollment | Between admission to 30 days, death, or hospital discharge, whichever occurs first | Yes/no, by criteria: 2 or more present simultaneously of temperature \>38c, WBC \>11k, S/F ratio \<215, and purulent secretions |
| Days Before Developing Pneumonia Criteria | Between admission to 30 days, death, or hospital discharge, whichever occurs first | By criteria: 2 or more present simultaneously of temperature \>38c, WBC \>11k, S/F ratio \<215, and purulent secretions |
| Number of Participants Prescribed Additional Antibiotics After Enrollment | Between admission to 30 days, death, or hospital discharge, whichever occurs first | Yes/no. Excluding prophylactic antibiotics and excluding perioperative prophylactic antibiotics. |
| Ventilator-free Days | From admission to 30 days, death, or hospital discharge, whichever occurs first | Number of days without any mechanical ventilation, between date of admission and 30 days afterwards. Death, discharge, or mechanical ventilation can both reduce this measure. |
| Number of Participants With Any Positive Culture With an Organism Resistant to Prophylactic Antibiotics | Between admission and 30 days, death, or hospital discharge, whichever occurs first | Yes/no |
| Number of Participants With a Positive C. Difficile Stool Toxin Assay After Enrollment | Between enrollment and 30 days, death, or hospital discharge, whichever occurs first | Yes/no |
| Number of Participants With a Temperature >38 Centigrade on Day 3 | Day 3 after enrollment | Yes/no |
| Number of Participants With a White Blood Cell Count >11k on Day 3 | Day 3 after enrollment | Yes/no |
| Number of Participants With Arterial Oxygen Saturation / Fraction of Inspired Oxygen (S/F) <215 on Day 3 | Day 3 after enrollment | Yes/no |
| Number of Participants With Purulent Secretions on Day 3 | Day 3 after enrollment | Yes/no |
| 30 Day Mortality | 30 days | Death within 30 days from enrollment |
| Number of Participants With a Positive Sputum Culture With a Presumed Pathogen | Between enrollment and 30 days, death, or hospital discharge, whichever occurs first | Yes/no |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Antibiotics 5 days of empiric antibiotics selected from a guideline-appropriate regimen. Alternate agents may be selected by the treating team if allergies or other patient factors mandate, but are still recommended for a 5 day course. Supportive care including oxygen and ventilation can be offered ad libitum.
Options include ceftriaxone, Augmentin, cefepime, vancomycin, levofloxacin.
Ceftriaxone: If there is low risk for P. aeruginosa and/or methicillin-resistant staphylococcus aureus (MRSA), as deemed by the treating team: Ceftriaxone 2 g IV, every 24 hours for 5 days
Amoxicillin clavulanic acid: At any point after 24 hours, clinicians may (but are not required to) transition stable patients on ceftriaxone to the oral agent Amoxicillin + clavulanate (Augmentin) 875 mg PO or per feeding tube, twice daily for the remainder of 5 days
Cefepime: If there is significant risk of P. aeruginosa and/or MRSA as deemed by the treating team: Cefepime 2 g IV, every 8 hours for 5 days, plus vancomycin
Vancomycin: If there is significant risk of P. aeruginosa and/or MRSA as deemed by the treating team: Vancomycin IV, dosed by trough or AUC/MIC (AUC/MIC) monitoring for 5 days, plus cefepime. Order nasal MRSA swab and consider discontinuing vancomycin if negative.
Levofloxacin: At any point after 24 hours, clinicians may (but are not required to) transition stable patients on cefepime to levofloxacin PO or per feeding tube, 750 mg every 24 hours for the remainder of 5 days | 2 |
| Control No initial antibiotic therapy unless clinical picture changes or worsens. Supportive care including oxygen and ventilation can be offered ad libitum. | 3 |
| Total | 5 |
Baseline characteristics
| Characteristic | Control | Total | Antibiotics |
|---|---|---|---|
| Age, Continuous | 76.7 years STANDARD_DEVIATION 19.4 | 72.8 years STANDARD_DEVIATION 14.9 | 67 years STANDARD_DEVIATION 4.2 |
| Chronic tracheostomy | 0 Participants | 0 Participants | 0 Participants |
| Current steroid use at time of enrollment | 1 Participants | 1 Participants | 0 Participants |
| Days between hospital admission and enrollment | 2 days STANDARD_DEVIATION 3.5 | 1.2 days STANDARD_DEVIATION 2.7 | 0 days STANDARD_DEVIATION 0 |
| Intubated prior to enrollment | 1 Participants | 2 Participants | 1 Participants |
| Pneumonia diagnosed prior to enrollment | 0 Participants | 0 Participants | 0 Participants |
| Positive serum ethanol at time of admission | 0 Participants | 0 Participants | 0 Participants |
| Positive sputum culture prior to enrollment | 0 Participants | 0 Participants | 0 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 1 Participants |
| Witnessed aspiration event, prior to admission | 1 Participants | 1 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 2 | 0 / 3 |
| other Total, other adverse events | 0 / 2 | 0 / 3 |
| serious Total, serious adverse events | 0 / 2 | 0 / 3 |
Outcome results
Primary
ICU-free Days
Number of days not spent in the ICU, between date of admission and 30 days afterwards. Death or discharge can both reduce this measure.
Time frame: From admission to 30 days, death, or hospital discharge, whichever occurs first
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Antibiotics | ICU-free Days | 14 days | Standard Deviation 14.1 |
| Control | ICU-free Days | 18.7 days | Standard Deviation 16.1 |
Secondary
30 Day Mortality
Death within 30 days from enrollment
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Antibiotics | 30 Day Mortality | 1 Participants |
| Control | 30 Day Mortality | 0 Participants |
Secondary
Antibiotic-free Days
Number of days without any antibiotics administered, between date of admission and 30 days afterwards. Death, discharge, or antibiotic use can all reduce this measure.
Time frame: Days with no antibiotics from admission to 30 days, death, or hospital discharge, whichever occurs first
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Antibiotics | Antibiotic-free Days | 12 days | Standard Deviation 17 |
| Control | Antibiotic-free Days | 14 days | Standard Deviation 14.5 |
Secondary
Days Before Developing Pneumonia Criteria
By criteria: 2 or more present simultaneously of temperature \>38c, WBC \>11k, S/F ratio \<215, and purulent secretions
Time frame: Between admission to 30 days, death, or hospital discharge, whichever occurs first
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Antibiotics | Days Before Developing Pneumonia Criteria | 0 days | Standard Deviation 0 |
| Control | Days Before Developing Pneumonia Criteria | 0 days | Standard Deviation 0 |
Secondary
Hospital-free Days
Number of days not spent in the hospital, between date of admission and 30 days afterwards. Death or discharge can both reduce this measure.
Time frame: From admission to 30 days, death, or hospital discharge, whichever occurs first
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Antibiotics | Hospital-free Days | 9 days | Standard Deviation 12.7 |
| Control | Hospital-free Days | 14.7 days | Standard Deviation 13.7 |
Secondary
Number of Participants Intubated After Enrollment
Yes/no
Time frame: Between admission to 30 days, death, or hospital discharge, whichever occurs first
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Antibiotics | Number of Participants Intubated After Enrollment | 0 Participants |
| Control | Number of Participants Intubated After Enrollment | 0 Participants |
Secondary
Number of Participants Prescribed Additional Antibiotics After Enrollment
Yes/no. Excluding prophylactic antibiotics and excluding perioperative prophylactic antibiotics.
Time frame: Between admission to 30 days, death, or hospital discharge, whichever occurs first
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Antibiotics | Number of Participants Prescribed Additional Antibiotics After Enrollment | 1 Participants |
| Control | Number of Participants Prescribed Additional Antibiotics After Enrollment | 2 Participants |
Secondary
Number of Participants Who Developed Pneumonia After Enrollment
Yes/no, by criteria: 2 or more present simultaneously of temperature \>38c, WBC \>11k, S/F ratio \<215, and purulent secretions
Time frame: Between admission to 30 days, death, or hospital discharge, whichever occurs first
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Antibiotics | Number of Participants Who Developed Pneumonia After Enrollment | 1 Participants |
| Control | Number of Participants Who Developed Pneumonia After Enrollment | 1 Participants |
Secondary
Number of Participants Who Underwent Tracheostomy After Enrollment
Yes/no
Time frame: Between admission to 30 days, death, or hospital discharge, whichever occurs first
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Antibiotics | Number of Participants Who Underwent Tracheostomy After Enrollment | 0 Participants |
| Control | Number of Participants Who Underwent Tracheostomy After Enrollment | 1 Participants |
Secondary
Number of Participants With Any Positive Culture With an Organism Resistant to Prophylactic Antibiotics
Yes/no
Time frame: Between admission and 30 days, death, or hospital discharge, whichever occurs first
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Antibiotics | Number of Participants With Any Positive Culture With an Organism Resistant to Prophylactic Antibiotics | 0 Participants |
| Control | Number of Participants With Any Positive Culture With an Organism Resistant to Prophylactic Antibiotics | 0 Participants |
Secondary
Number of Participants With a Positive C. Difficile Stool Toxin Assay After Enrollment
Yes/no
Time frame: Between enrollment and 30 days, death, or hospital discharge, whichever occurs first
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Antibiotics | Number of Participants With a Positive C. Difficile Stool Toxin Assay After Enrollment | 0 Participants |
| Control | Number of Participants With a Positive C. Difficile Stool Toxin Assay After Enrollment | 1 Participants |
Secondary
Number of Participants With a Positive Sputum Culture With a Presumed Pathogen
Yes/no
Time frame: Between enrollment and 30 days, death, or hospital discharge, whichever occurs first
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Antibiotics | Number of Participants With a Positive Sputum Culture With a Presumed Pathogen | 0 Participants |
| Control | Number of Participants With a Positive Sputum Culture With a Presumed Pathogen | 1 Participants |
Secondary
Number of Participants With Arterial Oxygen Saturation / Fraction of Inspired Oxygen (S/F) <215 on Day 3
Yes/no
Time frame: Day 3 after enrollment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Antibiotics | Number of Participants With Arterial Oxygen Saturation / Fraction of Inspired Oxygen (S/F) <215 on Day 3 | 0 Participants |
| Control | Number of Participants With Arterial Oxygen Saturation / Fraction of Inspired Oxygen (S/F) <215 on Day 3 | 1 Participants |
Secondary
Number of Participants With a Temperature >38 Centigrade on Day 3
Yes/no
Time frame: Day 3 after enrollment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Antibiotics | Number of Participants With a Temperature >38 Centigrade on Day 3 | 0 Participants |
| Control | Number of Participants With a Temperature >38 Centigrade on Day 3 | 1 Participants |
Secondary
Number of Participants With a White Blood Cell Count >11k on Day 3
Yes/no
Time frame: Day 3 after enrollment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Antibiotics | Number of Participants With a White Blood Cell Count >11k on Day 3 | 1 Participants |
| Control | Number of Participants With a White Blood Cell Count >11k on Day 3 | 2 Participants |
Secondary
Number of Participants With Purulent Secretions on Day 3
Yes/no
Time frame: Day 3 after enrollment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Antibiotics | Number of Participants With Purulent Secretions on Day 3 | 0 Participants |
| Control | Number of Participants With Purulent Secretions on Day 3 | 0 Participants |
Secondary
Ventilator-free Days
Number of days without any mechanical ventilation, between date of admission and 30 days afterwards. Death, discharge, or mechanical ventilation can both reduce this measure.
Time frame: From admission to 30 days, death, or hospital discharge, whichever occurs first
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Antibiotics | Ventilator-free Days | 19 days | Standard Deviation 15.6 |
| Control | Ventilator-free Days | 20 days | Standard Deviation 17.3 |