ventilator associated pneumonia by dr imran

60
VENTILATOR ASSOCIATED PNEUMONIA DR IMRAN GAFOOR DR DEBASHISH DHAR DEPTT OF CRITICAL CARE & EMERGENCY MEDI SIR GANGARAM HOSPITAL

Upload: imran80

Post on 07-Dec-2014

1.910 views

Category:

Health & Medicine


1 download

DESCRIPTION

 

TRANSCRIPT

Page 1: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

VENTILATOR ASSOCIATED PNEUMONIA

DR IMRAN GAFOOR DR DEBASHISH DHAR

DEPTT OF CRITICAL CARE & EMERGENCY MEDICINE

SIR GANGARAM HOSPITAL

Page 2: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

DEFINITIONS

VAP : ventilator associated pneumonia is a nosocomial pneumonia which develops in ICU patients who have been tracheally intubated/MV ≥ 2 days.

VAT : ventilator associated tracheobronchitis,↑

in volume & purulence of resp secretions,fever

leucocytosis but no radiological infiltrates.

Page 3: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

HCAP : health care associated pneumonia. RISK FACTORS - hospitalzn. For ≥ 2 days within preceding

90 days, - residencein nursing home or extended

care facility, - home infusion therapy (antibiotics) - chronic dialysis within 30 days, - home wound care - family member with MDR pathogens

Page 4: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

OTHER CLASSIFICATION : PRIMARY ENDOGENOUS PNEUMONIA – causative micro-organisms are isolated in surv- eillance cultures on admission. SECONDARY ENDOGENOUS PNEUMONIA- causative micro-organisms later on colonize

oropharynx/GIT & reach lower resp tract EXOGENOUS PNEUMONIA –

pt is not a previous carrier but colonised by ventilator tubes ,bronchoscopes,humidifiers etc.

Page 5: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

EARLY vs LATE ONSET VAP : EARLY ONSET (<4 days) – antibiotic sensitive,better

prognosis LATE ONSET (5 days or more) – MDR pathogens,increased

mortality There were no significant differences in the prevalence of

potential MDR pathogens associated with early-onset or

late-onset VAP, even in subjects with prior antibiotics.

Empiric therapy for early-onset VAP should also include

agents likely to be effective for potential MDR

pathogens.

Respir Care. 2013

Jul;58(7):1220-5.

Page 6: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

TROVILLET et al found that two variables were significant for predicting infection with MDR VAP :

- mechanical ventilation ≥ 7 days - prior antibiotic use esp broad

spectrum EPIDEMIOLOGY : second most common nosocomial infection

but leading cause of attributable mortality (33-50%)

Page 7: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

INCIDENCE IN INDIA :-

Incidence of HAP in india is 53.9%.

Incidence of VAP in india is 8.95/1000

ventilator days.

Mortality rate(attributable) is 37% -

47.3%

Park Es et al Am j inf

control(2000)

Page 8: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

VAP IN SGRH ICU (2012)

jan feb mar apr may june july aug sep oct nov dec0

1

2

3

4

5

6

7

8

9

10

Series 1Column1

Page 9: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

• It is estimated that 9-27% of patient undergoing

MV for > 2 days are affected by VAP.. Cook et al demonstrated that,risk of VAP is

3% on first 5 days of MV,2% from 5-10 days,&

1% for remaining days.MORTALITY : Several cross matching studies

have estimated that one third to half of all VAP related deaths are result of pseudomonas/acinetobacter pneumonia with bacteremia.

- mortality is inversely related to adequacy of initial empirical thereapy.

Page 10: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

- Correct & prompt treatment of pneumonia results in better patient survival.

- Inappropriate therapy is strongly associated with worse survival.

PATHOGENESIS : * Pulmonary aspiration of

colonised (whether endo/exogenous) oropharyngeal secretions across tracheal tube cuff is the main pathogenic mechanism for development of VAP.

Page 11: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN
Page 12: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

* Tracheal intubation is the “conditio sine qua non” for development of pneumonia because it

facilitates aspiration of pathogens & hinders

intrinsic respiratory defenses. * Normally ETT has ‘HVLP’ cuff,the

potential diameter of which is two to three times larger than tracheal diameter,so,when tracheal cuff

is inflated within trachea,folds invaraibly form along cuff surface,causing consistent micro/macro aspiration of oropharyngeal secretions.

Page 13: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN
Page 14: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

* ETT is commonly made of PVC & bacteria easily adhere to its internal surface forming a complex structure called BIOFILM (sessile

bacteria embedded within a self produced

exopolysaccharide matrix) * ETT biofilm is difficult to eradicate &

constitutes a persistent source of colonization.

SOURCES OF COLONIZATION : - hands of ICU staff - colonised bronchoscopes - water supply

Page 15: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN
Page 16: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

- respiratory equipments - humidifiers - ventilator temp sensors - nebulizers - contaminated environment.- In critically ill patients endogenous oral

flora shifts early to aerobic gram – pathogens (pse-

udomonas,MRSA),pulmonary aspiration of

which leads to pneumonia.

Page 17: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

* Azarpazhooh et al showed that improved oral

hygiene & frequent professional oral health

care reduces progression or occurrence of

respiratory infection among patients in ICU.

* Orotracheal as compared to nasotracheal intu-

bation is associated with a decreased incidence

of sinusitis & thus VAP. IMPAIREMENT OF RESPIRATORY

DEFENSES DURING CRITICAL ILLNESS & TRACHEAL INTUBATION : - no protection from adduction of

true/false vocal cords.

Page 18: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

- no protection from epiglottis - cough not possible - tracheally intubated patients have very

low muco ciliary velocity (0.8-1.4mm/min)–

higher risk for pulmonary complication. - Temporary immunoparalysis during

early course of ICU stay (low levels of HLA-

DR expression on monocytes),may

predispose to colonization.

Page 19: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

ETIOLOGIC AGENTS : * VAP is commonly caused by aerobic gram – bacilli(peudomonos,E.coli,klebsiella,acine- tobacter),while S.AUREUS is predominant gram + organism.• EPIC-II study confirmed that pseudomonos & staph aureus are most common isolated patho- gens in ICU. UNDERLYING DISEASES : - patients with COPD have higher risk for H.infl, moraxella,pseudomonos,pneumococcus, aspergillus

Page 20: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

In a study of nosocomial pneumonia in 51 ICU patients in india,the most commonly isolated organisms were P.auroginosa(20%), Acinetobacter spp (38%),klebsiella(23%),

MRSA(5%).The data also clearly demonstrate that the incidence

and prevalence of multidrug-resistant pathogens arerising in Asian countries. A. baumannii–calcoaceticus

complex is emerging as a major pathogen in

most of

the ICUs in these countries. MRSA, although present,

is not as big a problem as in the Western world; doi:10.1016/j.ajic.2007.05.011

Page 21: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

- Candida & aspergillus are m/c isolated fungi in

immunocompromised.- Recent reviews show that candida in

respiratory samples demonstrate only colonosation rather than pneumonia.

- Viruses causing VAP : HSV-I,CMV- PREVENTIVE STRATEGIES FOR

NOSOCOMIAL PNEUMONIA : 1) Implementation ,as VAP bundle,of noso- comial pneumonia preventive strategies that have proven efficacy in reducing

mo- rbidity & mortality.

Page 22: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

2) Implementation of education programmes

(respiratory care physicians & nurses being

primary recepients),& frequent performance feedbacks & compliance assesment.

3) Strict alcohol based hand hygiene.4) Avoidance of tracheal intubation & use of

NIV when indicated(acute exacebn. of COPD, acute hypoxemic resp

failure,immunocomp. with pulmonary infiltrates) -Recent reports emphasize role of

NIV in preventing re-intubation in recently

extubated pts at risk for relapse & respiratory

failure.

Page 23: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

5) Daily sedation vacation & implementation of weaning protocols.

6) No ventilatory circuit tube changes unless soiled or damaged.

7) Use of tracheal tubes with cuff made of novel materials(polyurethane; & LVLP cuffs made of silicone &latex) & shape(conical)

8)Application of low level PEEP(5-8cm H2O)during tracheal intubation.

9) Use of silver coated ETT – NASCENT trial concluded that silver coated ETT has ↓ incidence of VAP,↓ mortality in

pts with VAP,is cost effective & has greatest impact during first 10 days.

Page 24: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

10) Aspiration of subglottic secretions(every 4-6hrs)

11) Internal cuff pressure maintained within 25-30

cm H2O & carefully controlled during transport of patients outside ICU.

12) Earlier tracheostomised pts (mean~7 days)

had shorter length of M/V & ICU stay,a ↓trend

towards pneumonia but no survival benefit as

compared to late tracheostomy(mean~14 days)

13) Routine saline instillation before tracheal suctioning not recommended

Page 25: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

14) Intubated pts should be kept in semi-recumbent position(30-45°),rather than supine to prevent aspiration;especially when enterally fed.

15) Continuous lateral rotation of bed helps to reduce extravascular lung water,improveV/Q

& enhance mobilization of secretions.16) Post pyloric feeding in patients with

impaired gastric emptying17) Risk of VAP associated with early

enteral feeding didn`t translate into ↑ risk of death,so,early enteral feeding advised.

Page 27: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

18) Stress ulcer prophylaxis in high risk pts(coagulopathy,↑ duration of M/V,h/o

GI bleed.19) Oral care with 2% chlorhexidine.20) SELECTIVE CONTANINATION OF DIGESTIVE

TRACT (SDD) : - consists of nonabsorbable antibio. Against gram – (tobramycin.polymyxin E) +

nystatin/ ampho B for candida administered into GI to prevent oropharyngeal & gastric

colonization. - SDD reduces incidence of VAP & it’s the only strategy that has shown survival benefit

Page 28: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

- SDD may promote growth of MRSA & enterococcus,so,its highly recommended to

conduct appropriate surveillance of antibiotic resistance pattern.

21) Use of probiotics is promising but additional

evidence required.DIAGNOSIS : - fever,tachycardia,leucocytosis – too

nonspecific - tachypnea & consolidation – more

specific - in elderly & immunocomp. Lethargy &

confusion – main symptoms

Page 29: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN
Page 30: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

An imaginary vertical line from the sternal notch to the mouth, passing through the middle of the trachea should be used as a surface landmark in order to identify an orientation that could prevent

aspiration of oropharyngeal contents across the

cuff and improve drainage of airway scretions. - Lateral slight-Trendelenburg position

achieved with the bed tilted few degrees below horizontal

Current Opinion in Critical Care 2011,17:57–63

Page 31: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

- Chest x rays : difficult to interpret,limited technical quality,misses subtle lung infiltrates.

- D/d for infiltrates : - cardio/non cardiogenic pulmo.

Edema - atelectasis - pulmonary contusions - no radiographic sign has d/g accuracy of

>68%- Air bronchograms or alveolar opacities in

pts without ARDS co-related well with pneumonia.

- Pleural effusion seen with H.infl>pneumoco pneumonia

Page 32: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

- diarrhea/abdominal pain – legionella p.- Otitis media /pharyngitis – M.pneumonia- Herpes labialis – pneumococcal- Ecthyma gangrenosum – pseudomonos

septicemia- NOTE : >30 bpm & Na < 130 during

admission predict poor outcome.- CAVITATIONS : - multiple cavitory nodules – rt sided

endocarditis - rapid – gram (–) pneumonia - subacute – anaerobic/mycobacterial chronic – carcinoma,lymphoma,wegners

granulomatosis

Page 33: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN
Page 34: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

CLINICAL PULMONARY INFECTION SCORE (CPIS) :

CRITERION 0 1 2 tracheal secn. (-) not purulent

purulent x- ray infiltrates NO DIFFUSE

LOCALISED temp °C ≥36.5&≤38.4 ≥38.5&≤38.9

≥39or≤36 leucocytes ≥4000&≤11000 <4000or>11000

+immature

neutro>50% PaO2/FiO2 >240 or ARDS ≤240,noARDS

microbio (-) (+)

Page 35: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

CPIS ≥ 6 is regarded as threshold for pneumonia but value remains to be validated.

QUANTITATIVE CULTURES OF ENDOTRACHEAL ASPIRATES MAY HAVE AN ACCEPTABLE DIAGNOSTIC ACCURACY.

Current d/g threshold for tracheal aspirates is

10-10^ CFU/ml

“ “ “ “ contaminants is

10 CFU/ml

“ “ “ “ BAL is 10 CFU/ml

“ “ “ “ PBS is 10³ CFU/ml

Page 36: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

- NON INFECTIOUS CAUSES OF FEVER/INFILTRATES MIMICKING NOSOCOMIAL PNEUMONIA :

- chemical pneumonitis - atelectasis - pulm embolism - ARDS - pulmomary hemorrhage - lung contusion - infiltrative tumour - radiation pneumonitis - drug reaction - BOOP

Page 37: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

MOST RECENT IMPROVEMENTS IN D/G :

* direct antibiogram using E test strips

applied directly to resp samples have

proved to be reliable,effective &

anticipate susceptibility by

≥ 48 hrs

* q PCR for mecA gene - for MRSA

pneumonia

Page 38: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

Diagnostic strategies for hospital acquired pneumonia :

- new or progressive chest infiltrate + atleast 2 of

3 clinical criteria(fever>38°c,leucocytosis or leucopenia,purulent secretions) represent beginning of diagnostic procedures

- clinical,non invasive semiquantative strategy

major drawback is high sensitivity of semi quantative culture results which leads to over estimation of incidence of nosocomial pneumonia.

Page 39: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

Invasive and quantitative culturing strategy for VAP :

- strongly recommended that d/g sampling of

respiratory tract be obtained before starting any new antibiotic or changing previous antimicrobial therapy.

Page 40: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN
Page 41: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

PRACTICAL IMPLEMENTATION OF A DIAGNOSTIC STRATEGY

STEP I : pt admitted/intubated for> 2 days,with no evident alternative foci of infection with atleast 2 of 3 criteria :-

- fever > 37.8°c or hypothermia < 36°c

- TLC >12000/µl or <4000/µl - purulent respiratory secretions ↓ with new infiltrates in chest x ray : if yes(NP/VAP)||| if no (VAT)

Page 42: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

STEP II : before initiating new empirical antibiotics ,collect sample as follows :-

a) expectoration b) tracheo-bronchial aspirate c) BAL or mini –BAL d) PBS - 2 blood cultures - pleural fluid sample for parapneumonic

effusion - legionella/pneumococcal antigens in

urine - CBC/electrolytes/RFT/LFT/procal/ABG/ CRP

Page 43: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

STEP III : calculate CPIS (TO IMPROVE OBJECTIVE ASSESMENT OF CLINICAL PARAMETERS)

TREATMENT :- most frequently isolated organisms are

s.aureus,pseudomonos f/b enterobacteriacea(e coli,klebsiella,enterobacter) then gram – as acinetobacter,stenotrophomonas,burkholdheria & lastly h influenzae,pneumococcus.

selection of antimicrobial tailored to local prevelance of pathogens & antimicrobial patterns of resistance.

Page 44: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

DYNAMICS OF CHANGE OF ORAL FLORA

1) Healthy subjects → pneumococcus,N menin., strepto pyogenes2) acute/chronic

co→pneumococc,H.influen,enterobac. morbidities MSSA3) 2 + antibiotics for→ESBL+

enterobac.,pseudomonos 3-5 days MRSA4) 3 + antibiotics for→3 + non fermenting MDR

GNB 7 days

(peudomonos,stenotropho., acineto,candida)

Page 45: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

Choice of empiric anti microbials

ATS/IDSA recommendations t/t based on timing of onset & risk

factors for MDR pathogens

Page 46: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

Risk Factors for Multidrug-Resistant Pathogens Antimicrobial therapy in preceding 90 days Current hospitalization of at least 5 days High frequency of antibiotic resistance in the

community or in the specific hospital unit.

Presence of risk factors for HCAP:

—Hospitalization for at least 2 days in the preceding 90 days

—Residence in a nursing home or extended care facility—Home infusion therapy (including antibiotics)—Chronic dialysis within 30 days—Home wound care—Family member with infection involving MDR pathogen—Immunosuppressive disease and/or therapy

Page 47: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN
Page 48: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

Initial Intravenous Adult doses of Antibiotics

Niederman M. et al, AJRCCM, 2005 Antibiotics Dosage*

Antipseudomonal cephalosporinCefepime 1-2g every 8-12hCeftazidime 2g every 8h Carbapenems Imipenem 500mg every 6h or 1g every 8hMeropenem 1g every 8h ß-Lactam/ ß-lactamase inhibitorPiperacillin-tazobactam 4.5g every 6h AminoglycosidesGentamicin 5-7mg/kg per dTobramycin 7mg/kg per dAmikacin 20mg/kg per d Antipseudomonal quinolonesLevofloxacin 750mg every dCiprofloxacin 400mg every 8h Vancomycin 15mg/kg every 12hs Linezolid 600mg every 12h

Page 49: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

NOTE : for legionella → azithro + cipro/levoflox

- For resistant acineto → carbapenem or colistin +

tigecycline - Nebulised colistin/tobramycin are used

as adjunct to systemic antibiotics in severe gram – pneumonia,or,resistant bug eliminated only by high level local drug conc.

- DURATION OF T/T :- - majority of infections can be treated by

8 days course,for non fermenting gram( – ) 14 days

- prolonged t/t is required in : - legionella infection - biofilms/prosthetic devices

Page 50: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

- Tissue necrosis,abscess,empyema- persistence of original

infection(perforation, endocarditis)FAVOURABLE CLINICAL COURSE :- - defervescence - improved PaO2/FiO2 - ↓ CRP in 3-5 days - third day CPIS < 6

Page 51: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN
Page 52: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

PREVENTIVE APPROACHES TO VAP

- have focussed on ↓ cross transmission,pulm.

aspiration across ETT cuff, ↓ bacterial load in oropharynx.

HIGHLY EFFECTIVE INTERVENTIONS : 1. SEMIRECUMBENT POSITION 2. SEDATION VACATION 3. DAILY ORAL CLEANSING WITH 2% CHLORHEXIDINE 4. SUBGLOTTIC SECRETION DRAINAGE

Page 53: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

FERRER M (clinical infectious d/e 2010) :

- first study that validates 2005 ATS/IDSA guidelines

- the study demonstrated worse microbial prediction of 2005 guidelines,in comparison to previous guidelines,in pts considerd at low risk

for acquiring MDR pathogens & similar low prediction for fungi.

Page 54: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

Rather than focusing on VAP, the new surveillance definition

algorithm for adults broadens the surveillance spectrum to

ventilator associated events(VAE) A ventilator-associated

condition (VAC) is identified if, after a 2-day

period of stability or improvement on the

ventilator, the patient develops worsening oxygenation

(specific increases in levels of FIO2 or PEEP

over two or more calender years)

Page 55: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

Infection –related ventilator-associated complication (IVAC) is identified in pts with

VAC who meet 2 additional criteria of clinical signs of infection (specifically, defined values for an abnormal temperature or white

count) and antibiotics prescribed for atleast 4 days. Identification of possible & probable VAP within IVAC patients is determined by purulent respiratory secretions and/or specific laboratory and diagnostic tests. The

new algorithm remains complex and the CDC is developing additional guidance for its implementation

Page 56: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

Several features of the new VAE definition are important. First, chest radiographs, a

required component in the current definition of VAP,

are no longer used in the definitions of VAEs (including VAP).Second patients who

are receiving rescue ventilation are excluded. Third patients must have a period of at least 2 days of stability or improvent on

mechanical ventilation prior to worsening.fourth,

VAC (and by extension, IVAC and VAP) is limited to patients who have have

been mechanically ventilated for atleast 3 calendar days

Page 57: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

The VAP Surveillance Definition Working Group

recommended removing chest radiography from

the surveillance definition entirely. The CDC NHSN definition of VAP (and nowVAE, VAC, and IVAC) was developed to enablesurveillance of an important event; the CDC

specifically states that it should not be used for clinical diagnosis.

AMERICAN JOURNAL OF CRITICAL CARE, September 2012, Volume 21, No. 5

Page 58: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

VENTILATOR ASSOCIATED CONDITIONS :- pt on mechanical ventilation > 2 days ↓ baseline period of stability or

improvement,followed by sustained period of worsening

oxygenation ↓ VENTILATOR ASSOCIATED CONDITION(VAC) ↓ general objective evidence of

inflammation/infection ↓ INFECTION RELATED VENTILATOR ASSOCIATED COMPLICATION (IVAC) ↓

Page 59: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN

positive results of microbiological/laboratory testing

possible or probable VAP

April 2013 CDC/NHSN Protocol

Page 60: VENTILATOR ASSOCIATED PNEUMONIA BY DR IMRAN