Sex and resuscitationMore recently, Casey and Mumma studied a US-based patient discharge database,...

‘Evil humors’ in sepsis . . . . . . . . . . . . . 3

e-learning for infection prevention . . . . 6

Is it time for PICS to go? . . . . . . . . . . . . . . 10

A critique of the SSC guidelines . . . . . . . . . . . . . . 15

A number of studies have now shown that resuscita-tion may be affected by factors including sex and

age. These findings are difficult to interpret, however, and demand more detailed investigation of surrounding

circumstances to determine causal influences as well as prognosis and outcome. This topic will be discussed by Sharon Einav (Hebrew University Faculty of Medicine, Jerusalem, Israel) during her plenary lecture today.

In 2014, Kahn et al. reported that

younger age and female sex were associated with longer attempted CPR duration in patients who do not experience return of spontaneous circulation (ROSC) after in-hospital cardiac arrest, but that age and sex were not associated with attempted

CPR duration in those who experi-ence ROSC1.

More recently, Casey and Mumma studied a US-based patient discharge database, finding that female sex, non-white race, and Medicare insur-

Friday 23 March 2018 Day 4The official daily newsletter of the 38th ISICEM

Sex and resuscitationPotential bias, but more research needed

Continued on page 2

See you next year!Thank you for making the 38th ISICEM a great success. We look forward to welcoming you back in 2019!

2 ISICEM News Friday 23 March 2018 Issue 4

ance status were independently asso-ciated with worse neurologic recovery, lower rates of treatment at a 24/7 percutaneous coronary intervention (PCI) center and lower rates of cardiac catheterization. Female sex, white race, and Medicare insurance were associated with do-not-resuscitate orders within 24 hours of admission.2

Similarly, a 2016 retrospective study including 1,436,052 discharge records of patients suffering cardiac arrest between 2003 and 2012 found that women are less likely to undergo therapeutic procedures including coronary angiography, PCI, and tar-geted temperature management, and had higher in-hospital mortality than men during this period.3

Gender differences in out-of-hospital cardiac arrest have also been explored, but literature is inconsistent in this area, as discussed by Bosson et al, 20164.

In conversation with ISICEM News, Dr Einav summarized the work she has done in this topic, exploring the possibilities of culturally-driven uncon-scious biases that could feed into sex differences in resuscitation.

Her involvement in this area began with an epidemiology Master’s degree

project she completed in 2011, of which she recalled: “Originally, when I set out to do this project I was very cynical about finding anything. My as-sumption was that, contrary to heart disease, there should really be no dif-ference between men and women in resuscitation. If you are dead, you are dead. The presentation is similar, and why should there be any difference?”

Indeed, her work did find that pre-hospital resuscitation and actual treat-ment received by men and women was quite similar. However, once the patient reached hospital a significant difference in treatment was observed.

“I submitted this as a paper and got two types of answers from the reviewers. One of them was, ‘This is the Middle East, so what did you expect?’ This was a bit cynical given that we already had a female prime minister in the 1960s! The other was more professional – that we hadn’t looked at patient factors that could have affected this difference in treat-ment, which could possibly have been elicited more in hospital rather than out of hospital.”

Her continuing study over the subsequent five years revealed that women tend to be older and sicker, with greater comorbidity burden, noted Dr Einav. Their presenting rhythms are less conducive to reversal, she said, with greater rates of asystole than ventricular fibrillation relative to men. Correcting for these and other factors, however, indicated that a residual bias remained, with women still receiving less frequent post resus-citation interventions than men. “This got me thinking,” said Dr Einav. “But I don’t have answers. I think the study we have is probably more in depth than most, if not all other studies. I am quite convinced that this is not a conscious decision to treat women less.

“I tend to believe, having been looking at this for a number of years, that families would approach the medical team and say some-thing along the lines of: ‘Mother hasn’t been the same since father passed away, she lives alone, her qual-ity of life hasn’t been the same, she is not happy, and she has expressed a wish to not continue, etc.’ That is not the sort of thing you would hear from a female spouse. It is the sort of thing you would hear from the children.

“As women arrive to hospital older, the likelihood is that their chil-dren are taking care of them rather than their spouse. I think this is what

is underlying this phenomenon. I can-not prove it, but it warrants further investigation in the future.”

In terms of further study to identify what other biases could be in place, Dr Einav explained that the causes of non-performance of specific procedures not undertaken must be elicited. Examples include: the reasons a patient was not sent to a cardiac unit following CPR; the reasons a

patient did not undergo targeted temperature management after CPR, or why such a patient was not sent to the cath lab. “Those are the

first three things I would try to un-derstand in terms of clinical decision-making,” said Dr Einav, “Because these are clearly not decisions that are driven only by the family.

“Then, looking at withdrawal of care, I would ask whether the family had asked to withdraw care or to not perform specific interventions, and who had had this conversation with the family. The provider has a

Sex and resuscitation Gold Hall Friday 13:3

Sex and resuscitation Potential bias, but more research neededContinued from page 1

ISICEM NewsPublishing and ProductionMediFore Limited

Symposium ChairmanJean-Louis Vincent

Editor-in-ChiefPeter Stevenson

EditorsRysia BurmiczTatum AndersonBecky McCallJo Waters

DesignPeter Williams

Industry Liaison ManagerLorraine Tighe

Head Office51 Fox Hill, London, SE19 2XEUnited KingdomTelephone: +44 (0) 20 8771 [email protected] © 2018: 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 2018 Symposium Chairman, the ISICEM Scientific Advisors or Collaborators.

“Are we unconsciously driving these different decisions, if such a difference exists?”Sharon Einav

Issue 4 Friday 23 March 2018 ISICEM News 3

very important input in convincing the family of what would be the best course of care. The question is, are we unconsciously driving these different decisions, if such a difference exists? This requires very in-depth work.”

There are, of course, many other aspects of resuscitation that have been studied in the context of gender bias in the literature. In 2015, for example, Kramer et al. pub-lished a study suggesting that people were less prepared to unclothe a female CPR recipient5. Similar findings were more recently demonstrated by Blewer et al.6. While Dr Einav’s pres-entation will not focus on this, she commented on the notion: “This is interesting – but I cannot confirm that

there is a difference, because I found a similar rate of bystander CPR in men and women. It would be interesting to do a much more thorough study on this. There could be questions that

arise regarding whether it is a male or female rescuer, and whether a fe-male rescuer would eliminate the issue of discomfort. You could also consider – ridiculous as it may sound – the size of the breast.”

Other investiga-tions have been carried out to address whether a care provider being male or female affects chest compression depth. This, said Dr Einav, cannot be reduced to a gender difference – rather, compression depth depends upon the constitution of the individual doing the chest compressions. “You

could probably find a difference between men and women in a large sample size but I think it is very indi-vidual,” she said.

Drawing on her experience of training others in CPR in different regions of the world, she added: “There are people who definitely need to be taught how to do resus-citation, who seem to be physically weaker. When I see someone like that I would [tell them to] run the resusci-tation, rather than to actually perform chest compression. We were training CPR in Vietnam several years ago, where the society is very male-orient-ed. We had a difficult time teaching people to listen to instructions given by a female doctor. It tended to be that the male nurse took over and gave orders to the female doctor. It is very culturally-oriented in terms of who you take instruction from, how you perceive yourself in the whole scenario.”

Dr Einav’s Plenary lecture takes place this afternoon at 13:30 in the Gold Hall.

References1. Khan AM, Kirkpatrick JN, Yang L. Age, Sex,

and Hospital Factors Are Associated With the Duration of Cardiopulmonary Resuscitation in Hospitalized Patients Who Do Not Experience Sustained Return of Spontaneous Circulation. J Am Heart Assoc. 2014; 3(6): e001044.

2. Casey SD, Mumma BE. Sex, Race, and Insur-ance Status Differences in Hospital Treatment and Outcomes Following Out-of-Hospital Cardiac Arrest. Resuscitation. 2018. pii: S0300-9572(18)30095-9.

3. Bosson N, Kaji AH, Fang A et al. Sex Differ-ences in Survival From Out‐of‐Hospital Cardiac Arrest in the Era of Regionalized Systems and Advanced Post‐Resuscitation Care. JAHA. 2016;5:e004131.

4. Kim LK, Looser P, Swaminathan RV et al. Sex‐Based Disparities in Incidence, Treatment, and Outcomes of Cardiac Arrest in the United States, 2003–2012. JAHA 2016;5:e003704.

5. Kramer CE Does the sex of a simulated patient affect CPR? Resuscitation. 2015;86:82-7.

6. Blewer A, McGovern SK, Schmicker R et al. Gender disparities among patients receiving bystander cardiopulmonary resuscitation in the United States. American Heart Association 2017 Scientific Sessions. November 12, 2017; Anaheim, CA. Abstract RESS.AOS.11A. www.abstractsonline.com/pp8/#!/4412/presenta-tion/50125 (accessed Mar 2018).

What are the ‘evil humors’ in sepsis?

D uring Tuesday’s session on blood purification, Mervyn

Singer (University College London, UK) looked to the developments over recent years in the identification and removal of circulating fac-tors that may be released in trauma, and the immunologi-cal consequences.

“I like this concept of circulating factors which im-pact upon organ function,” he told delegates. “Perhaps, if we remove them, there may be some therapeu-tic benefits.”

Studies in this area go back a long time, he explained, citing first a 1984 study by Benassayag et al., which identified a lipid-soluble mediating factor from the sera of humans with septic shock that decreased contractility of cultured rat heart cells1. Similar work later carried out by Reilly et al. attempted to identify this myocardial depressant factor by fractionation experiments, identifying its presence only in fractions above 10 KDa and 30 KDa2.

Professor Singer then spoke about work currently going on examining the ef-fects of septic plasma at the mitochondrial level: “Quite a lot of groups have looked at taking healthy tissue, cells lines, animal tissues, etc., and incubating them with healthy or septic human serum. There is a decrease in respiration, but an increase in uncou-pling. In other words, there is a diversion away from ATP generation towards genera-tion of heat.”

In 2003, Boulos et al. found that septic sera incubated within healthy endothelial cells led to de-pression of mitochondrial res-piration at one and two hours after baseline. This effect was blocked by inhibition of nitric oxide synthase and poly(ADP-ribose) synthase.3

Then in 2007, Belikova et al. investigated the hypoth-esis of an energetic failure of immune cells to participate in immune dysfunction, to explain the changing responsiveness of immune cells. They found that oxygen consumption was higher

in septic peripheral blood mononuclear cells, with an attenuated response to ADP stimulation. Furthermore, oxy-gen consumption of healthy mononuclear cells incubated in septic plasma mimicked the septic cell response, with am-plitude depending on the particular time point during sepsis duration. Septic cells incu-bated in healthy plasma partially recovered nor-mal patterns.4

“At the time I didn’t really focus on this,” commented Professor Singer. “We are brought up badly in medical school to think that oxygen goes to ATP, but it ac-tually also goes towards heat generation, and depending on the tissue, a large propor-tion can go towards heat generation: not so much in the heart, but in the muscle, for example.”

Returning to the findings of Belikova et al.4, he added: “In these monocytes, in the healthy volunteers’ plasma,

the majority was being used for coupled respiration (oxygen being consumed to make ATP) and only 11% for non-coupled (predominantly lost as heat, but also free radical production). In the septic plasma, there was an

overall depression, but there was a much bigger increase in the amount of oxygen being diverted away towards heat and reactive oxygen species (ROS) production rather than ATP-coupled respiration. The uncoupling phenomenon is something we are inter-ested in.”

He then noted as-yet un-published work by Nishkantha Arulkumaran and Sean Pollen at University College London (UK) using live tissue dual

photon beam confocal mi-croscopy of healthy rat kidney incubated with either septic or sham serum, or saline, for 90 minutes. “Very early on in these healthy kidney slices incubated with septic serum there is an increase in signal

of dihydroeth-idium which signifies ROS production,” said Professor Singer. “ROS, right from the word go, are being stimulated. The sham serum shows no effect relative to control.

“The mem-brane potential of mitochon-dria drops significantly from 0-90 minutes in the [kidney slices incubated with] septic serum. The mitochondrial membrane potential drives the proton motor force that makes ATP.

“I was half expecting, before I saw the results, that NADH (the reduced form) would go up if there was an inhibition. But actually, it went down with the septic

Blood purification Terarken (Bozar) Tuesday 13:30

“It is known in sepsis that, for example, mitochondrial DNA goes up with injury. These mitochondrial DAMPs should not be in the circulation.”Mervyn Singer

“When I set out to do this project I was very cynical about finding anything.”Sharon Einav

Continued on page 4


serum – implying that there is likely to be uncoupling. And it’s happening very early on.”

The group then investi-gated the effect of administer-ing a mitochondrially-targeted antioxidant, MitoTempo, finding that it led to reversal of ROS production, recovery of membrane potential, and recovery of NADH redox state. “Whatever is happening, it is stimulating this effect on ROS production.

“A good advantage of uncoupling and dropping membrane potential, is that the mitochondria produces less ROS. Mitochondria are the major producers in the body of ROS. So as a way perhaps of self-preservation, if they are killing themselves by producing too much ROS and therefore overwhelming their antioxidant defenses, a way of reducing ROS production is reducing redox state. We are looking into whether we can identify what this magic depressant is.”

The group has just started experiments taking septic plasma, putting it through a filter at 50 kDa, and then testing combinations of the heavy septic plasma concen-trate with sham ‘thin’ filtrate, and vice versa. In this way, they found that a sepsis-like mitochondrial membrane potential effect was observed only in the group treated with the combination of septic concentrate plus sham filtrate – suggesting that most of the septic effect is mediated by the heavier septic serum frac-tion of over 50 kDa.

“What could the ‘evil humor’ or ‘evil humors’ be?” Asked Professor Singer, noting that cytokines are generally small molecular weight – while the presence of IL-6 and its effects on uncoupling is well known, it is only 26 kDa. However, IL-6 can bind to alpha-2-macroglobulin, which is much bigger at 720 kDa.

Another candidate is albumin, explained Profes-sor Singer, which, at 64 kDa, binds to nitrous oxide (NO),

amongst many other things, to form S-nitroso-albumin. There is some evidence that S-nitroso-albumin acts as a venodilator in vivo, and repre-sents a stable reservoir of NO that can release NO when the concentrations of low-molecu-lar-weight thiols are elevated, as demonstrated in rat by Orie et al. (2005)5.

Damage-associated mo-lecular patterns (DAMPs) such as cold-inducible RNA-binding protein (CIRP), are released into the blood stream and stimulate an inflamma-tory response. CIRP has been found to trigger inflamma-tory responses in a rat model of hemorrhagic shock and sepsis in work by Qiang et al6. In this work, blockade of CIRP attenuated inflammatory cytokine release and mortality after hemorrhage and sepsis. The authors also reported in-creased levels of cold-inducible RNA-binding protein (CIRP) in the blood of individuals admitted to the surgical inten-sive care unit with hemor-rhagic shock, compared to healthy controls.6

CIRP, however, has a mo-lecular weight of 28 kDa. But Professor Singer noted the existence of mitochon-drial DAMPs, which are known to cre-ate function-ally important immune consequences when released into the circula-tion through trauma and cellular disruption. Mitochondrial DAMPs include formyl peptides and mito-chondrial DNA.7 “It is known in sepsis that, for example, mitochondrial DNA goes up with injury,” said Professor

Singer. “These mitochondrial DAMPs should not be in the circulation, so when they are the body recognizes them as alien and generates an inflam-matory response.”

And, while formyl peptides are relatively small, mitochon-drial DNA can be up to around 13,000 base pairs assuming it

is intact – al-though, even when broken up the size will be large, said Profes-sor Singer.

Looking at possible ways of purifying blood of such mediators, Professor Singer noted that plasma-pheresis does remove up

to 100 kDa. In 2002, Busund et al. reported an absolute risk reduction of 20.5% with plasmapheresis relative to control in a single center pro-spective randomized trial of 106 consecutive patients with

severe sepsis or septic shock. The investigators concluded that a prospective randomized multicenter trial is warranted to confirm these findings and to determine which subgroups of septic patients will benefit most from this treatment mo-dality8.

Professor Singer also highlighted the CytoSorb Adsorber, which late last year saw the publication of interim results pertaining to its international registry9. “We need the prospective studies, although there is registry data. We don’t know if it’s going to adsorb the right thing, but it may work.

“We have exciting possibili-ties. But it would be nice to know what is causing harm. Is it the same thing that is affecting the mitochondria, for example, that is causing myocardial depression? We don’t know. Maybe there are different things having an ef-fect on inflammation.”

“I do think that removal [of circulating evil humors] offers the potential of benefit, and is something to be explored.”

References1. Benassayag C, Christeff N, Auclaire

M-C et al. Early released lipid‐soluble cardiodepressant factor and elevated oestrogenic substances in human septic shock. Eur J Clin Invest. 1984;14(4):288-94.

2. Reilly JM, Cunnion RE, Burch-Whit-man C et al. A circulating myocardial depressant substance is associated with cardiac dysfunction and periph-eral hypoperfusion (lactic acidemia) in patients with septic shock. Chest. 1989;95(5):1072-80.

3. Boulos M, Astiz ME, Barua RS et al. Impaired mitochondrial function induced by serum from septic shock patients is attenuated by inhibi-tion of nitric oxide synthase and poly(ADP-ribose) synthase. Crit Care Med. 2003;31(2):353-8.

4. Belikova I, Lukaszewicz AC, Faivre V et al. Oxygen consumption of hu-man peripheral blood mononuclear cells in severe human sepsis. Crit Care Med. 2007;35(12):2702-8.

5. Orie NN, Vallance P, Jones DP et al. S-nitroso-albumin carries a thiol-labile pool of nitric oxide, which causes venodilation in the rat. Am J Physiol Heart Circ Physiol. 2005;289:H916-H923.

6. Qiang X, Yang WL, Wu R et al. Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis. Nat Med. 2013;19(11):1489-95.

7. Zhang Q, Raoof M, Sumi Y et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464:104-7.

8. Busund R, Koukline V, Utrobin U et al. Plasmapheresis in severe sepsis and septic shock: a prospective, ran-domised, controlled trial. Intensive Care Med. 2002;28(10):1434-9.

9. Friesecke S, Träger K, Schittek GA et al. International registry on the use of the CytoSorb® adsorber in ICU patients : Study protocol and preliminary results. Med Klin Inten-sivmed Notfmed. 2017.

Blood purification Terarken (Bozar) Tuesday 13:30

“We have exciting possibilities. But it would be nice to know what is causing harm.”Mervyn Singer

“The uncoupling phenomenon is something we are interested in.”Mervyn Singer

What are the ‘evil humors’ in sepsis?Continued from page 3


Early mobilization for better long-term outcomes?

T he evidence surrounding early mobilization of ICU patients will be tackled this morn-ing by Carol Hodgson, Deputy Director of

the Australian and New Zealand Intensive Care Research Centre at Monash University, Mel-bourne, Australia.

A specialist intensive care physiotherapist for more than 10 years, and Fellow of the College of Physiotherapy in Australia, Dr Hodgson is pas-sionate about long-term outcomes. “I qualified in Australia, and I fell in love with intensive care and the critical care team from the moment I started,” she said. “I believe it is a place in the hospital where you can make a difference to patients’ survival and their long-term outcome.”

Dr Hodgson and colleagues have led several important research projects and publications that inform the research into early mobilization, such as the international consensus of the safety of early mobilization during mechanical ventila-tion, the validation and reliability of the ICU Mobility Scale, and a bi-national observational and pilot randomized study of early mobilization.

In the literature, several Phase II randomized trials have been published (as summarized in a recent systematic review1), with the largest studies (N=200-300) measuring the primary outcome at hospital discharge. But, crucially, this limits the durability of results: “We are interested in the longer-term effect of early mobilization on recovery,” said Dr Hodg-son. “The implementation research is telling us that early mobilization in ICU is a complex intervention that requires the multidisciplinary ICU team to find champions to lead early mobilization.”

Indeed, Dr Hodgson underlined that a hindrance to the existing body of data is that early mobiliza-tion studies are difficult to execute, as they are

complex, and involve the input of a multidisciplinary team. “For example, the ICU team needs to assess the patient with regards to sedation minimization or interruption to participate in exercise,” she said.

Other factors must also be taken into account, she added: “Physiological safety must be assessed and monitored throughout the treatment, invasive lines secured, staffing levels adequate to deliver the intervention, and staff must have adequate training with a clinical lead.”

With these challenges in mind, it is perhaps

unsurprising that to date there have been no Phase III trials of early mobilization focused on patient-centered outcomes. However, that is about to change. During her presentation today, Dr Hodgson will unveil a Phase III randomized controlled trial that will compare mobilization with standard care in the ICU. More than 30 international sites in Australia, New Zealand, Ireland, Germany and the UK will be included.

“As a physiotherapist I am ideally placed to lead studies in exercise prescription and functional recovery, and I am well supported by a multidisci-plinary management committee including intensive care specialists, research coordinators, nurses, physi-otherapists and an ICU survivor,” she said.

“We will assess whether early mobilization in the ICU improves outcomes at six months (a meas-ure that includes death, days in hospital, days in rehabilitation, nursing home and hospital readmis-sions),” she said. “We will also assess disability, quality of life, activities of daily living, and psycho-logical and cognitive function at six months.”

Going forward, a host of other issues should be addressed in research, said Dr Hodgson. “We should be looking at differences at baseline (prior to ICU admission) such as frailty and comorbidi-ties that may affect outcome, the ability to deliver the intervention, identifying a dose response to exercise, the trajectory of recovery as well as the core outcome measures for trials of acute respira-tory failure and measuring outcomes after hospital discharge,” she said.

“Reducing loss to follow-up and smaller trials of precision medicine rather than larger trials with patient heterogeneity would help too.”

References1. Tipping CJ, et al. The effects of active mobilisation and rehabilita-

tion in ICU on mortality and function: a systematic review. Intensive Care Med. 2017;43(2):171-183.

Mobilization: how feasible? Lippens Room Friday 09:50

“We will assess whether early mobilization in the ICU improves outcomes at six months.”Carol Hodgson


The value of e-learning in infection prevention and control

P revention of healthcare-associated infection remains a challenge, in large part due to

low adherence to infection-prevention guidelines. With that in mind, there is great potential for e-learning as a more attractive and approachable way to improve guideline-uptake, the Studio (Bozar) audience will hear this morning.

Stijn Blot, from the Department of Internal Medicine, Faculty of Medicine & Health Science at Ghent University, Belgium, will be taking to the podium to relay his experience in develop-ing e-learning initiatives for infection prevention and control.

Professor Blot is part of the EVIDENCE project1, which aims to promote knowledge of evidence-based measures for preventing healthcare-associated infection in healthcare professionals working in critical care. As part of their initia-tive, the EVIDENCE team has created a web-based interactive e-learning ‘Crash Course’ that bundles together the pertinent information relevant for preventing infections.

“The EVIDENCE research team was built around the doctoral research project of Sonia Labeau,” Professor Blot told ISICEM News. “Besides So-nia, the core team consisted of seven more people. Myself and Professor Koenraad Vandewoude promoted and copromoted Sonia’s PhD thesis, respectively. Professor Dominique Vandijck was involved because of his expertise in quality control projects, whereas Professor George Dimopou-los, Professor Jordi Rello, Professor Aklime Dicle and Professor Candan Öztürk were of key value for develop-ing and promoting the study on an international level.

“The core team was strongly sup-ported by national representatives and professional organisations worldwide, whose help in recruiting participants was priceless.”

Describing how the e-learning courses came to light, Professor Blot continued: “The e-course was devel-oped by Sonia in the Dutch language using opensource software, while a web designer subsequently embel-lished the look and feel. In order to increase the course’s accessibility, for-ward and backward translations of its contents were effectuated in English, Portuguese, Spanish, and Turkish.”

In total, the Course comprises seven chapters, with the first chapter dedicated to introducing the overall focus of evidence-based practice in the field of infection prevention. The second chapter tackles the problem of healthcare-associated infections, and emphasizes the importance of preven-tion. Hand hygiene, which is key to preventing infection, is discussed in the third chapter.

Chapters 4–7 then focus on the “Big Four” of infection: ventilator-as-sociated pneumonia (VAP); infections related to the use of central venous catheters; surgical site infections; and device-related urinary tract infections. Importantly, each chapter can be studied separately, and each

comprises different types of exercises with immediate feedback, such as case studies, cloze exercises (where words are omitted, and students must fill in the blanks) and multiple-choice knowledge tests.

“The course’s content validity was tested and approved by an interna-tional team of experts in infection prevention, while a sample of 50 potential users verified and acknowl-edged its face validity and usability by means of the Software Usability

Measurement Inventory®, which is a proven method of measuring software quality from the end user’s point of view,” said Professor Blot.

In their 2016 paper2, the EVIDENCE team reported on a large cohort of healthcare workers (HCWs) using the e-learning platform, with significant results. As the authors write, moderate time invested in e-learning yielded significant immediate and residual learning effects, at +24% and +18% respectively.

Briefly commenting on the imme-diate versus residual learning effect, Professor Blot continued: “People start retaining facts once they shift from their short-term to their long-term memory, but the time and num-ber of repetitions needed to obtain this shift varies between individuals, and is dependent of the level of expo-sure of that particular knowledge item in daily practice.

“When referring to our study, a median test score of 74% (interquar-tile range [IQR], 64%–84%) at the

second post-test, i.e. after three months without accessing the course, was obtained, while the overall score obtained immedi-ately after taking the test was 80% (IQR, 68%–88%). These findings suggest that reten-tion after three months is still quite good.”

With this in mind, Professor Blot reasoned that knowledge should be maintained long enough to allow repetition of the course on a yearly basis. How-ever, it could be offered more frequently if important updates to the evidence base have been implemented during that time.

Despite the promising outcomes from the e-learning initiative, continuation of study has been met with severe

roadblocks. “Given the positive and hopeful primary study results, we were very keen on continuing our research,” said Professor Blot. “How-ever, EVIDENCE was Sonia’s doctoral project and as such funded by a doc-toral grant from her employer, Univer-sity College Ghent, in addition to an unrestricted grant from the European Society of Intensive Care Medicine and Edwards (ECCRN-Edwards Nursing Science Award 2008). After complet-ing the study, no further funding for

Preventing infection Studio (Bozar) Friday 08:00

“People start retaining facts once they shift from their short-term to their long-term memory, but the time and number of repetitions needed to obtain this shift varies between individuals.”Stijn Blot


additional research was available.“Setting up a study that looks at

infection outcomes after following an e-learning program is challenging. Moreover, it does not make that much sense to look for a direct relationship between e-learning and a risk reduction in nosocomial infec-tions. A solid quality improve-ment initiative includes several steps including education, set-ting up a surveillance system for infection, selecting a set of evidence-based prevention measures through a consensus model with the team, adequate monitoring of processes (compli-ance) and outcomes (infections), and targeted feedback.”

Touching upon the possible limita-tions of the e-learning approach, Professor Blot first commented on the so-called Hawthorne effect, whereby the behaviour of subjects in a study (and therefore the outcomes) are affected by knowledge that they are being observed. “During the initial learning phase, a Hawthorn effect cannot be ruled out,” he said.

“However, quality improvement projects supported by e-learning should be organized for the long-term (if not continuous). With time, the Hawthorn effect will weaken.

Furthermore, in such a study, it is not the knowledge gains but the infec-tion rates that will be the primary outcomes of interest.”

Selection bias was also considered, as all of the students were volunteers

who might have been particularly motivated or interested in the topic. Indeed, Professor Blot relayed that the most motivated or interested among them may have completed the entire study path, thus generating better learning effects than if participation had been imposed on a random sample. “Yet, during the study course, numerous clinicians indicated that they participated specifically to obtain the certificate of participation issued by the ESICM. So, this motive for participation might at least partially alleviate selection bias caused by voluntary enrolment,” he said.

Additionally, said Professor Blot, the investigators found that better

pre-course knowledge was associated with lower immediate and residual learning effects. “This can be consid-ered a logical finding: the better the prior knowledge, the less room for improvement,” he said. “If, however,

these participants’ prior knowl-edge was higher than that of the general population of healthcare professionals, learn-ing effects in a random sample might exceed those identified in the current cohort.”

Drop-out rates were also high, with the original 3,587 volunteers that were registered

falling to 2,590 at the pre-test stage, and 1,410 by the post-test stage. The second post-test, scheduled after 12 weeks following the completion of post-test 1 and during which the participants had no longer access to the course, was executed by 1,011 students.

“Following the end of the study, we ran a dropout analysis by means of a small survey sent to all drop-outs, of which 525 responded,” said Professor Blot. “The main reason reported for opting out was a lack of time. As our sample merely consisted of volunteers involved in in-patient care, a high dropout rate was hardly unexpected. Work, family life and

personal commitments are easily and understandably prioritized over continuing education.

“Also, there is a well-documented relationship between high dropout rates and isolation of e-learners. Finally, our dropouts might have been less motivated for taking the course than their colleagues who completed the entire study, which may have con-tributed to the positive study results.”

Professor Blot plans to offer a select few take-home messages in summary of the e-learning approach. First, it should be emphasized that, clearly, it carries many advantages, with results outlining a considerable and sustained gain in knowledge from only moderate study time. As such, it is his suggestion that decision-makers should consider using e-learning for continued educa-tion. However, it is paramount to remember that knowledge does not guarantee adherence.

“Our data demonstrate that e-learning might be a valid option to invest in,” he said in closing.

References1. The EVIDENCE project. Available at: http://

www.evidenceproject.org/2. Labeau SO, et al. The Value of E-Learning

for the Prevention of Healthcare-Associated Infections. Infect Control Hosp Epidemiol 2016;37:1052–1059.

“Our data demonstrate that e-learning might be a valid option to invest in.”Stijn Blot

+44 (0) 20 8771 8046 [email protected] www.medifore.co.uk

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MediFore are the proud publishers of

As the 2018 edition of the International

Symposium on Intensive Care and Emer-

gency Medicine opens its doors, its with

great pleasure that we welcome you to

our 38th year.

We hope to see you all in the sprawling Henry

Le Bœuf auditorium this morning to witness the

opening session: a dazzling display of topics that

will set the tone for the rest of the four-day pro-

gram. It begins with a report from the Round Table

conference on metabolic care, delivered by Kenneth

Christopher and Jan Wernerman, before Kevin

Dhaliwal takes to the podium to show us amazing

and surprising pictures of the lung at the bedside.

We will also hear about the contributions from

military medicine, by Michael Reade. A lot to learn!

This year, Tom van der Poll will be invited to deliver

the Max Harry Weil lecture, a hotly anticipated ex-

ploration of the future of sepsis therapies, particu-

larly the targeting of selected patient populations.

Other “hot topics” include clinical trials on

interferon-beta in ARDS, selepressin in septic shock,

inhaled antibiotics in severe lung infections, alkaline

phosphatase in sepsis, a re-exploration of bicarbo-

nate administration in metabolic acidosis, the use of

pupillometry, and the long-term administration of

albumin, just to name a few. And of course, there will

be debates about fluid requirements, types of intrave-

nous fluids, corticosteroids in septic shock, and so on.

What’s then still to come is too much to even

begin to describe, but rest assured that over four

days, 12 rooms and hundreds of individual sessions,

there will be plenty to choose from. Round tables,

tutorials, workshops, pro-con debates, meet the ex-

perts sessions and clinical vignettes all sit alongside

a roster of standard presentations, and of course

our selection of esteemed plenary lectures.

As always, industry is a main driver of how this

meeting is possible, and I would like to sincerely

thank our sponsors for their continued support,

especially in this new regulatory era.

I wish you a truly enlightening ISICEM 2018, and

an enjoyable stay in the great city of Brussels. Don’t

forget to join us at the end of the sessions this even-

ing for the poster discussion, with hors d’oeuvres

and drinks, held in the scientific exhibition area.

See you next year!Jean-Louis Vincent

ISICEM Chairman;

Professor of Intensive Care Medicine, Université

Libre de Bruxelles;

Dept of Intensive Care, Erasme University Hospital

Tuesday 20 March 2018 Day 1

The official daily newsletter of the 38th ISICEM

Experience from the 2016 Nice attack . . . . . . . 5

The future of hemodynamic monitoring . . . . 8

Who should staff the ICU at night? . . . . . . 10

“Close the lungs

and keep them rested!” . . . . . . . 14

Welcome to Brussels!

The future of critical care . . . . . . . . . . . . . . . . 5

AKI: is it inevitable? . . . . . . . . . . . . . 9

Vasospasm a “silent menace” . . . . . . . . . . . . . 10

Should everyone be in a trial? . . . . . . . . . . . . . . 18

Tailored nutrition in and beyond the ICU

Throughout medicine, “one

size does not fit all”, thus

why should the same

nutrition be given at all

stages of the continuum of critical

illness? This will be the message of

Paul Wischmeyer (Department of

Anesthesiology and Surgery, Duke

Clinical Research Institute, Duke Uni-

versity School of Medicine, Durham,

NC, USA), who will take to the stage

today to argue that we must tailor nu-

trition during illness and recovery.

Professor Wischmeyer will spend a

significant amount of time discussing

the Minnesota Starvation Study, a

daring and pioneering exploration of

the physiological and psychological

impact of a calorie restricted diet.1 The

study, led by Dr Ansel Keys and col-

leagues at the University of Minneso-

ta, USA, restricted the diet of healthy

individuals for an initial six-month

period (1,800 kcal/day and ~0.8 g/kg/

day of protein), before trialing what

level of nutrition was needed to bring

them back to a healthy weight.

Wednesday 21 March 2018 Day 2

The official daily newsletter of the 38th ISICEM

Continued on page 2

Delegates of ISICEM 2018

fill the Henry Le Bœuf

auditorium during Tuesday’s

opening session.

L essons from the world of

military medicine were laid

bare on Tuesday morning,

with Michael Reade (Royal

Brisbane Clinical Unit,

Faculty of Medicine, Australia) begin-

ning his presentation by noting that

trauma is a neglected research topic,

both in the civilian and military world.

“Trauma kills more than any other dis-

ease process in patients under the age

of 45,” he said. “And yet in terms of

research funding, it receives substan-

tially less than cardiovascular medicine

and cancer for example.”

He went on to note that advances

in Combat Casualty Care have halved

case-fatality rates on the modern

battlefield in the last 17 years, and in-

deed Combat Casualty Care is now a

“credible academic discipline”. Many

of these innovations should translate

into civilian systems, and if we pause

fighting wars, further advances will

require civilian-military cooperation,

he added.“Most importantly, we’ve essen-

tially eliminated preventable mortality

for hospital care of military trauma

patients,” he said. “Any further im-

provements in case fatality rates will

have to be as result of the improve-

ments in pre-hospital care. And to

do that, we are going to have to

think a little bit beyond our conven-

tional ways.”

He added that clinical trials, if they

are to play a part in the future, will

need to be approached differently.

Thursday 22 March 2018 Day 3The official daily newsletter of the 38th ISICEM

Contributions from military medicine

Continued on page 2

“Military medical research has

a number of challenges, the

principle one being that it is

very difficult to get informed

consent from our patients.”

Michael Reade

From structure to function . . . . . . . . . . . . . 4

The LUNG-SAFE study . . . . . . . . . . . . . . 8

Sepsis in challenging populations . . . . . . . . . . . . . 12

Studying near-death experiences . . . . . . . . . . . . . . 16

‘Evil humors’ in sepsis . . . . . . . . . . . . . 3

e-learning for infection prevention . . . . 6

Is it time for PICS to go? . . . . . . . . . . . . . . 10

A critique of the SSC guidelines . . . . . . . . . . . . . . 15

A number of studies have now shown that resuscita-tion may be affected by factors including sex and

age. These findings are difficult to interpret, however, and demand more detailed investigation of surrounding

circumstances to determine causal influences as well as prognosis and outcome. This topic will be discussed by Sharon Einav (Hebrew University Faculty of Medicine, Jerusalem, Israel) during her plenary lecture today.

In 2014, Kahn et al. reported that

younger age and female sex were associated with longer attempted CPR duration in patients who do not experience return of spontaneous circulation (ROSC) after in-hospital cardiac arrest, but that age and sex were not associated with attempted

CPR duration in those who experi-ence ROSC1.

More recently, Casey and Mumma studied a US-based patient discharge database, finding that female sex, non-white race, and Medicare insur-

Friday 23 March 2018 Day 4The official daily newsletter of the 38th ISICEM

Sex and resuscitationPotential bias, but more research needed

Continued on page 2

See you next year!Thank you for making the 38th ISICEM a great success. We look forward to welcoming you back in 2019!


Can we do more in the week leading up to sepsis hospitalization?

H allie Prescott (VA Center for Clinical Management Research, Health Services

Research & Development Center of Innovation; and University of Michigan, Ann Arbor, MI, USA) will present this morning on recent find-ings of a study of healthcare utiliza-tion and infection in the week prior to sepsis hospitalization.

Dr Prescott has recently published on sepsis readmission1,2, long-term outcomes3-5, and timing of care6. In the retrospective study being presented today, Prescott and col-leagues aimed to identify potential opportunities to improve the recog-nition and treatment of sepsis prior to admission7.

They did this by quantifying encounters with clinicians, including those at hospitals, subacute nursing facilities, emergency departments, and urgent-, primary – and specialty-care centers. All subjects were sepsis patients hospitalized at one of two large integrated healthcare delivery systems in the US – Kaiser Perma-nente Northern California (KPNC), and the Veterans Health Administra-tion (VA) in Ann Arbor, MI.7

During an interview with ISICEM News, she described the motivations for carrying out the study: “All quality improvement programs for sepsis right now focus on getting antibiot-ics and fluids, etc. to patients sooner. They really all start at the time the patient presents to the hospital.

“We know that many patients present late. There have been some studies trying to get treatment to patients sooner. For example, there was recently a randomized controlled trial published where they gave patients antibiotics on the way to

the hospital8. The only study that has been done to try to do pre-hospital treatment is this – in the ambulance.”

The KPNC and VA are both very primary care-based, noted Dr Prescott, with a lot of patients pre-senting through the clinic rather than via ambulance. For this reason, she said, the investigators reasoned that there may be hours of delay on the path to admission, in contrast to the 20 minutes taken by the ambulance.

They sought to quantify how often patients are seen prior to reaching the emergency department, and where are they being seen. Telephone calls with the doctor were excluded. The cohorts from KPNC and VA included over 46,000 patients hospitalized for sepsis, 45% of whom were seen by clinicians in the week leading up to hospitalization, with sharp increases in utilization just prior to admission. Care visits increased particularly on admission day.

“Our question is, for these people [recommended] to go to the ER...could we give them an antibi-otic to take by mouth before they go? Anec-dotally, I can tell you that when people are [told to] go to the ER, a lot of patients

are thinking ‘I’m going to be admitted to the ER, so I’d better go home and get my bag!’. They then present to the hospital hours later.”

These findings presented pre-hospital opportunities for improving recognition and early treatment of sepsis, explained Dr Prescott, describ-ing the three principle characteristics of patients who were seen the week before sepsis admission. “There are people for whom sepsis is actu-ally a hospital readmission; 10% of people were hospitalized during the week prior. Recurrent sepsis is very common. That probably takes certain types of interventions.

The second group are people com-ing from nursing homes (about 8-9% of admissions), she said: “That is a very high-risk population. People get-

ting home help from a visiting nurse are also a high-risk

population, although they weren’t included

in the study. So there have been a couple of dif-ferent programs started in the US to implement daily screen-ing in nursing homes and for people getting home care. This is a 30-second screen, just [looking for]

signs and symp-

toms of infection, and whether there is any evidence of organ dysfunction – these would trigger a call to the doc-tor. The question is, can we identify it earlier? And can we give antibiotics and take bug cultures in the nursing home before we send them in, to jump-start their treatment?”

The final group includes people who have signs and symptoms of infection and go to their physician, or they happen to have a visit for some other reason, leading to initiation of antibiotics. “We don’t have any great tools right now to say what people’s risks of progression to sepsis are, and when we should see them back. The onus is left on the patient, and we don’t give them a ton of direction.”

Asked about any comorbid features that distinguished the 45% of patients who were seen in the week prior to admission for sepsis, Dr Prescott said: “We didn’t see a lot of difference in the patient characteristics between those who did have a visit and who didn’t – although there was a higher risk of death in the people who had a visit beforehand. There are definitely studies that suggest that if sepsis is a second hit, it is more deadly. When sepsis is a hospital readmission, or when it comes after another seri-ous event, survival is lower.”

She added that, despite there be-ing little difference between cohorts seen or not seen the week prior to sepsis hospitalization, the difference in frequency of visits during this week may also reflect an increase in overall frailty of patients in this group.

An overarching theme that has

emerged from this, and similar work, is the need for improved public education

of the warning signs of sepsis as distinguished

from infections manageable at

home. “The US National Center

Identifying the at-risk patient 400 Hall Friday 8:00

“For these people [recommended] to go to the ER...could we give them an antibiotic to take by mouth before they go?”Hallie Prescott

“We found that nearly half of patients were seen some time during that week beforehand in some healthcare setting.”Hallie Prescott


for Disease Control has started a pub-lic awareness campaign focusing on awareness of signs of organ dysfunc-tion,” said Dr Prescott, “saying that if you develop signs such as confusion, or no urine output, or clammy skin, that those are really dangerous signs.”

One avenue of further investiga-tion not covered as of yet would be the study of all patients displaying symptoms of sepsis, in order to distin-guish the risk factors associated with progression to sepsis versus recovery without sepsis. “There are some interventions already happening, to

screen nursing home patients,” said Dr Prescott. “In the outpatient setting, you would have to start from the other direction and look at the whole population of people who present to primary care who have any symptoms and signs of infection and try to predict who are at risk for progres-sion. Those studies are a little bit difficult because some of your risk for progression depends on the treatment that you get, and that varies. Some doctors are more likely than others to give antibiotics. But that is the next step, looking forward.”

Dr Prescott speaks during ‘Identifying the at-risk patient’ taking place in 400 Hall at 8:00 this morning.

References

1. DeMerle KM, Royer SC, Mikkelsen ME

et al. Readmissions for Recurrent Sepsis:

New or Relapsed Infection? Crit Care Med.

2017;45(10):1702-1708.

2. Prescott HC, Donnelly JP. Penalizing Readmis-

sions After Sepsis Could Do More Harm Than

Good. Crit Care Med. 2017;45(7):1243-1244.

3. Meyer N, Harhay MO, Small DS et al. Temporal

Trends in Incidence, Sepsis-Related Mortality,

and Hospital-Based Acute Care After Sepsis.

Crit Care Med. 2018;46(3):354-360.

4. Prescott HC, Angus DC. Enhancing

Recovery From Sepsis: A Review. JAMA.

2018;319(1):62-75.

5. Prescott HC, Costa DK. Improving Long-Term

Outcomes After Sepsis. Crit Care Clin.

2018;34(1):175-188.

6. Meyer N, Harhay MO, Small DS et al. Temporal

Trends in Incidence, Sepsis-Related Mortality,

and Hospital-Based Acute Care After Sepsis.

Crit Care Med. 2018;46(3):354-360.

7. Liu VX, Escobar GJ, Chaudhary R. Healthcare

Utilization and Infection in the Week Prior

to Sepsis Hospitalization. Crit Care Med.

2018;46(4):513-516.

8. Alam N, Oskam E, Stassen PM et al. Prehos-

pital antibiotics in the ambulance for sepsis:

a multicentre, open label, randomised trial.

Lancet Respir Med. 2018;6(1):40-50.

Women will WINImproving gender parity in intensive care medicine

T he Women in Intensive Care Network (WIN)1 was formed to address

the gender imbalance in Australasian intensive care medicine through advocacy, research and the provision of networking opportunities for female intensive care doctors.

Their vision is to improve the representation of women in all facets of intensive care medicine, explained Balasu-bramanian Venkatesh (Princess Alexandra Hospital and Wesley Hospital, University of Queensland, Australia) to ISICEM News.

“The College of Intensive Care Medicine in Australia and New Zealand (CICM), which oversees the training program for ICU doctors, has sponsored the international WIN study examining the representation of women in the International ICU workforce globally. WIN is also supported by ANZICS2 and the Intensive Care Net-work3,” he said.

The gender gap in intensive care medicine was described in 2013 by Victoria Metaxa4. While the participation of women has increased dramati-cally over the past 50 years, she wrote, equality continues to fall short when it comes to attainment, leadership roles, and salaries. This was found to be evident in head of depart-

ment roles, authorship of scientific papers, and member-ship of editorial boards.4

Metaxa also found that medical female representa-tion at the ESICM, SCCM and ANZICS/ACCCN meetings was 10%, 15% and 16%, respectively (non-medical participants, nurses and pharmacists were excluded). The proportion of female faculty members calculated to be 6% in the 32nd ISICEM meeting, and 15% in the 24th ESICM meeting.4

Dr Venkatesh will be presenting up-to-date data on gender in intensive care medi-cine during a session focused on to theme, held this morn-ing. He will also outline the upcoming WIN study, whose aim it is to gather reliable data globally on the representation of women in ICU across train-ing, teaching, clinical work and in research.

Describing the current gender gap in key positions in critical care, he noted: “Data from the CICM registry indicate that about 27% of the trainees and 19% of the fellows in intensive care are women.

“Available data suggest that females are under-repre-sented in training programs, specialist positions, academic faculty and leadership roles

in intensive care,” he said, before encouraging intensive care organizations to take a proactive role in both resolving the lack of data and tackling persistent issues in this arena: “We recommend that national societies and bodies collect more detailed demographic data of their membership, engage with training bodies to promote female enrolment into training programs, facilitate part-time training, and work with employers to develop policies to minimize bullying, discrimination and sexual harassment behaviors at the workplace.”

He concluded: “Increas-ing the awareness of this major social issue amongst the critical care community will engender the develop-

ment of proactive strategies to change culture, increase social accountability and ensure gender parity.”

‘Gender in intensive care medicine’ takes place in Lip-pens Room (kbr) from 11:55 to 12:50 today.

References

1. Women in Intensive Care. http://www.womenintensive.org (accessed Mar 2018).

2. Australian and New Zealand Intensive Care Society - Advocate for Intensive Care throughout Australia and New Zealand. http://www.anzics.com.au (accessed Mar 2018).

3. Intensive Care Network. https://intensivecarenetwork.com (accessed Mar 2018).

4. Metaxa V. Is this (still) a man’s world? Crit Care. 2013; 17(1): 112.

Gender in intensive care medicine Lippens Room (kbr) Friday 11:55

“Increasing the awareness of this major social issue amongst the critical care community will engender the development of proactive strategies.”Balasubramanian Venkatesh


Long-term outcomes 400 Hall Friday 13:30

Time to get rid of PICS?C hallenging the received wis-

dom on Post-Intensive Care Syndrome (PICS) will be focus

of a presentation by Jeremy Kahn, an intensivist physician and health services researcher and Professor of Critical Care Medicine and Health Policy & Management at the Univer-sity of Pittsburgh School of Medicine and Graduate School of Public Health, USA. Professor Kahn, who has a keen interest in the long-term outcomes of critically-ill patients, will speak at this afternoon’s ‘Long-term outcomes’ session. “I’ll be the first to admit that my argument is a bit contrarian. But it’s an important argument nonethe-less,” he told ISICEM News.

Getting straight to the point, Professor Kahn plans to ask the ISICEM audience whether they believe PICS really exists. “In the last five years we’ve taken to calling the constellations of signs and symp-toms experienced by ICU survivors as ‘PICS’,” he said. “In my talk I will take the somewhat controversial position that although the issues facing ICU survivors are real, PICS is not.

“Put another way, PICS is not an actual medical syndrome like Acquired Immune Deficiency Syndrome (AIDS), Cushing’s Syndrome, or Guillain–Barré syndrome,” he added.

Professor Kahn has an interest in ICU organization and management, especially strategies to improve ICU outcomes by targeting the critical care delivery system. That includes the ramifications of ICU treatment. “In the last two decades, we’ve greatly advanced our understanding of long-term outcomes, in particular the recognition that many ICU survivors experience serious emotional, neuro-cognitive, and physical deficits. This is undeniable,” he said. “In my own practice I rarely get to see survivors in follow-up but when I do, they fre-quently acknowledge their struggles with recovery.”

Professor Kahn said there are two reasons for his proposition. “First, the symptoms that make up a syndrome should share a common causal path-way,” he explained. Indeed, the three elements of PICS (emotional distress, neurocognitive deficits, and physical weakness) do not share a common biological mechanism. “The risk fac-tors are different for each, and what causes one does not cause another,” he said.

Secondly, the symptoms that make up a syndrome should track together:

“Having one should make you more likely to have another. That’s not true in PICS,” said Professor Kahn, who plans to show unpublished data demonstrating his standpoint. “Together, this evidence demon-strates that PICS is not a medical syn-drome; it’s just a name given to the bad things that have happened to ICU survivors, which may be re-lated to their ICU stay,” he said.

Although he disagrees with the notion of PICS, Professor Kahn said he understands why others don’t. ”Some think that it’s not necessarily bad that we’ve given a name to something that doesn’t really exist. By defining PICS we’ve greatly increased awareness of the problem,” he said. “That it is just marketing is a reasonable argument.”

The problem lies with potential harms, according to Professor Kahn. “First, by lumping unrelated symp-toms together into a syndrome, we create confusion for clinicians who may think they need to go looking for all of these things together,” he said.

“Second, we create the false no-tion that there is a common treatment for these problems, thus diverting our attention away from looking at the biological mechanisms specific to each one,” he explained. “As a result, we get non-specific treatments for a non-specific medical problem.”

He cited an example of post-ICU clinics that have mushroomed specifi-cally to care for ICU survivors. “There are no data to suggest that they do anything, but they continue to prolif-erate, based in part on the notion that PICS is real and can be treated,” he said. “In reality, these clinics end up

being just wasteful spending.”Professor Kahn added that creat-

ing syndromes where none exist runs counter to the scientific method. “Centuries of medical science has taught us that disease is caused by specific biologi-cal mechanisms,” he explained “Whenever we’ve succeeded in treating these dis-eases, it’s because we understood the specific mech-anisms.

“PICS is a step backward from that paradigm,

and we could do better,” he added.However, because the syndrome

has such traction amongst health

providers, it may be almost impos-sible to halt its usage. “The PICS train may have left the station. It may be too late to stop,” he cautioned. That being said, backtracking from a syndrome has happened in other fields. “For example, the ‘metabolic syndrome’, once thought to be a real thing, is now increasingly viewed as a conflation of diseases that don’t really go together,” he explained. “Cardiolo-gists and endocrinologists are moving away from the term, which many view as causing more harm than good.”

Taken as a whole, Professor Kahn will suggest that everybody should stop using the term PICS. Further-more, research must understand more about the causes and outcomes of the individual diseases that make up PICS. “The problems are real, and they should be approached as such – how-ever, they should be approached as in-dividual diseases, not as a syndrome,” he concluded.

“PICS is not a medical syndrome; it’s just a name given to the bad things that have happened to ICU survivors, which may be related to their ICU stay.”Jeremy Kahn

“… by lumping unrelated symptoms together into a syndrome, we create confusion for clinicians.”Jeremy Kahn


Innovative thinking in critical care for resource limited settings

I nternational perspectives in critical care will be showcased this afternoon, with topics includ-ing the burden of sepsis, the global emergence

of melioidosis and other economic and region-spe-cific challenges being laid bare. Discussing critical care in resource-limited countries will be Michael T McCurdy, an associate professor of both Pulmo-nary and Critical Care and Emergency Medicine at the University of Maryland, USA.

When Professor McCurdy and his colleagues helped establish an ICU in St. Luke’s Hospital in Port-au-Prince, Haiti, the poorest country in the Western hemisphere, he was asked why. “Many people asked me, why aren’t you working towards other things – like vaccinations – why are you even addressing critical care?” he told ISICEM News.

“If people arrive after a car crash to the emer-gency department in Port-au-Prince, for example, we still aggressively care for those individuals. Therefore, the issue is not whether we care for

them, but instead we should focus on how we choose to care for them. And if we are going to care for these critically-ill patients, it must be in the most clinically effective and cost-effective man-ner possible.”

Certainly, the lack of ICUs in countries like Haiti or sub-Saharan Africa has an impact on mortality, continued Professor McCurdy. “Mortality is much higher in resource-limited settings, there’s no doubt about it. And the numbers of critically ill patients are largely acquired from evaluations of individu-als that are actually able to arrive at the hospital, where the data can be collected,” he said. “So many individuals never make it to the hospital, and may never be tallied as critically ill. Whether it’s lack of transportation, or they just don’t want to leave their homes, insufficient data is a real problem.”

Of course, there are inherent problems that make setting up an ICU extremely difficult, said Pro-fessor McCurdy. “The ratio of physicians and nurses to patients, a dearth of directly relevant medical literature to provide clear-cut guidance for how to deliver optimal clinical care, and a lack of standard-ized education for medical specialty training are all definitely problems,” he added.

In addition, Professor McCurdy challenges the assumption that ICU models from US hospitals can

be applied in other regions. “It’s not just about taking our protocols and what’s suc-cessful for us in resource-rich settings, and then transporting and implementing them to different environments – it’s really about

studying whether or not our protocols even apply in these settings,” he said.

For example, a paper published last year on sepsis protocols in Zambia showed that some of those protocols actually end up making things worse1. “It begs the question, are we dedicating the right amount of effort into researching the right medical interventions there? Dupli-cating what we do here may very well produce worse outcomes,” he said.

Professor McCurdy said he will use his presentation today to look at ways in which critical care can be built up in resource-limited settings in a sustainable way: “We need to focus on sustainability, op-timizing care delivery and education, and delivering a more collaborative approach with on-the-ground providers who know much more than we do about how to be effective in their own environment. We need to be creative and adaptable in the absence of adequate oxygen or beds or x-rays or labora-tory data.”

For example, Professor McCurdy started a

website, which provides learning to fellow critical care specialists in the US and around the world. “I think key components to improving critical care delivery are education and research. I’d like to see more collaboration with physicians and nurses in resource-limited settings in order to adapt existing evidence-based clinical protocols to their environ-ments, as well as promote high quality education,” he explained.

“Having free, open-access medical education for physicians and nurses in resource-limited settings has helped. The Critical Care Project (ccproject.com) attempts to educate and prepare clinicians, and it’s been accessed in over 180 countries.”

Other initiatives are underway, noted Professor McCurdy, including the CERTAIN (Checklist for Early Recognition and Treatment of Acute Illness and iNjury) initiative – a standardized approach to the evaluation and treatment of acutely decompensat-ing patients through a checklist-based system. “We found that the checklist works for us in the United States to ensure that individual elements of quality care are performed,” he said.

Certainly, pragmatic thinking is also required to get around many of the seemingly intractable prob-lems associated with resource-limited settings, e.g. lack of access to medicines, X-ray provision, ICU beds, uninterrupted power sources and oxygen sup-plies. “We need to figure out sustainable ways for-ward,” he said. For example, Professor McCurdy’s wife is an environmental attorney, and her company donated solar panels to the hospital in Haiti to help provide a reliable energy source. Not stopping there, colleagues in Haiti also designed an oxygen concentrator to work with the power supply.

In fact, Professor McCurdy reasoned that this kind of collaborative approach could be a very fruitful model going forward: “Globalization has increased

awareness of the importance of critical care in resource-limited set-tings. This recognition has prompt-ed increased efforts to optimize how we approach medical care delivery in those environments.”

In conclusion, he said: “The doctors in these places are many times more skilled than we are in a lot of ways but are forced to function in a less than ideal envi-ronment, with limited resources. Financial assistance is great, but our primary focus should reside in comprehensive collaborative efforts with the providers in those

environments to vigorously develop, study, and implement locally relevant, evidence-based clinical protocols and support high-quality education to enable meaningful sustainable change.”

References1. Andrews B, et al. Effect of an Early Resuscitation Protocol on In-

hospital Mortality Among Adults With Sepsis and Hypotension. A Randomized Clinical Trial. JAMA. 2017;318(13):1233–1240.

International perspectives Lippens Room Friday 14:05

“Mortality is much higher in resource-limited settings, there’s no doubt about it.”Michael T McCurdy

“I’d like to see more collaboration with physicians and nurses in resource-limited settings in order to adapt existing evidence-based clinical protocols to their environments, as well as promote high quality education.”Michael T McCurdy


Congratulations to this year’s Poster Award winners! Head to isicem.esn.eu to read their work.P515 Organ failure and return to work after intensive care: S Riddersholm; S Chris-tensen; K Kragholm; CF Christiansen; BS Rasmussen. From Denmark

P228 The circadian clock protein BMAL1 regulates the severity of ventilator-induced lung injury in mice: M Felten; LG Teixeira-Alves; E Letsiou; HC Müller-Redetzky; N Sut-torp; A Kramer; B Maier; M Witzenrath. From Berlin, Ger-many

P141 Effect of positive end expira-tory pressure on left ventricu-lar contractility: M Gruebler; M Gruebler; O Wigger; S Bloechlinger; D Berger. From Bern, Switzerland

P7 Melusine protects from LPS - induced cardiomyopa-

thy through modulation of Calcium Channel signaling: P Arina; A Costamagna; L

Brazzi; M Brancaccio; R Gi-useppe; N Vitale; L Del Sorbo; P Capello; A Mazzeo; L

Mascia; VM Ranieri; M Sorge; V Fanelli. From Italy

P61 Short term antibiotics prevent early VAP in patients treated with mild therapeutic hypo-thermia after cardiac arrest: T Daix; A Cariou; F Meziani; PF Dequin; C Guitton; N Deye; G Plantefève; JP Quenot; A Desachy; T Kamel; S Bedon-Carte; JL Diehl; N Chudeau; E Karam; F RenonCarron; A Hernandez Padilla; P Vignon; A Le Gouge; B François

P78 Efficacy of phage therapy against lethal methicillin re-sistant Staphylococcus aureus (MRSA) ventilator associated pneumonia in rats (VAP): J Prazak; P Reichlin; D Grand-girard; G Resch; M Qiao; S Nansoz; Y Que; M Haenggi


First, do no harmEvidence-based medicine has been hijacked

I n what is likely the be a provoking discussion this morning, Giuseppe Citerio of the Università Milano

Bicocca, Italy, will be taking on the Guidelines for the Management of Traumatic Brain Injury (TBI), released by the Brain Trauma Foundation, the most authoritative entity releas-ing guidelines associated with the American Association of Neurological Surgeons, and Congress of Neurologi-cal Surgeons.

The TBI guidelines have been re-viewed every three to four years, but there are significant problems with the most recent edition according to Professor Citerio. “We found that the new guidelines are taking us in the wrong direction. They are not helping clinicians,” he told ISICEM News. “So as a clinician involved in TBI care, I’d like to discuss why the new guidelines are worsening over time.”

These most recent guidelines, published in January 2017, have quite rightly aimed at a higher level of rigor. But, said Professor Citerio – who has published on this topic1 – the pursuit of good-quality evidence means the guidelines have become less helpful to clinicians. “So, the exercise, mainly by American neurosurgeons, has only been to revise what the available evidence is, and by increasing the rigorousness they have reduced the information that was present in the previous release, and then downgrad-ed all the information we were given as clinicians,” he said. “We have an empty shell where nothing is written, because we don’t have any evidence on many topics.”

Take mannitol, a drug used to reduce intracranial pressure (ICP), for example. “If you look at the previous guidance, it said mannitol is effective in controlling ICP in real life situations. It’s been used since the ‘50s and, in my unit, almost daily,” he said.

But, as a result of too rigorous an appraisal of the available evidence, support for the use of mannitol has now been downgraded. “The prob-lem is, the new guidelines say this therapy may lower ICP, but there is insufficient evidence to support this specific recommenda-tion, or support any specific therapy,” he explained.

That phrase is particularly problem-atic for practicing clinicians, explained Professor Citerio: “If you have a drug that reduces ICP but, because there is not a clear strong effect on outcome within the trials, the guidelines don’t support any specific recommenda-tions, you don’t know whether to use the drug. There are physiological explanations that have to be taken in consideration, and the evidence is the same as we had for the previous editions. But, instead, we are giving no information to the clinician. If you don’t solve the problem the patient is not receiving any treatment.

“The clinician is going to a guid-ance source and needs a good quality evaluation of the evidence that, while perhaps a little strict, in the end pro-vides all the implementation informa-tion available,” said Professor Citerio. “It’s not just about using randomized controlled trials as evidence, because there are other sources of evidence.”

A lack of recommendations within the guidelines are not limited to the treatment of ICP with mannitol. Professor Citerio said he will discuss problems with recommendations on a range of other topics including advanced cerebral monitoring and threshold ICP levels. “The idea was that they were going to be more rig-orous, but they’ve ended up confus-ing the situation. They have removed the useful clinical suggestions from the guidelines,” he said.

In many cases, the available evidence has not actually changed, only the way in which the evidence is interpreted. “Evidence-based medicine needs to help the clinician to harness the best evidence when making decisions for their patients,” said Professor Citerio. “So, say you don’t have so much evidence, and the only evidence has been down-

graded – the message to the clinician disappears progressively.”

Professor Citerio added that he understands why it is important to

assess the effective-ness of treatments. “The guidance needs to be rigor-ous, which I accept – and I think that is the most important part, because you need to evaluate the evidence you have,” he said.

That being said, he suggested that there might be a more pragmatic approach to drawing up useful guidelines in the absence of the best possible evidence: “When you have a small

amounts of evidence, you can put together rigorously all the evidence you have, using the method suggested also by the father of Evidence-Based Medicine, Professor Sackett, and give to colleagues

less strong suggestions.” Indeed, a group led by Mauro Oddo and Giuseppe Citerio has tried to do just that developing an ESICM consensus

and clinical practice recommendations for fluid therapy in neurointensive care patients, with independent assess-ment, for example, of the effectiveness of mannitol. 2

Concluding, he said: “Otherwise we cannot understand

why you are producing guidelines that effectively say, ‘we know nothing on many topics’. We know the evidence may not be so strong, but if you downgrade the recommendations to the clinician for that reason – even if the evidence is always the same as before – the clinician thinks that is strange. You’re effectively giving less advice every time there is a new edition. We are hijacking evidence-based medicine.”

References1. Meyfroidt G, Citerio G. Letter: Guidelines for

the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery 2017;

2. Oddo M et al. Fluid therapy in neurointensive care patients: ESICM consensus and clinical practice recommendations. Intensive Care Med 2018; 1–15

Traumatic Brain Injury Copper Hall Friday 10:20

“We have an empty shell where nothing is written, because we don’t have any evidence on many topics.”Giuseppe Citerio

“We found that the new guidelines are taking us in the wrong direction. They are not helping clinicians.”Giuseppe Citerio


Early resuscitation in sepsis Copper Hall Thursday 08:00

Surviving Sepsis Campaign guidelines – an unreserved critique

T he 2016 Surviving Sepsis Campaign (SSC) guidelines came in for a provocative and highly critical analysis by leading intensivist

Jean-Louis Teboul, (Centre Hospitalier de Bicêtre, Le Kremlin-Bicêtre, France) in yesterday’s session dedicated to Early Resuscitation in Sepsis.

Professor Teboul warned delegates that he would be particularly provocative, without reserve, as he identified parts of the 2016 guidelines and provided his assessment of where his opinion dif-fered and why.

The Surviving Sepsis Campaign is an initiative of the Society of Critical Care Medicine, the European

Society of Intensive Care -Medicine and the Interna-tional Sepsis Forum. The most recent SSC guidelines for the management of severe sepsis and septic shock were released in 2016 and were compiled by a committee of around 70 critical care physicians, sponsored by Jointly sponsored by the European Society of Inten-sive Medicine (ESICM) and the Society of Critical Care Medicine (SCCM).

Professor Teboul began by noting the difference

between the 2012 and 2016 guidelines. He highlighted that the former guidelines for fluid and hemodynamic resus-citation utilized central venous pressure (CVP) and ScvO2.

“It was derived from the Rivers study1 published in

2001 that found a difference in mortality between a standard care group and early goal directed therapy (EGDT) with a difference according to ScvO2,” Professor Teboul commented.

New Study Investigates the Clinical Utility of ORi™, Masimo Oxygen Reserve Index™, in Obese Patients

New study presented at the annual meeting of the So-ciety for Technology in An-

esthesia (STA) in Miami, Florida. In the study, researchers at the UC Davis School of Medicine evalu-ated the potential clinical utility of Masimo Oxygen Reserve Index™ (ORi™) as an early warning of impending arterial hemoglobin desaturation in obese patients.1 This is the first published research investigating the utility of ORi in this particular population group.

ORi is a relative indicator of a patient’s oxygen reserve in the moderate hyperoxic region (partial pressure of oxygen in arterial blood [PaO2] in the range of 100 to 200 mmHg). As an “index” parameter with a unit-less scale between 0 and 1, ORi can be trended and has optional alarms to notify clinicians of changes in a patient’s oxygen re-serve.

In the prospective, observation-al study, Dr. Ayala and colleagues analyzed data from 36 adult patients with BMI between 30 and 40 kg/m2 who were scheduled for elective surgical procedures requiring general anesthesia and endotracheal intubation. The patients’ ORi values were meas-ured using a Masimo Root® Patient Monitoring and Connectivity Platform with Radical-7® Pulse

CO-Oximeter®. The researchers recorded the time elapsed from the start of ORi alarming (triggered by decrease in the absolute value and rate of change in ORi) to 98% oxy-gen saturation, and considered this interval to be the average increase in warning time provided by ORi.

The researchers found that among the patients, the average

time from the start of ORi alarm-ing to 98% oxygen saturation was 42 ± 49 seconds (ranging from 5 to 255 seconds). Excluding two outliers, the average increase in warning time provided by ORi was 33 ± 23 seconds (ranging from 5 to 107 seconds).

The researchers concluded that the study “demonstrates the

ability of ORi to provide advanced warning of arterial desaturation as an adjunct to SpO2 in this high risk patient population. This addi-tional warning time can potentially translate to improved patient safety by allowing earlier calls for help, assistance from a more experienced person, or modification of airway management. For this analysis we defined the advance warning to end at 98% SpO2, with a defined trigger for intervention at 94% SpO2.”

In another study, researchers at Children’s Medical Center in Dallas, Texas concluded that ORi could provide clinicians with a median of 31.5 seconds advanced warning of impending desaturation in pediatric patients with induced apnea after pre-oxygenation.2

UC Davis received funding from Masimo for the ORi study. ORi has not received FDA 510(k) clear-ance and is not available for sale in the United States.

References

1. Ayala S, Singh A, Applegate R, and Fleming N. Oxygen Reserve Index: Utility as Early Warning of Desaturation in Morbidly Obese Patients. Proceedings from the 2018 STA Annual Meeting, Miami, FL.

2. Szmuk P et al. Oxygen Reserve Index A Novel Noninvasive Measure of Oxygen Reserve–A Pilot Study. Anesthesiology. 4 2016, Vol. 124, 779-784. doi:10.1097/ALN.0000000000001009.

“… my opinion is that these SSC guidelines need to be revised.”Jean-Louis Teboul

Continued on page 16


The study found that EGDT provides significant benefits with respect to outcome in patients with severe sepsis and septic shock. “EGDT was pro-posed for guiding resuscitation in severe sepsis and septic shock patients,” he added.

However, Professor Teboul pointed out that these goals disappear in the 2016 guidelines. This includes CVP of 8-12 mmHg; central venous (supe-rior vena cava) or mixed venous oxygen saturation of 70% or 65% respectively. “CVP has disappeared because it cannot tell you anything about fluid responsiveness,” he stressed.

Use of ScvO2 has also disappeared, he added, because of the results of three randomized controlled trials (RCTs) that compared standard of care with EGDT, showing no benefit in terms of outcome. The results conflicted with the results of the Rivers study, he pointed out.

“By design these studies could not tell you anything about targeting ScvO2 above 70% when it is low. However, I still strongly believe that when ScvO2 is low, attempting to increase it makes sense,” Professor Teboul asserted.

Next, he turned to the 2016 recommendation that says that in the resuscita-tion of sepsis-induced hypop-erfusion, at least 30 ml/kg of IV crystalloid fluid be given in the first three hours. “I have been a senior intensivist for 30 years and I think it is unbelievable to read this,” he said, adding: “Of course, there is a risk of under-resuscitation in some patients with profound hypovolemia, and with fluid losses; but also over-resuscitation in some other patients for example sep-sis from lung infection. Again, one size does not fit all, and we cannot recommend a fixed volume of initial fluid.”

Also, it is recommended that after three hours, the patient should be reassessed, including an examination of physical and physiologic variables, among others. “I agree with reassess-ment, but not at three hours. We should not wait this long because in three hours the patient has time to die. We need to reassess ear-lier.”

Profes-sor Teboul

proposed that for a patient presenting with septic shock, he would recommend infusion at approxi-mately 10 ml/kg within the first 45 minutes to one hour. “You should adapt depending on the func-tion of the patient, for example, if there are evident fluid losses then we need to give more,” he said.

“Also if there is mottling, which is associated with profound hypovolemia, or abdominal sepsis, the patient will need more than for a lung infec-tion. Likewise, low pulse pressure will need more. But decrease the infusion if there is tachypnea or a

fall in O2 saturation.”He continued by saying that if the

shock persists after the 45-60 minutes, then it is time to test responsiveness. He drew attention to the fact that studies show only around 52% of patients respond to fluid administration in terms of cardiac output increase. “We need to identify patients who are not

fluid responders, given that we know fluid overload can

be harmful.”Also, he pointed

out, it is now recom-mended according to the report by the Task Force of the

European Soci-ety of Intensive Care

Monitoring, entitled ‘Consensus on circulator

shock and hemody-namic monitoring’,

to use dynamic over static vari-ables to predict fluid responsive-ness when ap-

plicable.If the

shock persists, and there is preload responsiveness, but no ARDS, then continue the fluid, advised Professor Teboul. “However, if there is associated ARDS, you should assess the benefits and risks of further fluid administration. If the benefit is higher than the risk, then consider another fluid bolus, if not, then consider other therapies. Also consider other therapies if the patient is not responsive after initial fluid resuscitation,” he said.

Briefly turning to vasopressors, Professor Teboul emphasized that the recent SSC guidelines were unclear about when norepinephrine should be initiated. “It might be understood that a decision should be made at the time of the first reassess-ment (three hours) but this is too late if the vaso-motor tone is depressed.”

He pointed out that he would recommend identifying low vasomotor tone by looking at the diastolic blood pressure. “If it is low, it usually means that the vasomotor tone is low.” He added that early initiation of norepinephrine cannot only correct hypotension, in the case of low vasomotor tone, but can also correct harmful fluid overload.

Finally, said Professor Teboul, the 2016 recom-mendations suggest normalizing lactate in patients with elevated lactate levels as a marker of tissue hy-poperfusion. He advised remembering that even in survivors, normalization of lactate needs time, more than 24 hours. “Since non hypoperfusion-related hyperlactatemia might predominate in an unknown number of patients, then aiming at strictly normal-izing lactate might lead to excessive resuscitation with inherent fluid and vasopressor overload, and eventually to increased morbidity and mortality.”

He concluded: “I think that ScvO2 is missing. I think that timing of the initiation of norepinephrine is poorly defined and my

opinion is that these SSC guidelines need to be revised.”

References1. Rivers E, et al. Early Goal-Directed Therapy in the

Treatment of Severe Sepsis and Septic Shock. NEJM. 2001;345(19):1368-1377.

Early resuscitation in sepsis Copper Hall Thursday 08:00

“I have been a senior intensivist for 30 years and I think it is unbelievable to read this.”Jean-Louis

Teboul

Surviving Sepsis Campaign guidelinesContinued from page 15

Moderators Ashish Khanna and Tarek Sharshar


50 years of ARDS: What have we learned?

A historical overview of the increasing knowledge base in acute respiratory distress

syndrome (ARDS) was shared yester-day at ISICEM, with Arthur S Slutsky (St. Michael’s Hospital, Toronto, ON, Canada) touching upon the key les-sons from more than half a century of ARDS treatment and research.

Although ARDS has been recog-nized since around the time of the Second World War, it was Ashbaugh et al.’s landmark paper in 1967 that arguably sparked the real beginnings of interest in the syndrome.1 Profes-sor Slutsky touched on several key perspectives from the 50-year ARDS journey thus far, and pointed towards what the next 50 years may bring.

Starting with the role of cellular and humoral components of inflam-matory response, he told ISICEM News: “We have learned (or we think that we have learned) a lot about the inflam-matory mechanisms underlying ARDS. This has led to a large number of publica-tions in well-respected journals, but not one therapeutic strategy has been shown to be helpful in humans. Negative trials have included: n-acetyl-cysteine, antioxidants, prostaglandin E1, neutrophil elastase inhibitors, activated protein-C, ketocona-zole, and statins.”

But there have been more definitive lessoned learned, con-tinued Professor Slutsky: “We have learned that a major defect in ARDS is increased alveolar-capillary permeabil-ity leading to increased fluid in the air-spaces of the lung, which leads to sur-factant dysfunction, collapse of lung units, with subsequent hypoxemia. Because of the collapse, and the fluid-filled lungs, large parts of the lung are not available for ventilation, leaving a relatively small portion [the so-called ‘baby lung’]. When one ventilates this lung with relatively normal-sized tidal volumes, this can lead to injury to the lung, i.e. ventilator-induced lung injury [VILI].”

Therefore, he added, the only therapies that have been shown to be effective in patients with ARDS are lung protective strategies, largely

based on our physiologic under-standing that there are iatrogenic con-sequences to mechanical ventilation – although at the same time it is a life-saving therapy.

Indeed, he emphasized that lung-protective strategies have seen proven mor-tality benefit. For instance, small tidal ventilation (6 ml versus 12 ml/kg; predicted body weight) decreased mortality by an absolute 9%. Further-more, ventilating ARDS with a PaO2/FiO2 (PF) ratio <150 for patients in the prone position versus the supine

position decreased mortality by about 15% (absolute). Thirdly, use of a neu-romuscular blocking agent over 48 hours for patients with PF ratio <150 decreased mortality, thought to be via its impact on decreasing patient-venti-lator synchrony and subsequent VILI.

“The important concept is that all of these interventions are based on our understanding of the physiologi-

cal underpinnings of ARDS, not any inflammatory or molecular mecha-nisms,” said Professor Slutsky.

“The consequences of VILI (in-

creased alveolar-capillary permeability, hypoxemia, stiff lungs, inflammation) are virtually identical in patients diag-nosed with ARDS,” he added. “There is evidence that patients who don’t have ARDS at baseline are more likely to develop it if they are ventilated with larger tidal volumes. An RCT-2demonstrated that patients with nor-mal lungs at baseline were more likely

to develop ARDS if they were treated with a non-lung protective ventilation strategy.”

Turning to the potential benefit of focusing on positive end-expiratory pressure (PEEP) – rather than improved gas exchange – to avoid constant opening and closing of

lungs (which in turn may cause VILI), Professor Slutsky commented that the use of PEEP in ARDS is somewhat

50 years of ARDS Salle M (Bozar) Thursday 08:00

“We have learned (or we think that we have learned) a lot about the inflammatory mechanisms underlying ARDS. This has led to a large number of publications in well-respected journals, but not one therapeutic strategy has been shown to be helpful in humans.”Arthur S Slutsky

Continued on page 18

“Clearly, we need a better understanding of the inflammatory responses underlying ARDS, which pathways are causally linked to outcomes, and which are simply ‘bystanders’.”Arthur S Slutsky


50 years of ARDS Salle M (Bozar) Thursday 08:00

controversial. “Human studies do not show as much benefit as one would expect … a meta-analysis demonstrat-ed a decreased mortality in patients with PF ratio <200,” he said.

Professor Slutsky argued that the less than dramatic clinical effects of PEEP may be due to the fact that in studies, the ‘low PEEP’ groups still receive PEEP greater than 5 cmH2O. He also noted that there is heteroge-neity in response, with some patients having recruitable lungs (i.e. would be more likely to benefit from PEEP) and some patients having non-recruitable lungs (i.e. they are more likely to be harmed). “No RCTs to date have focused on the more recruitable patients,” he said.

“In any event, to the extent that PEEP does decrease mortality in ARDS, it is most likely due to decreased VILI rather than the increase in PaO2.”

Quality of life (QoL) has also seen more focus in recent years, with a lot of work showing that patients with ARDS have an impacted QoL for up to five years or more. This includes physi-ological consequences (decreased exercise capacity) and psychological sequelae3, said Professor Slutsky.

Still a lot to learn?Looking to the future, Professor Slutsky stressed that we need better comprehension regarding the role of neutrophils, alveolar macrophages, platelets, the complement system, and inflam-matory mediators in the precise sequence of events leading to ARDS. “Clearly, we need a better understanding of the inflamma-tory responses underlying ARDS, which pathways are causally linked to outcomes, and which are simply ‘bystanders’,” he said.

“We need a better under-standing in individual patients – all patients may not have identical pathways turned on. We need to know if there is a genetic predis-position to ARDS, to identify which patients are more likely to develop ARDS, and which are most likely to die from ARDS. Also, perhaps those which are more susceptible to the inflammatory consequences of VILI – so-called ventilogenomics.”

Reprising the discussion on PEEP, he cautioned that optimal PEEP levels still allude consensus. ”We’ve been playing with optimum levels … varying by +/- 5 cmH2O for 50 years,

with no great resolution to this issue – likely because of the physiological factors described above (the need to identify patients with recruitable lungs versus non-recruitable lungs).”

Adding his conclusions as to what might be important in the next 50 years of ARDS, Professor Slutsky first emphasized that we need a much better definition of the syndrome, along with biomarkers that can better characterize patients. “We need defi-nitions based on biology, not simply based on physiology,” he said. “We

would then be able to (hope-fully) identify specific drugs for patients who have specific molecular derangements.”

Given that the fundamen-tal abnormality in ARDS is increased alveolar-capillary permeability, he underlined the importance of finding a better way to measure at the bedside. Furthermore, we need drugs that focus on improving alveolar-capillary permeability, he added.

Finally, Professor Slutsky noted that the future of ARDS would benefit from finding bet-ter ways to set optimal ventila-tory strategies and, similarly, we

need to achieve better understanding of role of supportive therapies such as ECMO and extracorporeal carbon dioxide removal (ECCO2R).

References1. Slutsky AS, Villar J and Pesenti A. Happy

50th birthday ARDS! Intensive Care Med. 2016;42:637–639.

2. Determann RM, et al. Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial. Crit Care. 2010; 14(1): R1.

3. Herridge M, et al. Functional Disability 5 Years after Acute Respiratory Distress Syndrome. N Engl J Med 2011; 364:1293-1304.

50 years of ARDS: What have we learned?Continued from page 17

“We need definitions

based on biology,

not simply based on

physiology. We would

then be able to (hopefully)

identify specific drugs for

patients who have specific

molecular derangements.”Arthur S Slutsky

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