Ventilator-associated pneumonia (VAP)

The definition of VAP is any pneumonia which occurs after 48 hours of invasive ventilation.

How do you know its "ventilator-associated"?

Well. Its not called "ventilator-induced pneumonia", is it.

Pneumonia which occurs in ventilated patients is united into a subgroup of hospital-acquired pneumonia. It is associated with ventilation in the same way as hospital-acquired pneumonia is associated with being in hospital. Ventilation happens to be a common feature of these infections, and being intubated plays a role in its pathogenesis. Question 1c from the first paper of 2000 from the first paper of 2003 discusses VAP in the context of a patient with motor neuron disease. Question 25 from the first paper of 2015 instead asks about some policy changes which might influence a rising trend of VAP incidence.

Incidence of VAP

This 2000 (JAMA) review article puts the incidence at 8 to 28% of mechanically ventilated patients. The mortality from it is around 25 to 50%.

Weirdly, the same article reports that risk falls to 2% per day for days 5 to 10 of intubation, and down to 1% per day for the subsequent days.

Those who develop VAP early tend to do better, and it seems this is because the organisms which cause it in these people are more antibiotic-sensitive. Later VAP tends to be multi-drug resistant.

The likely microbial culprits

The 2005 American Thoracic Society Guidelines describe a menagerie of VAP organisms.

In short, its mainly aerobic gram-negatives, with an occasional garnish of MRSA.
Pseudomonas and S.aureus together comprise 50% of the isolated bugs. It is typically a polymicrobial zoo in there. These organisms originate in the oropharynx, as well as the infected biofilm which coats the endotracheal tube.

Certainly, one might be tempted to collect some samples from the lung. Tracheal aspirate culture, BAL sample or PSB (protected specimen brush) - its all the same, it seems the method of sampling really does not influence survival.

Blood cultures should also be collected, but one collects them with the knowledge that the organism cultured from the blood may not represent the organism causing the VAP.

Direct patient care strategies to reduce the risk of VAP

In brief summary, the following are strategies to reduce the risk of VAP, and nosocomial pneumonia in general:

In detail:

Don't intubate them. Or, extubate them early.

Obviously, without the huge tube in your larynx, your respiratory defences remain intact, and you stand a lesser risk of developing pneumonia. Is this assertion supported by evidence?

Yes it is.

These guys published a study in JAMA in 2000, where among a series of COPD and pulmonary oedema patients they demonstrated that the risk of nosocomial pneumonia decreased from 22% to 8% by using NIV. They also demonstrated quite a handsome mortality benefit (4% vs 26%) among these patients.

Indeed, this seems to show that intubating patients with COPD actually decreases their survival.

Try not to reintubate them: it increases the risk of VAP.

Avoid NG tubes

Nasogastric tubes create a swamp-like environment in the nasopharynx, and act as a vehicle to deliver nasopharyngeal secretions into the posterior pharynx and down on to the vocal cords. Additionlly, the relaxation of the gastro-oesophageal sphincter results in microaspiration of NG feeds.

In either case, the NGT is associated with increased incidence of VAP.

Cuff pressure and subglottic suction

If you are going to intubate them, keep the cuff pressure up around 20cmH₂O, and suction above the cuff. The high cuff pressure supposedly prevents microaspiration of upper tracheal secretions. Similarly, a tube with a subglottic suction port allows for "upper tracheal toilet" and prevents VAP.

Minimise sedation and paralysis

Keep their sedation minimal. Let them cough.

Sit them upright, to 45 degrees.

Supine position just about triples the risk of VAP, specifically in people receiving enteral feeding.

If for whatever reason you need to keep them supine, try to advance the tube beyond the pylorus, for whatever its worth. This has been shown to reduce the incidence of VAP in one controversial study; a meta-analysis which excluded this study had found that there is no increase in the incidence with VAP among NG-fed and NJ-fed patients. Indeed, it appears that enteral feeds (and their intolerance) does not significantly increase your risk of ventilator-associated pneumonia.

Reduce the use of stress ulcer prophylaxis

The use of H1 antihistamines and PPIs has been shown to be an independent risk factor for VAP. Sucralfate seems to reduce the incidence of VAP when compared to ranitidine and antacids (from 21% to 5%)

The selective digestive tract decontamination controversy

The consensus of scholarly opinion is that there is no consensus. Some studies have show a benefit to selectively decontaminating the oropharynx with chlorhexidine mouthwash or a cocktail of antibiotics.

In units with high endemic rates of antibiotic resistance, this is not an effective strategy.

The role of systemic antibiotics is even less clear. However, the published data seems to favour the use of SDD.

There are currently projects in the pipeline which will hopefully put an end to this debate.

The present American Thoracic Society guidelines recommend that although individual trial data is promising regarding selective decontamination (or mouthwashes, or prophylactic systemic antibiotics), their "routine use is not recommended until more data become available"

Empiric antibiotic selection for VAP

This has come up in Question 13 from the first paper of 2019. There are numerous possible resources to support decisionmaking in this scenario, or to at least cloak with some intelligent-sounding deliberation the inevitable decisison to start the patient on piperacillin-tazobactam. Good resources include the (freely available) article by Swanson & Wells (2013) and an older but more generous article by Park (2005). Another excellent resource for this is antimicrobe.org.

Factors which influence antibiotic agent selection:

• Duration of ventilation
  • Early VAP: less than five days of ventilation- more likely to have normal respiratory pathogens sensitive to third-generation cephalosporins
  • Late VAP: more than five days of ventilation - more likely to have enteric Gram-negatives, S.aureus and Pseudomonas.
• Previous use of antibiotics:
  • If they haven't had any antibiotics in the previous month, it may be ok to use a monotherapy with a non-antipseudomonal beta-lactam eg. ceftriaxone or amoxycillin-clavulanate.
  • If they have had some antibiotics recently, you may need to escalate to an antipseudomonal beta-lactam or a carbapenem, eg. tazocin, meropenem, cefepime, and so forth.
• Local prevalence of resistance
• Risk factors for resistant pathogens (eg. prolonged hospitalisation, residence in a nursing home, chronic dialysis, etc) 
• Host defence factors (eg. immunocompetence)
• Lung and intracellular penetration of the drug
  • If MRSA is suspected, linezolid is a better choice than vancomycin.
  • If Legionella is suspected, a fluoroquinolone should be added, as they have better intracellular penetration.

Factors which influence antibiotic course timing and duration:

• Confirmation of the diagnosis of VAP
  • Therapy should begin immediately, i.e. there is a survival disadvantage in waiting for sputum results
• Appearance of culture and sensitivity results 
  • Deescalation and the narrowing of the antimicrobial spectrum should be based on culture findings.
• Response to therapy 
• Empiric duration: 7 days.  In the classical era of intensive care medicine, people were treated with quite long courses of antibiotics (14-21 days) but this does not appear to confer any sort of survival advantage (Pugh et al, 2011).

Nebulised antibiotics in the management of VAP

In Question 13 from the first paper of 2019, this strange and very specific topic emerged surprisingly (why VAP? Why not for other sorts of pneumonia?) and was allocated a substantial amount of marks. That 2019 paper followed the publication of an article by Xu et al in November of 2018, which was a meta-analysis of aerosolised antibiotic therapy in VAP. Another good review is Ehrmann et al (2017).

Rationale for use of nebulised antibiotics for VAP

• Clinical response to antibiotics in VAP is poor even in highly susceptible organisms
• The bacteria involved often have high MICs 
• Drugs which are most effective for VAP (eg. vancomycin, aminoglycosides) have poor lung tissue penetration
• Logically, clinical response should improve if one were to deliver these agents directly to the affected tissue
• The patient is already intubated, permitting a convenient route of delivery which bypasses the upper airway mucosa and negates some of the patient tolerance factors
• A higher local concentration could be achieved thereby

Advantages

• Higher local concentration should be well above MIC even for intermediately sensitive strains; these concentrations woild not be tolerated if given intravenously
• The concentration may be sufficiently high to prevent the emergence of resistance
• Systemic toxicity should be reduced:
  • Lower total antibiotic doses may be used
  • The drugs which are most toxic (eg. aminoglycosides) are absorbed the least
  • Microflora of the gut will not be altered
• A shorter course may be possible

Disadvantages

• Bronchospasm may occur
• Circuit filters will get obstructed
• Pulmonary accumulation of the drug may occur, which may have local toxic effects (often this is due to excipients rather than the antibiotic itself)
• The exact dose is difficult to determine
• Measuring serum levels is not reassuring of a satisfactory effect

Practical constraints

• A special nebuliser is required
• Continuous nebulisation is possible for drugs with time-dependent killing, but this will also kill the expiratory circuit filter.
• Not all antibiotics can be delivered in this fashion (the greatest amount of experience is with tobramycin)
• The drug needs to be diluted in a carrier fluid, which affects the chemical stability of the drug
• Viscosity of the solution increases with added antibiotic molecules, and this increases the droplet size.  Those droplets have to stay somewhere between 0.5 to 3 µm in diameter, otherwise they will just uselessly deposit on the tubing and mucosa.

Evidence

• The 2018 meta-analysis by Xu et al pooled data from 15 studies and found a signficantly higher rate of clinical recovery with nebulised antibiotics.
• Microbial eradication was also improved, although the benefit was only observed with colistin
• There was no signal for improved mortality, but also no evidence of any increase in toxicity
• These studies were numerous and small in scale, which decreases the methodological quality of the meta-analysis, and they were pooled with observational studies. 
• The meta-analysis of trials on this topic is generally frustrated by poor research design and lack of standards. "Investigators have often used off the shelf nebulizers with no standardized dosing", lamented Lucy Palmer in her 2019 article titled  "Why have trials of inhaled antibiotics for ventilator-associated infections failed?" 

Society support

• The 2016 IDSA guidelines recommend inhaled antibotics only for VAP when it is caused by Gram negatives for which aminoglycosides or colistin are the only choices based on suceptibility testing.
• The European Society of Clinical Microbiology and Infectious Diseases disagreed, making a recommendation for "avoiding the use of nebulized antibiotics in clinical practice, due to a weak level of evidence of their efficacy"  (Rello et al, 2017)

Organisation-level strategies to reduce the risk of VAP

Question 25 from the first paper of 2015 puts the candidate in the shoes of an unit director, asking that they "outline the strategies you would recommend implementing in your unit in an effort to reduce the incidence of VAP." Apart from the direct patient care strategies discussed above (which are mentioned in the college answer) there are also broad policy changes. Unfortunately, the exam candidate needs to also be aware of these. They are unimaginative, and need to be memorised as a list, in case some viva examiner somewhere asks you what you might do in this situation. In the college answer to Question 25, a list of strategies is offered which is quite detailed, and probably represents a 8.0-9.0 mark answer. This list has been dissected, subjected to some scrutiny, and recombined into the table offered below. Probably the best non-college resource for this is a review from Respiratory Care by Crnich et al (2005).

Organisation-level Strategies for the Prevention of VAP

Strategies	Specific interventions	Rationale and literature support
Education	Distribution of materials Meetings Outreach visits	According to the abovequoted review (Crnich et al, 2005) this has a  modest and shortlived effect on the process of care. Furthermore, most survey respondents (in a 2004 systematic review) felt that they were only sufficiently resourced to disseminated printed material and to hold informal lunchtime meetings.
Infection control procedures	Hand-washing PPE Isolation policies for resistant organisms	The literature in support of this is Standard 3, ACSQHC: this stuff is actually as mandatory as your compulsory annual fire training. The rationale for it is that scupulous attention to infection control might prevent VAP by preventing the transmission of multi-resistant organisms. Does it help with VAP? Probably,. At least one study (Koff et al, 2011) has found an improvement in VAP after the introduction of a comprehensive hand hygiene program.
Antibiotic stewardship	Regulated antibiotic prescribing Mandatory ID input Review of prescribing practice	The college hastens to add that there "is no high level evidence" to demonstrate that antibiotic stewardship has very much effect on the rates of VAP. In fact some reasonable quality studies do exist (Gruson et al, 2000). The authors were able to decrease both their VAP rates and the incidence of multi-resistant bacteria by starting a program of antibiotic supervision and regular rotation. However, this was a French hospital where the random wanton use of ceftazidime and ciprofloxacin was rampant prior to the study protocol.
Environmental decontamination	Compliance with the (already strict) practice protocols Air filtration Hygiene of the ventilator circuit Decontamination of potable tap water Single-use airway devices	This does not refer exclusively to the "terminal cleanining" of a bed space, and is inclusive of the ventilator tubing, the bed itself, the bedside sink, the room air conditioner filter, etc etc. But the bed space is probably the most important: for example, This Irish infection control protocol (2011) cites a brilliant review from Respiratory Care (Crnich et al, 2005). Crnich et al produce a massive table of environmental factors which influence the risk of VAP, including contaminated respiratory equipment, poor ambient air filtration, dislogement of Aspergillus spores during construction activities, and so forth. The review quotes evidence for the importance of these factors among its 388 references.
Audit of activities	Reliable definition of VAP, consistent over the course of audit Data collection protocol Scheduled reviews Allocation of auditor responsiilities	Is there a point to this? To many it seems like pointless busywork. Indeed, a widely cited 2004 meta-analysis (Grimshaw et al, 2004) found that "the effect of audit and feedback on improving professional practice was small to moderate", and that "variability in the study quality and reporting transparency makes it difficult to recommend widespreaduse of audit and feedback". This was not specific to infection control, but pertaining to the broader tendency of healthcare staff to spontaneously self-organise into committees and auditing bodies.