because of the interplay between Welcome to - ISICEMintensive.org/ISICEM_News/2016 ISICEM...

A s the 2016 edition of the International Sym-posium on Intensive Care and Emergency Medicine dawns, it is

with great pleasure that I welcome you to the Square for a comprehen-sive program packed with the latest and greatest topics in the field.

Over the next four days, physicians, nurses, and allied healthcare profes-

sionals the world over will join together for a fascinating program of lectures, tutorials, workshop, debates and more, with hundreds of individuals taking to the stage to share their expertize.

As always, discussions will center on a multitude of front-line issues, facilitating an open forum in which we can all share the most clinically relevant advances, research develop-ments, therapeutic nuances, and

management techniques. Of course, we thank our spon-

sors for helping make this pos-sible – and we encourage you to spend some time in the scientific exhibition to see the latest medical and scientific equipment, phar-maceutical products, books, and services related to intensive care and emergency medicine laid bare. Technology and techniques flourish

because of the interplay between industry and the clinic, and we want to continue that bond.

We begin today, as we always do, with a rich and informative opening session that will be a particular highlight of the program, filled with key lectures, as well as the eagerly-anticipated Report of the Round Table Conference on Recovery after Critical Illness. Held in the expansive yet immersive Henry Le Bœuf auditorium, it is perhaps the only chance during the four days that we can all sit together to share in several vital topics, so I do look forward to seeing you there.

But there is also much more to come, and depending on your specialty, interests or treatment goals, I’m sure there will be plenty of ses-sions to stimulate your interest.

Finally, I must thank you all for your understanding with regards to the elevated security this year. We do hope it did not cause any inconven-ience for you.

I wish you a very enjoyable and enlightening meeting, and invite you to join us this evening for the open-ing cocktail welcome in the scientific exhibition area.Jean-Louis Vincent ISICEM Chairman Professor of intensive care medicine Dept of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles President of the World Federation of Societies of Intensive and Critical Care Medicine

Tuesday 15 March 2016 Day 1The official daily newsletter of the 36th ISICEM

Hemodynamic monitoring in 2025 . . . . . . . . . . . . . . 3

Paradigm shift for stem cells in sepsis . . . . . . . . . 8

Turning up the HEAT on fever control . . 12

Ushering in a new era of antibiotic stewardship . . . . . . . . 18

Welcome to Brussels…

2 ISICEM News Tuesday 15 March 2016 Issue 1

Controversies in CPR Jerry Nolan (Royal United Hospital, Bath, UK) will be presenting a number of controversies in CPR during his plenary lecture this afternoon, focussing on areas where insufficient or contradictory evidence is bring-ing about closer study. In an interview with ISICEM News, he introduced some of the most pressing issues, highlighting a number of ongoing trials that hope to settle them over the coming years.

Layperson compression-only CPR in out-of-hospital cardiac arrestBystander CPR remains a major deter-minant of survival in out-of-hospital cardiac arrest, and compression-only CPR may be the easiest technique for laypeople to willingly learn, retain, and apply effectively. “We want to get as many people trained and will-ing to do some form of CPR until the emergency medical services arrive,” said Professor Nolan.

“I think we’ve realized for some time that, although in an ideal world we would be able to train laypeo-ple to do chest compressions and mouth-to-mouth rescue breathing, for a variety of reasons mouth-to-mouth rescue breathing is more chal-lenging for them to do,” he added.

“And there are a whole load of very large observation studies – particu-larly from Japan, for example – that are suggesting that just doing chest compressions only, at least for the first 4 or 5 minutes, may be just as effective as standard CPR in termsv of outcomes – survival to hospital discharge.”1,2

While on the whole, evidence indicates that bystander compres-sion-only CPR is associated with increased survival rates compared to conventional CPR, there remains a great deal of variation dictated by the scenario at hand. For example, children and victims of drowning fare significantly better with the inclusion of mouth-to-mouth in the CPR protocol.

Despite this, a balance must still be struck between an ideal world – in which every layperson is trained and willing to perform standard CPR – and cold reality: “Of course there are a whole number of people that might not be willing to do it,” said Professor Nolan, “As well as those who don’t have the time to spend a few hours being taught standard CPR.

“Instead, they could become ca-pable of doing simple chest compres-sions almost by watching an online video and just being told what to do. By making it very simple, you can train a whole load of people who are then capable and willing to do it.”

Continuous chest compressions by emergency medical services (EMS)A recently published paper by Nichol et al.3 compared standard CPR with uninterrupted chest compressions in patients with out-of-hospital cardiac arrest, questioning whether the reduced blood flow from interruption of chest compressions in standard CPR is significant enough to impact survival – with the rationale that con-tinuous compressions are more effec-tive in producing a higher coronary

and cerebral perfusion pressure. The trial was randomized with

crossover, recruiting 114 EMS agen-cies, and including 12,653 adults with non-trauma-related cardiac arrest as-signed to continuous chest compres-sions (intervention group), and 11,058 to interrupted chest compressions (i.e. standard CPR; control group). Continuous compressions were given at a rate of 100 compressions per minute accompanied by asynchronous bag mask ventilation at a rate of 10 per minute (intervention group). Inter-rupted compressions consisted of 30 compressions followed by 2 breaths. Each was performed for three 2-min-ute cycles, between which patients were shocked if a shockable rhythm was present.

No statistically significant differ-ences were found in survival until discharge – the primary outcome – or survival with favourable neurologi-cal function at discharge. However, hospital-free survival was significantly shorter in the intervention group.3

“The slight difficulty I had with the study is that it is quite compli-cated,” commented Professor Nolan.

“In essence, they have shown that they can probably improve the chest compression fraction, which is the proportion of time that compressions are given in total. But really surprisingly, although the primary outcome was survival

to discharge, they actually showed no statistical difference between the two groups, and if anything there is a trend favouring the control group (the 30:2 group). That was based on the intention-to-treat analysis.

“The study was done with special defibrillators that would record all the chest compression data,” he continued. “And when they actually worked out those who were getting the 30:2 and those who got the continuous compressions, they found a stronger difference in favour of the control group which actually was significant. In summary, it certainly looks like continuous chest compres-sions was if anything harmful. So that supports the current guidelines which recommend a compression-ventilation ratio of 30:2 until an advanced airway is inserted.

“But I could go into various reasons why this difference occurred. The most obvious reason is that, if I just use a bag and a mask to try and ventilate a person’s lungs while continually compressing the chest, it is probably very difficult to ventilate the lungs at all. So my suggestion

Controversies in CPR Studio (Bozar) Tuesday 16:15

ISICEM NewsPublishing and ProductionMediFore Limited

Symposium ChairmanJean-Louis Vincent

Editor-in-ChiefPeter Stevenson

EditorsRysia BurmiczBecky McCall

DesignPeter Williams

Industry Liaison ManagerAmanda D’rojcas

Head Office51 Fox Hill London SE19 2XE Telephone: +44 (0) 7506 345 283 [email protected] www.medifore.co.uk

Copyright © 2016: Université Libre de Bruxelles. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, transmitted in any form or by any other means, electronic, mechanical, photocopying, recording or otherwise without prior permission in writing of ISICEM. The content of ISICEM News does not necessarily reflect the opinion of the ISICEM 2016 Symposium Chairman, the ISICEM Scientific Advisors or Collaborators.

“By making it very simple, you can train a whole load of people who are then capable and willing to do [CPR].”

Jerry Nolan

Issue 1 Tuesday 15 March 2016 ISICEM News 3

for why the outcome is worse in the intervention arm is because they are not being properly ventilated.”

Mechanical devicesRecent randomized trials have indicated that the use of mechanical chest compression devices does not bear any advantage over manual CPR despite their increasing use, explained Professor Nolan – although they still have a niche role under specific circumstances.

“There have been now several studies of the two main mechani-cal chest compression devices, the LUCAS-2 [Jolife AB / Physio-Control, Medtronic, USA] and the Autopulse [Zoll, UK],” he noted. “The rand-omized trials of those devices have failed to show any benefit overall in outcome in out-of-hospital car-diac arrest.4,5 There has also been a meta-analysis, which has shown no difference, with a very strong trend in favour of manual CPR.6”

The most recent study on the topic, published in Lancet in 2015, compared the LUCAS-2 device with manual CPR within a UK-based co-hort, cluster randomized by ambu-lance vehicle.7 “Overall 30-day survival was no different in the two arms of the trial,” said Professor Nolan, “But the highlight – which makes it slightly more controversial – was that in a (pre-planned) sub-analysis of those patients who had shockable rhythms, outcomes were statistically worse with the LUCAS-2 device.”

Given such findings, where does the home lie for mechanical chest compression systems? “There are specific indications for the devices,” stressed Professor Nolan. “They probably should not be used for all out-of-hospital cardiac arrests, but there is a role for them under certain circumstances – if for some reason a person is requiring prolonged CPR, for example, and specifically if there is a reversible problem which we think we can fix. Then, because CPR is very tiring, it makes sense to use a me-chanical device. Whenever a patient needs to be transported with ongoing CPR, they almost always should be using a mechanical device. The other very important area is as a bridge to enable the patient to get to a cardiac catheterisation lab.”

Adrenaline and airwaysAdrenaline, a mainstay resuscitation agent for decades, has always been assumed to be essential part of ad-vanced life support, explained Profes-sor Nolan. But recently several large observational studies have suggested that long-term outcomes in those who have received adrenaline appear to be worse than those who have not - although adrenaline is associated with more hearts being restarted.8,9 “We don’t know if adrenaline is beneficial in out-of-hospital cardiac arrest,” said Professor Nolan.

“There is now, finally, a very large ongoing placebo-controlled trial – again in the UK – the PARAMEDIC-2

trial (I am an investigator in that trial). It will recruit 8,000 patients, and hopefully will be finished towards the end of 2017.”10

In addition to his plenary lecture, Professor Nolan will be speaking more extensively on the topic of airway management in CPR on Friday after-noon in Copper Hall (14:00–14:15), and on the topic of adrenaline later on at 15:00 in Copper Hall.

Airway management during CPRvAlthough the traditional approach to airway management during out-of-hospital cardiac arrest has been tracheal intubation, a number of observational studies suggest that patients who have received tracheal intubation may fare worse than those who do not.

“This is again very complicated, because there are lots of confound-ers,” said Professor Nolan. “We really don’t know the best way of managing the airway. The alternative to tracheal intubation is either to just use a bag mask – a very basic airway manage-ment technique, or to use a supra-glottic airway. And it is complicated because in many cases all three of those devices could be used for a single patient as part of a step-wise approach to airway management.

“To try and address that, we have an ongoing randomized controlled trial in the UK, AIRWAYS-2. The interesting fact is that between the PARAMEDICS-2 and AIRWAYS-2 trials,

virtually every ambulance service in the UK is involved in one of those two studies. The AIRWAYS-2 study will also be completed in 2017.”11

Professor Nolan will present his plenary lecture on controversies in CPR this afternoon from 16:15 in the Studio (Bozar) .

References1. Iwami T et al. Chest compression-only cardio-

pulmonary resuscitation for out-of-hospital cardiac arrest with public-access defibrillation: a nationwide cohort study. Circulation. 2012 Dec 11;126(24):2844-51.

2. Iwami T et al. Dissemination of Chest Compression-Only Cardiopulmonary Resuscita-tion and Survival After Out-of-Hospital Cardiac Arrest. Circulation. 2015 Aug 4;132(5):415-22.

3. Nichol G. Trial of Continuous or Interrupted Chest Compressions during CPR. N Engl J Med. 2015 Dec 3;373(23):2203-14.

4. Rubertsson S et al. Mechanical chest com-pressions and simultaneous defibrillation vs conventional cardiopulmonary resuscitation in out-of-hospital cardiac arrest: the LINC rand-omized trial. JAMA. 2014 Jan 1;311(1):53-61.

5. Wik L et al. Manual versus integrated auto-matic load-distributing band CPR with equal survival after out of hospital cardiac arrest. The randomized CIRC trial. Resuscitation 2014;85:741–8.

6. Gates S et al. Mechanical chest compression for out-of-hospital cardiac arrest: System-atic review and meta-analysis. Resuscitation 2015;94:91–97.

7. Perkins GD et al. Mechanical versus manual chest compression for out-of-hospital cardi-ac arrest (PARAMEDIC): a pragmatic, cluster randomized controlled trial. Lancet. 2015 Mar 14;385(9972):947-55.

8. Patanwala AE, Slack MK, Martin JR, Basken RL, Nolan PE. Effect of epinephrine on survival after cardiac arrest: a systematic review and meta-analysis. Minerva Anestesiol 2013. 5. Lin

9. S, Callaway CW, Shah PS, et al. Adrenaline for out-of-hospital cardiac arrest resuscita-tion: A systematic review and meta-analysis of randomized controlled trials. Resuscitation 2014;85:732-40.

10. PARAMEDIC 2: The Adrenaline Trial. ISRCTN registry. http://www.controlled-trials.com/ISRCTN73485024 (retrieved March 2016)

11. Airway management in out of hospital cardiac arrest patients. ISRCTN registry. http://www.isrctn.com/ISRCTN08256118 (retrieved March 2016)

Controversies in CPR Studio (Bozar) Tuesday 16:15

Hemodynamic monitoring in 2025 HLB Tuesday 17:10

A plenary lecture that focuses on the tech-nological advances,

usage trends and healthcare priorities that we might expect in 2025 – particularly in terms of hemodynamic monitoring – will take place this afternoon at ISICEM.

Delivered by Maxime Cannesson, Professor of Anesthesiology and Vice Chair for Perioperative Medicine at the Depart-ment of Anesthesiol-ogy & Perioperative Medicine, University of California, Los Angeles,

USA, the lecture will serve as a comprehensive exploration of some of the important considerations and predictions going forward.

With that in mind, ISICEM News caught up with Professor Cannesson to ask him about some of the highlights we can

expect from him later today.

By way of introduction, what are some of the im-portant concepts here?I want to emphasize that healthcare is undergoing a tremendous revolution all around the world. Don

Berwick’s [Institute for Healthcare Improve-ment, USA] triple aim of medicine applies literally everywhere and any new develop-ment in technologies, drugs, or healthcare delivery systems will

have to fit this new paradigm. And this new paradigm is sim-ple: The triple aim of medicine is to lead to better patient outcome, better patient and provider satisfaction, and at a lower cost. Development of new technologies will have to be articulated around these three major aims.If we look at the past 20 years of development for hemody-namic monitoring, the main advances have been non-invasive monitoring, and more functional monitoring. In the past, technologies have been blamed for increasing the cost

of healthcare, so in the next 10 years, new technologies will have to bring value to pa-tient care, and the way value will be measured is going to be based on this triple aim.

On the other hand, a brand new field of healthcare technologies is exploding with a boom in consumer medical devices. This relatively new development is completely different from the old model. Regulation is different, pay-ment is different, customers are different, and the market is different. Whether we like

2025: A hemodynamic odyssey?

“In the next 10 years, new technologies will have to bring value to patient care.”

Maxime Cannesson Continued on page 4


it or not, these changes are going to be the drivers for how healthcare technologies and monitoring technologies are going to evolve during the next decade.

Looking at the overall picture, in 2025, is it reasonable to imagine that advancements in information technology will usher in a new era where, for example, we will see home-based, implantable monitors speak to the data ‘cloud’ for analysis, and where revolutionary, minia-turized tech – which is largely automated – be-comes a new standard?Yes, these are all great op-portunities and very exciting potential developments. How-ever, 2025 is tomorrow, and we have to be realistic in terms of expectations and not get too excited with buzz words and the whole revolution we see with information technol-ogy outside of medicine.

The main difference between healthcare and consumer medical device tech-nologies is that one is highly regulated, while the other is not. So the evolution in the regulated part of medicine (the one used by physicians to make medical decisions) will probably go slower than the part that is not regulated (the one used by consumers / patients to measure or track their own health). This will have tremendous implications on the whole medical moni-toring world. Basically, we will probably observe an “uberifi-cation” of medicine, and more specifically an “uberification” of medical technologies. This will impact patients, physi-cians, the healthcare systems, payers, and industry.

To give a brief overview and set the stage: Yesterday, monitoring (including hemo-dynamic monitoring), was developed by the healthcare industry, was highly regulated, and was used by healthcare providers to make medical

decisions. Outside of the tight regulatory agency pathways, monitoring devices used by consumers were basically lim-ited to weight scales and heart rate monitors for joggers and cyclists… Tomorrow, patients (or to be more specific in this context: consumers) will be able to monitor, track, and record a wide range of physi-

ological variables in their daily lives. We have already started to measure our heart rate on a daily basis using the camera of our cellphones. Soon, we will be able to measure and monitor cardiac output and other hemodynamic variables very easily.

This leads to two main observations: First, while in the past monitoring was limited to disease states, in the near future we will have monitor-ing information even during healthy states, outside of the hospital. Second, this constant biofeedback will probably lead us (patients, consumers of these monitoring devices) to modify our lifestyle and / or to seek medical expertise earlier. In the same way that measuring weight on a daily basis leads to changes in eat-ing habits and subsequent weight loss, measuring heart rate or arterial pressure every day might lead to more exer-cise and earlier detection of pathology for example. What this induces is that patients will have more control over their own health. Patients will also be the consumers of these monitors while in the past we (healthcare providers) were the consumers.

The questions that these new devices raise are then: Will clinicians be allowed to use these non-FDA regu-lated devices to make clinical

decisions for their patients, and who is going to regulate these devices and test their accuracy?

Implantable monitors and nanotechnologies for hemodynamic monitoring are probably not there yet, and the regulatory burden for this will be massive. Simple usually wins over complicated when it

comes to technology.

Getting into specifics, are improvements in sensors (e .g . micro- and nano-electro mechanical systems, biochemical updates, 3D-printed small-scale apparatus) important?They are important for

research. 3D printing is excit-ing to a lot of people today but one has to keep in mind that this approach still needs to be controlled by regulatory agencies in order to be used by physicians in the medical setting. In the US for example, even for research purposes, a device developed using 3D printing would probably need to be regulated by the FDA before its use for a clinical research protocol (Investi-gational Device Exemption).

And micro and nano-electro mechanical systems will probably have some impact at some point, but it may not be before 2025 for clinical use.

All in all, I want to stress something very important here: Before moving to these moonshot applications that might have a limited impact on our patients lives, what we need as clinicians, to take better care of our patients, are better devices. All of these ‘sexy’ but highly-regulated

technologies will be helpful if they are more accurate, easier to use, associated with less complications and lead to bet-ter outcomes than what we currently have.

But the current healthcare system is not looking for bet-ter looking devices and more expensive technologies. On the contrary, the triple aim of medicine today is better outcome, better patients

experience and lower cost. Technologies that fit into this paradigm will take the lead and be adopted.

What about improvements in regional perfusion and metabolic monitoring?These developments are important too. While regional perfusion and metabolic moni-toring are already here – and we can already monitor brain


2025: A hemodynamic odyssey?

“Simple usually wins over complicated when it comes to technology.”

Maxime Cannesson

“The triple aim of medicine today is better outcome, better patients experience and lower cost. Technologies that fits into this paradigm will take the lead and be adopted.”

Maxime Cannesson

Continued from page 3


oxygenation, kidney perfusion, or glucose – soon, prob-ably before 2025, we will be able to continuously monitor lactate, pH, and many other metabolic parameters.

With regards to home monitoring, what are your thoughts on how it can it be regulated, and how will the information be received and put into practice do you think? Would you agree it is one of the most important aspects to focus on moving forward?I personally think that home monitoring will be right at the intersection between the consumer medical devices field and the healthcare devices industry. It is a capital future aspect of monitoring and of medicine as a whole, and is crucial for many reasons.

It seems like in the future hospitals will be more chiefly dedicated to acute care, and to the sickest patients, in which case the concept of home care will increase dramatically. In the periopera-tive setting, for example, it is becoming clear that the dis-charge disposition of our pa-tients is a major driver of cost for the healthcare system. Ide-ally, we would like patients to be sent home after a surgery. In order to do that, we need to expand monitoring at home and develop ways to send this data back to a healthcare pro-vider. This monitoring does not need to be continuous, but we can imagine home moni-toring systems that would send alerts to a healthcare provider when a critical limit has been reached. This home monitoring could be based on consumer medical devices, but when a critical limit is reached a regulatory-approved device would be used to make a medical decision.

What about data integra-tion, including automatic calculation of multiple parameters, and predic-tive analysis (e .g . machine learning, predictive model-ling of adverse events)?

How have you seen ad-vancements in information technology take hold?Data is becoming more and more integrated. All of the data we are talking about will have to be integrated, and today the Electronic Medical Record (EMR) is becoming the core of all medical technolo-gies. It is likely that the role of the EMR is only going to increase in the next 10 years, and hemodynamic monitor-ing will have to be connected to EMRs in order to survive.

Then, the next step, which is already developed but not yet commercially available, is the creation of predic-tive algorithms and decision support systems with smart alarms. Some systems can al-ready predict sepsis up to 48 hours before it occurs. This approach relies on complex analyses of massive amounts of data (numerical and waveforms) which leads to the identification of patterns that are associated statistically with the occurrence of an event. This will impact monitoring dramatically.

Today, if we compare monitoring to weather as-sessment, monitoring would just be like opening the door of your house, looking at the sky, and then knowing if the weather is rainy, sunny or windy right then. But we usually like to know what the weather is going to be in the afternoon, tomorrow and over the weekend; we want to know what is the forecast, and monitoring is going there too. Today, it is nice to know what the arterial pressure, the cardiac output, and the heart rate is now. In 2025, monitors will be able to forecast what these parameters will be 10 to 30 minutes later. We would have the forecast and thus we would be able to be prepared, and intervene earlier.

I am personally very excited by predictive algorithms. We will see more and more of these technologies in the very near future. Real time risk prediction of complications, diseases and hypotension are

all coming to the bedside, and should be here soon.

Are there other devices / technologies in the pipeline that you know of that are particularly intriguing?I am also very excited by the development of closed-loop or automated systems. The beau-ty of these systems is that they allow communication between the monitors and the drug

infusion devices. How come, in the environment we are living in, monitors do not com-municate with pumps? This, over the years, has probably been responsible for dozens and dozens of accidents and deaths. When respiratory rate decreases in a patient who is receiving intravenous opioids, how come the respiratory rate monitor does not send a signal that would automatically stop the opioid infusion? Dozens of patients have been hurt because such systems do not exist and because devices do not communicate, and are not interoperable

We should not be afraid of automation. Automation will not replace us, that’s not its goal. It will serve us in order to better take care of our patients. It will allow us to deliver therapies such as goaldirected therapy consist-ently. It will help us maintain blood pressure within tight ranges, and above critical values – in a consistent way – and it will increase safety and improve quality of care. But it will never replace us because we will remain the experts and we will define the strategy.

I am also intrigued about the development of more accurate hemodynamic moni-

toring systems. It is notorious that cardiac output monitoring systems lack accuracy. When these classic technologies get challenged by consumer medical devices that measure cardiac output in a way that’s cheaper and not much worse than what they do now, the industry will be forced to really improve their device accuracy to remain competitive. Again this is the “uberification” of

medicine. For the regulated in-dustry, the only way to survive will probably be to up their game to a very high standard, to remain competitive. That’s exactly what we want for our patients.

What’s your take-home message for the ISICEM audience?In 2011, I was invited at ISICEM to give a talk on the future of technologies in the critical care and perioperative settings, and in 2014 I gave a talk here in Brussels on Big Data. Looking back, it is interesting to see that some of what we discussed then is

now very close to become a reality. We start to understand what big data brings to the development of technologies and to the understanding of our patients’ health and disease states.

We are moving toward the concept of closed loop drug administration quicker than expected and by 2025 these systems will be a no-brainer. Hemodynamic monitoring will of course be part of these evolutions. It is going to move outside of the hospital through the consumer medi-cal devices industry and in the hospital it will become more accurate, more metabolic, and more integrated with the rest of the technological ecosystem.

Finally, some of these tech-nologies already exist and are in use in certain places, while elsewhere it will take much longer for these technologies to be adopted. But the laws and finance models regulating healthcare systems will drive adoption and development of these technologies (as long as they bring value).

Some systems are very conservative, and some key opinion leaders are very conservative – evidencebased medicine can be a major limitation to the widespread implementation of innovation. And at the end of the day, to quote William Gibson: ‘The future is already here – it is just not evenly distributed.’


“We should not be afraid of automation. Automation will not replace us, that’s not its goal. It will serve us in order to better take care of our patients.”

Maxime Cannesson

ISSUE 2Availabletomorrow


I n cardiovascular disease, more work is needed to improve understanding of both normal

physiology and pathophysiology as well as diagnostic and therapeutic ac-curacy. With this in mind, recent use of simulation models in extracorpor-eal membrane oxygenation (ECMO) in particular has helped with clinical training. One example is the new Aplysia CardioVascular Lab (Aplysia Medical AB, Sweden) interactive computer simulation model,(1) which is showing great promise as a sup-port tool in making patient specific-decisions, demonstrating real-time decision-making and incredible accuracy.

ISICEM News was fortunate to catch up with Dirk Donker (University Medical Center Utrecht, the Nether-lands) who will be heading up today’s workshop ‘Clinical Decision Support to optimize ECLS/ ECMO’. Dr Donker and his colleague Michael Broomé (ECMO Department, Karolinska University Hospital, Stockholm, Swe-den) are both experienced intensive care clinicians with a keen interest in ECMO support, especially the Aplysia CardioVascular Lab system. Dr Donker began: “Michael is the key developer of this system – he has developed a fantastic model – a computer simulation which actually simulates a patient with all aspects of the CV system.”

Dr Broomé then explained the philosophical background to the development of this system: “In the last few decades there has been a huge emphasis on randomized controlled trials and evidence-based medicine, and rightly so. However, in intensive care units, this approach is not good enough for handling individual patients, where we have so many variations and so many add-on problems. Now there is a trend for in-dividualized treatments, and this tool is a perfect example of individualizing treatment, while still using intellectu-ally- and scientifically-driven sound methods.”

Describing his involvement in the ECMO computer simulation project, Dr Broomé continued: ‘I had been working for 10 years as an anesthe-tist, and then 10 years as an intensiv-ist in adult cardiac surgery and now in a dedicated ECMO unit where we do neonatal, pediatric and adult ECMO treatment.

“All of this clinical experience has led to an interest in hemodynamic

and cardiovascular func-tion, so in parallel with my clinical work – and initially as a hobby – I began de-veloping this computer simulation model and doing some programming.

“About five years ago I was recruited by the engineering depart-ment at the KTH School of Technol-ogy, Stockholm to work part-time in validating and developing this into a more scientific project. I got in contact with Dirk Donker for more clinical reasons after he visited our unit. Our goal with the com-puter simulation model is first as a high-level educational tool where we can have fruitful sessions with intensivists, cardiologists and cardiac surgeons.”

He added: “Our second goal is to develop it as a clinical decision sup-port tool, where you can enter data from an individual patient to predict or get clues about what treatments are appropriate. We hope to achieve this with further validation.”

Dr Broomé was keen to empha-

size that the uses of this model are much broader than ECMO and life support, saying: “It can also be used in congenital heart disease and with left ventricular assist devices and other types of cardiac problems. Basic oxygenation properties can be mod-eled, as well as circulatory aspects and the ECMO physiology(2, 3).”

The workshop will be set-up as an interactive ‘meet-the-experts’ course, emphasizing comprehensive learning and optimizing medical and interventional therapies on the basis of individual patients. Focusing on the understanding of complex hemo-dynamics and circulatory demands in ICU patients, it will also demonstrate optimization of myocardial oxygen balance in left and/or right heart failure, coronary artery and valvular disease, and patient-specific tailoring of short- and long-term mechanical support devices.

Dr Donker spoke about what he

hopes to achieve through the work-shop: “I will outline the basic nature of the model’s components. We have adapted this to also show left ven-tricular unloading during ECMO and I will use a few general clinical cases of severe heart failure.

“The audience will recognize these as familiar cases: severe heart failure, with severe and refractory cardiogenic shock, as is commonly seen in clinical practice (about 10% of patients with an acute myocardial infarction). This situation is quite difficult to handle and it should be dealt with quickly. We need a way to choose the appropriate way to sup-port such a patient.

“I will show different therapeutic options and strategies: firstly the straightforward conservative, medical treatment; secondly the different interventions that can be offered, providing relevant literature that supports/discourages the choices that they might make.”

The intention is that Dr Donker’s interactive workshop will encourage discussion and audience engagement by asking delegates what they would propose, and then he will simulate this decision using the model.

He commented: “The great advantage of this system is that it runs on an ordinary laptop, and it is real-time, so you can instantaneously see what

happens. This is striking to the audience; this fits into the ultimate goal of using it for clinical decision-making.”

Dr Broomé then pointed out, “it is very useful to have the com-puter simulation in real-time, as it is much easier to understand what’s going on, and you don’t have to understand what the model is doing underneath. What you see are the parameters and variables that you are familiar with, so clinicians can rapidly grasp what’s going on. You can also change one parameter at a time, allowing a question to be dissected in a much clearer way than when you are looking at a patient.”

Highlighting another unique aspect of this collaboration, Dr Donker said: “While most models are designed by physicists and engineers, this is modeled by clinicians, for clinicians. We have the feedback and

Clinical Decision Support to optimize ECLS/ ECMO – Interactive computer simulation Tuesday 100 Hall 17:20

Workshop will exhibit computer simulation of clinical decision-making in ECMO

“The great advantage of this system is that it runs on an ordinary laptop, and it is real-time, so you can instantaneously see what happens. This is striking to the audience; this fits into the ultimate goal of using it for clinical decision-making.”

Dirk Donker


intuition from our experience and this is a huge advantage. We speak the same language as the users.”

Looking to the future, Dr Donker then described some validation experiments, noting: “Recently we started this validation and we came across a group in the Czech Republic who had experimental animal data.(4) We simulated their experiments and got the same results. I then had a case in the ECMO unit, which we simulated and again predicted the same outcomes.(5)

“For those who would like to see it in action, we have downloadable links [via the website,[6]]to demon-strate the Aplysia CardioVascular Lab software application in systolic left heart failure and mitral regurgitation, and volume loading, increase in HR, IABP, Impella, ECMO and LVAD, [as well as] a short sequence illustrating

neonatal normal physiology.”Dr Broomé concluded saying:

“We are very enthusiastic. Of course, we cannot claim now that it can be used for patient-specific decisions until we do a huge load of valida-tion, but while the official version is that it is a teaching session, clinical decision support is, of course, our future goal.”References

1. Broome M, Maksuti E, Bjallmark A, Frenckner B, Janerot-Sjoberg B. Closed-loop real-time simulation model of hemodynamics and oxy-gen transport in the cardiovascular system. Biomedical engineering online. 2013;12:69. Epub 2013/07/12.

2. Broman M, Frenckner B, Bjallmark A, Broome M. Recirculation during veno-venous extra-corporeal membrane oxygenation--a simulation study. The International journal of artificial organs. 2015;38(1):23-30. Epub 2015/01/16.

3. Lindfors M, Frenckner B, Sartipy U, Bjällmark A, Broomé M. Venous cannula positioning in arterial deoxygenation during veno-arterial extra-corporeal membrane oxygenation – a simulation study and case report. Artificial Organs 2016;In Press.

4. Ostadal P, Mlcek M, Kruger A, Hala P, Lacko S, Mates M, et al. Increasing venoarterial extracorporeal membrane oxygenation flow negatively affects left ventricular perfor-mance in a porcine model of cardiogenic shock. Journal of translational medicine. 2015;13:266. Epub 2015/08/16.

5. Broome M, Donker DW. Individualized real-time clinical decision support to monitor cardiac loading during venoarterial ECMO. Journal of translational medicine. 2016;14(1):4. Epub 2016/01/08.

6. http://www.aplysia.se

Clinical Decision Support to optimize ECLS/ ECMO – Interactive computer simulation Tuesday 100 Hall 17:20

Workshop will exhibit computer simulation of clinical decision-making in ECMO

“Now there is a trend for individualized treatments, and this tool is a perfect example of individualizing treatment, while still using intellectually- and scientifically-driven sound methods.”

Michael Broomé


S eptic shock is a devastating condition, with massive burden

for intensive care units, and astronomical mortality rates.1 As such, it follows that the quest for novel therapies that can revolutionize treatment are very much at the forefront of researcher’s minds.

One potential avenue of therapeutic advancement is the use of stem cells – a prom-ising and burgeoning area of research that has led to a number of trials assessing their safety and efficacy.1,2

Speaking to ISICEM News, Claudia dos Santos (St Michael’s Hospital, Toronto, Canada) – an experienced stem-cell investigator – shared her perspectives on the potential of the therapy in sepsis, first by framing the illness itself, especially in terms of study data. “Most trials in sepsis have failed,” she said. “There are a variety of possible explanations for that: there are many seminal papers that have been written trying to understand why we have failed in identifying a therapeutic strategy that could be beneficial in sepsis.”

She continued, noting that from both clinical and basic science perspectives, there are things we could have done better: “From my perspective, the really difficult part about managing sepsis is trying to understand what is the patho-physiology, and I think that the literature now has moved to a general understanding of what we call ‘sepsis’ – this grab-bag syndrome in which we put a lot of things. But it is quite a complex syndrome, and perhaps the definition of sepsis needs to be redefined, both from a preclinical and clinical trial perspective.”

For Professor dos Santos, part of the problem is that the pathophysiology of sepsis is involved both in the activa-tion of the immune system, and down-regulation of the immune system (i.e. immune suppression). “For the most part, therapeutic strategies have focused on the over-acti-

vation of the innate immune system,” she said, adding that endothelial dysfunction and the loss of compartmentalized immune responses have now emerged as perhaps “the real pathophysiology.”

She continued, comment-ing on the new definition of sepsis: “Now microcirculatory failure with endothelial dys-function is the real underlying pathophysiology. Number two, the relevance and the importance of the anti-inflammatory cascade, and potentially the immune suppres-sion which happens in the context of sepsis, will become much more appar-ent.”

Getting to the core of her presentation on stem cells at ISICEM, she began by relay-ing why stem cells may offer a paradigm shift – a really “transformative and disrup-tive” one, as she puts it – in the way we think about sepsis. “Stem cells do not treat a single mediator. They are not targeted against one particular molecular target, or one par-ticular pathology, for example.

“They are anti-inflammato-ry, as well as anti-bacterial.”

She continued, stress-ing more of their distinctive attributes: “Contrary to a lot of our treatment strategies, they have this unique ability to reprogramme: they both downregulate something, and upregulate other things. So it is a real reprogram-ming of the innate immune response, by not having either a suppressive role, or an activating role. I.e. they can both decrease the effect of SIRS, the systemic inflam-matory response, that seems to be detrimental when dysregulated, and they can also increase the ability of cells to get rid of pathogens.3

“Also, not only do they change the immune reaction by decreasing the pro-inflammatory response – they

seem to be able to promote repair [including restoration of endothelial function4. So they work through a variety of different pathways by capital-izing on those cell-cell contact mediated mechanisms, as well as contact-independent mechanisms. They can also send out signals from them-selves – so for example a stem cell can send out micropar-ticles or extracellular vesicles that contain both cellular and genetic information within them, such as micro RNAs or MRNAs that can order another cell what to do. They seem to be able to also generate a mi-croenvironment around them

that promotes the activity of endogenous progenitor cells, to sort of take over the role of repair. They can actually stimu-late progenitor cells within the injured tissue to activate their

own endogenous defense mechanism.”

With this in mind, Pro-fessor dos Santos spoke of how we might soon be able to actually prepare the cells to respond in a

way that we want for specific diseases, such as sepsis, ARDS or arthritis.

Another important aspect of stem cells is that they ap-pear to be immuno-privileged, i.e. they do not elicit an immune response, which Professor dos Santos empha-sized was quite the opposite of most other cell therapies we are familiar with, such as blood transfusions. What’s more, when injected into an organism, the stem cells seem to head to the site of injury – a fascinating trait that, frankly, still baffles reasoning. “Nobody really knows exactly how they do that,” said Pro-

fessor dos Santos, adding: “By honing to sites of injury, [stem cells] therefore make it pos-sible for you to actually deliver a therapy which is knowledge-able enough itself to go where

it is most needed.“And the dynamics of this

is that the cells change their behavior according to the inflammatory milieu in which they are deposited. It appears to be a ‘smart therapy’; the cells seem to know what needs to be done to re-estab-lish balance.”

Leading work in this field includes the CISS (Cellular Immunotherapy for Septic Shock) trial,1 led by principle investigator Lauralyn McIntyre (Ottawa Hospital Research Institute, Canada). “This is very similar to the START trial2 in the US,” said Professor dos Santos. “They are both dose escalation trials that have been, in my opinion, well defined.”

The CISS trial is the first in-human trial of stem cells in septic shock, with two main goals: assessment of safety and patient-tolerability of the cells, and establishment of the best dose of cells to give. “The CISS trial has performed a first phase, which essentially is an observational phase, documenting what patients are going to look like if they do not get the cells.

With an enrolment of nine patients, the dose escalation begins with randomization of the first three patients to receive 0.3-million cells per kg via a single injected dose. “The patients will be observed by the clinician for the first six hours of the cell infusion, and then [followed-up] for the next week. If they are okay, with absolutely no side effects … then the next three patients receive 1-million cells per kg,” said Professor dos Santos. Similarly, a dose of 3-mil-lion cells per kg will be used for the final three patients if there are no side effects at the 1-million cells per kg dose.

“If at any point they observe any side effects (those deemed as an established, important event) then that is classed as a maximum toler-able dose to aim under.”

Comparing CISS to the START trial, Professor dos Santos noted that one key

New therapies in the pipeline Tent Tuesday 15:15

Stem cells could offer paradigm shift in sepsis

“By honing to sites of injury, [stem cells] therefore make it possible for you to actually deliver a therapy which is knowledgeable enough itself to go where it is most needed.”

Claudia dos Santos

“This is potentially one of the biggest things that has happened since the advent of the mechanical ventilator.”

Claudia dos Santos


New therapies in the pipeline Tent Tuesday 15:15

difference is that while START utilized frozen, amplified stem-cell stock, the CISS trial used fresh cultures.

Given this promising outlook, Professor dos Santos took a moment to comment on the potential challenges, concerns, and complications that may still need due focus.

“There are a lot of discus-sions at different levels regard-ing the important aspects of instituting stem cells as a therapy – i.e. going from the experimental phase, to actu-ally becoming a therapeutic choice,” she said. “One of the important [considerations] in-cludes how to obtain enough cells – i.e. the expansion of cells – as well as the variability between batches (we don’t know if that is going to be a problem.”

In addition, there are other aspects to consider including how to measure the potency

of cells, and making sure they have actually worked after delivery. “There are, for the time being, no biomarkers of biological activity, and that has obviously been a limitation. Nobody wants to wait for the 28-day mortality outcome to figure that out.

“There are also other im-portant features, for example will we be able to inject them twice? For the time being, most studies are only looking at a single administration of cells. We don’t know – al-though we do [think] they are

immuno-privileged.”Finally, while tumorigenesis

may be a note of concern for some, Professor dos Santos reasoned that because stem cell therapies have been used in other areas of medicine for much longer, one would hope that this would be a non-issue. “There doesn’t seem to be con-vincing evidence of increased tumorigenicity,” she said.

In her closing remarks, Professor dos Santos com-mented on the prospect of stem cell therapy finding its way into the armamentarium

for sepsis, and other critical care disorders, first turning to the role of the funding agencies, and the regulatory bodies. “They are going to be working with us all over the world to try and come up with appropriate protocols and assessments – i.e. how are we going to keep this all safe?” she said.

Taken as a whole, Professor dos Santos stressed that stem cells could be absolutely para-digm shifting: “I don’t think we have every had the oppor-tunity to have such a powerful tool in our hands,” she said, moving on to comment on how important collaboration between trial leaders will be: “Certain questions that may not be addressed in one trial are then addressed in the next trial. We need to work together, not in a competitive way, but in a collaborative way to make sure that therapy

comes to fruition.“The field is moving very

quickly, and it is a great oppor-tunity for immense collabora-tion and immense advance-ment. If we work smart, and we help each other out.”

She concluded: “This is potentially one of the biggest things that has happened since the advent of the me-chanical ventilator.”References1. ClinicalTrials.gov. Cellular Immuno-

therapy for Septic Shock: A Phase I Trial (CISS) (https://clinicaltrials.gov/ct2/show/NCT02421484)

2. Wilson JG et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med. 2015;3(1):24-32

3. Mei SH, et al. Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Ameri-can journal of respiratory and critical care medicine. 2010;182:1047-57

4. Lee JW, et al. Allogeneic human mesenchymal stem cells for treat-ment of e. Coli endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proceedings of the National Academy of Sciences of the United States of America. 2009;106:16357-62

“There are a lot of discussions at different levels regarding the important aspects of instituting stem cells as a therapy – i.e. going from the experimental phase, to actually becoming a therapeutic choice.”

Claudia dos Santos


I n one of this afternoon’s es-teemed plenary lectures, Miguel Sánchez García (Hospital Clínico

San Carlos, Madrid, Spain), a mem-ber of the Spanish Scientific Expert Committee for the ‘Zero Resistance’ project, will discuss the project, and aims to minimize ICU-acquired infec-tions through a number of preventa-tive and management measures.

Zero Resistance was finalized in December 2015, and consists of an evidence-based bundle of recommended practices, which are coordinated at the national, regional and local level. Its aim is to reduce the cumulative incidence of patients with ICU-acquired multidrug-resistant (MDR) infections by 20%, while building an epidemiological understanding of MDR infections in Spanish ICUs.1

The predecessors of Zero Resist-ance, ‘Zero Bacteremia’ and ‘Zero VAP’ were led by the Spanish Soci-ety of Intensive Care Medicine and Coronary Care Units (SEMICYUC) and the Spanish Society of Intensive Care Nursing (SEEIUC), and worked towards the prevention of catheter-related bloodstream infection and ventilator-associated pneumonia.

These measures were undertaken by numerous Spanish ICUs successfully – and are now being implemented across the country.

Dr Sánchez García will be speaking about the global common structure and organization of Zero Resistance during his lecture, as well as its methods and results. “Now is the time to think about how to conserve the achieved goals,” he told ISICEM News. “And, secondly, to try to approach the important gap that still exists between empiric antimi-crobial therapy and documented infection.”

The aim of the Zero Resistance bundle is to deal with the three central causal factors in the MDR crisis: namely, the prescription of antibiotics, the early detection and prevention of cross-colonization of MDR, and the elimination of MDR microorganism reservoirs (where they may colonize, without causing infec-tion). The recently-published meth-odological details of Zero Resistance include a set of 10 recommendations that realize these aims. To facilitate the implementations of these recommendations, a patient safety program and educational

modules are included. In addition, adherence to the project and its results will be evaluation through a number of indicators.1

Asked how important it is for similar approaches to be implement-ed further afield, Dr Sánchez García replied: “The methods and measures have been published for everyone to adopt as is, or in modified versions.

“The two most important aspects contributing to its success in my opinion, and which are shared by other national projects, are the impli-cation of healthcare authorities and the identification of healthcare work-ers with the goals of the projects.”

Indeed, perhaps one of the greatest obstacles in overcoming MDR is a cultural one – attitudes towards antibiotic use from the general public to the healthcare profession, vary greatly across the world. “We are unfortunately still far from reaching significant goals in that area,” noted Dr Sánchez García. “There are certain ICUs that have made progress, but reductions in antibiotic use, also evidenced in

the Spanish Projects, are marginal.”What, therefore, is the role of

general public education, as well as the education of healthcare profes-sionals in regions where antibiotics are too readily available? Outlining the principles of the surveillance and the prevention of disseminat-ing MDR strains, Dr Sánchez García responded: “Education of the public can be relevant in primary care if the demand for antibiotics can be re-duced. Very important would also be if prudent use of antibiotics is taught in medical school.

“A baseline situation is differ-ent from an outbreak, where many more resources are needed. The prevention of the development of resistance should rest on a list or bundle of measures, including: learning to distinguish infection from non-infectious inflammation; distinguishing situations that require immediate [measures] from those in which delayed therapy waiting for microbiological results is warranted; the use of check-lists of risk factors for resistance and rapid bedside tests;

shortening antibiotic courses; de-escalation, etc.”

The feasibility of rolling such measures out to different hospitals must of course take into account differences in individual hospitals’ strengths and resourc-es, as well as regional economic disparities that are yet more pro-nounced on the European-wide

or world-wide stage. “The implemen-tation of preventive measures requires implication of healthcare authorities,” said Dr Sánchez García. “Even our Zero Project, only concerning ICUs (which are usually less than 10% of hospital beds), needed this.

“But healthcare systems differ between countries. Some have fewer resources for infection control, which implies that the baseline character-istics of the resistance problem are more difficult to tackle.”

Dr Sánchez García speaks more exten-sively on the structure, implementa-tion and results of the Zero Resistance project during this afternoon’s plenary lecture, ‘No bacteremia, no VAP, no re-sistance,’ taking place in HLB at 17:35 .

References

1. Garnacho Montero J et al. Combatting resist-ance in intensive care: the multimodal ap-proach of the Spanish ICU “Zero Resistance” program. Crit Care. 2015 Mar 16;19:114.

No bacteremia, no VAP, no resistance HLB Tuesday 17:35

Plenary lecture delivers update on Spanish Zero Resistance project

“The implementation of preventive measures requires implication of healthcare authorities.”

Miguel Sánchez García


email: [email protected] or call +44 (0) 7506 345 283

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C oncluding this morning’s session on the topic of fever control, Paul Young (Wel-

lington Regional Hospital, Welling-ton, New Zealand) reveals some new, as-yet unpublished analysis from the HEAT study1, which looks in more de-tail at the physiological effects of par-acetamol. He also explores in greater detail the relationship between the physiological effects of paracetamol and the differential effects on ICU length of stay, in patients that went either died or went on to recover from infection.2

In an interview with ISICEM News, Dr Young discussed the rationale and findings of the HEAT study, as well as its implications both for clinical practice and for future study.

“It has been really interesting see-ing the response to the HEAT study,” he said. “Some people have taken the view that there is a really strong rationale for not giving paracetamol, because there is no benefit. Other people have taken the rationale that it is reassuring that giving paraceta-mol to treat fever is not harmful. I think both of those perspectives are okay.”

The driver behind the HEAT study was to explore the hypothesis that the administration of paracetamol to treat fever in ICU patients with expected

infection would be harmful. The study did not demonstrate that to be true, said Dr Young, noting that despite this there were lessons to be learned: “I think overall, it turned out to be a re-ally useful study not so much in terms of changing practice, but informing people about what their practice might actually be doing to patients.”

A number of questions follow on logically from the HEAT study, Dr Young explained. One of its second-ary findings was that patients al-located to paracetamol who survived remained in the ICU for shorter peri-ods; and among patients who were allocated to paracetamol and died

had longer ICU stays. This suggests that, although it did not appear to influence mortality, paracetamol can potentially speed up recovery and delay death when treating

for fever.“One thing to point out is that

it is directly opposed to the original study hypothesis,” said Dr Young. “So it is entirely possible that this dif-ferential association with ICU length of stay that we observed was just a statistical anomaly.

“But on the other hand, par-acetamol looked like it was really well tolerated, and it is a really cheap medication. If this actually does truly represent a biological effect, there seems to be a potential new hypoth-esis. That hypothesis is that if you are critically ill and you are being sup-ported right at the limits of extended

physiological homeostasis (which you get from intensive care-level support), then maybe treating fever actually allows you to stay alive so that you can get better.”

Overall, the HEAT study included a very low illness acuity population overall. Hence, one of the questions it throws up is whether the admin-istration of prolonged paracetamol for sicker patients could enhance recovery and, hence, reduce mortality rather than simply delaying death.

“We are exploring that through a series of ongoing studies,” said Dr Young. “The first thing we are doing is a study I will present the details of during the session, where we look at giving strict, regular intravenous paracetamol to a really sick cohort of patients and compare that to a standard-of-care approach where we just give it as needed. And that is ex-ploring the fact that paracetamol has a whole range of effects beyond just

its effect on body temperature. So maybe it is those additional effects that are important to the differential association with lengths of stay that we observed.

“So this new study will do two things: it will replicate the first study, in the sense that we will see whether that differential association is reproduced; and it will tell us about the feasibility of doing a much larger Phase III study in a really sick popula-tion of patients.”

An alternative line of thought on the HEAT findings is that temperature control, rather than paracetamol per se, is conferring the effects found. And the three most high-quality stud-ies in the literature seem to support this notion.2-4

“So we, the investigators on those three studies, are working together to first of all do a literature review and meta-analysis of studies looking at temperature control strategies. Subsequently, we are going to do an individual patient data meta-analysis, where we select out the group of pa-tients at baseline who have really high illness acuity, to see whether there is a signal of benefit of temperature control in the patients who are the sickest. Maybe, then, in two or three years’ time we will be in a position to decide whether or not this is some-thing that needs to be investigated further in a big Phase III study.”

Dr Young presents ‘Can paracetamol save lives?’ during the ‘Fever control’ session, taking place this morning in HLB from 11:00 .

References1. Permissive HyperthErmiA Through Avoidance

of Paracetamol in Known or Suspected Infection in the Intensive Care Unit (ICU). Australian New Zealand Clinical Trials Registry www.anzctr.org.au. ACTRN12612000513819 (retrieved March 2016)

2. Young P et al. Acetaminophen for Fever in Critically Ill Patients with Suspected Infection.N Engl J Med 2015; 373:2215-2224

3. Schortgen F et al. Fever control using external cooling in septic shock: a randomized con-trolled trial. Am J Respir Crit Care Med. 2012 May 15;185(10):1088-95.

4. Bernard GR et al. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med. 1997 Mar 27;336(13):912-8.

Fever control HLB Tuesday 11:00

New HEAT data unveiled this morning

“It has been really interesting seeing the response to the HEAT study.”

Paul Young

“We, the investigators on those three studies, are working together to first of all do a literature review and meta-analysis of studies looking at temperature control strategies.”

Paul Young



Should we modify temperature in patients with severe infections?

T he ‘how and when’ of fever control will be discussed this morning at ISICEM 2016, with a look at severe infection as well as neuro-

logical patients. Manoj Saxena (St. George Hospital at University of New South Wales, Sydney, Australia) joins others in the session to discuss the evidence surrounding the benefit of temperature reduction, his talk focusing particularly on severe infection.

Speaking to ISICEM News, he suggested that while fever is part of the normal inflammatory response to an infection, reducing fever may in fact be helpful in the specific situation of fever in critically ill patients.

“It is, generally, reasonably well appreciated that the response to infection including mounting a fever might benefit the host and particularly the immune response, whilst impeding the invading infection,” he began. “What contrasts with this and what makes it tricky for people is that a lot of people are parents too and they have observed what happens when they give their child – who is hot and feels awful during an infective illness – a dose of paracetamol.”

The often profound change in demeanor and comfort that accompanies paracetamol administra-tion represents a powerful subconscious influence, explained Dr Saxena. The wide availability of cheap

paracetamol, as well as its perceived safety profile have also helped to cement its place in everyday clinical care.

Although clearly, the issue is complex: factors pertinent to the issue of fever control include the extremity of the fever, as well as the nature of the infection, the state of the patient (in terms of immune function, for example), and the proposed method of temperature control.

“There is a tension between two things here,”

noted Dr Saxena. “On the one hand, the natural way that our body repairs injured or infected tissue is to inflame the infected area. As a result, cells are attracted, blood flow is increased, and temperature

“On the one hand, the natural way that our body repairs injured or infected tissue is to inflame the infected area.”

Manoj Saxena

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Masimo Root Wins the GOLD 2015 Medical Design Excellence Award

Continued on page 14


is increased in the region that is affected. That is something that has evolved over millions of years across different species, and it is quite a strong response to injury and infection. The response may provide optimal conditions for repair and recovery.

“In contrast, it might be possible to modify that re-sponse using either drugs or physical cooling to improve the way that the body heals. Particularly strong here is that there are data in animal and observational studies that suggest that the brain might heal better with fever removed from the equation. But the majority of work done for the brain is quite preliminary and experimental rather than reliable and translatable into clinical practice.”

Also, as Dr Saxena was keen to point out, the questions and objectives surrounding temperature control in brain injury and in infection are two sepa-rate subjects. Indeed, while he focusses on fever in infection during this morning’s session, Dr Raimund Helbok will cover fever control in brain injury in the same session. In addition, Dr Saxena will be speaking on target temperature management in traumatic brain injury during Thursday afternoon’s session in Copper Hall (13:45–16:45).

In investigating the role of fever in infection, Dr Saxena and colleagues started out with the hypoth-esis that fever was protective and beneficial. But an

accumulating body of evidence, from high-quality investigations of paracetamol, non-steroidal drugs and physical cooling, has suggested an opposing hypothesis; namely, that in critically ill patients, who in general have exaggerated metabolic responses to

stress because of the severity of their illness, reducing the burden of fever might be of benefit. “That is interest-ing for us as researchers to watch that narrative shift,” said Dr Saxena. “We need to do more to explore that preliminary signal.”

He added that the best evidence that supports this suggestion comes from three clinical trials. The first,

by Frederique Schortgen and colleagues at Henri Mondor Hospital, Créteil, France asked whether fever control by external cooling diminishes vaso-pressor requirements in septic shock. This study re-ported that external cooling decreased vasopressor requirements and early mortality in septic shock.1 “These are surrogate outcomes,” commented Dr Saxena, “And, in my opinion, need further explora-tion in larger clinical trials.”

The second study was done by Gordon Ber-nard (Vanderbilt University Medical Center, TN, USA) and colleagues, and looked at the effects of ibuprofen versus placebo on the physiology and survival of patients with sepsis.2 “This was not strictly a fever control trial, but a lot of the patients were febrile when they were adminis-

tered the study drug. Again, the mortality signal (which doesn’t quite reach statistical significance) seems to suggest benefit with fever control for ibuprofen. Also there was an associated reduction in heart rate and temperature that occurs with the ibuprofen.”

Turning to the findings from the HEAT study3, Dr Saxena said: “In HEAT, it is the survivor and non-survivor subgroup that seems to suggest giving paracetamol might be doing something beneficial. Survivors get out of ICU quicker than we expect, and non-survivors seem to survive a bit longer with paracetamol. Again, you have to be very cautious interpreting subgroups.

“Taken together, the three trials could sug-gest that fever control is reducing metabolic rate, and that maybe there is a beneficial signal with a reduction in vasopressor dose and early mortality. It is intriguing that all three trials, all trying to control fever by three different means, suggest benefit with fever control. We didn’t really anticipate that to be a possibility when we started HEAT.”

Dr Saxena presents ‘Should we modify temperature in patients with severe infections?’ during this morn-ing’s ‘Fever control’ session, taking place in the HLB auditorium at 11:00 .

References1. Schortgen F et al. Fever control using external cooling in septic

shock: a randomized controlled trial. Am J Respir Crit Care Med. 2012 May 15;185(10):1088-95.

2. Bernard GR et al. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med. 1997 Mar 27;336(13):912-8.

3. Young P et al. Acetaminophen for Fever in Critically Ill Patients with Suspected Infection.N Engl J Med 2015; 373:2215-2224


Should we modify temperature in patients with severe infections?

“In contrast, it might be possible to modify that response using either drugs or physical cooling to improve the way that the body heals.”

Manoj Saxena

Highlights from this year’s ISICEM pre-courses...

Continued from page 13


T he primary goal of nutritional support in critically ill patients is to alter the course of the ill-

ness. However, due to the lack of ad-equate randomized controlled trials, the nutritional needs of the critically ill are still poorly understood. Studies have shown that maintaining lean mass is very important in critically ill patients, and the loss of lean mass is related to worsened outcome, particularly in those who have suffered multiple traumas.1 One promising goal of nutritional support involves supplemented protein to mitigate the detrimental breakdown of muscle proteins into amino acids.

To address these issues, Peter Weijs (Amsterdam University of Applied Sciences, the Netherlands) will present on the protein needs of critically ill patients during today’s program. Dr Weijs is involved in nutri-tional research concerning intensive care, obesity, diabetes, and nutrition-al assessment, ultimately focusing on optimizing nutritional treatment.

“In order to avoid massive loss of lean body mass, one thing we can do is provide at least enough protein; glucose is generated and fatty acids are derived from intrinsic stores, but amino acids are derived from functional protein, so the reduction in their levels, therefore, has func-tional consequences,” he told ISICEM News. “But the question is, how much protein is needed?”

Although expert opinions recom-mend more than 1.2 g/kg/day by day four of admission,2 we are in urgent need of randomized controlled trials comparing enteral protein feeding at

this level with current clinical practice.Dr Weijs added: “Energy feeding

should be conservative because energy overfeeding is also counterproductive. Early mobilization of patients – in fact, physical exercise – may also help in this regard, as well as insulin therapy.”

Both overfeeding and underfeed-ing in critically ill patients are associ-

ated with deleterious outcomes. Early and adequate feeding should be the optimal feeding strategy, according to the specific energy needs, which can be evaluated using a variety of tech-niques. However, they are challenging in critically ill patients; the reference method used to evaluate energy needs involves measuring energy expenditure by indirect calorimetry, itself requiring costly equipment and technical skills that are not widely available. Indirect calorimetry is also limited to patients within a certain range of inspired oxygen concentra-tion (0.6-0.7) and it is very time-consuming.3 Therefore, in practice, a pragmatic estimate of total energy requirements is often used.4,5

Dr Weijs commented on this approach: “Estimation of energy requirements results in large percent-ages (30–70%) of patients being either overfed or underfed, and overfeeding is especially detrimental to the patient.”

Considering the feasibility of individualized measurements, in terms of affordability and practicality, he continued: “Of course, energy requirements are individual and can be assessed on an individual basis either by VCO2 from a ventilator, or preferably by indirect calorimetry.

“Since the indirect calorimetric measurement of energy require-ment has been performed in only a few randomized controlled trials on supplemental parenteral nutrition,(6) the results cannot be adequately interpreted. There is a private initiative … to make an affordable, indirect calorimeter, and testing is underway by leading scientist Professor Claude Pichard

[University of Geneva, Switzerland]. We don’t know yet how practical it will be, as this all takes time.”

Dr Weijs emphasized the need for a rigorous approach, saying: “Just measuring energy expenditure is not enough because we still cannot measure endogenous energy sources such as glucose and fatty acids; they should be subtracted from the energy expenditure measurement in order to more accurately assess the ‘dietary’ requirement for an individual patient.”

Whether critically ill adult patients actually need a constant positive pro-tein balance is still up for debate, as Dr Weijs commented, “I think it is a misunderstanding that all adult ICU patients could have a positive protein (or nitrogen) balance. But we ought to find out how much we can decrease the loss of lean body mass and therefore how much we can reduce the negative protein balance (at least in part).

“A larger influx of the correct amount and constituency of amino acids into the muscle may stimulate muscle protein synthesis while the influx of amino acids from the gut may decrease protein breakdown in the splanchnic area; at this stage, however, we don’t know how much this affects protein balance.”

Dr Weijs concluded by emphasiz-ing the importance of addressing ICU nutrition quickly, “Our goal is to minimize protein loss in the early days of an ICU stay (for example up to 20% loss of thigh muscle). This may benefit the surviving patient dur-ing rehabilitation and in trying to find a new life worth living after the ICU: not just surviving, but walking, living and enjoying life.”References1. Tashiro T, Mashima Y, Yamamori H, Horibe K,

Nishizawa M, Okui K. Alteration of whole-body protein kinetics according to severity of surgical trauma in patients receiving total par-enteral nutrition. JPEN Journal of parenteral and enteral nutrition. 1991;15(2):169-72. Epub 1991/03/01.

2. Strack van Schijndel RJ, Weijs PJ, Koopmans RH, Sauerwein HP, Beishuizen A, Girbes AR. Optimal nutrition during the period of mechanical ventilation decreases mortality in critically ill, long-term acute female patients: a prospective observational cohort study. Crit Care. 2009;13(4):R132. Epub 2009/08/13.

3. Graf S, Pichard C, Genton L, Oshima T, Hei-degger CP. Energy expenditure in mechani-cally ventilated patients: The weight of body weight! Clin Nutr. 2015. Epub 2015/12/15.

4. Harris JA, Benedict FG. A Biometric Study of Human Basal Metabolism. Proceedings of the National Academy of Sciences of the United States of America. 1918;4(12):370-3. Epub 1918/12/01.

5. Faisy C, Guerot E, Diehl JL, Labrousse J, Fagon JY. Assessment of resting energy ex-penditure in mechanically ventilated patients. The American journal of clinical nutrition. 2003;78(2):241-9. Epub 2003/07/30.

6. Heidegger CP, Berger MM, Graf S, Zingg W, Darmon P, Costanza MC, et al. Optimisa-tion of energy provision with supplemental parenteral nutrition in critically ill patients: a randomized controlled clinical trial. Lancet. 2013;381(9864):385-93. Epub 2012/12/12.

Nutritional support Tuesday 400 Hall 11:00

Nutritional care after critical illness: How much protein is enough?

“Energy feeding should be conservative because energy overfeeding is also counterproductive.”

Peter Weijs


O ne of the most pressing issues in intensive care and emergency care – and even

perhaps the medical field in general – is rising antibiotic resistance, which has the potential of turning back the treatment clock to the ‘dark ages’ before antimicrobials were standard practice.

With world-wide recognition be-ing crucial in ensuring steps are taken to address its potentially hazardous escalation, antibiotic stewardship is one piece of the puzzle that needs due focus. To that end, Michael Pulia (University of Wisconsin School of Medicine and Public Health, Madi-son, USA) will take to the podium today to discuss antibiotic steward-ship, with particular emphasis on its role in an emergency department (ED) setting.

“Antibiotic stewardship has not previously been a big focus in the emergency departments here in the US at least,” he told ISICEM News, adding: “I think that is a combination of a few things, one being people who have been working outside of our area then coming in to the emergency department and not fully understanding why we are doing what we are doing, or the param-eters we are working within.

“Second, I think people don’t re-ally understand what goes on in an emergency setting, what the differ-ent pressures are, and what different clinical scenarios we encounter that lead to our antibiotic decision making.”

As he stressed, until recently, antibiotic use is his and other similar centers actually erred on the side of generous, rather than judicious, use, as bedded within the principles of re-ducing risk to the patient. “With this in mind, my research agenda largely focuses on changing that, partly by building new interventions to improve stewardship in the ED setting.”

At his center in the University of Wisconsin, Dr Pulia and colleagues started what they believe is the first emergency department-based stewardship program in the country. Underpinned by physician leadership, and directed by Dr Pulia himself, the initiative customizes interventions and education towards emergency physicians. “We feel that is a unique group, and a unique environment that requires unique considerations,” he said.

After setting up the stewardship

program in-house, the initiative caught the eye of the stewardship division at the national Centers for Disease Control and Prevention (CDC)1, who were searching for leaders who would be prepared to head-up projects in the domain. In addition, Dr Pulia also began a lead-ership role in the American Academy of Emergency Medicine (AAEM) – which did not go unnoticed by the CDC. “CDC saw an opportunity to partner with a national organiza-tion in emergency medicine, and because I had both the interest in stewardship, and also the leadership experience with AAEM, I became the link between the two,” explained Dr Pulia. “That really came together with a nice synergy.”

Because of this partnership, in 2013 the CDCs ‘Get Smart About

Antibiotics Week’ was aimed specifi-cally at emergency departments. “I served as the liaison for that, and it has gone on every year since then,” said Dr Pulia.

Crucially, as he described, that relationship led to the creation of the ‘Antimicrobial Taskforce’ within the AAEM, backed by a very important invitation extended to AAEM to the White House’s One Health Forum on antimicrobial stewardship, held in June of 2015.2

The event brought together over 150 representatives from the cutting-edge of the infectious disease field, including representatives from key professional societies, high-ranking government officials and leaders

from the medical diagnostic, pharma-ceutical, agriculture, and food/retail industries.2 AAEM was the only voice representing emergency medicine at the historic event.

“It is a very exciting time to be working in this area, because again while very little had been done previously in terms of stewardship in ED, suddenly we have the CDC, the White House, and also the World Health Organization [WHO]3 taking interest,” said Dr Pulia. “Everyone is really keen on the stewardship topic, so it was really timely that we had set up this unique program here at the University.”

After discussion with the White House, Dr Pulia explained that this led to the Task Force setting out several commitments they would pursue, including a focus primar-ily on education, both at national meetings and through dissemina-tion of research that focusses on stewardship in the ED setting. “The vast majority of emergency physicians work in community hospitals, and academic centers, and I think that is where most of the antibiotic use still goes on, and that is probably where most education needs to take place,” said Dr Pulia.

A focus across the boardLooking at the overarching threat posed by antibiotic resistance, Dr Pulia stressed that it will require a multi-faceted approach, with responsibilities for stewardship presenting at many echelons of the care structure. For example, at the moment of interaction between patient and physician, both parties have something to bring to the equation. For the

patient, education can help them in their understanding that antibiotics may not be required. And for the physician, it is important to remem-ber that as well as a public health issue, there is also an immediate patient safety issue, which can often be left behind. “We would like physi-cians to think about the public health issue always, but ultimately their true responsibility at that moment is the patient in front of them,” he said.

“If I can educate the physicians that they are potentially putting their patient in harm’s way by using injudi-cious antibiotics (such as the risk of clostridium difficile, the risk of serious adverse allergic drug reactions etc.) I think that will actually resonate bet-

In the emergency room 100 Hall Tuesday 11:00

‘Hard to resist’ Ushering in a new era of antibiotic stewardship

“Antibiotic stewardship has not previously been a big focus in the emergency department.”

Michael Pulia


ter with a physician then the public health perspective will.

“There is even recent emerging literature that suggests that a lot of antibiotics are associated with delirium, and altered mental status in elders as well. So there is actually re-ally true patient-level impact with this problem as well. Those are two key parallel things that we need to focus on, and again educating the public is a part of this that we cannot ignore.”

Big pharma’s roleOf course, one possible partial solution to the antibiotic crisis is the develop-ment of new agents, which is where pharmaceutical companies will come into the fray. “I believe we are turning the tide around in the right direction,” said Dr Pulia. “There are definitely some things in the pipeline that will be coming out, even within the next year, which are very promising.”

Overall, however, the pharmaceu-tical industry’s role is very complex, which will make development all the more difficult, as Dr Pulia explained: “The companies are being encour-aged to develop new products, so that we can deal with these new bugs that are be-coming more and more resistant. But part of the problem – part of the natural course of things – is that any time a new drug is released, resist-ance will follow, and it will follow with a direct correlation to how often that antibiotic is used.

“So from a financial point of view, while the companies are expected to put in an incredible amount of money into getting these drugs de-veloped, on the back of that, when they are finally approved, everyone in the stewardship community will be cautious not to use it yet. But the problem is then the companies cannot make any money on the product, and are thus in a very tough situation. Therefore, in all honesty, from my perspective I think that the government should subsidize development of those drugs. There is a critical need for them.”

Aside from new agents, there is also substantial hope that that refined or novel methods to combat antibiotic-resistant bacteria will come into play. For instance, Dr Pulia

stressed that pharmaceutical compa-nies are already trying to be prudent about developing antibiotics that have more blocks in the molecular design to prevent resistance develop-ing as quickly.

Intriguingly, as detailed by Jean Chastre (Hospital Pitié-Salpêtrière, Paris, France) previously at ISICEM,4 there is also substantial effort being invested in targeting virulence fac-tors (thereby leaving the microorganism intact, but harmless), as well as bacteriophages – viruses that infect and replicate within bacteria to tackle them from within.

“It sounds incredible to basically let you own immune system do what it does naturally, and kill the bugs ourselves,” said Dr Pulia.

The futureCommenting on what initiatives

or actions are likely to be most important moving forward, Dr Pulia first touched on the creation of hospital rules that state that, in order to receive proper reimbursement, they have to have an antimicrobial stewardship program in place. And importantly, implementing better quality tracking measures. “Once the payers, whether that is the govern-ment or private insurers or whoever, start to be held accountable, like they have in other areas of quality care, that will be a big drive to get people thinking much more deeply about stewardship,” he said.

“And that is happening. All those gears are turning right now, and will be in the pipeline in the next few years. Certainly they will start requir-ing that every hospital that is partici-pating in government programs here in the US is going to have to have a stewardship program of some sort. And then there are a lot of commit-tees that I am working with right now who are working on developing

these initial quality measures around stewardship.”

For emergency medicine in particular, another crucial aspect moving forward will be emphasis on interventions that are customized to the time-sensitive nature of the

ED, rather than trying to retro-fit existing policies from intensive care, for example.

This is particularly applicable to rapid diagnostics, as Dr Pulia described. “As you can imagine there are incredible time pressures. Whereas traditional cultures or specimens from infections take days to come back, now there is emerging technology where we can quickly identify the organism, what kind of bacteria it is, and in some cases we can even identify if there is a resist-ance gene for the organism as well. So that can actually guide a decision of which antibiotic to use in the emergency setting, which previously was impossible.

“Before I would be pretty much guessing, but now I can tailor the

therapy much more specifically, and not use as broad a spectrum of antibiotics.”

Specifically, investigatory biomark-ers such as procalcitonin (which can tell you whether you do or do not need an antibiotic), or rapid organ-

ism-identification PCR tests that can actually tell you what the bug is, are both very helpful tools. “And we need more of those tools, with coverage of a wider range or organ-isms and conditions as well,” said Dr Pulia.

Of course, staffing and expertise needs

to be in place to make sure this po-tential is realized. “You really either have to have a point-of-care setup, which we can run ourselves, or you have to have a very close relation-ship with your clinical lab, who can run those specimens in a timely fashion,” said Dr Pulia in closing.References

1. The Centers for Disease Control and Preven-tion (http://www.cdc.gov/)

2. The White House. FACT SHEET: Over 150 Animal and Health Stakeholders Join White House Effort to Combat Antibiotic Resistance (https://www.whitehouse.gov/the-press-of-fice/2015/06/02/fact-sheet-over-150-animal-and-health-stakeholders-join-white-house-effo)

3. WHO | Antimicrobial resistance: global report on surveillance 2014. WHO. Available at: http://www.who.int/drugresistance/docu-ments/surveillancereport/

4. ISICEM News. Resistance is futile: New approaches for tackling severe infections. ISICEM congress newspaper, 2014.

“Once the payers … start to be held accountable, like they have in other areas of quality care, that will be a big drive to get people thinking much more deeply about stewardship.”

Michael Pulia

“Any time a new drug is released, resistance will follow, and it will follow with a direct correlation to how often that antibiotic is used.”

Michael Pulia

‘Hard to resist’ Ushering in a new era of antibiotic stewardship

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