February 29, 2024

The PROPHY-VAP Trial: Ceftriaxone to Prevent VAP in Patients with Acute Brain Injury

Written by Kelly Sandall, DO
REBEL Crit
Medical Category: Neurology, Thoracic and Respiratory

Background: Ventilator-associated pneumonia (VAP), or what the CDC recently renamed infection-related ventilator-associated complication (IVAC), is defined as a nosocomial pneumonia occurring on day 3 of mechanical ventilation that was preceded by 2 days of stable or decreasing ventilator requirements.^{1, 2} Its occurrence often portends worse outcomes in intubated patients, whose projected hospital course was already tenuous.^{3, 4} It is the most common nosocomial infection in patients on mechanical ventilation, and one of the leading causes of nosocomial infection among all patients in the ICU.⁵ Onset of VAP has been repeatedly shown to increase the number of ventilator days, intensive care length of stay, use of antimicrobials, medical costs, and mortality risk.^{1, 4, 6}

The overall incidence of VAP is somewhere around 5%-40% of all intubated patients, depending on the study and country from which it is reported.^{3, 6} Among patients with stroke or traumatic brain injury (TBI), the risk may be as high as 28%-76% and 23%-60%, respectively.^{2, 4} The enhanced risk of VAP in patients with severe neurological insult is attributed to multiple factors, some which include glottic dysfunction prior to intubation and the direct immunosuppressive effects of brain injury.⁷

The use of prophylactic antibiotics as an adjunct to, but not a replacement for, the standard anti-VAP precautions (head of bed > 30°, minimizing sedation, early mobility) has been addressed in previous studies.^{4, 6} Some of these investigations produced data supportive of the use of early antibiotic prophylaxis to prevent VAP, but they all failed to show a reduction in mortality.^{4, 8}

Paper: Dahyot-Fizelier, C., S. Lasocki, T. Kerforne, P. F. Perrigault, T. Geeraerts, K. Asehnoune, R. Cinotti, Y. Launey, V. Cottenceau, M. Laffon, T. Gaillard, M. Boisson, C. Aleyrat, D. Frasca and O. Mimoz (2024). “Ceftriaxone to prevent early ventilator-associated pneumonia in patients with acute brain injury: a multicentre, randomised, double-blind, placebo-controlled, assessor-masked superiority trial.” Lancet Respir Med. PMID: 38262428

Clinical Question: Does antibiotic prophylaxis with a single dose of ceftriaxone reduce the incidence of early VAP in adults with severe brain injury who require mechanical ventilation?

What They Did

Multicenter, randomized, double-blinded, placebo-controlled, assessor-masked, superiority trial
Nine different ICUs at eight French university hospitals from October 2015 to May 2020
Randomized eligible patients to receive either one 30-minute infusion of 2g ceftriaxone or saline
Determined if VAP occurred between ventilator day 3 – 7 (AKA early VAP)
Standard VAP-preventative measures employed in both groups, including:
1. Hand washing before any care
2. Head of bed elevation at 30 degrees mounted every 4 hours
3. Preferential use of heat and humidity exchange filters, changed only when soiled
4. Monitoring of cuff pressure of tracheal tube every 8 hours to maintain pressure between 25-30 cmH₂0
5. Tracheal aspiration using sterile equipment, and only when required
6. Mouth care every 8 hours at minimum
7. No systemic changes of the respirator circuits
8. Preferential oral insertion of feeding tubes
9. Starting enteral feeding as soon as possible
10. Blood glucose monitoring every 4 hours
11. Ulcer prophylaxis
12. Extubation as soon as possible

Inclusion Criteria

Adults ≥ 18y with GCS ≤ 12 requiring intubation after acute brain injury
- Where brain injury was defined as head trauma, stroke, subarachnoid hemorrhage.
Within 12 hours of intubation
Within 48 hours of hospitalization

Exclusion Criteria

Coma secondary to tumor
Presence of infectious disease
Cardiac arrest
High risk of death within 48hrs after admission
Ongoing antibiotic treatment
Hospitalization within 1 month prior to inclusion
Expected to need antibiotic prophylaxis within 24hr after randomization
Nasotracheal intubation
Subglottic secretion drainage
Tracheostomy
Contraindication to β-lactam agents
Participation in another conflicting research protocol
Patient/family refusal
Patients in custody of law enforcement or state agency

Outcomes

PRIMARY: Development of early VAP (2^nd to 7^th day of mechanical ventilation)
- VAP confirmed by 2-3 intensivist committee based on clinical, radiological, microbiological criteria outlined by American Thoracic Society (ATS)
  - Clinical criteria: temperature ≥38°C or <36°C, white blood cell count >12,000/mm³ or <4000/mm³, purulent tracheal aspirates
  - Radiological criteria: new or changed chest X-ray infiltrate
  - Micro criteria: positive respiratory cultures
SECONDARY
- At ICU discharge or day 28 (whichever came first)
  - Development of late VAP (>7 days after intubation)
  - Organism identified with development of VAP
  - # ventilator-free days
  - # antibiotic-free days
  - Development of ventilator-associated events (VAE)
  - Comparison to global # of VAE
  - Time from inclusion to first spontaneous breathing trial
  - # patients with ESBL-producing Enterobacteriaceae
  - Neuro outcomes: Modified Rankin score (mRS) and Glasgow Coma Score (GCS)
  - Mortality
  - Safety
- At day 60
  - # ICU-free days
  - # hospital-free days
  - Neuro outcomes: mRS and GCS
  - Mortality

Results

319 patients ultimately included in intention-to-treat analysis
- 162 received ceftriaxone / 157 received placebo
PRIMARY OUTCOME: VAP on day 3-7 diagnosed in 14% of ceftriaxone group, 32% of placebo group (p=0.030)
- Hazard ratio 0.60
SECONDARY OUTCOMES
- At day 28, ceftriaxone group had (vs placebo):
  - Lower VAP risk (20% vs 36%); hazard ratio 0.62
  - Fewer median ventilator days (9 vs 5)
  - Fewer median antibiotic-free days (21 vs 15)
  - Improved mRS
  - Lower mortality
- At day 60, ceftriaxone group had (vs placebo):
  - More median ICU-free days (34 vs 26)
  - Fewer median hospital days (23 vs 8)
  - No difference in neurological outcomes
  - No difference in mortality
- 93 total cases of VAP occurred among both groups, 59% of which were polymicrobial
  - Most common isolates: MSSA, Streptococcus sp, Hemophilus sp, E. coli
- Need for broad-spectrum antibiotics after randomization was not different between groups.

Strengths

Multiple centers, double-blinded, placebo-controlled
- Opaque bottle and tubing of medication to prevent unblinding.
- Medication prepared by nurses in another unit not involved in the patients’ care.
- Patient data anonymized when presented to adjudication committee to avoid detection bias
Well-balanced patient characteristics between groups.
Included traumatic and nontraumatic brain injuries.
Stratified by center (different hospital practices may affect results) and GCS (<8 or ≥8) (higher VAP risk inherent to lower GCS).
Central adjudication committee, composed of two senior intensivists masked to study group assignment, reviewed all cases of VAP to prevent reporting bias
- Two intensivists (+ third if tiebreaker needed) evaluated patient data and followed predefined ATS guidelines when making the diagnosis of VAP.
A single dose of antibiotic for prophylaxis would have less impact on bacterial flora and reduce the emergence of bacterial resistance compared to prolonged intravenous antibiotic prophylaxis (i.e. 3 to 4 days).
Patients, healthcare providers, assessors, and the study statistician were masked to the allocation group.
Identical vials of ceftriaxone and sodium chloride were labelled “PROPHY-VAP”, infusions were prepared by a nurse from a neighboring unit not involved in patient care, and infusions were given in opaque syringes and infusion lines to maintain blinding.
To confirm VAP, events were defined in a standardized approach using the American Thoracic Society criteria.⁹
Used a cutoff of 7 days following tracheal intubation for primary outcome instead of 5 days because in patients with brain injury the risk of developing VAP due to antibiotic resistance microorganisms remains low until day 8.
Used a VAP incidence of 30% in the control group based off precious randomized studies of patients with brain injury for sample size calculation.
Study funder had no role in study design, data collection, data analysis, data interpretation, or writing of the manuscript.

Limitations

Overall incidence of VAP was 28% in this study. The low incidence could be a result of the systematic implementation of bundles known to decrease VAP incidence in the ICU.
Existence of pneumonia before randomization cannot be totally excluded.
It is possible that the ceftriaxone altered baseline bacterial colonization within the respiratory tract, causing cultures to be negative despite positive clinical and radiological signs, leaving room for a false negative diagnosis.
Two major entities, the CDC and ATS, have put out diagnostic algorithms for VAP, and agreement between the two is not absolute. This study used ATS criteria, and in favor of specificity, required all microbiological and clinical criteria to be present. ATS guidelines only require one or the other, e.g. microbiological or clinical criteria, before starting treatment for VAP.^{1, 9} Obviously, increasing specificity will decrease sensitivity, so cases of VAP definitely could have been missed.
ATS and CDC criteria to diagnose VAP are still inferior to lung histopathology, which was not used in this study.
Baseline chest X-ray before randomization was not part of study protocol, so pneumonia prior to VAP diagnosis possible.
Limited to academic hospitals in one country, which may call generalizability into question.

Discussion

In patients with brain injury who required ICU admission and mechanical ventilation, the PROPHY-VAP trial found that early administration of a single dose of ceftriaxone decreased the risk of VAP, exposure to ventilation, exposure to antibiotics, prolonged ICU and hospital stay, and mortality, with no safety concerns.
Past data has shown that on ventilator day 8, the risk of VAP secondary to antimicrobial-resistant organisms sharply increases. Prior to this, coli (non-ESBL producing), H. influenzae, S. aureus, S. pneumoniae predominately comprise the subset of positive airway cultures in early VAP among brain-injured patients.¹⁰ Since ceftriaxone provides adequate coverage against all of these, it seems to be a reasonable choice as prophylaxis against early VAP. Further, it is a very commonly used antibiotic, which increases provider comfort with its use, and will stick around for 24 hours without having to repeat the dose.
The authors rightfully note future research targets should include how/if the routine use of ceftriaxone increases antibiotic resistance in a population that is already quite vulnerable to devastating infection.
VAP has been shown to be the most common nosocomial infection in the ICU, with a prevalence between 9-27%. Mortality is variable by study, but ranges from 16-70%.¹¹ Curiously, VAP in patients with traumatic head injury does not appear to increase mortality, but does increase ventilator time, ICU, and hospital length of stay.²
Regardless of the type of brain injury, it has already been established that VAP significantly increases morbidity and/or mortality; results of this study indicate that single dose antibiotic prophylaxis with ceftriaxone decreased incidence of VAP and improves patient outcome.
It was hypothesized that ceftriaxone may impact bacterial colonization, and further research should characterize respiratory flora prior to initiation of prophylactic antibiotics. Additional studies should also define impact of the duration of antibiotic use, e.g. comparison of 1 versus 3 days of prophylactic antibiotics, or risk vs benefit of antibiotics other than ceftriaxone (and amoxicillin-clavulanic acid from the ANTHARTIC trial).⁸

Author’s Conclusion: “In patients with acute brain injury, a single ceftriaxone dose decreased the risk of early VAP.”

Clinical Bottom Line: A single dose of ceftriaxone might be useful in prevention of early ventilator-associated pneumonia in brain-injured patients who require intubation.

For More On This Topic Checkout:

PulmCrit Hot Take: VAP Prophylaxis (PROPHY-VAP Trial)

References

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Robba, C.; Rebora, P.; Banzato, E.; Wiegers, E. J. A.; Stocchetti, N.; Menon, D. K.; Citerio, G. Incidence, Risk Factors, and Effects on Outcome of Ventilator-Associated Pneumonia in Patients With Traumatic Brain Injury: Analysis of a Large, Multicenter, Prospective, Observational Longitudinal Study. Chest 2020, 158 (6), 2292-2303. DOI: 10.1016/j.chest.2020.06.064 From NLM.
Dahyot-Fizelier, C.; Lasocki, S.; Kerforne, T.; Perrigault, P. F.; Geeraerts, T.; Asehnoune, K.; Cinotti, R.; Launey, Y.; Cottenceau, V.; Laffon, M.; et al. Ceftriaxone to prevent early ventilator-associated pneumonia in patients with acute brain injury: a multicentre, randomised, double-blind, placebo-controlled, assessor-masked superiority trial. Lancet Respir Med 2024. DOI: 10.1016/s2213-2600(23)00471-x From NLM.
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François, B.; Cariou, A.; Clere-Jehl, R.; Dequin, P. F.; Renon-Carron, F.; Daix, T.; Guitton, C.; Deye, N.; Legriel, S.; Plantefève, G.; et al. Prevention of Early Ventilator-Associated Pneumonia after Cardiac Arrest. N Engl J Med 2019, 381(19), 1831-1842. DOI: 10.1056/NEJMoa1812379 From NLM.
(9) Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005, 171 (4), 388-416. DOI: 10.1164/rccm.200405-644ST From NLM.
Ewig, S.; Torres, A.; El-Ebiary, M.; Fábregas, N.; Hernández, C.; González, J.; Nicolás, J. M.; Soto, L. Bacterial colonization patterns in mechanically ventilated patients with traumatic and medical head injury. Incidence, risk factors, and association with ventilator-associated pneumonia. Am J Respir Crit Care Med 1999, 159 (1), 188-198. DOI: 10.1164/ajrccm.159.1.9803097 From NLM.
Chouhdari, A.; Shokouhi, S.; Bashar, F. R.; Vahedian Azimi, A.; Shojaei, S. P.; Fathi, M.; Goharani, R.; Sahraei, Z.; Hajiesmaeili, M. Is a Low Incidence Rate of Ventilation Associated Pneumonia Associated with Lower Mortality? a Descriptive Longitudinal Study in Iran. Tanaffos 2018, 17 (2), 110-116. From NLM.

GUEST POST BY

Kelly Sandall, DO
Emergency Medicine Resident
Christus Health/Texas A&M University School of Medicine

Mary Hamblen, DO
Emergency Medicine Resident
Christus Health/Texas A&M University School of Medicine

Brook Danboise, MD, PhD
Assistant Professor
Department of Emergency Medicine
Christus Health/Texas A&M University School of Medicine

Post Peer Reviewed By: Salim R. Rezaie, MD (Twitter/X: @srrezaie)

Cite this article as: Kelly Sandall, DO, "The PROPHY-VAP Trial: Ceftriaxone to Prevent VAP in Patients with Acute Brain Injury", REBEL EM blog, February 29, 2024. Available at: https://rebelem.com/the-prophy-vap-trial-ceftriaxone-to-prevent-vap-in-patients-with-acute-brain-injury/.