Ventilator Associated Pneumonia

Dr.Ashish Kumar Department of Anaesthesia, Critical Care Medanta , The Medicity Gurgaon

Definition

Nosocomial Pneumonia that develops in someone who has been intubated for mechanical ventilation; Typically in studies, patients are only included if intubated greater than 48 hours - Early onset= less than 4 days (<96Hrs) - Late onset= greater than 4 days(>96Hrs) - Very early onset = with in 48 hrs Endotracheal intubation increases risk of developing pneumonia by 6 to 21 fold Accounts for 90% of infections in mechanically ventilated patients

American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia

Why Do We Care?

VAP increases: Medical costs Ventilator days ICU and hospital lengths of stay Estimated direct cost of excess hospital stay due to VAP is $40,000 per patient. Mortality ranges from 20 to 41%, depending on infecting organism, antimicrobial therapy, and underlying disease (Incidence of VAP 9.7% of patients receiving MV)

17% in medical units 9.1% in combined medical surgical units

Risk of pneumonia 3-10 fold higher in intubated patients Crude mortality 24-50%, upto 76% if MDR pathogens 2-10 times higher mortality if pneumonia present, than if absent Attributable mortality > 25%, range 5-39%
CDC.gov. Guidelines for preventing health-care-associated pneumonia, 2003.
Safdar N
2

et al. Clincial and economic consequences of ventilator-associated pneumonia: a systematic review

When does VAP occur? intubation and risk.

Cook et al showed . . .

40.1% developed before day 5 41.2% developed between days 6 and 10 11.3% developed between days 11-15 2.8% developed between days 16 and 20

4.5% developed after day 21

3.3% per day at day 5

Risk of pneumonia at intubation days

2.3% per day at day 10

1.3% per day at day 15

Cook et al. Incidence of and risk factors for ventilator-associated pneumoniain critically ill patients. Cook, D. J. et. al. Ann Intern Med 1998;129:433-440

Who gets VAP? (Risk factors)

Patient related;

Male sex, Age, Malnutrition, Immunosupression, Diagnosis; - Burns (risk ratio=5.09), - Trauma (risk ratio=5.0) , - Respiratory disease (risk ratio=2.79) , - CNS disease(Comatose) (risk ratio=3.4) - Cardiac disease (risk ratio=2.73)

Treatment related
- Intubation,rentubation & mechanical ventilation
- Enteral feeding, Parenteral nutrition - Antibiotics - Hyperglycemia - Supine position - Immobilization, sedation, muscle relaxants - Surgery of head/neck/thorax/upper abdomen -

Risk for MDR

Antimicrobials in 90 days Hospital stay > 5 days Hospitalised > 2 days in last 90 days Nursing home or chronic care facility Chemotherapy or wound care within 30 days Home infusions Chronic dialysis in 30 days Home wound care

ATS Guidelines AJRCCM 2005;171:388-416

Pathogenesis;
OROPHARYNX COLONIZATION BACTERIAL PATHOGENS

CUFF LEAK / BIOFILM

Bacterial pathogens Number,Types & Virulence Tracheal Colonization Lung Defences Cilia, Humoral, Cellular

VAP

Etiology

David R Park MD presented a version of this article at the 35th RESPIRATORYCARE Journal Conference, Ventilator-Associated Pneumonia, held February 2527, 2005, in Cancun, Mexico

MDR Pathogens : Definitions

Multidrug-resistant (MDR) Acinetobacter baumannii, Pseudomonas aeruginosa, or Klebsiella pneumoniae strains

Resistance to 5 out of the 7 anti-pseudomonal classes of antimicrobial agents

antipseudomonal penicillins, cephalosporins, carbapenems, monobactams, quinolones, aminoglycosides, and colistin.

CCOS-colistin-carbapenem-only-sensitive

sensitive only to colistin and carbapenems

Colistin-only-sensitive (COS)

resistant to all anti-pseudomonal agents, except colistin,

PDR if it exhibited resistant to all 7 anti-pseudomonal antimicrobial agents, including colistin.

Diagnosis of VAP

Clinical approach : CPIS Radiological approach Bacteriological approach : -Blood and pleural fluid culture -Semiquantitative airway sampling -Quantitative Cultures

Modified CPIS

CPIS at baseline assessed on the basis of first 5 variables CPIS at 72 hours assessed on all 7 variables

Takes progression of infiltrate and results of qualitative culture of tracheal aspirate into account

Score of > 6 indicates at baseline or at 72 hours indicates pneumonia CPIS is not superior to classical clinical criteria to define suspicion of VAP. However, it is useful to follow the evolution under therapy

Singh et al AJRCCM 2000;162:505-11 Torres et al. ICM 2008; DOI 10.1007/s00134-008-1336-9

Modified Clinical Pulmonary Infection Score

0 Temperature oC WCC /mm3 >36.5 <38.4 > 4000 < 11000 1 > 38.5 < 38.9 <4000 >11000 2 > 39.0 < 36.5 Band forms > 50%, +1 Remarks

Tracheal secretions PaO2/FiO2

Infiltrate on CXR

Absent >200 or ARDS

Nonpurulent

purulent <200 and no ARDS

Localised Yes

No infiltrate Diffuse or patchy None-light Mod-heavy

Progression of infiltrate None Trach asp Culture

GMS seen,+1

Singh et al AJRCCM 2000;162:505-11

Radiological features

A new and persistent (>48-h) infiltrate on chest radiograph is the commonest finding in VAP. The overall specificity of a pulmonary radiographic opacity consistent with pneumonia is only 27% to 35% Radiograph findings can be useful in establishing the diagnosis because of their high specificity. -air space process abutting a fissure (specificity, 96%) -air bronchogram, especially if single (specificity,96%)

Blood and pleural fluid cultures

Evaluation of suspected VAP Two sets of blood cultures & Thoracentesis for nonloculated pleural effusions of >10 mm in diameter on a lateral decubitus chest radiograph.

Sensitivity of blood cultures for the diagnosis of VAP is less than 25%.

Bacteriologic Diagnosis of VAP

Quantitiative cultures of lower respiratory secretions Non-bronchoscopic techniques

Tracheal aspirates NDBAL Blind PSB BAL, mini-BAL PSB

Bronchoscopic

Growth above a threshold concentration (cfu / ml) to distinguish colonisers from pathogens

> 106 for tracheal aspirates > 105 for NDBAL > 104 for BAL > 103 for PSB

Use of Surveillance Cultures to Guide Empiric Therapy?

Generally not recommended Recent study

good positive predictive values (6794%) and negative predictive values (73100%) for VAP caused by Acinetobacter, Pseudomonas, or Klebsiella species surveillance-guided initial antibiotic therapy was appropriate in 91% of patients with VAP

Another study found rate of empiric appropriate therapy was 85%, which was significantly higher than what would have been achieved by following the ATS guidelines

Papadomichelakis et al. ICM. doi:10.1007/s00134-008-1247-9 Jung et al. Intensive Care Med. Doi:10.1007/s00134-008-1248-8

Initial Empiric Therapy Recommendations

Choice of specific agents should be guided by local microbiology, cost, etc Inappropriate therapy is a major risk factor for mortality and excess LOS Early, appropriate, broad spectrum antibiotic therapy must be given in appropriate doses When patients have recently received an antibiotic, the empiric antibiotic for VAP should be from a different class

ATS Guidelines AJRCCM 2005;171:388-416

Recommendations

If high probability of pneumonia, or if sepsis is present, prompt antibiotic therapy is essential

Antibiotic therapy should not be delayed to perform diagnostic studies in unstable patients

Either bronchoscopic sampling or non-bronchoscopic techniques can reliably obtain lower respiratory secretions Semiquantitative or Quantitative culture data may be used

Semiquantitative cultures are not as reliable as quantitative cultures Quantitative cultures increase specificity of diagnosis of VAP

ATS Guidelines AJRCCM 2005;171:388-416

Clinical VAP Patient Unstable, deteriorating

Clinical VAP Patient Stable Bronchoscpic expertise Microbiology facilities Yes

ET Aspirate

No

Broad-spectrum antibiotics

PSB and BAL

ETA Culture -ve STOP antibiotics Modify Change Continue antibiotics +ve

>50% neutrophils >5% intracellular organisms Gram stain positive +ve Antibiotics -ve No antibiotics

-ve

BAL culture

Initial Empiric Therapy Early VAP, no risk factors for MDR pathogens

Potential pathogen Strep. Pneumoniae H. influenzae MSSA Sensitive EGNB

Klebsiella E. Coli Enterobacter Proteus Serratia

Recommended Antibiotic Ceftriaxone Or Levofloxacin, Ciprofloxacin Or Ampicillin / sulbactam Or Ertapenem

ATS Guidelines AJRCCM 2005;171:388-416

Initial Empiric Therapy Late VAP, Risk factors for MDR pathogens

Potential pathogen All Early VAP pathogens MDR Pathogens

Pseudomonas Acinetobacter Klebsiella (ESBL producers) Acinetobacter

MRSA Legionella

Recommended Antibiotic Ceftazidime or cepfepime Or Carbapenem (Imipenem, Meropenem) Or B-lactam /Blactamase inhibitor Piperacillin - tazobactam PLUS Ciprofloxacin or levofloxacin Or Aminoglycoside PLUS Linezolid or Vancomycin

ATS Guidelines AJRCCM 2005;171:388-416

Use Appropriate Antibiotic Doses

Antipseudomonal cephalosporin

Aminoglycosides

Cefepime 12 g every 812 h Ceftazidime 2 g every 8 h

Gentamicin 7 mg/kg per d Tobramycin 7 mg/kg per d Amikacin 20 mg/kg per d Levofloxacin 750 mg every d Ciprofloxacin 400 mg every 8 h

Carbepenems

Antipseudomonal quinolones

Imipenem 500 mg every 6 h or 1 g every 8 h Meropenem 1 g every 8 h Piperacillintazobactam 4.5 g every 6 h

-Lactam/-lactamase inhibitor

Vancomycin 15mg/kg 12 h Linezolid 600 mg every 12 h

ATS Guidelines AJRCCM 2005;171:388-416

Penetration into the lung

Aminoglycosides are not ideal drugs

lung tissue penetration reaches only 3040% of the serum-level. b-lactams also exert a penetration of 50%.

In contrast, quinolones achieve a cellular and lung tissue penetration 1,000% higher than the serum-level Continuous IV infusion targeting a serum level 2030 mg/ml is superior to discontinuous IV

Linezolid has better lung pentration than vancomycin

Torres et al. ICM 2008; DOI 10.1007/s00134-008-1336-9

Clinical cure rates for linezolid and vancomycin therapy in patients with Gram-positive, nosocomial pneumonia

Torres et al. ICM 2008; DOI 10.1007/s00134-008-1336-9

Antibiotic therapy

Linezolid is an alternative to vancomycin for MRSA VAP

De-escalation of antibiotics must be considered based on culture results and patients clinical response
A short duration of antibiotic (8 days instead of 14-21 days) is recommended for patients with

Uncomplicated VAP Initial appropriate therapy No evidence of Pseudomonas, other Gram negative non-lactose fermenters

ATS Guidelines AJRCCM 2005;171:388-416

Pulmonary infiltrates on Antibiotics

Patient on antibiotics > 3 days develops VAP

Current anitbitoic Rx, high chance of organisms being resistant PSB, BAL are sensitive
Recent Antibiotic Rx PSB, BAL less sensitive

Patient on antibiotics <24 hours develops VAP

In practice, when antimicrobials have been recently modified, a negative finding indicates

patient has been successfully treated and the bacteria are eradicated (but deescalation is impossible) or that the lung infection was not present to begin with (leading to an active research of other diseases and cessation or modification of antibiotics).

Combination Therapy vs. Monotherapy

Combination therapy

Combinations to provide broad spectrum cover with activity against MDR pathogens, esp. Pseudomonas In immunocompromised patients
Cheaper, does not expose patient to too many antibiotics Successful with early, mild VAP For documented Gram positive pneumonia

Monotherapy

Combination therapy may be converted to monotherapy if dictated by culture results

ATS Guidelines AJRCCM 2005;171:388-416

Combination Therapy or Monotherapy?

Combination treatment may still be advisable as initial treatment (e.g. for the first 48 h)

Decreases the probability of inadequate treatment

Switch to monotherapy once the susceptibility is documented Therapy could be switched to monotherapy in most patients after 35 days, provided that

initial therapy was appropriate clinical course appears favourable, and microbiological data do not suggest a very difficult-to treat microorganism

Torres et al. ICM 2008; DOI 10.1007/s00134-008-1336-9

Assessing Response to therapy

Clinical improvement takes 48-72 hours. Therapy should not be changed unless there is deterioration CPIS may be useful Biomarkers - PCT Responding patient should have de-escalation of therapy based on culture data Non-responding patient should be evaluated further

Duration of Therapy

8-day regimen can probably be standard for patients with HAP vs 15-21 days. Exceptions to this include

pneumonia due to Psedumonas & S. aureus immunosuppressed patients those whose initial antimicrobial treatment was not appropriate patients whose infection was caused by very difficult-to-treat microorganisms no improvement in clinical signs of infection

In these patients needing prolonged treatment, consider change of antimicrobial agents after 8 days if possible. Serial PCT measurement may allow reduction of antibiotic treatment duration and exposure without apparent harm Patients infected with P aeruginosa had a higher infection-recurrence rate when treated for 8 days but did not have a difference in length of mechanical ventilation, ICU length of stay, or mortality
Clin Chest Med 32 (2011) 507515

Biomarkers status

PCT provides no guiding light for clinicians to start antibiotics, as confirmed by the PRORATA trial results. PNEUMA trial, the antibiotic duration for patients with MDR VAP,based on biomarkers remains controversial A prospective, observational study examined the value of PCT kinetics as a prognostic factor during VAP. CRP use for diagnostic purposes has yielded widely conflicting data sTREM-1 measurement in BAL fluid for VAP diagnosis remains unclear: although it was apparently a reliable marker of pneumonia, especially VAP, more recent studies obtained contradictory findings, thereby raising doubt as to its usefulness for VAP patients. Others- Endotoxin levels in BAL, bacterial permeability increasing protein & Soluble E-selectin
Clin Chest Med 32 (2011) 431438 doi:10.1016/j.ccm.2011.05.004

Recommendations for antimicrobial stewardship have used specific PCT cutoffs. These specify 1 of 4 recommendations, ranging from strongly discourage and discourage torecommend and strongly recommend, respectively. Schuetz P, Albrich W, Christ-Crain M, et al. Procalcitoninfor guidance of antibiotic
therapy. Expert RevAnti Infect Ther 2010;8:57587.

Topical Antibiotics

Topical antibiotics instillation or aerosolisation

Improved microbiological eradication but not mortality with tobramycin May be useful for organisms with high MICs, unresponsive to systemic therapy

ATS Guidelines AJRCCM 2005;171:388-416

Inhaled antibiotics
Meta-analysis of 5 RCTs In 4 / 5 RCTs, patients received concurrent systematic antibiotics Higher treatment success with aerosolised / ET instilled antibiotics No differences with regard to mortality, emergence of resistance and drug-related adverse events Aminoglycosides and Colistin

JAC 2007; 60:12161226

Non - Responders
Wrong Organism
Resistant pathogen Mycobacteria, virus, fungus Inappropriate antimicrobial Rx

Wrong Diagnosis
Atelectass, PE, ARDS Pulmonary hemorrhage Underlying disease Neoplasm

Complication
Empyema or lung abscess Cl .difficile colitis Occult infection Drug fever
ATS Guidelines AJRCCM 2005;171:388-416

Preventions

Hand washing Non-invasive ventilation Avoid reintubation Use HMEs Regular circuit changes Drain condensates from circuit Closed suction systems Continuous subglottic suction Semirecumbent position Postpyloric feeding SDD GUP Tight glycemic control Restricted transfusion Sedation protocol

Yes Yes Yes ? No Yes ? Yes Yes ? ? yes ? Yes Yes

Positional Strategies

Pharmacological strategies

Physical Strategies

Prospective, RCT, single-blind, 54 centers in North America 2003 patients expected to require MV > 24 hrs Intubation with standard ETT or silver coated ETT VAP in 4.8% (37/766 patients) with silver-coated tube vs. and 7.5% (56/743; P=.03) Relative risk reduction of 35.9% (95% CI, 3.6%-69.0%; ) The silver-coated tube was associated with delayed occurrence of VAP (P=.005) No statistically significant differences in durations of intubation, ICU or hospital stay, mortality and frequency and severity of adverse events

Is the Silver Tube the final frontier?

3 additional episodes of VAP in the group receiving the silver-coated tube would have sufficed to render the trial statistically inconclusive Absence of robustness of the results is worrisome

investigators were not blinded, which could have introduced a bias in favor of the new device. quantitative culture results from BAL could be negatively influenced by the introduction of new antibiotics statistically significant imbalance in the proportion of patients with preexisting COPD favoring the silver ETT group

Should not be viewed as the definitive answer for VAP prevention Use should be restricted to high-risk patients treated in ICUs with benchmark valuebased infection rates that remain above institutional goals despite implementation of a comprehensive strategy

Chastre. JAMA. 2008;300(7):842-844