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Wednesday 18 March 2015 Day 2The official daily newsletter of the 35th ISICEM

Hitting the right notes to kick-start ISICEM 2015

D elegates attending yesterday’s opening session were treated first to a musical introduction on the piano, before Profes-

sor Jean-Louis Vincent began his welcome address with one key message: we should “Say YES!” to intensive care medicine.

This message was followed by an extensive ses-

sion that saw a number of invited experts take to the podium to discuss topics including: The Round Table conference on ‘Reducing the global burden of sepsis – developing a roadmap’; results of the ProM-ISEe trial; whether the age of blood transfusions affects patient outcomes; SIRS; and personalised medicine as a future staple of intensive care.

Personalised medicine is the future! . . . . . . . . . . . . . . . . . 3

Digesting the role of the microbiome in critical illness . . . . . . . . . . . . . . .6

Keeping patients’ best interests at heart . . . . . . . . . . . . . . .10

Are sepsis rates on the rise? . . . . . . . . . . . . . . . . 13

2 ISICEM News Wednesday 18 March 2015 Issue 2

C oncluding yesterday morn-ing’s opening session was Hector Wong (Cincinnati

Children’s Hospital Medical Center, and University of Cincinnati), who explored the future of personalized medicine, with a look to the path-ways being forged in this direction in sepsis research. The hope here, he explained, is to bring new tools to the bedside to better understand individual patients’ risks and opti-mal therapies.

“In a recent State of the Union address back in February, president Obama declared what he called his Precision Medicine Initiative1, which sets aside a very large sum of money in the next budget season to actually address personalized medicine, think-ing through the differences in the gene variants and the genome and so forth to really impact how we go about targeting patients in the future for specific therapies.”

A recent editorial piece by Harold Varmus and Francis Collins, two leading US scientists, advocated for this initiative, although it marked out oncology as the most prominent

target for personalized medicine2, wherein the targets lie within identifying tumor gene variants that might affect disease course or respond in certain ways to chemo-therapeutic agents.

But, explained Dr Wong, per-sonalized medicine means different things to many people: “In general, when people think about person-alized medicine they think about DNA, about how variations in gene function and gene structure can impact responses to therapy, disease outcome and perhaps how medica-tion can be better used.

“But where does that leave us in critical care medicine?” He asked, seeking to illustrate how the field is crying out for similar principles in order to improve the way that we deal with patients in conditions such as septic shock, acute respiratory distress (ARDS), sepsis, acute kidney injury and multiple organ dysfunction: “I would say that, in theory, based on the many things that we have talked about here today, is that we deal primarily with very heterogene-

ous syndromes rather than actual diseases. So I would argue that these concepts of personalized medicine are very, very applicable to what we do.

“The general concept is focused on diagnostic testing, and how one uses this to customize therapy increasingly based both on genetics and biological characteristics. In criti-cal care, we can apply those concepts with a little bit of a twist, in that be-cause we are dealing with syndromes we really need to define sub-classes – what we call ‘endotypes’ – of a disease, and then customize accord-ing to these biologically-defined endotypes.”

Sepsis, and all the research en-compassing it, is heavily intertwined with such concepts. However, stark differences must also be highlighted between a field such as oncology and any topic within intensive care

– namely, the time-critical nature of critical illness. Dr Wong explained that, in oncology, the fact that whole-exome sequencing takes weeks to complete has little bearing on outcomes. Not so in critical care, and as such a new paradigm must be thought out in order to gain useful data from genetic testing in a time-frame that is meaningful to patients: “Any approach that we are thinking about developing must take this into account, and David Maslave recently wrote very elegantly to this point.3”

“We have been very thought-ful about this over the years,” he continued, describing some examples of the sort of work that has shown promise up to now: “Dr Annane’s paper back in 2002 looked for responders and non-responders to the cortisol stimulation test.4 That is a very basic principle of personalized medicine. It turns out that things aren’t as easy as we had thought, but nevertheless it is very good example of this concept.

“Dr Mira, back in 1999 in JAMA published an article showing that variations in the TNF-alpha promo-tor had function consequences not only for how much TNF is produced

during sepsis but also how it is related to outcome.5 It is re-markable that this paper came out sixteen years ago and we haven’t done anything about it. This is not a critique of Dr Mira; it is a critique of all of us. We have done this kind of work but we have had a much harder time translating this

to the bedside to apply personalized medicine.

“More recently, Nuala Meyer has hit upon a coding variant for the interleukin-1 receptor antagonist gene that, again, is associated with different levels of production of this antagonist as well as outcomes related to ARDS.6 She has also ex-tended this recently to patients with septic shock.”

All of these studies, noted Dr Wong, have failed to move beyond the interest of science into the clinical realm, as we are simply not designing trials with these concepts in mind. He explained that, at least in sepsis, can-didates are enrolled based on clinical criteria, inclusion and exclusion cri-teria, and perhaps mortality risk. Of course, sepsis is a highly heterogene-ous syndrome, so the fact that such

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Copyright © 2015: Université Libre de Bruxelles. All rights reserved. No part of this publication may be reproduced, stored in a etrieval 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 2015 Symposium Chairman, the ISICEM Scientific Advisors or Collaborators.

Opening Henry Le Boeuf Room Tuesday 8:30-10:25

Personalized medicine is the future

“Personalized medicine is a very powerful way of dealing with heterogeneity.”

Hector Wong

Continued on page 4


studies typically show no efficacy is not surprising. But in the absence of more detailed criteria with which to guide patient selection, we are at an impasse in terms of development new understanding and new treat-ment strategies.

“Let’s try to do it differently,” continued Dr Wong. “Perhaps in the future we need to define sepsis based more on both molecular bio-logical data along with some of the things that we talked about here. In other words: who actually has sepsis? Those are the patients we should be enrolling. Who is actually at risk – who is really sick, and therefore who stands to benefit from therapy? Then we actually have to assess the sepsis biology – what is the endotype, and how does the endotype affect the response to the therapy? And then perhaps we can enroll a more homo-geneous cohort that actually has sep-sis and that actually stands to benefit from the experimental therapy.”

Over the past decade, Dr Wong and others have been trying to ad-dress this notion with transcriptom-ics. “We have a multicenter biologi-cal clinical repository. We are doing genome-wide expression profiling to try to address these questions, to try to find candidate diagnostic biomark-

ers to be able to say who actually has sepsis; discovering stratification biomarkers for saying who is at risk for poor outcome; finally, discovering sepsis subclasses.”

Using this technique to explore the concept of endotypes, which are defined as a subclass of a condition defined by either function or biology, the group addressed a cohort of pediatric septic shock patients and identified possible subclasses defined by the expression of 8,000 genes.7

But it is another ques-tion whether this would be applicable given the time pressures faced within the critical care environment. In a post-hoc analysis, Wong and colleagues looked for other differences between the subclasses they had identified by genome-wide expression profiling. “It turns out that the patients who are subclass A tend to be younger, sicker and have greater organ failure and a much higher mortality rate,” he confirmed.

The group also performed logisti-cal regression to look at the effect of factors such as illness severity, age, and comorbidity, finding that alloca-tion to subclass A is independently associated with worse outcome.

“We validated about 300 patients with the very pragmatic goal of de-veloping a clinical test that meets the time-sensitive demands. One of the first steps we made was reducing the 8,000 genes to 100 genes which were more manageable based on their abil-ity to predict the class. We used this database, GEDI (the gene expression dynamics inspector)8. We give expres-sion data a face that is recognizable

by intuitive pattern recognition. “The next step we took was

measuring genes with multiplex assay that allows a very rapid qualification of mRNA expression, not dependent on PCR, and can be done in solution phase. We have a dedicated labora-tory, and from patient to data takes about 8-10 hours.”

The genes themselves corre-sponded to adaptive immunity and glucocorticoid receptor expression, with these genes largely repressed

or underexpressed in subclass A patients. “This has so-called ‘theron-ostic’ implications,” noted Dr Wong. “Theronostics is a part of personal-ized medicine where the diagnostic test drives therapy decisions.”

Dr Wong’s group are now con-templating the prospect of immune modulation or immune enhancement in order to augment the adaptive im-munity in patients with sepsis. This is

an important fresh look at what have previously been failed ven-tures, given the dynamic time-course of the immune response in sepsis. Given the subclasses that have emerged from their study, it is feasible that different patients will respond differ-ently to attempts to enhance adaptive immunity, because the genes that correspond to that

pathway are variably expressed. And the same goes for therapies

targeting glucocorticoid receptors: “One would predict that if you give steroids to these patients they are going to have different responses. We were able to assess this in a post-hoc manner because we had steroid data for all of these patients. To our surprise, the kids from subclass A, if they get steroids, have four times the risk of dying. These kids are very sick, and the genes corresponding to


“We have done this kind of work but we have had a much harder time translating this to the bedside to apply personalized medicine.”

Hector Wong

Personalized medicine is the futureContinued from page 2

Issue 2 Wednesday 18 March 2015 ISICEM News 5


the glucocorticoid receptor signaling pathway are repressed.”

Given this work, Dr Wong con-cluded that personalized medicine will form an intrinsic part of diag-nostics and treatment strategy in the future. “Personalized medicine is a very powerful way of dealing with heterogeneity. It is going to require

very broad collaboration, not just across health systems and countries, but also across pediatric and adult medicine, and so on.”References

1 The Precision Medicine Initiative. www.whitehouse.gov/precisionmedicine (retrieved March 2015).

2 Collins FS & Varmus H. A New Initiative on Precision Medicine. N Engl J Med 2015;

372:793-795.

3 Maslave DM & Wong HR. Gene expression profiling in sepsis: timing, tissue, and transla-tional considerations. Trends Mol Med. 2014 Apr;20(4):204-13.

4 Annane D et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002 Aug 21;288(7):862-71.

5 Mira JP et al. Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortal-ity: a multicenter study. JAMA. 1999 Aug

11;282(6):561-8.6 NJ Meyer et al. IL1RN Coding Variant Is As-

sociated with Lower Risk of Acute Respiratory Distress Syndrome and Increased Plasma IL-1 Receptor Antagonist. Am J Respir Crit Care Med. 2013 May 1; 187(9): 950–959.

7 Wong HR et al. Identification of pediatric septic shock subclasses based on genome-wide expression profiling. BMC Med. 2009 Jul 22;7:34.

8 GEDI: The Gene Expression Dynamics Inspector. https://apps.childrenshospital.org/clinical/research/ingber/GEDI/gedihome.htm (retrieved March 2015).

Pawel J. Ciesielczyk, PhD, EVER Pharma GmbH

Cognitive impairment (CI) is frequently associated with critical illness and can be

defined as the loss or decline of higher mental functions (memory, attention, calculation, language, orientation and speed of information processing) that modify a person’s activity and social interaction. Decline in cognitive func-tions can have an evolving course. The patient has the ability to perform daily living activities, except those that require complex cognitive in-struments. The therapeutic and socio-econom-ical challenge of CI and dementia is enormous. Development of suitable biomarkers together with accurate definition of risk factors is of key importance. Long-term cognitive impairment after critical illness (CIACI) is an emerging medical concept that was first described in 1999 in a report of a cohort of 55 patients with acute respiratory distress syndrome (ARDS) among whom 78% had CI at one year.1 CIACI is an example of a pathophysiological mecha-nism in which secondary injury generates neurological lesions in a previously healthy brain. Recently, the group of Wes Ely (2013) associated CIACI with period of delirium and intubation.2 This breakthrough finding offers unique opportunity to test and develop new treatments in appropriately designed clinical

trials. It could also advance our knowledge of key underlying biological factors of cognitive impairment/dementia. Finally, this work might advance our therapeutic approaches to CI treatment (if not prevention) in both acute and degenerative disorders.

Analyzing the pathological situation underly-ing development of CIACI in terms of mecha-nisms of cell damage, (identifying sources of excitotoxicity, inflammation, necrosis and apop-tosis) but also in terms of natural mechanisms of endogenous repair should help devising the effective treatments.3,4 Current prevention strat-egies and treatments, including tests of awaken-ing and physical and cognitive rehabilitation are therapeutic approaches that promote neuropro-tection and neurorehabilitation. In fact, these strategies can stimulate the endogenous repair processes that are regulated in the brain tissue by the neurotrophic factors. The hypothesis of delirium and its underlying pathology could support the use of pleiotropic therapeutic agents stimulating neurotrophic regulatory pathways.5

Also the pharmacological and physiological properties of neutrophic factors and neurotroph-ic-like agents (e.g. Cerebrolysin) make them suitable for use in the prevention and treatment of CIACI. Importantly, neurotrophic agents are safe and may be administered when the patient arrives at the ICU and also during the critical

period; there is no restriction for the treatment window. The results of research investigations and clinical studies of Cerebrolysin in stroke, traumatic brain injuries (TBI), Alzheimer’s disease and vascular dementia suggest a suitable pharmacological profile for prevention/treat-ment of CIACI. For example, acute Cerebroly-sin treatment of mild TBI patients resulted in prevention of cognitive decline as measured three months post injury. Mild to moderate (but not severe) TBI induces similar cognitive decline picture to that found in CIACI.6

The satellite symposium sponsored by EVER Neuro Pharma GmbH presents latest research and clinical data in the therapeutic field of neurotrophic treatment/prevention of cognitive decline after acute brain injuries. The research data indicate dose dependence as well as potent and fast stimulation of endogenous defense mechanisms and protection against secondary brain injuries. These pharmacological properties of Cerebrolysin will be discussed in the context of clinical application within the intensive care unit. References1 Am J Respir Crit Care Med, 1999;160:50-6.2 N Engl J Med, 2013; Oct 3;369(14):1306-163 J Neurol Sci, 2007;257:38-43.4 BMC Neurol, 2011;11:75.5 Drugs of Today 2012, 48(Supplement A):1-696 Br J Neurosurg. 2013 Dec;27(6):803-7.

Neurotrophic treatment for the prevention of complications and cognitive impairment after brain injuries


A plenary lecture that delved into how critical illness can affect the gut, and therefore

disrupt the important workings of the microbiome took place yesterday afternoon at ISICEM. Delivering the lecture was Paul Wischmeyer (Univer-sity of Colorado School of Medi-cine, Aurora, CO, USA) who spoke to ISICEM News to frame current knowledge in the field, beginning by sharing the role that the gut may have in the inflammatory response and immune response in general, as well as organ failure in critical illness. “We’ve hypothesized that changes in things like the microbiome of the gut might lead to major changes in outcome in sepsis patients,” said Professor Wischmeyer.

“But we’ve always been limited by the fact that the only way we have been able to really deter-mine what bacteria or other microbes live in our gut, mouth or skin was either by culture, or looking under a microscope. And it turns out only a very small number of microbes can be cultured. And so we’ve been very limited in our ability to understand what is happening, until the existence of microbi-ome genetic techniques, 16S rRNA sequencing, as we call it. This has allowed us to look at all the bacterial constituents of our intes-tines, of which there are numerous ones we cannot culture.”

He continued: “It is a lot like

taking a finger print of what is grow-ing in the mouth, the intestine and stools, or the skin of an individual. So it is very specific. And the reality is we are much more made up of microbes

than we are of human cells. There are 10 times the number of microbial cells in our body than there are human cells. And there are 100 times as many genes … there is only 1% of us that is human DNA, and about 99% microbial DNA lives within us, or on us.”

As such there is an enormous determinant of who we are as humans, that actually comes from the microbes that live in our body.

Plenary lecture: Role of the microbiome in critical illness Studio (Bozar) Tuesday 15:45

Digesting the role of the gut in critical illness

“We’ve hypothesized that changes in things like the microbiome of the gut might lead to major changes in outcome in sepsis patients.”

Paul Wischmeyer

“Some of the normal bacteria in healthy people

… are depleted quite severely in ICU patients.”

Paul Wischmeyer


As Professor Wischmeyer stressed, this means the microbiome plays an enormous role in a lot of human diseases, one more obvious example being obesity. “If you for instance take an obese mouse, and you trans-fer the stool from an obese mouse into the colon of a non-obese mouse, the non-obese mouse will become obese,” he said, adding that this effect also happens when you apply human stool to non-obese mice.

“So it does marked things to change the heath and physiology of humans. And in fact we can predict, with 90% accuracy, who is obese just by looking at their stools. If you looked at their DNA it would only be able to predict with 60% accuracy, but if you look at their stools it is 90% accurate.”

Intriguingly, this concept is beginning to take on a life of its own, with stool transplants from family members being used to treat Clostridium difficile colitis – a significant problem in the high-dependency unit – with a cure rate of 90% or above. Similarly, Profes-sor Wischmeyer described how, at the Massachusetts Institute of Technology [MIT] in the United States, a company is now selling stools samples – derived from MIT students, and packaged as freeze-dried pills – as a medical therapy.

Moving on to discuss his work in the field, Professor Wischmeyer com-mented: “The point of our study was to take, for the first time, longitudi-nal collection of stool, oral samples and skin swabs from critically ill patients on a ventilator. Around 150 patients across four centers in the US

and Canada were studied, and a main finding was that when people get sicker and get exposed to antibiotics, they lose diversity in their guts, with a negative impact on outcomes.

“There is a growing body of data that say probiotics, e.g. bacterial pills, are becoming more and more effective in preventing pneumonia on the ventilator, pre-venting C difficile infections, and in-fection in general,” he said. Working with the National Institutes of Health, the study compared the probiotic environment of critically ill patients, compared to controls, leading to a kind of personalized medicine ap-proach in terms of returning patients back to normal bacterial function.

“We collected samples at a num-ber of time points during patients’ ICU stays, who were on average

quite sick (APACHE score of 22), and classed as one of a range of medical and surgical critical care patients that had to be on the ventilator for more than two days. We found all of them basically required antibiotics of some sort,” said Professor Wischmeyer.

His team then compared the 150 patients studied to over 1200 healthy

individuals from a project in America that had been categorizing the mi-crobiomes of healthy people who had sent in their samples for testing.

Professor Wischmeyer continued: “What we saw was a clear shift in how the microbiome changes. ICU patients look very different from healthy patients. There is a clear shift to pathogens – proteobacteria we call them – and away from the nor-mal healthy flora that helps our gut absorb nutrients and protect itself. Interestingly, there is a great separa-tion typically between the bacteria of your skin, your mouth and your intes-

tines. By way of example, there is more separation between the bacteria that live in your mouth and your intestines than there is between bacteria that is found in Australia and those of the plains of the United States.

“What happens in critically ill patients is these groups begin to come to-gether, and then the bac-

teria of stool begin to look like the bacteria of the mouth … so the body begins to lose the ability to change and differentiate it, and if you lose diversity, everything begins to look the same. We found that some of the normal bacteria in healthy people, and those which have been found to be inflammatory in diseases

such as inflammatory bowel syndrome, are depleted quite severely in ICU patients … the normal bacteria cannot suppress the bad bacteria like they do in most of our intestines, and then the bad bacteria grow to

a greater proportion.”There is also potential for assess-

ment of pathogens to be used as a predictive measure of mortality, as certain ones, easily swabbed from the skin, have been found to be elevated in those who did not survive the ICU.

In his closing remarks, Professor Wischmeyer touched upon whether therapies based on the microbiome would filter more into daily practice. “We do think it is, and in fact I think some of these stool pills and stool transplants are becoming much more commonplace around the world, and people are starting to take them to treat infectious diarrhea and other things, to correct the normal micro-biome,” he said. “And then I think another thing that may become more mainstream is the cost of doing the fingerprint identification of bacte-rial sequences, has come down in price by many orders of magnitude, and while it used to be prohibitively expensive, now it is not, and it can be done in 24 to 48 hours.

“It’s a personalized medicine reality come true. Stool is very easy to obtain, a swab of the tongue is very quick to do, and I think the day will come where perhaps we can predict those who are at greater risk for certain later infections or diseases. So not only will we use it to treat people, but also to identify how to early-diagnose people as well.”

“Stool is very easy to obtain, a swab of the tongue is very quick to do, and I think the day will come where perhaps we can predict those who are at greater risk for certain later infections or diseases.”

Paul Wischmeyer

“There is a growing body of data that say probiotics, e.g. bacterial pills, are becoming more and more effective in preventing pneumonia on the ventilator, preventing C difficile infections, and infection in general.”

Paul Wischmeyer

Plenary lecture: Role of the microbiome in critical illness Studio (Bozar) Tuesday 15:45

Digesting the role of the gut in critical illness


S peaking at today’s debate on Polymyxin-B hemoperfusion: A rescue therapy for septic shock, Claudio Ronco, Director of the

Nephrology Department at St. Bortolo Hospital, Vicenza, Italy, said that it was time to look past drugs – most of which fail - and towards devices in the treatment of septic shock and sepsis.

“Most pharmacological attempts to resolve sepsis have failed. Today we aim to find an alterna-tive with a tool that removes endotoxin – the trigger for sepsis which can cause high morbidity and mortality at certain high levels,” said Professor Ronco.

“If there is something damaging circulating in the blood then its removal is a logical approach,” he remarked. “But unfortunately previous attempts with antibodies have failed due to lack of specific-ity and weak binding.”

Sepsis is a serious medical condition character-ized by systemic inflammatory response caused by bacterial infection, usually gram-negative bacteria and the lipopolysaccharide, lipid A portion, which is a key component of the bacterial membrane. Infection with endotoxin induces elevations in cytokines,

including TNF-α , interleukin (IL)-6, and IL-8. The clinical responses include pyrexia, chills, hypoten-sion, and, at higher doses, shock, organ failure and death.

Attempts to provide antibiotics systemically

have not proven sufficient to patients, and one specific antibiotic called polymyxin B cannot be infused because it is toxic.

Polymyxin B antibiotics are derived from Bacillus polymyxa, and are well known to bind endotoxin selectively and neutralize its toxicity. “Polymyxin B is very sticky to endotoxin because in addition to hydrogen bonds, it has hydrophobic bonds,” said Professor Ronco.

Studies have shown that systemic polymyxin B blunts the TNF-α response to endotoxin, and it also blocks the formation of lipopolysaccharide-LPS binding protein complexes through its high binding affinity for the LPS molecule. However, infusion of polymyxin B in humans results in nephrotoxicity and neurotoxicity, and for this reason the optimal way to treat septic shock is by using an extracor-poreal hemoperfusion device.

Impressed by what he saw in the early stages of development of a device to deliver polymyxin B outside of the body, Professor Ronco identified a need for more substantial evidence to determine the efficacy and safety of its use. “We designed a meta-analysis of all studies conducted to date. We found a significant reduction in mortality in all cases treated with the device. However more stud-ies were needed,” remarked Professor Ronco.

A series of European studies were initiated. One study, Early Use of Polymyxin Hemoperfusion in Abdominal Septic Shock (EUPHAS) trial1, which

was a randomized, unblinded study of 64 patients in 10 tertiary Italian ICUs, demonstrated statistically significant improvements in the primary endpoints of hemodynamics and organ dysfunction. It was published in JAMA. “In patients with post-surgical abdominal sepsis or septic shock, reduction in car-diovascular severity scores and mortality [absolute risk of death at 28 days], was approximately 53% to 32%, similar to that observed in the meta-analysis.”

However, this study was still underpowered and the numbers too small for conclusions to be drawn, so the EUPHAS 2 study was started. This is a prospective web-based registry of patients treated with polymyxin B and designed to validate the reproducibility of randomized clinical trial results and to observe the ‘real world’ efficacy of the investigative therapy. A wider variety of patient populations were assessed than those included in clinical trials. Because EUPHAS 2 was a registry study, the control group in the EUPHAS trial was also used for EUPHAS 2. “We have now recruited 300 patients. One phase is retrospective and this is complete, and this showed a lower level of reduc-tion in mortality than the EUPHAS study, but still statistically significant. However, in those patients who had abdominal sepsis and septic shock showed exactly the same mortality reduction as the previous study [EUPHAS]. There is also a prospec-tive part of the study which is ongoing.”

The second study of note is the EUPHRATES trial (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized Controlled Trial of Adults Treated for Endotoxemia and Septic Shock; ClinicalTrials.Gov NCT01046669), which is a multi-centered, blinded, randomized controlled trial of polymyxin B in patients with septic shock and confirmed endotoxemia using endotoxin activity assay (EAA) greater than 0.60. A total of 50 ICUs in the US and Canada are participating, and it aims to enroll 360 patients.

“Patients are treated with the cartridge [of poly-myxin B] or the sham in a double- blinded study.

Results will be available in the next six months,” added Professor Ronco.

One other study is on the Effects of Hemoperfusion With a Polymyxin B Membrane in Peritonitis With Sep-tic Shock (ABDO-MIX). The purpose of this randomized, comparative, open and multicenter study across France is to show that two sessions of hemoperfusion with Toraymyxin [polymyxin B] performed within maximum 36 hours after the surgery of a peritonitis by hollow organ perforation reduce the mortality in patients suffering from septic shock.

The study is being led by Dr Didier Payen from Lariboisière University Hospital, France. Dr Payen is presenting an argument that questions the use of polymyxin B in patients with sepsis or septic shock. Dr Payen writes that recent studies into the use of polymyxin B either include

The debate on Polymyxin-B hemoperfusion: A rescue therapy for septic shock [Pro-con debate] 400 Hall Wednesday 11:35

Look beyond drugs to devices in tackling sepsis

“If there is something damaging circulating in the blood then its removal is a logical approach. But unfortunately previous attempts with antibodies have failed due to lack of specificity and weak binding.”

Claudio Ronco


Quote

The debate on Polymyxin-B hemoperfusion: A rescue therapy for septic shock [Pro-con debate] 400 Hall Wednesday 11:35

Quote

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only a limited number of patients or are not randomized prospective studies. Despite a post-hoc analysis of a recent randomized study in a limited number of patients with abdominal septic shock showing a significant reduction in mortality after factor adjustment, and limited side effects, the cost of polymyxin B is high. For these reasons, Dr Payen pointed out that extensive prospective studies are necessary to confirm its effectiveness.

Professor Ronco added that: “Some studies may have failed using polymyxin B hemoperfu-sion because the general population was recruited instead of targeting a specific population. The EUPRATES trial was targeted specifically to patients with endotoxin levels of 0.6 while EUPHAS trial was targeted at patients who had a specific origin of sepsis- abdominal or surgical- with a certain level of severity.”

Professor Ronco agrees that further studies are warranted and raises questions himself. He asked whether mortality is indeed the right endpoint to measure the benefit of this therapy? “If I have this cartridge, that causes improvement in organ func-tion and stabilization, then maybe other therapies that induce benefit can be used at this point,” he said. “Perhaps we should take incremental targets as a measure by firstly aiming to keep the patient alive, then stabilize the patient, and improve func-tion and then aim for the patient to exit ICU, and finally leave the hospital.” References: 1. https://clinicaltrials.gov/ct2/show/NCT01222663


P alliative care has grown in significance in the critical care setting over the past decade,

but there is still a way to go in terms of defining and implementing good ICU palliative care. Discussing this topic during a session dedicated to end-of-life issues is Jared Randall Curtis (Harborview Medical Center, and University of Washington, Seat-tle, USA), who spoke to ISICEM News about how far we have come and what must yet be done to meet the values and goals of patients with serious illness.

“I used to have to spend my time defending the importance of

including palliative care in the critical care setting,” said Dr Curtis, who has recently published on the relationship between advance palliative planning and ICU utilization, as well as the perception of quality of dying from the perspectives of both families and clinicians.1,2 “Now I don’t feel that I have to do that anymore. There is an increasing awareness of the impor-tance of palliative care in the ICU.”

In the past, palliative and end-of-life care have been equated, which has meant that such care needs tended to be considered only after a patient’s death was considered imminent. But palliative care, defined

as care for patients with serious ill-ness that focuses on patient’s values and maximizing quality of life, can be used alongside curative therapies too. As such, as Dr Curtis explained, the now-broader definition of pal-liative care encompasses care for all patients with serious illness, whether that illness turns out to be life limiting or whether a patient dies or makes a full recovery.

Palliative care explicitly encompasses families, too, especially given the stress and burden placed upon them in terms of after-care; as such, support for families’ as well as patients’ psychological, emotional, and spiritual wellbeing are a cornerstone of palliative care. “Each patient and family has different needs,” said Dr Curtis. “The task at hand is to figure out what those needs are for a specific patient and their family and how we can best fulfil them.

“If a patient does not survive, bereavement support is an important part of palliative care. But even if a patient survives, families are often very involved in providing support and caregiving for those patients, and they are going to have ongoing care needs. So making sure that we know what the families’ needs are is similarly important.”

Palliative makes certain demands on the part of the physician, in ascertaining which factors can be addressed to maximize an individual’s quality of life: “A lot of this requires that we talk with the patient if they are able to do so, or the family if they are not able,” said Dr Curtis. “We find out what is important to the patient about their quality of life. Again, this might be different for dif-

ferent patients.” Indeed, qual-

ity of life has many dimensions, including mini-mizing clinical symptoms as well as understanding and addressing goals and values. As such, provid-ing the appropri-ate care in the critical setting

that matches each patient’s values and goals is crucial. Professor Curtis noted that, while this is an important

step, it is accomplished with varying success across ICUs and with differ-ent physicians.

“There is a developing consensus about how we should be doing this, but this is only just developing. In medical care when there is no con-sensus, it is no surprise that doctors and ICUs do it differently.”

Interestingly, while cultural at-titudes towards illness, death and

palliative care differ greatly between countries and even between regions, Dr Curtis believes that these differ-ences in care are often not driven by differences in the values of patients and their family: “The research sug-gests that most of the variability is actually driven by different cultures and attitudes of the physicians, more so than of the families,” he said. “There is some overlap there, of course. But studies suggest that a lot of palliative care variability is driven by physicians’ preferences and biases.”

Dr Curtis and colleagues at the University of Washington are in the process of developing a consensus on the definition of best palliative care in the ICU, with a look to defining markers of quality for that care. “We need to do this work to make sure that all patients and families have access to the best care, making sure that their symptoms are assessed and addressed, making sure that we have discussions with them about their goals of care and what is important to them about their quality of life, so that we are not providing care that cannot get them to a quality of life that they would find acceptable.”

Dr Curtis will speak about the integra-tion of palliative and critical care during the session, ‘End-of-life issues,’ taking place this afternoon in the Arc Room from 13:45.

References1 Khandelwal N et al. Estimating the Effect of

Palliative Care Interventions and Advance Care Planning on ICU Utilization: A System-atic Review. Crit Care Med. 2015 Jan 9.

2 Khandelwal N et al. End-of-life expenditure in the ICU and perceived quality of dying. Chest. 2014 Dec;146(6):1594-603.

End-of-life issues Arc Room Wednesday 13:45

Keeping patients’ best interests at heart

“Each patient and family has different needs. The task at hand is to figure out what those needs are for a specific patient and their family and how we can best fulfil them.”

Jared Randall Curtis

“Studies suggest that a lot of palliative care variability is driven by physicians’ preferences and biases.”

Jared Randall Curtis


Post-surgical complications can be decreased with hemody-namic optimization during operations and intensive care,

a finding supported by numerous randomized controlled trials (RCTs) and a range of national guidelines.

“Hemodynamic monitoring is useful to prevent both hypo-volemia and fluid overload, and ultimately decreases post-surgical complications, hospital length of stay and costs,” says Frederic Michard (Vice President, Global Medical Strategy at Edwards Lifesciences), who was the first speaker at a satellite symposium held on Tuesday afternoon, sponsored by Ed-wards, titled: ‘Hemodynamic monitoring: new perspectives’.

Speaking to ISICEM News, he described the value of hemodynamic monitoring during major surgeries to guide fluid management. “Many randomized controlled trials, meta-analyses and quality improvement programs support this claim,” he said.

Hemodynamic monitoring, which involves monitoring of parameters including stroke volume, cardiac output and addi-tional derived parameters provides information about volume status, cardiac function and vascular tone.

Many postoperative complications are related to hypo-volemia or fluid overload, according to Dr. Michard. “For instance, hypovolemia may induce acute renal failure by decreasing kidney perfusion, and surgical site infections by inducing tissue hypoxia. Furthermore, fluid overload may de-lay weaning from mechanical ventilation, and favor infectious complications and anastomotic leakage by inducing tissue edema,” he added, describing complications that were likely to lead to extended hospital stays as well as intensive care and associated costs.

An eight-year follow-up study conducted in more than 100,000 surgical patients showed that the most important determinant of post-surgical survival was the occurrence, within 30 days post-surgery, of any complication. Independent of preoperative patient risk, the occurrence of a complication reduced median patient long-term survival by 69%.1

It is possible to decrease post-operative complications by using effec-tive and proven methods of hemodynamic monitoring.

In the operating room, simple methods such as minimally invasive and non-invasive pulse contour methods are now recommended to guide fluid management, as Dr. Michard highlighted: “In the ICU, more invasive but also more informative techniques such as pulmonary and transpulmonary thermodilution are useful to treat critically ill patients with acute circulatory and/or respiratory failure,” he said.

Following Dr. Michard’s introduction, Maurizio Cecconi, Chair Com-munication Committee at European Society of Intensive Care Medi-cine – ESICM and Consultant in Anaesthesia and Intensive Care at St. Georges Healthcare NHS Trust, London, UK, discussed recent published guidelines regarding the use of hemodynamic monitoring tools both in the operating room and in the ICU.

Dr. Cecconi noted that the guidelines for hemodynamic monitoring focus on two key points. Firstly, optimizing the hemodynamics during the perioperative period in order to reduce postoperative complications; and secondly, when a patient is in shock, to select the right level of advanced hemodynamic monitoring to titrate fluid and vasoactive drugs in patients not responding to the initial therapy.

Fuelled by the growing number of clinical studies and meta-analyses demonstrating the value of Perioperative Goal-Directed Therapy, official recommendations have been published in the UK by the Enhanced Recovery Partnership (ERP) and the Association of Surgeons of Great Britain and Ireland, in France by the French Society of Anesthesiology

(SFAR), and in Europe by the Enhanced Recovery After Surgery (ERAS) Society. The Patient Safety Foundation of the European Society of Anesthesiology (ESA) recently released a Safety Kit, which contains a summary of PGDT treatment protocols.

Given the now well-established clinical and economic benefits of PGDT protocols, and the above recommendations, more and more hos-pitals are interested in implementing hemodynamic optimization both to improve quality of care and to decrease costs.

“The main message about patients with shock is that while we do not recommend routine measurement of cardiac output, these measurements are recommended to evaluate the response to fluids or inotropes in pa-tients that are not responding to initial therapy,” emphasized Dr. Cecconi.

The third and final speaker was ISICEM Chairman Jean-Louis Vincent (Department of Intensive Care, Erasme University Hospital, Brussels) who discussed the pros and cons of randomized controlled trials (RCTs) when investigating the value of hemodynamic monitoring techniques in general.

In his closing remarks, Dr. Michard also commented on the value of RCTs for hemodynamic monitoring and noted that RCTs may be not the panacea to demonstrate the value of hemodynamic monitoring for several reasons. “Monitoring is not treating,” he said. “A monitor by itself does not have the possibility to improve outcome. A monitor is a diagnostic tool, not a treatment. Also, the way patients are treated in the intervention group is going to influence the treatment of the control group as per the training and Hawthorne effect.”

He added that quality improvement programs (QIPs) are more ap-propriate to study changes in behavior than RCTs. References

1 Khuri et al. Determinants of long-term survival after major surgery and the adverse effect of post-

operative complications. Ann Surg 2005.

Optimize hemodynamics and improve post-operative outcomes

Frederic Michard


F luid management will be under the spotlight this afternoon at ISICEM 2015,

with particular attention to deci-sions within specific circumstances including brain injury, trauma, burns, diabetic ketoacidosis and acute respiratory distress. In addition, Philippe Van Der Linden (Brugmann University Hospital, Belgium) will be addressing the perioperative period, and he spoke to ISICEM News ahead of the session to share his thoughts on the topic.

During the course of the inter-view, Dr Van Der Linden discussed the place that the various fluid options on offer have in fluid man-agement: “We have many different solutions that have the potential to address more specifically the deficits exhibited by patients, in order to give the most suitable fluid for this particular patient in this particular situation. But of course, this re-quires a high level of knowledge of the fluids that you have available at your hospital.”

Addressing the point more finely, Dr Van Der Linden noted that a broad range of indications for therapy emerge during the periop-erative period. “Of course, blood loss is certainly one of the best known,” he said. “But you may also have patients coming into the operating room with dehydration because of their medical treatment or because of their underlying conditions.

“Also, in high-risk patients you may want to optimize the circulating blood volume in order to optimize cardiac output and oxygen delivery to the tissues. All of these indica-tions may demand the administra-tion of fluids. Of course, according to the indication, different kinds of fluid may be required in order to achieve your goals.”

Dr Van Der Linden acknowl-edged a distinct variability in the way that different fluids are adminis-tered in different centers. With a look towards the milieu of literature, a similar variability in recommenda-tions emerges, which he boiled down to the sparsity or poor quality of evidence: “From my point of view, the major problem

with the administration of fluids within the perioperative period is related to the relative low knowledge about, first, what the composition is of the different kinds of fluids that are available, whether they are crystalloids or colloids. Most of the clinicians are not completely aware about the compositions of the fluids. This is particularly true with the new balanced crystalloid or colloid solu-tions.”

Commenting on the second source of inadequate knowledge, he continued: “The knowledge about the pharmacokinetics of the different fluids is also relatively low. The complication associated with the different fluids is relatively low, and most of the clinicians are giving fluids according to what is done in their specific unit – if you are in a unit where they are giving more colloids, then you tend to give more colloids. If you are in a unit where they give more crystalloids, you will give more

crystalloids [as shown by Finfer et al. (2010) 1.”

On this topic, Dr Van Der Linden concluded that the controversy between crystalloids and colloids is no more related to scientific evidence than it is to opinion. So why does knowledge dissemina-tion seemingly lag so far behind the emergence of data? “First (because I can’t just speak about my university), there are no specific education programs regarding the use of fluids. Second, fluids are changing over time.

“People speak about gelatins, or starch, or albu-min, or balanced crystalloids – but clearly they don’t know what they are speaking about. To give an example, I found in the litera-ture recently some papers speaking about fluids, saying simply ‘we used starch’ or ‘we used gelatin’; you are

not aware of what kind of starch or gelatin they have used, or what their composition is.”

While optimal fluid management is essential in reducing perioperative risk, rates of complications during

this period are very low (relative to rates from studies performed in the ICU population), which makes evidence-based data on the potential benefit or harmful effect of any given fluid very difficult to demonstrate in this setting. This is true for colloids, as much as it is for crystalloids.2“You therefore have to go back to retro-spective studies,” said Dr Van Der Linden. “Retrospective studies on the one hand may represent real life, but on the other hand the interpretation of these results is complicated by the presence of bias. Whatever the statistical analysis, they will not be completely exempt of this bias.”

The crucial message stressed by Dr Van Der Linden was that, despite a wealth of options that offers the great opportunity of optimiz-ing fluid management for each patient’s particular needs, the wrong choice on the part of physicians can nevertheless spell negative conse-quences. As such, physicians need to be better informed of the options: “The problem for me is that it is not the solution – it is the way that you give the solution. It is like the simple phrase: it is not the weapon which is dangerous; it is the people using the weapon that are dangerous!”

Dr Van Der Linden will speak in greater depth during the session, ‘Fluid choices in special conditions,’ taking place this afternoon from 16:00 until 18:00 in 100 Hall.

References1 Finfer S et al. Resuscitation fluid use in criti-

cally ill adults: an international cross-sectional study in 391 intensive care units. Critical Care 2010, 14:R185

2 Raghunathan K et al. Choice of fluid in acute illness: what should be given? An international consensus. Br J Anaesth 2014; 113:772-783

Fluid choices in special conditions 100 Hall Wednesday 16:00

Perioperative fluid choice matters

“People speak about gelatins, or starch, or albumin, or balanced crystalloids – but clearly they don’t know what they are speaking about.”

Philippe Van Der Linden

“The problem for me is that it is not the solution – it is the way that you give the solution. It is like the simple phrase: it is not the weapon which is dangerous; it is the people using the weapon that are dangerous!”

Philippe Van Der Linden


A t this year’s ISICEM congress, Maurizio Cecconi (St George’s Hospital and Medical School, London, UK) will be presenting in

seven different sessions, during which he will share his perspectives as a thought leader in hemody-namic monitoring (Round-table on Tuesday); a speaker in “The physiological approach to fluid management” (Gold Hall on Thursday); a speaker of “GDT after cardiac surgery” (Silver Hall on Tuesday) and central venous pressure (on Tuesday in the Gold hall).

Maurizio Cecconi is a consultant and honor-ary Senior Lecturer in anesthesia and intensive care medicine, with a high interest in hemody-namic monitoring and physiology, specializing in the perioperative hemodynamic optimization of the high-risk surgical patient. He has authored more than 70 articles and has been the Research Lead for the Adult Critical Care Directorate at St George’s Hospital in London since 2011. He is the chair of the Editorial and Publishing Committee for the European Society of Intensive Care Medicine (ESICM) and an associate editor for several spe-cialty journals.

Speaking with ISICEM News, Dr Cecconi said: “The need for the precise quantification of cardiac function in high-risk patients, both in the operative room and the intensive care unit is vital in modern medical practice. Evidence shows that monitoring cardiac physiology using different techniques is key to determining the appropriate procedures and op-timizing perioperative hemodynamic and outcome for patients.”

Circulatory shock is a life-threatening, general-ized form of acute circulatory failure associated with inadequate oxygen utilization by the cells. On that topic, Dr Cecconi commented: “We have a new consensus on circulatory shock1: Not every patient needs advanced monitoring, but those who don’t respond to initial therapy within the first few hours of admission should have access advanced hemodynamic monitoring (such as echocardiogra-phy, etc. ). It is important that assessments are car-ried out on a patient-by-patient basis and decisions pertaining to managing their condition must be made accordingly. “

“We have learned that decisions and strate-gies put in place quickly, based on in-depth and accurate hemodynamic and cardiac function

monitoring, will make a different in stabilizing criti-cal patients.

In his seminal study on early goal-directed therapy (EGDT) using ScVO2, published in the NEJM in 2001, Rivers et al2 demonstrated the con-cept of aggressive recognition and treatment for sepsis. The fact that the ARISE and PROCESS trials failed to replicate the results of Rivers, is the proof that clinicians have learnt to recognize and treat shock very early rather than showing that ScVO2 is not useful anymore.

In statements from the consensus, Cecconi et al. state: “Advanced monitoring includes cardiac output monitoring and we recommend further hemodynamic assessment (such as assessing cardiac function) to deter-mine the type of shock if the clinical examination does not lead to a clear di-agnosis1. As an adjunct we suggest that when further hemodynamic assessment is needed, echocardiog-raphy is the preferred modality to initially evalu-ate the type of shock as opposed to more invasive technologies.”

“Fluid resuscitation forms part of EGDT,” explained Dr Cecconi, add-ing: “The issue of fluid overload is very important. The main aim in hemodynamic monitoring in patients with shock is to improve perfusion, but not all patients respond to fluids. Sometimes this can worsen edema, impact organs, and ultimately worsen perfusion. The consensus is to try to assess and predict fluid responsiveness, and when the decision for fluid administration is made, we nor-mally perform a carefully-observed fluid challenge and recommend subsequent titration to prevent overload1”.

Dr Cecconi went on to describe the ground breaking research aim to develop innovative tools (hTEE) to assess advanced hemodynamic variables during fluid resuscitation of critically ill patients at the bedside. “The advent of new technologies is allowing us to look at the circulation in a new way. The miniaturized, monoplane transesophageal

echocardiography probe (mTEE), [also known as hTEE] for instance is a noninvasive and allows for continual visualization of the heart’s chambers from four views3. This allows for echocardiography to be used as continuous echo monitoring. Being able to visualize cardiac function in such a way al-

lows increasingly accurate assessment, for example a clinician may distinguish between ventricular dys-function and general hypovolemia and importantly, decide whether it is appropriate to give fluid.”

Dr Cecconi concluded by saying: “Use of these new techniques allows for repeated assessment and complementary information which in turn helps guide management decisions regarding the patient at the bedside.”References1. M. Cecconi M et al. Consensus on circulatory shock and

hemodynamic monitoring. Task force of the European Soci-ety of Intensive Care Medicine. Intensive Care Med (2014); 40:1795–1815

2. Rivers E et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77.

3. Fletcher N. Initial Clinical Experience With a Miniaturized Transesophageal Echocardiography Probe in a Cardiac Intensive Care Unit. J Cardiothorac Vasc Anesth. 2015 Jan 6. (ahead of print)

Hemodynamics and fluid management laid bare

“The main aim in hemodynamic monitoring in patients with shock is to improve perfusion, but not all patients respond to fluids.”

Maurizio Cecconi


Optimal peri-operative management of patients with significantly reduced cardiac function is a major determinant of good outcome.

Achieving supranormal cardiac output and oxygen delivery, in high risk patients may reflect better tolerance to stress induced by trauma, sur-gery and sepsis. In the absence of concrete long-term outcome benefit, however, there is still no consensus on the role of catecholamine in-duced supranormal parameters through pre-operative enhancement of cardiac output of these patients. In patients with significantly reduced intrinsic cardiac function, the clinical imperative in peri-operative optimization is strong. The best ways to achieve optimization gaols remain debatable.

In a satellite symposium, Fabio Guarracino presents ventriculo-arterial coupling assessment, defined as the ratio of arterial to ventricular elastance, and gives a new perspective in understanding the pathophysi-ology of CV dysfunction and a novel approach to optimise cardiovascular performance and managing the traditional concept of stroke volume, contractility and afterload to improve cardiac output. The role of inodila-tors Levosimendan in the perioperative optimization of patients with severe cardiomyopathy and low ejection fraction undergoing cardiac surgery, presented by Wolfgang Toller, describes the distinct benefits and the clinical application in this context. The support for using these agents in coordinated perioperative optimization strategy rather than a rescue therapy is growing. This view is supported by recent meta-anal-

ysis and randomized controlled trial comparing these novel agents with the classical approach using catecholamines.

The development of agitation and delirium in the context of critical illness, irrespective of the underlying pathophysiology is an ominous sign in particular when prolonged and intractable. Patients with respira-tory failure are at an increasing risk of acute brain dysfunction. Failure to liberate from mechanical ventilation is only partly due to pulmonary causes with agitation, delirium and anxiety a significant driver for con-tinued need for mechanical ventilation.

Dr Georg-Christian Funk presents his personal experience in manag-ing pain, agitation and delirium in this group of high risk patients focus-ing on maintain light sedation. This can be achieved with a combination of low dose remifentanil, propofol and/or dexmedetomidine. Improving tolerance to non-invasive ventilation and reducing ventilator dyssynchro-ny is an important goal for sedation of patients with respiratory failure, a strategy to achieve these goals is also described.

The use of non-pharmacologic interventions to reduce the burden of delirium is very attractive, simple and non-expensive and can be effec-tive. Highlighting the risks associated with delirium and sleep depriva-tion, including neuro-humeral, endocrine and psychological consequenc-es, Dr Daniel Conway calls for a change in ICU culture to provide a “sleep bundle” to promote high quality sleep for critically ill patients and improve patients’ journey in the ICU.

Making a difference, expert’s insight into managing at high risk hearts and brains


T he incidence of sepsis in the US and other parts of the world have been reportedly increasing

over recent decades,1 but what biases might be hidden beneath these data? During a pro and con debate closing today’s proceedings in Studio Bozar, Michael Klompas (Harvard Medical School, Boston, USA) will present his arguments against Konrad Reinhart (University Hospital, Jena, Germany), who defends rising sepsis rates. In an interview with ISICEM News, Dr Klom-pas took a detailed look at the data on the topic, describing how reporting methodologies might be interfering with at least some of the conclusions that are being made at present.

The clinical definition of sepsis reached consensus in the early 1990s. National and international data pertaining to its incidence is typ-ically extracted from administrative databases and emerges in the form of diagnosis codes. This, however, can impose several biases that may impact data down the line, explained Dr Klompas: “When doctors assign diagnosis codes, the primary mission is not to give a comprehensive clinical description of the patient per se, but rather to support billings. The doctors describe what is really going on in the clinical charts, whereas the

diagnosis codes are a short-hand. They rarely capture the fullness or complexity of any given patient.

“What we do know from lots of other lines of work is that diagnosis codes have highly variable accuracy, and that the way in which we use diagnosis codes can change over time. And there are a number of external influences on the way we use the codes.”

In the US, where much of the increase in sepsis rates has been reported, Dr Klompas noted that, while the clinical definition of sepsis has remained relatively stable, the sensitivity to the usage of sepsis di-agnosis codes has increased over the years. “People are using them more completely and more thoroughly,” he said, adding: “This has been driven by reimbursement rules, whereby hospitals are given more money for taking care of more complex patients.

“To prove that the patient is more complex, you have to assign the corresponding diagnosis codes, and so there is a great deal of emphasis from hospitals’ compliance and bill-ing departments to get physicians to code more thoroughly and more accurately. Therefore this is leading to better quality coding over time.

That means that there is an apparent trend of increase in sepsis that could simply be explained by increasingly complete coding.”

Of course, there has been a tan-dem improvement in clinical aware-ness of the signs of sepsis, too. This increasing clinical pressure is indebted to the highly successful Surviving Sep-sis campaign, which has promoted an increased awareness of sepsis since its inception in 2002, along with improvements in early diagnosis, management and education.2

“I think the sterling success of this campaign has led all doctors, all over the world, to be much more on the lookout for patients who might have sepsis, and to diagnose and treat ac-cordingly,” commented Dr Klompas. “That also has been contributing to more patients being given a formal diagnosis code of sepsis. In the past, there may have been patients that had sepsis, but who did not actually make it to being given a diagnosis code for it. These are the sorts of

concerns surrounding administrative codes that make them a questionable basis for trying to assess sepsis.”

In order to test these notions, Dr Klompas and colleagues compared data collected via diagnosis codes against what might be considered the gold standard – namely, review-ing medical data contained in clinical records. In order to achieve this they calculating linear trends in annual incidences of septicemia, sepsis and severe sepsis in two hospitals, evalu-ating health records between the years 2003 and 2012.3

“In this day and age you can take advantage of the richness and breadth of electronic health record information,” said Dr Klompas. “This can give us detailed clinical infor-mation on patients that can tell us whether they have severe sepsis-like events or not, regardless of what code the doctor chose to assign to the patient. This is an independent and much more clinical way to gauge what the patient might have.”

Are sepsis rates really rising? [Pro-con debate] Studio (Bozar) Wednesday 17:30

Sepsis rates: on the rise?

“Diagnosis codes have highly variable accuracy, and that the way in which we use diagnosis codes can change over time.”

Michael Klompas


Are sepsis rates really rising? [Pro-con debate] Studio (Bozar) Wednesday 17:30

Findings Presented at American Society of Anesthesiologists Annual Meeting

Results of a retrospective study of an Enhanced Recovery After Sur-gery (ERAS) program in colorectal surgery patients, which included

Masimo’s PVI® monitoring were presented at the American Society of Anesthesiologists (ASA) Annual Meeting in New Orleans, the largest gathering of anesthesiologists in the world. The ERAS program, which included fluid therapy tailored to PVI, resulted in reduced length of hospital stay, significantly reduced hospital costs, lower fluid administra-tion, lower morphine administration, and earlier return of bowl function.

In the retrospective study of the ERAS program implemented at the University of Virginia, Dr. Robert H. Thiele and colleagues compared the results of 108 patients managed with the ERAS program to 98 consecutive patients before the ERAS program was implemented. The ERAS program included goal-directed therapy with PVI, ingestion of a carbohydrate drink two hours prior to surgery, pre-operative multimodal analgesic regimen, intraoperative low-dose spinal morphine, limiting in-traoperative opiates, intraoperative infusions of ketamine and lidocaine (continued 48 hours post-operatively), early mobilization, and oral intake post-operatively.

Patients whose care was guided by the ERAS program with PVI had less fluid administered (973 ml vs 3,000 ml, p<0.001), lower morphine equivalents (0.1 vs. 20, p<0.001), earlier return of bowel function (p<0.03), lower pain score (2.33 vs. 4.85, p<0.001), fewer days of hos-pitalization (3 vs 5 days, P<0.001), and lower hospital costs ($18,017 vs $15,150, P<0.01).

The investigators concluded: “While this program includes several measures, most significantly patients received markedly less fluid and opiates in the operating room. Our program is novel in the use of PVI to guide therapy. This work highlights the importance of selection of anesthesia technique in determining outcomes for patients. Our ongoing work is in applying the lessons learned from this program to patients undergoing other types of surgery.”

1 Colquhoun D, Turrentine F, Rea K, Friel C, Hedrick T, Thiele R. Implementing a Health System Wide Enhanced Recovery Program for Patients Undergoing Colorectal Surgery – The Anesthesiologists Perspec-tive. Proceedings of the American Society of Anesthesiologists, Oct.12, 2014, New Orleans, A2010, Room 245

About Masimo Masimo (NASDAQ: MASI) is the global leader in innovative noninvasive monitoring technologies that significantly improve patient care—helping solve “unsolvable” problems. In 1995, the company debuted Measure-Through Motion and Low Perfusion pulse oximetry, known as Masimo SET®,

which virtually eliminated false alarms and increased pulse oximetry’s ability to help clinicians detect life-threatening events. More than 100 independent and objective studies have shown that Masimo SET® outperforms other pulse oximetry technologies, even under the most challenging clinical conditions, including patient motion and low peripheral perfusion. In 2005, Masimo introduced rainbow ® Pulse CO-Oximetry™ technology, allowing noninvasive and continuous monitoring of blood constituents that previously required invasive procedures; total hemoglobin (SpHb®), oxygen content (SpOC™), carboxyhemoglobin (SpCO®), methemoglobin (SpMet®), PVI®, and perfu-sion index (PI), in addition to measure-through motion SpO2 , and pulse rate. In 2008, Masimo introduced Patient SafetyNet™, a remote monitoring and wireless clinician notification system designed to help hospitals avoid preventable deaths and injuries associated with failure to rescue events. In 2009, Masimo introduced rainbow® Acoustic Monitoring™, the first-ever commercially available noninvasive and continuous monitoring of acoustic respiration rate (RRa™).?Masimo SET® and Masimo rainbow® technologies also can be found in over 100 multiparameter patient monitors from over 50 medical device manufacturers around the world. Founded in 1989, Masimo has the mission of “Improving Patient Outcome and Reducing Cost of Care … by Taking Noninvasive Monitoring to New Sites and Applications® ” Ad-ditional information about Masimo and its products may be found at www.masimo.com.

ERAS Programme, Including Fluid Therapy Tailored to Masimo’s PVI®, Shows Reduced Length of Stay and Cost Savings

The group used selected clini-cal markers, such as positive blood cultures (indicating bacteremia), vaso-pressors (indicating severe hypoten-sion), and lactic acid levels, in order to identify cases of severe sepsis or sepsis shock. They then tracked event rates over time. Over the 10-year study period, there was a marked increase in the incidence of patients with diagno-sis codes suggesting severe sepsis but no change in the incidence of sepsis

using objective clinical measures. “Our study is very suggestive, but

we would be the first to admit that our data only comes from two hos-pitals,” cautioned Dr Klompas. “So whether we can make any generaliza-tions about the US as a whole or the rest of the world remains to be seen.”

The feasibility of rolling out such a study nationally was acknowledged by Dr Klompas as presenting a formi-dable challenge, despite a broaden-

ing adoption of electronic health records. “The issue is that, whereas there are lots of national systems now that can aggregate diagno-sis codes from across many, many hospitals, there are relatively few consolidated systems with consoli-dated electronic health record data spanning many years.”.

“The general policy direction in the US though (and I think in other countries as well) is moving towards

more digitization of medical records. So in the future this will be increas-ingly possible.”References1 Dombrovskiy VY et al. Rapid increase in

hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med. 2007 May;35(5):1244-50.

2 Surviving Sepsis Campaign. www.surviving-sepsis.org (retrieved March 2015).

3 Rhee C et al. Comparison of trends in sepsis incidence and coding using administrative claims versus objective clinical data. Clin Infect Dis. 2015 Jan 1;60(1):88-95.


T he highly protected nature of the brainstem accounts for the prognosis value of abolition of some brainstem reflexes in particular

conditions, such as anoxia. In a session on some of the important but less prominent markers of mor-tality in ICU care, Tarek Sharshar (Hôpital Raymond Poincaré, Garches, France) speaks on the topic of brainstem dysfunction, outlining the role it plays in health, and how it could be used as a valuable clinical predictor to guide patient management.

Prospective observational study published by Dr Sharshar and colleagues1 on the neurological examination of non-brain injured patients who re-quired sedation raised the hypothesis of brainstem dysfunction in critically ill patients. “The original purpose of this study was to determine whether or not sedation hampers the interpretation of brain-stem reflexes, whose examination is recommended in comatose patients but has never been assessed in sedated patients, surprisingly,” said Dr Sharshar, in an interview with ISICEM News.

“We found that this exam was reliable and that abolition of brainstem reflexes was not at random. Indeed, some responses were more preserved (i.e. corneal, pupillary light or cough reflexes) than oth-ers (i.e. grimace, oculocephalic reflex or blinking

to strong light). It has to be said that this pattern does not correspond to a vascular systematization, and it cannot result from a lesion at a particular region of the brainstem. It suggests a functional neuroanatomy in which some centers are more susceptible than others to critical illness and/or sedatives agents.”

The group is currently addressing this question by determining how their findings relate to particu-lar syndromes, pro-files or phenotypes. In addition, they are looking more closely at particular facets of brainstem function, seeing whether they are abolished or preserved globally or selectively, according to substructure and function.

“Moreover, abolition of the cough reflex was independently associated with increased mortality (with an odds ratio of about 5) and absence of the oculocephalic response (OCR) with the occurrence of delirium after discontinuation of sedation,”

he continued. In other words, for a given level of sedation or of sedatives doses and for a given intensity of critical illness severity, cough reflex or OCR may or may not be abolished, but when absent they are associated with bad outcomes.

The absence of cough reflex, it is thought, reflects a dysfunction at the level of the medulla, which controls vital functions. The absence of OCR implies dysfunction of the ascendant activatory re-

ticular system (AARS), which could then account for the fluctu-ating course of arousal (a major feature of delirium).

Clinical markers that are able to pin-point local brainstem impairments are potentially immensely

useful to practitioners. Previous studies, noted Dr Sharshar, have certainly suggested this, based on methods such as spectral analysis of cardiovas-cular or respiratory signals. These methods have demonstrated impairments associated with in-creased mortality, such as heart variability (related

The hidden killers Studio (Bozar) Wednesday 13:45

Hidden killer: Brainstem dysfunction in critical illness

“We think that brainstem dysfunction might be the missing link between mortality and brain dysfunction or deep sedation.”

Tarek Sharshar


to impaired sympathetic tone), baroreflex and respiratory rate variability.

“The immune system and the autonomic system are also interacting,” said Dr Sharshar. “For instance, according to the model of cholin-ergic reflex (proposed by Kevin J Tracey and col-leagues), the vagal nerve detects inflammation and modulates the immune response. The hypothesis that critical illness results from impairment of the cholinergic reflex, or more largely of neuroimmune interactions, is in agreement with the concept of brainstem dysfunction. Brainstem dysfunction could also explain the relationship of mortality with delirium or deep sedation, evidenced by Ely et al.2 and Shehabi et al.3 respectively.”

Dr Sharshar acknowledged that the findings of his group were limited to sedated critically ill patients, who nevertheless present a significant cohort because of the seriousness of their condi-tion. His work, he said, also raises issues as to whether or not the relations they identified occur in non-sedated critically ill patients, and whether or not sedation is a revealing or a causing factor of this brainstem dysfunction.

Moreover, this brainstem dysfunction was evidenced in critically ill patients requiring seda-tion by midazolam or sufentanyl, which raises further questions about drug choice. “Whether this brainstem dysfunction exists with other sedatives agents, such propofol or dexmedetod-midine, remains to be assessed,” said Dr Sharshar, adding: “Whether titration of sedation in order to preserve cough reflex or OCR reduced mortality in deeply sedated critically ill patients would be very interesting, but such a trial would be difficult to design. It may be that dexmedetomidine could be better than midazolam or propofol regarding brainstem dysfunction.”

This neuropharmacological mechanism of brainstem dysfunction is accompanied by two other factors, the first being the neuroinflamma-tory process that accompanies critical illness and is correlated with its severity. “We have shown that the brainstem is liable to neuroinflammation and neuronal apoptosis in patients who had died from septic shock,” said Dr Sharshar, going on to describe some of the mechanisms that might be at

play: “It has been experimentally shown that this apoptosis within medullar cardiovascular centers precedes hypotension in an endotoxin model. One pathway involved in the brain-immune interactions is the area postrema, which is deprived of blood-brain barrier and allows circulating factors (such as cytokines) to signal the brainstem structures. This physiological pathway is essential for an adapted neuroimmune response. It is however conceivable

that the passage of inflammatory mediators in excess can trigger a neuroinflammatory process.”

The third process is neurodegeneration, as evidenced by reports that brainstem reflexes are more frequently abolished in elderly sedated patients. Of course, it is also known that aging and neurodegenerative disease (such as Parkin-son’s syndromes or Alzheimer’s dementia) impairs brainstem functions.

Regarding the prevalence of brainstem dysfunc-tion in the ICU, Dr Sharshar was certain only as to the sparseness of data. “The underlying issue is which brainstem functions to consider, and these are difficult or impossible to assess clinically. To our knowledge, prevalence in brainstem reflexes in se-dated patients and heart rate variability in critically ill patients have been assessed. Thus, cough reflex and OCR are absent in 30% and 50%.

“It is difficult to infer from these numbers the prevalence of brainstem dysfunction in ICU. Thus, in non-sedated critically ill patients, brainstem reflexes would be certainly preserved but this does not mean that other brainstem symptoms will not be present. This should require an accurate neuro-logical examination.”

With so much data up in the air, how would Dr Sharshar proceeding at present with detecting and

minimizing brainstem dysfunction? “The detection should be based on clinical examination, especially the assessment of brainstem reflexes in sedated pa-tients. Other methods include somatosensory and auditory evoked potentials and spectral analysis of heart rate.

“The former cannot be done in routine but we will start soon a multicenter observational study on prognosis value of neurophysiological brainstem

responses. Current technology facilitates the spectral analysis of heart rate recording at the bedside. It would be interesting to determine if mortality decreases when heart rate variability is restored – this is a pharmaceutic challenge, and beta-blockers have been proposed.”

Hence, the integration of the assessment of brainstem reflexes in the evaluation of sedated critically

ill patients would be a good start, given that this is the cohort at most severe risk of developing brain dysfunction during and after sedation.

“In addition to its prognosis value, neurological examination enables us to detect a focal neurologi-cal signs. We have found that 20% of patients with septic shock developed ischemic stroke while they were sedated – this was revealed by focal neurological signs.4

“We need more data to support the hypothesis of brainstem dysfunction during critical illness, but there is no reason to think that the brainstem is spared – that only the frontal lobe or the hip-pocampus are involved. We think that brainstem dysfunction might be the missing link between mortality and brain dysfunction or deep sedation.”References

1 Sharshar T et al. Brainstem responses can predict death and delirium in sedated patients in intensive care unit. Crit Care Med. 2011 Aug;39(8):1960-7.

2 Ely EW et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004 Apr 14;291(14):1753-62.

3 Shehabi Y et al. Sedation depth and long-term mortality in mechanically ventilated critically ill adults: a prospective longitu-dinal multicentre cohort study. Intensive Care Med. 2013 May; 39(5): 910–918.

4 Polito A et al. Pattern of brain injury in the acute setting of hu-

man septic shock. Critical Care 2013, 17:R204.

“We will start soon a multicenter observational study on prognosis value of neurophysiological brainstem responses.”

Tarek Sharshar

The hidden killers Studio (Bozar) Wednesday 13:45

Hidden killer: Brainstem dysfunction in critical illness

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