Our Work

Antimicrobial resistance

The ICU is an important venue for the acquisition and transmission of antimicrobial resistance (AMR).  It also provides a unique perspective on the risk factors for the development of ICU-acquired infection.  Despite efforts to reduce the risk of ICU-acquired infection through the use of infection control measures such as hand-washing and isolation, and bundled approaches to prevent ventilator-associated pneumonia or catheter-related bacteremia, and to reduce antibiotic pressures through antimicrobial stewardship programs, on any given day, more than half of all ICU patients are assessed to be infected, and more than 70% are receiving systemic antibiotics. International collaboration provides unique and important opportunities to understand the epidemiology of ICU-acquired infection and antimicrobial resistance, and to evaluate strategies to reduce these.

The Antimicrobial Resistance in Intensive Care (AMRIC) program, funded in pilot form by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR), seeks to develop a globally representative ICU-based network for surveillance of AMR.  Our hypothesis is that a better understanding of geographic variability in rates and bacteriology of nosocomial infection, and in rates of AMR can point to potentially modifiable risk factors. 

The ICU Microbiome project will test the hypothesis that patterns of ICU-acquired infection will reflect the local ICU microbiome, as sampled from water sources, inanimate surfaces, and ventilation systems in the ICU.  Applications have been submitted to the Bill and Melinda Gates Foundation Grand Challenges competition to support preliminary studies in South Africa, India, and Brazil, leveraging expertise in environmental microbiology at the University of Stellenbosch in South Africa.

Ignacio Martin-Loeches is leading an application to the JPIAMR to build expertise in understanding the lung microbiome and its disruption in critical illness, and to relate these changes to the development of ventilator-associated pneumonia.

The Acinetobacter: A Study of Colonization, Emergence, and Transmission in Intensive Care (ASCETIC) study is seeking funding for a multinational study to test the hypothesis that Acinetobacter can be transmitted to critically ill patients through their exposure to the hospital water supply, and so prevented by minimizing exposure.

InFACT studies in antimicrobial resistance focus on an important international threat to acutely ill patients.  They also provide a unique opportunity to build research capacity in emerging groups in low and middle income countries outside the EU/North America/Australia axis.

Pandemic Preparedness

The 2009 H1N1 influenza pandemic confronted critical care researchers with a challenge: how to mobilize a research response to a rapidly emerging and incompletely understood international threat, and how to communicate the data emerging from any studies to decision-makers who were charged with leading a global clinical response.  This challenge framed InFACT’s initial forays into international research collaboration.  It is fair to say that we were largely unsuccessful, but that failure shaped ideas about how we might respond more effectively to future challenges.

Building on a CIHR- and PHAC-funded meeting in Toronto in 2011, and on a follow-up meeting in Pittsburgh later that year, and working in close collaboration with the International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC), we embraced the concept of creating, in the inter-pandemic period, the research architecture that could be seconded to rapidly launch one or more clinical trials in response to an acute need.

The model we embraced was the platform trial.  A platform trial uses Bayesian models, and evaluates multiple interventions, simultaneously and sequentially; it is, in essence, a hybrid model of research and continuous quality improvement.  The resulting trial – the Randomized, Embedded Multinational Adaptive Platform (REMAP) trial – selected as its focus severe community-acquired pneumonia (CAP) as the dominant phenotype for an emerging infectious disease.  REMAP-CAP has now been funded in the EU as part of the PREPARE initiative, in Australia, New Zealand, and most recently, Canada.  Additional funding applications are being considered for the USA, Brazil, and Africa. 

REMAP-CAP will not only explore the creation of a platform for global collaboration in pandemic research, but also build a mechanism for better international research collaboration in investigator-led clinical trials.  The opportunities for, and barriers to this are a key focus of this preliminary work.

education and mentoring

One of the most important priorities for InFACT is to build research capacity outside of North America and Europe, and to empower groups in Central and South America, Africa, and Asia to assume their legitimate leadership roles in framing an international research agenda for the best care of critically ill patients.

InFACT members include four groups in Asia, four in Latin America, and two in Africa.   Building on the success of the BASIC (Basic Assessment and Support in Intensive Care Course), developed and led by Charles Gomersall, chair of the Asian Critical Care Clinical Trials Group, InFACT has developed a course in BASIC research, structured as a two day train the trainer program, and supported by a manual on basic research principles.  Led by Charles, by Shay McGuinness and Rachael Parke (ANZICS CTG), and by Rob Fowler and Neill Adhikari (Canadian Critical Care Trials Group), the course has now been given in Karachi Pakistan, Sydney Australia, Hong Kong, and Addis Ababa Ethiopia.

In addition, InFACT is developing a fellowship program to support the education and mentorship of trainees and junior investigators from areas where critical care research is under-developed.  The model entails co-funding by the mentor and by the student’s home country, and seeks to create a cohort of skilled and dedicated researchers who can be the future leaders of critical care research in their own countries.

outcome measures working group

Clinical research is only as impactful as the measures used to understand its consequences.  Mortality at an early landmark time point (usually 28 or 30 days) has been the most common outcome used in acute care trials.  However it is apparent that mortality is insensitive, and non-informative for the vast majority of patients who survive their ICU stays, and that the assumptions that guide its use are poorly understood.  Moreover outcome measurement in critical illness is chaotic and poorly standardized, with the result that it is challenging to pool the results of multiple trials into meta-analyses.

                The activities of the InFACT Outcome Measures working group are focused on four key areas:

·               Development of a taxonomy and framework for outcome measures for acute care research

·               Development of core outcome measure sets for specific areas of acute care research

·               Characterization of the strengths, limitations and performance characteristics of commonly used outcome measures

·               Development of novel measures to meet unmet needs in clinical research

To these ends, we have launched a number of key collaborative initiatives:

·         Creation of an international Delphi panel that has facilitated the development of core outcome measures sets for studies of mechanical ventilation and long term outcomes from intensive care.

·         Promotion of core outcome sets for sepsis, subarachnoid hemorrhage, delirium, cardiac arrest using the methodologic framework developed by the COMET (Core Outcome Measures in Effectiveness Trials) initiative.

·         Creation of a novel taxonomy for outcome measures

·         Evaluation of the performance characteristics of mortality as an outcome measure in critical care clinical trials

Moving forward we see a role analogous to that played by the OMERACT (Outcome Measures in Rheumatology Clinical Trials) initiative that has achieved international consensus on the selection of outcomes for clinical trials in rheumatic diseases.  Moreover we see an opportunity to use clinical trials conducted by member groups as a platform to evaluate novel, non-mortal measures of therapeutic efficacy.

stratification and Staging

Critical illness has traditionally been defined by syndromes – Acute Respiratory Distress Syndrome, sepsis, Multiple Organ Dysfunction Syndrome.  While these reflect a clinical phenotype of critical illness, they do not correspond well to underlying biologic or pathologic mechanisms, and so have proven inadequate to inform diagnostic and, therapeutic decision-making.  Unresolved biologic heterogeneity has been a recurring factor in our failure to develop and use effective biologic therapies, or even to use those we have most effectively.

Heterogeneity is an intrinsic element in other diseases such as cancer or heart disease.  Advances in these disciplines has come through a better understanding of natural history and the development of better taxonomic classifications that identify sub-populations of patients who are more likely to respond to particular treatment strategies.

InFACT has been promoting a collaboration amongst trialists, as well as amongst investigators with an interest in large scale “omics” technologies and those with expertise in the aggregation and interpretation of large data sets with a view to rethinking how we classify acutely ill patients to better match biologic derangements to available treatments.

This is an ambitious project whose time frame is measured in decades, and whose success depends on finding common ground amongst a scientifically diverse group of researchers.  Yet there is an extraordinary sense of willingness to explore the potential of such a collaboration.  The potential projects to move this program forward include:

·      Developing a common taxonomy to describe the process

·      Standardizing sample collection and data annotation

·      Optimizing and harmonizing data platforms

·      Sharing samples and data, and developing agreements for doing so

·      Hosting colloquia and symposia

·      Developing large collaborative funding applications

·      Developing and testing candidate models

·      Encouraging trialists to collect samples to use the RCT as a platform for study

·      Secondary analyses of completed clinical trials to look for signals of differential treatment responsiveness

Benjamin Tang from Australia has drafted an initial overview of the project.  We have had discussions at a variety of meetings in Toronto, San Francisco, Bangkok, and Paris, and are working to develop an organizational structure and research program to move the initiative forward.