pneumoinspire study protocol

PneumoINSPIRE study protocol, Version 1.2

A PROJECT OF THE WG ON PNEUMONIA OF THE INFECTION SECTION OF ESICM 1

PneumoINSPIRE

International Study on NoSocomial

Pneumonia in Intensive CaRE

An international multi-centre prospective observational cohort

study of nosocomial pneumonia in intensive care units

Study protocol

Version 1.2, 30.09.2015



TABLE OF CONTENTS

TABLE OF CONTENTS ........................................................................................................ 2

INVESTIGATIVE TEAM ......................................................................................................... 3

STUDY SYNOPSIS ............................................................................................................... 5

RESEARCH AIMS AND SIGNIFICANCE .............................................................................. 8

PRIMARY AND SECONDARY OBJECTIVES .............................................................................. 8

EXPECTED RESULTS ........................................................................................................... 9

METHODS ........................................................................................................................... 10

STUDY DESIGN ................................................................................................................. 10

POPULATION AND SAMPLE ................................................................................................. 10

ORGANISATION AND COLLABORATION ................................................................................ 10

SITE RECRUITMENT .......................................................................................................... 11

National Coordinator Responsibilities .......................................................................... 11

Local Principal Investigator Responsibilities ................................................................ 11

DATA COLLECTION ............................................................................................................ 12

DATA RECORDED .............................................................................................................. 12

STATISTICAL ANALYSIS ...................................................................................................... 15

OUTCOMES OF INTEREST .................................................................................................. 15

ETHICAL CONSIDERATIONS ............................................................................................ 16

FINANCIAL CONSIDERATIONS ......................................................................................... 16

DATA MANAGEMENT AND DISSEMINATION OF FINDINGS ........................................... 16

AUTHORSHIP AND PUBLICATIONS ................................................................................. 16

STUDY TIMELINES ............................................................................................................. 16

REFERENCES .................................................................................................................... 18

APPENDIX 1 ....................................................................................................................... 21

DEFINITIONS ..................................................................................................................... 21

APPENDIX 2 ....................................................................................................................... 23

ABBREVIATIONS ................................................................................................................ 23



INVESTIGATIVE TEAM

Coordinating Centre

Burns, Trauma and Critical Care Research Centre (BTCCRC), School of Medicine (SoM),

The University of Queensland (UQ), and Royal Brisbane and Women’s (RBWH), Brisbane,

Australia

Chief investigator

Dr Despoina Koulenti, MD, PhD

Burns Trauma and Critical Care Research Centre

Medical School, The University of Queensland

Health Sciences Building, Level 9

Royal Brisbane and Women’s Hospital

Herston, Brisbane 4029, Australia

Tel: +61 7 3346 5176, Fax: +61 7 3646 3542

E-mail: [email protected]

[email protected]

Steering Committee

Prof Apostolos ARMAGANIDIS, Greece; 2nd Critical Care Department, Attikon University

Hospital, Medical School, University of Athens, Greece

Prof Stijn BLOT, Belgium; Department of Internal Medicine, Faculty of Medicine & Health

Science, Ghent University, Ghent, Belgium

Dr Lila BOUADMA, France; Université Paris Diderot / Hopital Bichat - Réanimation

Medicale et des Maladies Infectieuses, Paris, France

Prof Maria DEJA, Germany; Department of Anaesthesiology and Intensive Care Medicine,

Campus Charité Mitte and Campus Virchow-Klinikum, School of Medicine, Charité-

University, Berlin, Germany

Prof Jan DEWAELE, Belgium; Department of Critical Care Medicine, Ghent University

Hospital, Ghent, Belgium

Dr Joel DULHUNTY, Australia; Burns Trauma and Critical Care Research Centre, The

University of Queensland, Brisbane, Australia, &Department of Intensive Care Medicine,

Royal Brisbane and Women’s Hospital, Brisbane, Australia

Mr Paul JARRETT, Australia; Department of Intensive Care Medicine, Royal Brisbane and

Women’s Hospital, Brisbane, Australia

Prof Jose GARNACHO-MONTERO, University Hospital Virgen del Rocio, University of

Seville, Spain

Dr Despoina KOULENTI [CI], Australia/Greece; Burns Trauma and Critical Care Research

Centre Medical School, The University of Queensland, Brisbane, Australia, & 2nd Critical

Care Department, Attikon University Hospital, Medical School, University of Athens,

Greece

Dr Dimitrios LATHYRIS, Greece; Department of Critical Care Medicine, Gennimatas

Hospital, Thessaloniki, Greece

mailto:[email protected]

mailto:[email protected]



Prof Jeffrey LIPMAN [Director of the Coordinating Centre], Australia; Burns Trauma

and Critical Care Research Centre, The University of Queensland, Brisbane, Australia, &

Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital,

Brisbane, Australia

Prof David PATERSON, Australia;Centre for Healthcare Related Infection Surveillance

and Prevention, Queensland Health & The University of Queensland Centre for Clinical

Research, Brisbane, Australia

Prof Jason Phua, Division of Respiratory and Critical Care Medicine, University Medicine

Cluster, National University Hospital, National University Health System &Department of

Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Prof Jordi RELLO, Spain; Critical Care Department, Vall d’ Hebron University Hospital,

Barcelona, Vall d' Hebron Institute of Research, Universitat Autonoma de Barcelona,

Barcelona, Spain

Prof Marcos I RESTREPO, USA; University of Texas Health Science Centre, Medicine,

San Antonio, Texas, USA

Prof Jason ROBERTS, Australia / United Kingdom; Burns Trauma and Critical Care

Research Centre, The University of Queensland, Brisbane, Australia, &Department of

Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Australia &

Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom

Prof Jean-Francois TIMSIT, France; Université Paris Diderot/Hopital Bichat - Réanimation

Medicale et des Maladies Infectieuses, Paris, France

Prof Jean-Ralph ZAHAR, France; Unité de Prévention et de Lutte contre les Infections

Nosocomiales, CHU Angers - Université D'Angers, Angers, France

Monitoring Committee (Provisional)

Dr Kostoula ARVANITI, Greece, Department of Intensive Care Medicine, Papageorgiou

General Hospital, Thessaloniki, Greece

Mr Paul JARRETT, Australia; Department of Intensive Care Medicine, Royal Brisbane and

Women’s Hospital, Brisbane, Australia

Dr Despoina KOULENTI, Australia/Greece; Burns Trauma and Critical Care Research

Centre Medical School, The University of Queensland, Brisbane, Australia, & 2nd Critical

Care Department, Attikon University Hospital, Medical School, University of Athens,

Greece

Dr Dimitrios LATHYRIS, Greece; Department of Critical Care Medicine, Gennimatas

Hospital, Thessaloniki, Greece

Assist. Prof Anna-Bettina HEIDICH; Department of Hygiene and Epidemiology, Aristotle

University of Thessaloniki, School of Medicine, Thessaloniki, Greece.

Dr Alexis TABAH, Australia; Burns Trauma and Critical Care Research Centre, The

University of Queensland, Brisbane, Australia, &Department of Intensive Care Medicine,

Royal Brisbane and Women’s Hospital, Brisbane, Australia



STUDY SYNOPSIS

Short title PneumoINSPIRE Study

Design Prospective, international, multicentre, observational, cohort study

Aim

The study aims to provide up-to-date and generalisable information on

current worldwide epidemiology and clinical practice associated with

diagnosis and management of nosocomial pneumonia in Intensive

Care Unit (ICU) patients.

Specifically, the study aims to:

a) evaluate the global epidemiology of nosocomial pneumonia in the

ICU setting, analysing responsible pathogens, time course of

resolution, ICU and hospital outcome, and

b) describe on a global scale current clinical practice regarding

diagnosis (and concordance with official guidelines) as well as

management of ICU nosocomial pneumonia, including, type, dosing

and appropriateness of administered antimicrobials, de-escalation

strategies and treatment duration.

Significance This international study will explore clinical details for nosocomial

pneumonia in the ICU setting: practice variations among countries and

continents, diagnostic and treatment modalities, implicated pathogens

and their resistance patterns, resolution patterns and risk factors for

unfavourable outcomes. In view of these, this global multicentre study

shall provide useful information for the elaboration of future

recommendations on diagnostic and treatment approaches for

nosocomial pneumonia in the ICU.

Inclusion Criteria ICU patients with a diagnosis of nosocomial pneumonia, including:

Admission to the ICU with diagnosis of HAP that developed in the

ward in non-intubated patients (Ward HAP)

The first episode of ICU-acquired pneumonia that developed in

non-intubated patients

The first episode of ICU-acquired pneumonia that developed in

patients receiving invasive ventilation (i.e. Ventilator-Associated

Pneumonia (VAP)).

Exclusion Criteria Age < 18 years

Patients with nosocomial pneumonia receiving palliative treatment

at the time of assessment for eligibility

Previous inclusion in the study

Research Sites Approximately 150 ICUs from 20 or more countries worldwide that will

agree to participate in the study.



Sample Size A minimum of 10 consecutive ICU patients with nosocomial pneumonia

as described above will be recruited per site. A sample size of at least

1000 ICU patients with nosocomial pneumonia is anticipated to

comprise the dataset. This sample size has been chosen to provide

generalisable data for each geographic region and to satisfy power

considerations.

Statistical Analysis Descriptive analytic, techniques and parametric and non-parametric

tests will be used to explore diagnostic, microbiological or subgroup

differences as well as clinical outcomes of nosocomial pneumonia. Cox

regression will be used to predict dichotomous outcomes of interest,

including mortality and pneumonia resolution. Independent predictors

and associated hazard ratios with 95% confidence intervals will be

reported. A two-sided p-value less than 0.05 will be considered

statistically significant.

Proposed Start

and End Date

The first site is anticipated to commence recruitment in January 2016

with staggered site recruitment; however, sites are anticipated to start

recruitment during the first half of 2016; each site will commence

recruitment as soon as relevant Institutional Review Board approvals

have been obtained. Recruitment will continue until the minimum target

of 10 patients has been reached. Sites will have the opportunity for

further recruitment while the study is active. Completion of recruitment

is anticipated to occur by July 2017.

Dissemination of

Findings

Data will be presented in a timely manner at national and international

conferences and in peer-reviewed journals.



INTRODUCTION

Nosocomial pneumonia in the ICU setting includes a) Hospital-Acquired Pneumonia (HAP)

that develops outside the ICU in non-intubated patients who are subsequently transferred to

the ICU, b) HAP that develops in non-intubated ICU patients and c) Ventilator-Associated

Pneumonia (VAP). HAP is defined as a lung infection presenting in non-intubated patients

48 hours or more after hospital admission and not incubating at the time of hospital

admission [1]. VAP is defined as pneumonia arising 48 hours or more after endotracheal

intubation [1]. Despite general advances in the management of ICU patients, nosocomial pneumonia

remains a major problem in the critical care setting [1-3]. It has been reported as the second

most common Health-care Associated Infection (HAI), the most common nosocomial

infection in the ICU and the most common nosocomial infection contributing to death [1-3].

The reported incidence of nosocomial pneumonia varies widely, ranging from 3.1 to 18.6

cases per 1,000 hospital admissions, while the presence of an artificial airway increases the

incidence by 6-20-fold [1, 4-6]. The wide variation in reported incidence may be attributed to

differences in definitions, study methodology and patient population evaluated [1]. VAP

represents approximately 80% of all episodes of nosocomial pneumonia in the ICU,

occurring in 9-27% of intubated patients [1].The incidence of VAP has been reported as

ranging from 1.9 to 3.8 cases of VAP per 1,000 ventilator-days in the United States to 18 or

more cases per 1,000 ventilator-days in Europe, while the incidence increases the longer the

duration of mechanical ventilation is [1, 7, 8]. VAP accounts for more than half of all ICU

antibiotic prescriptions and is associated with significant crude mortality rates, ranging from

20-71% [1-3]. Although controversy exists, most experts suggest that the attributable to VAP

mortality is 33-55%, especially for VAP with bacteraemia or VAP caused by difficult to treat

pathogens such as Pseudomonas aeruginosa [1]. In addition, VAP is associated with an

average increase of hospital length of stay by 7-9 days and increased health-care costs of

more than 40,000 US$ per patient [1]. Especially for nosocomial pneumonia in non-intubated

ICU patients, it should be emphasized that studies are limited with most information arbitrary

extrapolated from studies on VAP [1].

The large reported variety of both VAP incidence and mortality can be attributed not only to

existent differences between ICUs and geographic regions, but, also, to the lack of a ‘gold

standard’ for VAP diagnosis [1, 9-12]. Clinical criteria for VAP are subjective, non-specific

and, even for microbiologically-confirmed VAP episodes, there is significant inter-observer

variability. Additionally, a poor correlation between clinical interpretation and administrative

surveillance methods for VAP definition is already reported in the United States (US) [1, 9-

13]. Diagnosis of VAP (and similarly of HAP) is of clinical significance as false positive

results increases the risk of adverse events from unnecessary treatment and the emergence

of resistant organisms, while false negative results can jeopardise patients’ lives through

inadequate and delayed therapies [1-3,14-16]. Recently, the Centre for Disease Control

(CDC) introduced new streamlined criteria in order to make VAP diagnosis more objective,

enhance VAP surveillance and improve VAP care [17-21]. Accordingly, the term Ventilator-

Associate events (VAE) has been introduced and a VAE algorithm has been developed with

three definition tiers: 1) Ventilator-Associated Condition (VAC), 2) Infection-related Ventilator

Associated Complication (IVAC), 3) Possible VAP (PVAP) [21]. The VAE algorithm has been

implemented in the National Healthcare Safety Network (NHSN) in the United States (US)



since January 2013 [17-21]. The practical validity of VAEs surveillance has not been

established worldwide yet [22]. At present, there are no global prospective studies

examining how the new CDC criteria correlate with VAP diagnosis in clinical practice or

comparing patients’ characteristics and outcomes using various definitions of VAP. A study

conducted in six centres in the US reported a 9.3% VAP and a 23% VAC prevalence [23],

while a single-centre retrospective Australian study found that 28% of the cohort (543

patients) had VAC, while only 7.4% had VAP diagnosis [24]. A multicentre study conducted

in 10 Canadian and 1 US ICUs reported a similar prevalence of VAC and VAP (10.5% and

11.2%, respectively), however the concordance was poor, with 79% of the VAP patients

having neither VAC nor IVAC [25]. Another study conducted in 2 centres in Netherlands

reported, also, poor concordance between VAE and VAP definitions, with novel VAE criteria

identifying only 32% of patients with VAP [26]. Finally, a very recent single-centre US study

reported a low sensitivity of the VAC criteria for the detection of VAP (25.9%) [27].

On the other hand, successful treatment of nosocomial pneumonia remains difficult and

complex [1]. Initial empiric antibiotic treatment, in terms of timeliness, dose and spectrum of

cover, is a key element for effective management, with higher morbidity, mortality and cost

associated with inappropriate treatment [1-3, 28]. Up-to-date, global data about the everyday

clinical practice regarding the above, as well as regarding the de-escalation and

discontinuation practices and their effect on treatment outcomes, would be an essential step

in the development of interventions to improve and rationalise treatment choices.

Furthermore, exploration of the timeframe of resolution of ICU nosocomial pneumonia,

validation of previously-identified predictors [29-41] and investigation of additional predictors

of adverse outcomes could be of clinical importance by means of a large multicentre cohort.

Finally, the existing literature is scarce regarding clinical characteristics and outcomes of

nosocomial pneumonia in specific ICU sub-groups (e.g. patients with chronic obstructive

pulmonary disease (COPD) [42-44] or the elderly ones [45]). A large cohort study would

improve understanding and assist in identifying optimised treatment approaches for these

specific patients groups in the ICU.

RESEARCH AIMS AND SIGNIFICANCE

The aim of the project is to perform an international multicentre prospective observational

cohort study of nosocomial pneumonia in ICUs worldwide in order to provide up-to-date and

comprehensive descriptive data on diagnosis, microbiology, time course of resolution,

management and outcomes in a global ICU population.

Primary and Secondary Objectives

The primary objectives of the project are as follows:

- Evaluate the global epidemiology of nosocomial pneumonia in ICU patients, analysing

responsible pathogens and resistance pattern by type of pneumonia and geographical

region.

- Describe on a global scale current clinical practice regarding diagnosis and determine the

degree of concordance between the diagnosis of nosocomial pneumonia in routine clinical

practice and the official definitions including: a) ATS/IDSA 2005 guidelines [1]; b)

CDC/NHSN Surveillance Definitions (version January 2015, modified April 2015) [20, 21].



- Identify on a global scale variable treatment decisions with emphasis on therapeutic

schemas, appropriateness, de-escalation decisions and their relation to outcomes.

- Evaluate in a large cohort, the time course of resolution and identify early predictors of

unfavourable outcome.

The Secondary Objectives of the project are as follows:

- Evaluate nosocomial pneumonia in specific subgroups of critically ill patients (such as,

chronic obstructive pulmonary disease [COPD], the elderly, postoperative, trauma patients).

- Describe the differences between nosocomial pneumonia in non-intubated ICU patients

and VAP.

- Compare the characteristics and outcomes between patients with nosocomial pneumonia

in ward patients later transferred to the ICU and non-intubated ICU patients with nosocomial

pneumonia.

Expected Results

This global project will explore previously unquantified clinical details relating to nosocomial

pneumonia in the ICU setting, including: practice variations among countries and continents,

diagnostic and treatment modalities, implicated pathogens and their resistance patterns,

resolution patterns and risk factors for unfavourable outcomes.

It is expected to be the first project to provide data on the relationship between clinical

diagnosis and official definitions, on a worldwide level. Also, it is expected to provide

important data on early predictors of mortality, as well as on potential predictors of treatment

success, including validation of previously identified predictors, in a large international ICU

sample.

As a result, this multicentre international study shall provide useful information for the

elaboration of future recommendations on diagnostic and treatment approaches for

nosocomial pneumonia in the ICU. In parallel, the identification of early predictors of adverse

outcomes is crucial for the design and development of interventional studies aimed to

determine management strategies for nosocomial pneumonia.

In detail, the project is expected to provide insights into the following clinical and research

questions:

- How is ICU nosocomial pneumonia in the ICU diagnosed in real-world and what is the

degree of concordance with official definitions?

- What are the key factors for treatment initiation in ICU nosocomial pneumonia?

- What is the time course relationship between clinical suspicion of ICU nosocomial

pneumonia, diagnostic procedures and initiation of empirical antibiotic treatment?

- Is antibiotic dosing for nosocomial pneumonia in ICU patients adequate? What is the

overall duration of treatment? How empirical antibiotic treatment is modified (de-escalation,

escalation, termination) in light of microbiological data?

- What is the microbiology of ICU nosocomial pneumonia, in terms of responsible

microorganisms and antibiotic susceptibility?

- What are the differences between microbiologically confirmed and non-confirmed

nosocomial pneumonia?

- What are the predictors of resolution, recurrence and day 28 mortality in ICU patients with

nosocomial pneumonia? Are there any predictors for early identification of non-responders

to initial treatment patients (i.e. non-resolving pneumonia)?



- What are the differences in terms of microbiology, time course and outcomes between

nosocomial pneumonia that develops in non-intubated ICU patients vs. intubated ICU

patients (VAP)?

- What are the differences in terms of microbiology, time course and outcomes between

nosocomial pneumonia that develops in non-intubated ICU patients and pneumonia that

develops in non-intubated ward patients transferred in the ICU?

- What are the characteristics of nosocomial pneumonia in specific ICU subgroups, such as

COPD, post-operative, trauma patients or the elderly?

METHODS

Study Design

Prospective, international, multicentre, observational, cohort study

Population and Sample

All adult ICUs can apply for participation in the PneumoINSPIRE study with consideration to

the following requirements: (i) ICUs agree to collect unit and patient related data on site; (ii)

ICUs agree to transfer the collected data to the coordinating centre; (iii) ICUs pursue and

obtain ethics committee approval or a waiver. Participating ICUs will collect data from a

nominated start date until the minimum target number of 10 consecutive ICU patients with

an episode of nosocomial pneumonia has been reached (episodes diagnosed and treated

as nosocomial pneumonia by the attending clinicians). The participating ICUs will be allowed

to continue recruitment after they have reached the 10 patients if they wish to do so,

provided that recruitment period of the study is still open. No maximum site targets will be

set. The first site is expected to start in January 2016, but sites are anticipated to start

recruitment during the first half of 2016, with starting dates depending on when relevant local

institutional review board approval is obtained.

Study inclusion criteria are as follows:

Admission to the ICU with diagnosis of HAP that developed in the ward in non-intubated

patients (Ward HAP)

The first episode of ICU-acquired pneumonia that developed in non-intubated patients

(ICU HAP)

The first episode of ICU-acquired pneumonia in patients receiving invasive ventilation

(i.e. VAP).

Study exclusion criteria are as follows:

Age < 18 years

Nosocomial pneumonia in patients receiving palliative treatment only at the time of

assessment for eligibility (i.e. the time of clinical diagnosis).

Previous inclusion in the study

Organisation and Collaboration

Endorsement for this study has been sought from the European Society for Intensive Care

Medicine (ESICM), with application for endorsement submitted in September 2015 (outcome

pending). A synopsis of the study has been presented in the meeting of the Working Group

on Pneumonia at the ESICM Annual Congress in 2013 and a more detailed version



presented at the Working Group on Pneumonia at the ESICM Annual Congress in 2014. The

final protocol and dataset was developed with input from the Working Group on Pneumonia.

The Steering Committee includes members of the Working Group on Pneumonia and the

Infection Section of ESICM, other international experts in the field and investigators at the

Coordinating Centre. A Monitoring Committee, which at the minimum includes a clinician

and a statistician, will be responsible for the quality control of the data entry (a provisional

monitoring committee has been established).

Site Recruitment

We aim to recruit at least 150 intensive care units (ICUs) from at least 20 countries

worldwide. There will be no limit set on the number of ICUs allowed to participate.

In order to facilitate site recruitment, National Coordinators (NCs) among members of the

Working Group on Pneumonia and/or Infection section or intensivists highly esteemed in

their country will be identified. The NCs will have a key role in the conduct of the study in the

individual countries as project leads. An expression of interest and nomination process for

NCs was commenced during the Working Group on Pneumonia meeting in September

2014. At each participating centre, a Local Principal Investigator (LPI) will be nominated and

assisted by up to one other co-investigator.

National Coordinator Responsibilities

The role and responsibilities of the NCs are to:

Advertise the study in the individual countries and identify participating sites and LPIs in

their country.

Apply for regulatory approval at a national level where applicable and ensure that ethical

committee (EC) approvals, or waivers of EC approvals, are obtained for all the

participating sites in their country prior to the initiation of the study.

Assist with the translation of the study protocol and case report form where required.

Ensure the distribution of study material to the centres (protocol, case report form,

instruction manuals, etc.) and that the LPIs are familiar with the study material prior to

the start of recruitment.

Ensure good communication with the participating sites in their country, including

monitoring and encouraging LPIs to achieve optimal recruitment and follow-up during the

period of the study.

Assist the Monitoring Committee in communicating with sites in regard to data queries.

Local Principal Investigator Responsibilities

The role and responsibilities of the LPIs are to:

Lead the study at their site.

Inform the respective NC of their interest to participate in the study.

Apply for EC and/or local site approvals in collaboration with the NC and ensure that

local approvals are in place prior to the initiation of the study.

Notify and send scanned copies of local sites approval to the NC.

Ensure accurate and timely data collection and entry in to the electronic Case Report

Form (eCRF). For participating sites that do not have access to the eCRF, copies of the



paper Case Report Form (CRF) should be sent to the relevant party, as determined by

the NC and Coordinating Centre.

Reply promptly to data queries from the Coordinating Centre.

Guarantee the integrity, consistency and quality of data collection and ensure that the

EC approval and the paper CRFs will be kept in a safe and locked place for the period of

time stipulated by the study protocol or local EC, whichever is longer.

Maintain effective communication with the NC and Coordination Centre.

Data Collection

The CRF will be made available to the participating sites as a printable paper-based CRF.

Research coordinators will enter all required data described in the protocol onto the CRFs

directly from the source data (i.e. the patient record). Information recorded in the CRF

should accurately reflect the patient record. Paper CRFs will be numbered with a

consecutive site code and participant ID number. Patient identifiers (name and unique

record number) will be contained separately in a site recruitment log. Data will be entered in

the eCRF from the paper CRF using a username and password provided by the

Coordinating Centre. Paper CRFs and eCRFs will be signed and dated by the LPI and a

record kept of all changes made in the eCRF. The Coordinating Centre will routinely monitor

data entry in the web-based database for completeness and consistency. A process of data

validation, e.g. range, logic and missing data analysis, will be conducted prior to database

lock. In cases where data clarification is required, the Coordinating Centre will send data

queries to the LPI.

The eCRF will not contain identifiable data, apart from age and admission dates. A site

recruitment log that contains site recruitment details and participant identifiers will be kept by

the LPI in a secure and locked location. Data will only be re-identifiable by the LPI. The data

will be non-identifiable by the Coordinating Centre.

A data collection guide will be provided to the participating sites. A study site file with all

material related to study (e.g. protocol, paper CRFs and EC approval) will be stored in

secure location by the LPI and/or site research coordinators. The LPI must maintain

confidential all study documentation and take measures to prevent accidental or premature

destruction of these documents. Study materials must be kept for at least 5 years from the

completion of the study (i.e. the timing of the first publication) or as directed by local site

approvals. The Coordinating Centre will take all appropriate measures to safeguard and

prevent access to the study data by an unauthorised third party. The Coordinating Centre

will retain study data for a minimum of 15 years from the completion of the study.

Data Recorded

For each participating ICU, site-specific information will be collected once. Each ICU will

record a limited dataset for all consecutive adult patients (≥ 18 years of age) admitted to the

ICU for the duration of the study, i.e. the total number of admissions during the study period

and the total number of admissions of patients on mechanical ventilation for more than 48

hours. For each patient with a clinical diagnosis of nosocomial pneumonia, detailed data will

be obtained relating to the study objectives. For each patient with a diagnosis of nosocomial

pneumonia, detailed data will be obtained relating to the study objectives. Note: with regard

to laboratory and imaging data, participating sites are not obliged to perform the specific

tests in order to complete the required information in the CRF if it is not part of standard



clinical practise. That means: a) there will be no variation to standard clinical practice, b) the

study will not incur any extra costs to the participating sites, and c) the routine clinical

practise will be recorded.

Site specific variables will include the following:

Location: country and city.

Type of hospital: primary, secondary, tertiary; public vs. private; university/teaching vs.

other.

ICU type: medical/surgical/mixed or specialised ICU; closed vs. open.

Number of hospital beds

Number of ICU beds

Average nurse/patient ratio

Number of full-time equivalent physiotherapists/respiratory therapists

Presence of 24-hour ICU physician cover

Details for the antibiotic policy in the ICU including: availability of pharmacists in the ICU,

availability of infectious disease specialist in the ICU (full-time or part-time), presence of

written antibiotic policies/guidelines, presence of antibiotic stewardship program in the

hospital/ICU, presence of restrictions in the administration of certain antibiotics), infection

control measures in the ICU, measures for VAP prevention, presence of surveillance for

multidrug resistant pathogens in the hospital/ICU, routine performance of surveillance

cultures in the ICU, infection control measures, including measures for extended

spectrum beta-lactamase (ESBL) producing gram-negative bacilli (GNB), multidrug-

resistant (MDR) Pseudomonas, methicillin-resistant Staphylococcus aureus (MRSA) etc.,

incidence or prevalence of MDR-GNB in the ICU, including ESBL and MDR-

Pseudomonas, incidence or prevalence of MRSA, availability of plasma antibiotic

concentration for specify antibiotics and antibiotic breakpoints.

For previous calendar year: number of ICU admissions, mean length of ICU stay,

number of mechanically ventilated patients, mean severity of ICU patients at admission,

i.e. Simplified Acute Physiology Score (SAPS) II or Acute Physiology and Chronic Health

Evaluation (APACHE) II score, and overall ICU mortality.

Details on the diagnosis pneumonia in the ICU: invasive vs. non-invasive techniques and

reason; quantitative vs. semi-quantitative vs. qualitative cultures; performance of Gram-

stain of respiratory samples and time from sampling to results; use of rapid diagnostic

techniques; presence of written protocols (paper or web-based) for the diagnosis and

management of nosocomial pneumonia in the ICU.

The following individual patient data for study participants will be collected:

Patient demographics: age, sex, race, weight, height and residence prior to hospital

admission

Presence of risk factors for healthcare-associated infections

Date of hospital admission

Diagnosis at hospital admission

Date of ICU admission

Location prior to ICU admission

Type of ICU admission: medical, surgical or trauma; planned vs. unplanned.



Diagnosis at ICU admission,

Severity on ICU admission: Acute Physiology and Chronic Health Evaluation II (APACHE

II); SAPS II score (Simplified Acute Physiology Score); SOFA score (Sequential Organ

Failure Assessment)

Co-morbidities/underlying diseases: COPD and Global Initiative for Chronic Obstructive

Lung Disease (GOLD) stage (if available); chronic respiratory insufficiency; chronic heart

failure (New York Heart Association class III-IV); insulin-dependent diabetes mellitus;

chronic renal failure; malignancy (metastatic/non-metastatic); bone marrow transplant or

solid organ transplant; cirrhosis; haematologic malignancy; immunosuppression and

type.

Type of ventilation on ICU admission

Date of initiation of non-invasive mechanical ventilation (NIMV) and discontinuation of

NIMV

Date of intubation and date of extubation; location of intubation (ward/operating

theatre/emergency department/ICU)

Date of initiation invasive mechanical ventilation (IMV) and discontinuation of IMV

(duration of IMV)

Presence of shock at ICU admission

Presence of sepsis at ICU admission, including severity (sepsis/severe sepsis/septic

shock)

Date/time of nosocomial pneumonia onset (suspicion of pneumonia)

Type of nosocomial pneumonia: developed outside the ICU in non-intubated patients vs.

developed in the ICU in non-intubated patients vs. developed in intubated ICU patients

(VAP)

Prior to the onset of nosocomial pneumonia: antibiotic use (type of antibiotics)

For the day of pneumonia onset (for HAP that developed in the wards and for the day of

ICU admission): Clinical signs and symptoms [including PaO2/FiO2 and positive end-

expiratory pressure (PEEP)], laboratory data, radiological signs, sepsis severity

(sepsis/severe sepsis/septic shock), SOFA score, Clinical Pulmonary Infection Score

(CPIS), diagnostic procedures (invasive/non-invasive; type of specimen for culture;

serology; polymerase chain reaction [PCR]), date and time of diagnostic procedures

Microbiological data: cultures qualitative/semi-quantitative/quantitative; Gram stain of

respiratory samples; isolated microorganisms and sensitivity pattern (MICs where

available); presence of bacteraemia.

Antibiotic management: commencement and cessation dates for each antibiotic used to

treat the episode of pneumonia; date/time and details about the initial empirical antibiotic

treatment; reasons for antibiotic alterations (de-escalation, escalation, termination of

antibiotic treatment); modification of antibiotic dosing based on antibiotic levels;

administration of adjuvant therapy.

SOFA score, sepsis severity, radiological signs, fever, secretions, white blood cell count

(WBC), (worst) PaO2/FiO2& PEEP, C-reactive protein (CRP) (if available) and

procalcitonin (if available) – recorded on the day of pneumonia onset (day of ICU

admission for Ward HAP) and, where available, daily until day 7 and then day 10 and 14

(optional D1 to D14). For VAP, (worst) PaO2/FiO2 & PEEP for up to four days prior VAP

onset and WBC & temperature for two days prior to VAP onset.



On day 3, 7 and 14: assessment of nosocomial pneumonia outcome on day as judged

by the attending team (resolution, partial resolution, non-resolving/persistent)

On day 14 and day 28 assessment for recurrence of nosocomial pneumonia or super-

infection or development of infection at another focus; if recurrence or super-infection,

type of isolated microorganisms.

ICU mortality (censored at Day 28 after ICU admission for HAP arising at the wards and

Day 28 after pneumonia onset for ICU HAP or VAP)

Vital status at day 28 after ICU admission for HAP arising in the wards and day 28 after

pneumonia onset for ICU HAP and VAP (coded as “alive” if discharged alive from the

hospital prior to day 28).

Statistical Analysis

Descriptive analytic techniques, parametric and non-parametric tests will be used to explore

diagnosis, microbiology, subgroup differences and clinical outcomes of nosocomial

pneumonia. Cox regression will be used to predict dichotomous outcomes of interest,

including mortality and resolution. Site will be entered as an independent variable in logistic

regression. Independent predictors and associated hazard ratios with 95% confidence

intervals will be reported. A two-sided p-value less than 0.05 will be considered statistically

significant.

Sample Size

A sample size of at least 1000 ICU patients with nosocomial pneumonia is anticipated to

comprise the dataset. This sample size has been chosen to provide generalisable data for

each geographic region and sufficient power for multivariate analysis.

Re-classification

In order to explore the concordance between the diagnosis of pneumonia in routine clinical

practise and official definitions [1, 20, 21], members of the monitoring committee will

reclassify the cases based on the recorded data. Outcome analysis will be repeated using

re-classifications for pneumonia.

Outcomes of Interest

ICU and hospital mortality censored at Day 28

Resolution of pneumonia at Day 3, Day 7 and Day 14

Recurrence of pneumonia at Day 14 and Day 28

Concordance of clinical diagnosis of nosocomial pneumonia (HAP/VAP) with official

definitions [see appendix 1]

Mechanical ventilation free days at day 28 (censored at ICU discharge if discharged prior

to Day 28)

Antibiotic free days at D 28 (censored at ICU discharge if discharged prior to Day 28)

Note:

- For nosocomial pneumonia with ward onset, Day 1 is defined as the calendar day of ICU

admission.

- For nosocomial pneumonia with ICU onset, Day 1 is defined as the calendar day of

pneumonia is suspected.



ETHICAL CONSIDERATIONS

This study will be conducted in accordance with the ethical principles laid down by the

International Conference on Harmonization guidelines for Good Clinical Practice (GCP) that

have their origin in the Declaration of Helsinki and the applicable local regulatory

requirements.

This study is considered to be low-negligible risk as is an observational, non-interventional

study with collection of de-identified data. Each participating ICU will seek relevant EC and

institutional approvals, including a waiver of ethics review where appropriate. A waiver of

individual participant consent will be sought for collection of de-identified clinical data

recorded as part of routine clinical care. The NCs and LPIs will be responsible for

determining the need for relevant national and local site EC approvals and obtaining it if

needed, respectively.

FINANCIAL CONSIDERATIONS

Site participation will be on a voluntary basis and largely conducted with in-kind support.

NCs will consider options for regional research funding to supplement in-kind support where

available. Funding has been obtained from the Royal Brisbane and Women’s Hospital to

enable study set-up.

DATA MANAGEMENT AND DISSEMINATION OF FINDINGS

The Coordinating Centre will act as a custodian of the data on behalf of the Steering

Committee. Progress and final reports will be presented in a timely manner at national and

international conferences, with priority given to presentation during the ESICM annual

congresses. Study results will be published in appropriate peer-reviewed journals. Only de-

identified aggregate data will be presented publicly.

AUTHORSHIP AND PUBLICATIONS

Authorship in all primary and secondary publications will be “The PneumoINSPIRE Study

Investigators” or a named writing committee “and The PneumoINSPIRE Study

Investigators”. All PneumoINSPIRE Study Investigators will be listed as Collaborators in any

resultant journal publications. Following the primary manuscript, study investigators may

pursue secondary analyses, provided that the manuscript proposal is approved by the

Steering Committee based on the quality and validity of the proposal. Each NC on behalf of

the national group may request the respective data for secondary analysis specific to their

region of oversight. The final version of all manuscripts must be approved by the Steering

Committee prior to submission for publication (including abstracts and conference

presentations) where they relate to all or a part of the PneumoINSPIRE Study dataset.

STUDY TIMELINES

Study development commenced with the Working Group on Pneumonia meeting at the

ESICM 2014 Annual Congress. Commencement of patient recruitment will occur in January

2016. Database closure, final query resolution and analysis will occur from August to



December 2017. The first publication will be prepared for submission in July 2017. Study

milestones are listed in the following table.

Timeframe Indicators Study Milestones

October 2013 Presentation of a synopsis of the protocol during the WG on

Pneumonia meeting; feedback by the WG members

September 2014 Detailed Presentation of the protocol during the WG on

Pneumonia meeting; feedback by the WG members;

Initiation of NC recruitment

February 2015 Ethics approval of version 1 of the study protocol by the EC

of RBWH

March 2015 Ethics approval of version 1 of the study protocol by UQ

September 2015 Application for endorsement by ESICM submitted

NC & site recruitment ongoing

Final protocol of the study sent to NCs (end September)

January –July 2016 (approx.) Sites’ recruitment, EC approvals applications in local level

(where needed) and national level (where needed); sites that

have obtained EC approval initiate patient recruitment

July 2017 Patient’ recruitment closes

August - December 2017 Quality validation; data queries to be addressed by the LPIs

January 2018 Database lock

January-May 2018 Statistical analysis

July 2018 First manuscript to be submitted for publication in a peer-

reviewed scientific journal



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APPENDIX 1

Definitions

Nosocomial pneumonia is defined as a pulmonary infection arising >48 hours after hospital

admission with no evidence of pneumonia at the time of admission. Early-onset nosocomial

pneumonia is defined as pneumonia developing 2 to 4 days after hospital admission, while

late-onset pneumonia is defined as developing >5 days after hospital admission.

Nosocomial pneumonia can develop in (non-intubated) ward patients, in non-invasively

ventilated ICU patients and in invasively ventilated (intubated) ICU patients.

Nosocomial pneumonia in the ICU setting includes patients that develop pneumonia during

their ICU stay and patients that developed nosocomial pneumonia in the wards and

transferred to the ICU.

Hospital-acquired pneumonia (HAP) – clinician defined: HAP is defined as a pulmonary

infection arising >48 hours after hospital admission with no evidence of pneumonia at the

time of admission. Early-onset HAP is defined as HAP developing 2 to 4 days after hospital

admission, while late-onset HAP is defined as developing >5 days after hospital admission.

Ventilator-associated pneumonia (VAP) – clinician defined: VAP is defined as a

pulmonary infection arising >48 hours after endotracheal intubation with no evidence of

pneumonia at the time of intubation or the diagnosis of a new pulmonary infection if the initial

admission to ICU was for pneumonia. Early-onset VAP is defined as VAP developing 2 to 4

days after intubation, while late-onset VAP is defined as developing >5 days after

intubation.

The following definitions for pneumonia will be applied to the data set for

reclassifications (for the analysis only, not for use by the site investigators):

Reclassification I: Nosocomial Pneumonia (HAP/VAP)

Reclassification will be based on criteria cited in ATS/IDSA guidelines on

HAP/VAP/HCAP 2005 [Reference 1: Am J Respir Crit Care Med 2005; 171:388-416]

Reclassification II:

Ventilator-Associated Event (VAE), Infection-related Ventilator Associated

Complication (IVAC), Possible VAP (PVAP)

Reclassification will be based on CDC/NHSN Surveillance definition for Ventilator-

Associated Event (VAE), 2015 [Reference 20: Ventilator-Associated event (VAE) (For use in

adult ICUs only). In: Device-associated Module, VAE, CDC January 2015 (modified April

2015), pages 10-1 to 10-41, accessed 28 September 2015,

http://www.cdc.gov/nhsn/PDFs/pscManual/10-VAE_FINAL.pdf )]

Pneumonia (Ventilator-associated [VAP] and non-ventilator-associated [PNEU]) Event

Reclassification will be based on CDC/NHSN Surveillance definition for Pneumonia

(Ventilator-associated [VAP] and non-ventilator-associated [PNEU]) Event , 2015 [Reference




21: Pneumonia (Ventilator-associated [VAP] and non-ventilator-associated [PNEU]) Event,

In: Device-associated Module, PNEU/VAP, CDC January 2015 (modified April 2015), pages

6-1 to 6-15, accessed 28 September 2015,

http://www.cdc.gov/nhsn/PDFs/pscManual/6pscVAPcurrent.pdf]




APPENDIX 2

Abbreviations

APACHEII: Acute Physiology and Chronic Health Evaluation II

BAL: Bronchoalveolar lavage

CAP: C-acquired pneumonia

CDC: Centres for Disease Control and Prevention

COPD: Chronic obstructive pulmonary disease

CPIS: Clinical Pulmonary Infection Score

CRF: Case report form

CRP: C-reactive protein

EC: Ethics committee

eCRF: Electronic case report form

ESBL: Extended spectrum beta-lactamase

ESICM: European Society of Intensive Care Medicine

GNB: Gram-negative bacilli

GOLD: Global Initiative for Chronic Obstructive Lung Disease

HCAP: Healthcare-associate pneumonia

HAP: Hospital acquired pneumonia

ICU: Intensive care unit

ICH-GCP: Good Clinical Practise

IMV: Invasive mechanical ventilation

IRB: Institutional review board

IVAC: Infection-related Ventilator-Associated Complication

LPI: Local principal investigator

MDR: Multidrug-resistant

MRSA: Methicillin-resistant Staphylococcus aureus

MV: Mechanical ventilation

NIMV: Non-invasive mechanical ventilation

NC: National coordinator

NHSN: National Healthcare Safety Network

PNEU: Pneumonia

PSB: Protected specimen brush

PVAP: Possible VAP

SAPSII: Simplified Acute Physiology Score

SOFA: Sequential organ failure assessment

TA: Tracheal aspirate

VAC: Ventilator-Associated Condition

VAE: Ventilator-Associated Event

VAP: Ventilator-associated pneumonia

WG: Working group

pneumoinspire study protocol

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