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2017 annual updates


Annual Update
in Intensive Care
and Emergency
Medicine 2017


Edited by J.-L.Vincent


Annual Update in Intensive Care and
Emergency Medicine 2017

The series Annual Update in Intensive Care and Emergency Medicine is the continuation of the series entitled Yearbook of Intensive Care Medicine in Europe and
Intensive Care Medicine: Annual Update in the United States.

Jean-Louis Vincent

Annual Update in
Intensive Care and
Emergency Medicine 2017

Prof. Jean-Louis Vincent
Dept. of Intensive Care
Erasme Hospital
Université libre de Bruxelles
Brussels, Belgium

ISSN 2191-5709
ISSN 2191-5717 (electronic)
Annual Update in Intensive Care and Emergency Medicine
ISBN 978-3-319-51907-4
ISBN 978-3-319-51908-1 (eBook)
DOI 10.1007/978-3-319-51908-1
© Springer International Publishing AG 2017
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Common Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Part I



Severe Influenza Infection: Pathogenesis, Diagnosis, Management
and Future Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
B. M. Tang and A. S. McLean


Implementing Antimicrobial Stewardship in Critical Care:
A Practical Guide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
J. Schouten and J. J. De Waele


Part II


Microvesicles in Sepsis: Implications for the Activated Coagulation System 29
G. F. Lehner, A. K. Brandtner, and M. Joannidis
Mesenchymal Stem/Stromal Cells for Sepsis . . . . . . . . . . . . . . . . . . .
C. Keane and J. G. Laffey

Part III



Fluid Balance During Septic Shock: It’s Time to Optimize . . . . . . . . . .
X. Chapalain, T. Gargadennec, and O. Huet


How to Use Fluid Responsiveness in Sepsis . . . . . . . . . . . . . . . . . . . .
V. Mukherjee, S. B. Brosnahan, and J. Bakker





Use of ‘Tidal Volume Challenge’ to Improve the Reliability
of Pulse Pressure Variation . . . . . . . . . . . . . . . . . . . . . . . . . . .
S. N. Myatra, X. Monnet, and J.-L. Teboul


Distribution of Crystalloids and Colloids During Fluid Resuscitation:
All Fluids Can be Good and Bad? . . . . . . . . . . . . . . . . . . . . . .
I. László, N. Öveges, and Z. Molnár


Part IV

Renal Issues

New Diagnostic Approaches in Acute Kidney Injury . . . . . . . . . . . . . . 107
M. Meersch and A. Zarbock
When Should Renal Replacement Therapy Start? . . . . . . . . . . . . . . . 119
J. Izawa, A. Zarbock, and J. A. Kellum
An Overview of Complications Associated with Continuous
Renal Replacement Therapy in Critically Ill Patients . . . . . . . . . . 129
S. De Rosa, F. Ferrari, and C. Ronco
Measuring Quality in the Care of Patients with Acute Kidney Injury . . . 139
M. H. Rosner
Characteristics and Outcomes of Chronic Dialysis Patients Admitted
to the Intensive Care Unit . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
M. Chan, M. Varrier, and M. Ostermann

Part V

Metabolic Support

Energy Expenditure During Extracorporeal Circulation . . . . . . . . . . . 159
E. De Waele, P. M. Honore, and H. D. Spapen
Vitamin D, Hospital-Acquired Infections and Mortality
in Critically Ill Patients: Emerging Evidence . . . . . . . . . . . . . . . 169
G. De Pascale, M. Antonelli, and S. A. Quraishi

Part VI

Cardiac Conditions

Anemia and Blood Transfusion in the Critically Ill Patient
with Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 187
A. B. Docherty and T. S. Walsh
Right Ventriculo-Arterial Coupling in the Critically Ill . . . . . . . . . . . . 203
F. Guarracino, P. Bertini, and M. R. Pinsky


Part VII


Cardiopulmonary Resuscitation

Antiarrhythmic Drugs for Out-of-Hospital Cardiac Arrest
with Refractory Ventricular Fibrillation . . . . . . . . . . . . . . . . . . 213
T. Tagami, H. Yasunaga, and H. Yokota
Airway and Ventilation During Cardiopulmonary Resuscitation . . . . . . 223
C. J. R. Gough and J. P. Nolan


Oxygenation and Respiratory Failure

High-Flow Nasal Cannula Support Therapy:
New Insights and Improving Performance . . . . . . . . . . . . . . . . . 237
G. Hernández, O. Roca, and L. Colinas
Urgent Endotracheal Intubation in the ICU: Rapid Sequence Intubation
Versus Graded Sedation Approach . . . . . . . . . . . . . . . . . . . . . . 255
G. Zaidi and P. H. Mayo
Sedation in ARDS: An Evidence-Based Challenge . . . . . . . . . . . . . . . 263
D. Chiumello, O. F. Cozzi, and G. Mistraletti
Mechanical Ventilation in Obese ICU Patients:
From Intubation to Extubation . . . . . . . . . . . . . . . . . . . . . . . . 277
A. De Jong, G. Chanques, and S. Jaber
Novel Insights in ICU-Acquired Respiratory Muscle Dysfunction:
Implications for Clinical Care . . . . . . . . . . . . . . . . . . . . . . . . . 291
A. Jonkman, D. Jansen, and L. M. A. Heunks

Part IX

Neurological Conditions

Neuroanatomy of Sepsis-Associated Encephalopathy . . . . . . . . . . . . . 305
N. Heming, A. Mazeraud, and F. Verdonk
Clinical Utility of Blood-Based Protein Biomarkers
in Traumatic Brain Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
S. Mondello, A. I. R. Maas, and A. Buki
Novel Metabolic Substrates for Feeding the Injured Brain . . . . . . . . . . 329
H. White, P. Kruger, and B. Venkatesh


Part X


Burn Patients

Fluid Therapy for Critically Ill Burn Patients . . . . . . . . . . . . . . . . . . 345
A. Dijkstra, C. H. van der Vlies, and C. Ince
Burn Patients and Blood Product Transfusion Practice:
Time for a Consensus? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
A. Holley, A. Cook, and J. Lipman

Part XI

Drug Development and Pharmaceutical Issues

Bridging the Translational Gap: The Challenges
of Novel Drug Development in Critical Care . . . . . . . . . . . . . . . . 375
S. Lambden and C. Summers
Medicating Patients During Extracorporeal Membrane Oxygenation:
The Evidence is Building . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
A. L. Dzierba, D. Abrams, and D. Brodie
Anti-Inflammatory Properties of Anesthetic Agents . . . . . . . . . . . . . . 401
F. F. Cruz, P. R. M. Rocco, and P. Pelosi

Part XII

The Extremes of Age

Facing the Ongoing Challenge of the Febrile Young Infant . . . . . . . . . . 417
A. DePorre, P. L. Aronson, and R. McCulloh
Post-Discharge Morbidity and Mortality in Children with Sepsis . . . . . . 431
O. C. Nwankwor, M. O. Wiens, and N. Kissoon
Emergency Abdominal Surgery in the Elderly:
How Can We Reduce the Risk in a Challenging Population? . . . . . 445
X. Watson and M. Cecconi



Patient-Specific Real-Time Cardiovascular Simulation as Clinical Decision
Support in Intensive Care Medicine . . . . . . . . . . . . . . . . . . . . . 459
M. Broomé and D. W. Donker
Making the Best Use of Simulation Training in Critical Care Medicine . . 477
A. Mahoney, J. Vassiliadis, and M. C. Reade


Part XIV


Organization and Quality of Care

We Have Good Enough Data to Support Sepsis Performance Measurement 495
H. C. Prescott and V. X. Liu
The Use of Health Information Technology to Improve Sepsis Care . . . . 505
J. L. Darby and J. M. Kahn
Beyond Semantics: ‘Disproportionate Use of Intensive Care Resources’
or ‘Medical Futility’? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517
E. J. O. Kompanje and J. Bakker
Reflections on Work-Related Stress Among Intensive Care Professionals:
An Historical Impression . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527
M. M. C. van Mol, E. J. O. Kompanje, and J. Bakker
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539

Common Abbreviations


Acute kidney injury
Acute respiratory distress syndrome
Area under the curve
Body mass index
Chronic obstructive pulmonary disease
Cardiopulmonary resuscitation
C-reactive protein
Continuous renal replacement therapy
Computed tomography
Central venous pressure
Extracorporeal membrane oxygenation
Intensive care unit
Left ventricular
Mean arterial pressure
Magnetic resonance imaging
Odds ratio
Pulmonary artery occlusion pressure
Positive end-expiratory pressure
Pulse pressure variation
Randomized controlled trial
Renal replacement therapy
Right ventricular
Systematic inflammatory response syndrome
Sequential organ failure assessment
Stroke volume variation
Toll-like receptor
Tumor necrosis factor

Part I

Severe Influenza Infection: Pathogenesis,
Diagnosis, Management and Future Therapy
B. M. Tang and A. S. McLean

Severe influenza infection is an important cause of acute lung injury. Although other
respiratory viruses (e. g., respiratory syncytial virus, human metapneumovirus) can
also cause considerable pulmonary damage, influenza virus remains the main cause
of respiratory failure in patients with suspected viral respiratory tract infection. In
addition, influenza virus is the only respiratory virus that has caused four pandemics
over the last 100 years, making it one of the most transmissible and virulent viruses
in the world. Here, we review the pathogenesis, diagnosis, current management and
future therapy of severe influenza infection.

Understanding the pathogenesis of severe influenza infection is the key to developing new therapeutic strategies. Although the basic process of a mild influenza
infection is well understood, our understanding of how a mild illness progresses
to a potentially lethal pulmonary infection remains poor. In this section, we will
review recent advances in the immunopathology of severe influenza infection.
Pulmonary epithelial cells are the first target of invasion by influenza virus. Like
most cells, epithelial cells constitutionally upregulate the interferon pathway in response to infection by viruses. Types I and III interferon pathways are the natural
B. M. Tang ( )
Department of Intensive Care Medicine, Level 2, North Block, Nepean Hospital
Derby Street, Kingswood, NSW 2747, Australia
Centre for Immunology and Allergy Research, Westmead Institute for Medical Research
Westmead, NSW 2145, Australia
e-mail: benjamin.tang@sydney.edu.au
A. S. McLean
Department of Intensive Care Medicine, Level 2, North Block, Nepean Hospital
Derby Street, Kingswood, NSW 2747, Australia
© Springer International Publishing AG 2017
J.-L. Vincent (ed.), Annual Update in Intensive Care and Emergency Medicine 2017,
DOI 10.1007/978-3-319-51908-1_1



B. M. Tang and A. S. McLean

defense mechanism against influenza virus. Upon infection, epithelial cells upregulate interferon regulatory factors (IRF), such as IRF-3 and IRF-7. This leads to
transcription and translation of a downstream interferon pathway, which in turn
produces a family of interferon-stimulated genes/proteins. This vast family of interferon-stimulated genes/proteins (> 300) provides a wide spectrum of anti-viral
effects, ranging from inhibition of viral replication to sensing of influenza virus inside the host cells. This response is immediate and effective, making it a critical
part of the innate immune response against influenza virus.
Whilst essential, the interferon response alone is not sufficient to prevent virus
replication in severely infected cases. Multiple subsets of immune cells (e. g.,
macrophages, dendritic cells and neutrophils) are required to mount an effective
immune response. The failure of this immune response is the hallmark of severe
infection, which is characterized by multiple defects in immune cell recruitment,
activation or proliferation, as described below.
Alveolar macrophages are among the early responders to influenza virus. They
phagocytose infected cells containing influenza virus and initiate other cells of
innate and adaptive immunity. Failure of alveolar macrophages to mount an effective early response is associated with increased viral dissemination and increased
morbidity/mortality. Neutrophils are also early responders in severe influenza infection. Similar to alveolar macrophages, failure of this early neutrophil response is
a prominent feature of severe influenza infection. Paradoxically, an exuberant or inappropriately exaggerated neutrophil response is also a feature of severe influenza
infection. For example, in severe H1N1 and H5N1 infection, the large influx of
neutrophils into the alveolar space is a classic feature [1]. During this massive
neutrophil influx, the neutrophils release a large amount of cytokines, extracellular proteases and histones. This leads to a breakdown of the epithelial barrier,
accumulation of reactive oxygen species (ROS), flooding of alveolar spaces by inflammatory fluid and increased barrier to oxygenation, all of which contribute to
the clinical picture of acute lung injury commonly observed in patients with severe
influenza infection.
Other immune cells are also involved in this early phase of infection (and
contribute to pathogenesis). Monocytes, for example, traffic into the infected pulmonary tissue and participate in a pro-inflammatory response. Not surprisingly,
inhibition of monocytes and preventing their subsequent participation in the proinflammatory response has been shown to decrease the extent of acute lung injury in
animal models [2, 3]. Pulmonary dendritic cells are another important immune cell
subset that contributes to pathogenesis. In a murine model of influenza infection,
pulmonary dendritic depletion increased macrophage recruitment and enhanced
pro-inflammatory responses (tumor necrosis factor [TNF]-˛/interleukin [IL]-6 increased 5–35 fold) [4]. In another murine model, pulmonary dendritic cells induced
T-regulatory cell responses that suppressed antigen-specific CD8 cells, thereby preventing an effective immune response [5]. Hence, the pathogenic role of dendritic
cells seems to be to cause a dysregulated immune response, which either causes
excessive lung injury (by causing increased inflammation) or impairs the effective
clearance of influenza virus (by limiting CD8 cell response).

Severe Influenza Infection: Pathogenesis, Diagnosis, Management and Future Therapy


In the later phase of the host response, adaptive immunity becomes the dominant player. Here, activated CD8 T-lymphocytes cause lysis of the influenza-infected epithelial cells, which facilitates virus clearance. Impaired CD8 responses
are a prominent feature of highly pathogenic influenza infection, such as the recently reported H7N9 outbreak in China [6]. In addition to cell lysis, CD8 cells
also enhance the pro-inflammatory response, which could either contribute to host
defense or, in some cases, worsen lung inflammation and cause further pulmonary

The detection of influenza virus is the first step in establishing a diagnosis. Rapid
antigen detection assays offer a low-cost approach with a short turn-around time.
However, a recent review demonstrated that such assays have an unacceptably low
sensitivity [7]. Nucleic acid amplification (e. g., multiplex viral polymerase chain
reaction [PCR]) has recently gained a much greater prominence due to its high sensitivity and specificity. Currently, this is the most accepted gold standard for virus
detection in the initial evaluation of suspected influenza infection. However, there
are three important caveats regarding the clinical utility of nucleic acid amplification assay:
(1) The reliability of such an assay is dependent on the fact that the viral genome
is known. An unknown viral genome, mutant strain or new pandemic influenza
virus will be difficult to detect.
(2) The sensitivity is affected by the way the sample is collected. Poor sample collection, inability to access lower airway or reduced virus shedding (due to prior
anti-viral administration) all reduce detection sensitivity.
(3) Detection does not imply infection because the presence of influenza virus in
the upper airway may be a co-incidental finding or active infection. In fact, 18%
of exposed individuals show no clinical symptoms; therefore, the presence of
the virus does not always imply that it is the causative agent. Furthermore, detection of an incomplete virus segment (by nucleic acid amplification) does not
constitute sufficient proof that active viral replication is present.
In addition to virus detection, clinicians need to identify which patients are more
likely to progress to severe disease or require admission to the intensive care unit
(ICU). Table 1 summarizes virus-related and host factors that may contribute to
progression to more severe disease. Some of these factors are clinically obvious
(e. g., age, pre-existing medical conditions). Other factors (e. g., genetic susceptibility) require highly sophisticated laboratory testing (e. g., high-throughput genome
sequencing), which are not yet available in the routine clinical setting.
Following the initial diagnostic work-up, the influenza infected patient needs to
be continuously monitored for signs of bacterial co-infection. Several studies have
shown that a significant proportion of influenza infected patients admitted to the


B. M. Tang and A. S. McLean

Table 1 Risk factors for progression to severe influenza infection
Viral factors
Subtype of influenza virus (e. g., H7N9)
Viral load (e. g., high viral load increases
Mutation in viral genome (e. g., PB2 gene
mutation enhances viral replication)

Host factors
Genetic susceptibility (e. g., IFITM3)
Pregnancy, obesity and extremes of age
(elderly and neonates)
Pre-existing medical conditions (e. g., chronic
lung diseases, cancer, chemotherapy)

IFITM3: interferon-induced transmembrane protein 3

ICU develop bacterial co-infection as a complication [8]. The causative bacterial
co-pathogens are most likely to be Streptococcus pneumoniae or Staphylococcus
aureus. The basis for increased susceptibility is thought to be due to production
of type I interferon, which is increased initially in response to influenza virus infection, but also decreases the synthesis of IL-1B, IL-23, IL-17 and IL-22, which
in turn inhibit the production of antimicrobial peptides [9]. Furthermore, the proinflammatory milieu caused by the influx of neutrophils also contributes towards
increased susceptibility to bacterial super-infection. Other immune-related factors
also contribute towards increased susceptibility including reduced type 17 immune
response, impaired antimicrobial peptide (AMP) production by lung epithelia and
reduced phagocyte function [9].
Host response biomarkers should form an important part of the diagnostic evaluation of an infected patient. Biomarkers assist clinical evaluation by providing
additional information that is not available by conventional virus detection assay.
This additional information includes an improved ability to distinguish between coincidental ‘bystander’ virus and true infection, to predict clinical risk for further deterioration and to monitor treatment response. Table 2 summarizes the host response
biomarkers that have been recently investigated in the literature.
Gene expression biomarkers are the most recent development in biomarker research. These biomarkers differ from conventional biomarkers (e. g., C-reactive
protein [CRP] or procalcitonin [PCT]) in that they are much more influenza specific,
due to the fact that many of them are interferon derived genes, which are upregulated in response to respiratory virus infection. A recently published landmark study

Table 2 Host response biomarkers for influenza infection
Low antibody titer in serum
HLA-DR expression in monocytes
Procalcitonin (PCT) and C-reactive protein
(CRP) in blood
Mid-regional pro-adrenomedullin (MRproADM)
Gene expression biomarkers

Current evidence
Could indicate increased risk of death
Suggests immune suppression
May have some role in excluding bacterial coinfection
May predict mortality or the need for mechanical ventilation
May distinguish between virus detection and
active infection

Severe Influenza Infection: Pathogenesis, Diagnosis, Management and Future Therapy


showed that these biomarkers could address several important clinical questions simultaneously (whereas conventional biomarkers could address only one question
at a time) [10]. First, these biomarkers could assist clinicians to identify patients
most likely to have infection (bacterial and viral) in a heterogeneous population
of patients with undifferentiated respiratory illnesses. Second, among infected patients, the biomarkers could distinguish between bacterial and viral infection. Third,
among infected patients, the biomarkers could prognosticate and predict clinical
outcomes. In addition, the biomarkers could be easily measured in most clinical
settings due to the ease of sampling (only 2.5 ml of whole blood is required) and
the wide availability of PCR machines (to measure gene-expression). Importantly,
because these biomarkers reflect changes in the immune pathway during influenza
infection, they provide additional diagnostic information not offered by conventional pathogen detection assay (e. g., virus nucleic amplification). Although further
validation studies are necessary before these biomarkers can be widely adopted in
clinical practice, it is highly likely that they will be incorporated into the diagnostic
armamentaria of modern laboratories in the future.

The management of severe influenza infection is mainly supportive. Standard measures should include those used for the management of acute respiratory distress
syndrome (ARDS). Therapeutic agents for severe influenza infection are limited,
with oseltamivir being the most commonly used anti-viral agent. A recent metaanalysis showed that oseltamivir could reduce symptom duration and the risk of
developing lower respiratory tract complications (e. g., viral pneumonia) [11]. However, its efficacy is dependent on oseltamivir being administered in the early phase
of the illness. This may pose difficulty in the management of ICU patients, because
these patients often present in the late phase of their illness. Regardless of the timing of presentation, oseltamivir should be considered in all high-risk patients. The
current recommendation by the World Health Organization (WHO) indicates that
it should be administered in immunocompromised patients, patients with severe
comorbidities or underlying chronic lung diseases, age < 2 or > 65 years, morbid
obesity, nursing home residents, women who are pregnant or post-partum, and patients with signs of severe respiratory disease.
Low-dose steroids are best avoided, as suggested by a recently published metaanalysis [12]. In this meta-analysis, the authors analyzed data from nine cohort
studies (n = 1,405) and 14 case-control studies (n = 4,700). They found increased
mortality associated with corticosteroid treatment in cohort studies (relative risk
[RR] 1.85; 95% confidence interval [CI] 1.46–2.33; p < 0.0001) and in case-control studies (odds ratio [OR] 4.22; 95% CI 3.10–5.76; p < 0.0001). This increased
mortality was consistent regardless of the quality of the included studies or the sample size of the individual studies. Other worrying findings are that corticosteroid
use was associated with a higher incidence of hospital-acquired pneumonia, longer
duration of mechanical ventilation and longer hospital stay. Therefore, the use of


B. M. Tang and A. S. McLean

corticosteroids in severe influenza infection is not recommended in routine clinical
care and should be restricted to patients in the setting of clinical trials.

Future Therapy
Although conventional treatment for severe influenza infection is limited, novel
therapeutic agents have shown great promise. These novel agents consist of mainly
two classes: immune agents that modulate host response and anti-viral agents that
inhibit viral replication.

Immune Agents that Modulate Host Response
Host Factors that Control Viral RNA Replication
In order to replicate successfully, the influenza virus mRNA undergoes transcription. Initiation of primary viral RNA transcription depends on the activity of host
RNA polymerase. Inhibition of this transcription process provides a therapeutic opportunity to halt the commencement of viral RNA replication. Inhibitors of this
process, such as CDK9 inhibitor, have undergone preclinical evaluation.
Host Signaling Pathways Influenced by Redox Balance
The influenza virus hijacks the host cell signaling pathway to benefit its own propagation. Phosphorylation of the mitogen-activated protein kinase (MAPK) pathway
has been shown to facilitate viral nucleoprotein trafficking [13]. Therefore, inhibition of the MAPK pathway could potentially reduce spread of the influenza virus.
Of particular relevance to the intensivist is the fact that the activity of the MAPK
pathway is determined by the oxidative-reductive state of the host cell. N-acetylcysteine, a well-established drug already commonly used in ICU patients, could
modulate the oxidative-reductive state of the host cell, thereby affecting influenza
virus propagation. A recent study has demonstrated the potential efficacy of this
agent in treating severe influenza infection in an animal model [14]. Other antioxidant agents, such as p38 inhibitor or glutathione, are also potential new hostbased therapeutic agents that modulate the redox balance within the host cell. In
addition to the MAPK pathway, the PI3K pathway is also sensitive to the effect of
redox balance. PI3K is a signaling pathway implicated in influenza infection [15].
An in vitro study showed that inhibition of this pathway could reduce influenza
virus replication [16]. Importantly, PI3K inhibitors have already been approved as
anticancer drugs. Therefore, the possibility of extending their use as anti-influenza
agent offers a promising new avenue for future investigation.
Host Factors that Regulate Inflammation
Nuclear factor kappa B (NF-ÄB) is a family of transcription factors that initiate inflammation. Influenza virus benefits from the activation of the NF-ÄB pathway as
the virus exploits the pathway machinery to facilitate viral replication. NF-ÄB path-

Severe Influenza Infection: Pathogenesis, Diagnosis, Management and Future Therapy


way inhibitors, such as acetyl-salicylic acid, could block influenza virus replication
and propagation. Other pathway inhibitors, such as SC75741, also decrease viral
replication. This agent has the unique feature of having a low potential in selecting
viral resistant variants, therefore making it unlikely to result in anti-viral resistance
[17]. Furthermore, SC75741 has recently been shown to reduce viral replication and
cytokine expression in highly pathogenic strains (e. g., H5N1 and H7N7), making
it a potential candidate for further investigation in severe influenza infection [18].
The cyclooxygenase (COX) pathway is another pro-inflammatory pathway
that has been implicated in influenza virus infection. Highly pathogenic influenza
strains, such as H5N1, strongly upregulate COX-2 mediated pro-inflammatory signaling that causes hypercytokinemia during severe H5N1 infection. A non-steroidal
COX-2 inhibitor has been shown to inhibit H5N1 infection in human macrophages,
making it another potential agent for severe influenza infection [19].

Host Interferon Pathway
The interferon pathways (type I and type II) are the most potent defense of the
host cell against influenza virus infection. Activation of interferon pathways leads
to upregulation of more than 300 interferon-stimulated genes. Many of these interferon-stimulated genes have potent anti-influenza activity, such as MX1 (antiinfluenza), ISG15 (inhibits influenza virus replication), OAS1, OAS2, OAS3 (degrades viral RNA), EIF2AK2 (inhibits viral replication), HERC5 (positive regulator
of anti-viral response) and IFIT2 (inhibits expression of viral mRNA). In addition,
these genes activate the adaptive immune response and induce programmed cell
death of virally infected cells.
Novel therapeutic strategies take advantage of this endogenous anti-influenza
defense by identifying trigger points that activate the interferon pathway. Several
molecular pathways are known to trigger the interferon pathway. For example,
Toll-like receptor (TLR) 3 and 7 are known to activate the interferon pathway in
lung epithelium and immune cells. In plasmacytoid dendritic cells, TLR7 activation produces massive interferon release at 1,000 times that of any other immune
cell in the human host. Ligands that selectively target TLR7 in plasmacytoid dendritic cells could be potential therapeutic targets. Other TLR ligands, such as CpG
oligodeoxynucleotides (TLR9), have been shown to protect against lethal influenza
infection in experimental settings [20]. In lung epithelium, TLR3 is the dominant
pathway leading to interferon pathway activation. A large number of TLR3 and
TLR9 agonists are currently in clinical trial phase for the treatment of autoimmune conditions, cancer and viruses. It is possible to extend the application of these
agents to treat severe influenza infection. Further investigation on these promising
new agents may open the door for developing new treatments in severe influenza
Host Factors Implicated in Virus Entry into Human Cells
Before influenza virus replicates in human cells, it needs to gain entry successfully
into the cells. The influenza virus harnesses host proteolytic enzymes to achieve
this process. One example of such an enzyme is the transmembrane protease serine


B. M. Tang and A. S. McLean

S1 (TMPRSS) that belongs to the type II transmembrane serine protease family.
This enzyme is located in the human airway epithelium and plays an important
role in permitting influenza virus to gain entry into the host cell. Consequently,
a protease inhibitor that binds to the TMPRSS molecule is a potential drug target in the treatment of influenza infection. Recent studies have identified three
TMPRSS molecules, namely TMPRSS2, TMPRSS4 and TMPRSS11D, as potential drug targets [21]. These molecules have been detected in multiple locations
within the human respiratory tract, including nasal mucosa, the trachea, the distal
airway and the lung. Aprotinin, a drug familiar to most intensivists, is a protease
inhibitor and has been shown to reduce influenza virus replication. In addition to
reducing viral replication, aprotinin has also been shown to reduce inflammatory
cytokines, suggesting a further benefit other than its impact on viral replication. So
far, findings with the TMPRSS molecule have been derived mainly from in vitro
models. Further studies in animal models and human clinical trials are needed in
the future.

Anti-Viral Agents that Inhibit Viral Replication
Neuraminidase is a glycoside hydrolase that removes a sialic acid residue of the
host cellular receptor recognized by influenza virus hemagglutinin. Therefore, it
is an essential component of a process that allows virus penetration through mucosal barriers and subsequently to gain entry into the host cell. In addition, after
virus replication, neuraminidase detaches the virion from the infected cells, thereby
facilitating release and subsequent spread of the viral progeny. Consequently, neuraminidase is essential for viral infectivity to host cells. Therefore, inhibiting neuraminidase is the primary therapeutic strategy currently used in clinical practice.
Most clinicians will be familiar with two neuraminidase inhibitors, zanamivir and
Unfortunately, the true efficacy of these agents in treating patients with severe
influenza infection in the ICU is yet to be established. The vast majority of the clinical trials on these drugs were performed in non-ICU patients. Furthermore, to be
effective, these drugs need to be administered during the very early phase of the disease. Consequently, the clinical utility of current neuraminidase inhibitors is limited
in ICU patients. To improve the clinical utility of these drugs, a recently developed
strategy has been used to increase the efficacy of the approved neuraminidase inhibitors. This strategy involved use of multivalent inhibitors and conjugating the
compounds to a biocompatible polymer. Using this innovative approach, recent
studies have shown that neuraminidase inhibitors significantly increase their antiviral potency, to 1,000–10,000 times higher than their predecessors [22]. If proven in
clinical trials, these newer formulations could become extremely valuable in treating patients with severe influenza infection.

Severe Influenza Infection: Pathogenesis, Diagnosis, Management and Future Therapy


Table 3 Drugs that block the two critical processes in hemagglutinin function
Virus interacting with cell surface
Carbohydrate-binding agents that recognize
glycosylation sites on hemagglutinin
Peptides against hemagglutinin

Virus fusion with cell membrane
Molecules that inhibit confirmation change in
Neutralizing antibodies directed against the
stem region of hemagglutinin

Decoy receptor or sialic acid-containing inhibitors
Neutralizing monoclonal antibodies directed
against the globular head domain of hemagglutinin

Hemagglutinin is pivotal for the interaction between influenza virus and the sialic
acid on the surface of the host cells. In addition, it is required for the fusion between the viral envelop and the endosomal membrane of the host cell, which is
the final step in the virus’s entry into the host cell. Inhibiting hemagglutinin could
be achieved by two methods: (1) preventing the interaction between viral surface
molecules and the host cell surface receptor; and (2) blocking the fusion of the viral
envelop with the host cell membrane. Table 3 summarizes the recent development
in the new drugs that utilize the above two strategies.
M2 Ion Channel
The M2 protein is a proton channel inside the influenza virus. After gaining entry
into the host cell, the influenza virus activates the M2 protein by sensing a drop
in the pH value inside the enveloped vesicle (the endosome). The activation of the
M2 proton channel results in a proton flux from the endosome into the virion core.
Acidification of the virus interior leads to dissociation of the viral ribonucleoprotein complexes. Subsequent membrane fusion releases the ribonucleoprotein into
the cytoplasm. This release allows the virus to be imported into the nucleus to start
viral replication. Other important functions of the M2 protein are: formation of the
filamentous strains of the virus; release of the budding virion; and stabilization of
the virion budding site. Due to these important functions, inhibition of M2 protein
represents an ideal therapeutic target. A well-known licensed antiviral drug, amantadine, is an M2 blocker that binds the N-terminal channel lumen of the M2 pore
resulting in repulsion of protons and subsequently prevent virus uncoating. Unfortunately, this class of drug is not active against all strains of influenza virus (e. g.,
influenza B). In addition, the emergence of drug-resistant virus variants has been
reported. These drawbacks have significantly limited the use of M2 blockers.

Severe influenza infection remains an important clinical challenge for intensivists.
The potentially high morbidity and mortality of this condition has remained un-


B. M. Tang and A. S. McLean

changed over the last few decades, due mainly to a lack of effective new therapies
with which to treat such patients.
However, we have gained a much better understanding of the mechanisms of
the disease in recent years. This improved understanding points to the pivotal roles
played by immune dysregulation in causing severe disease. Furthermore, our ability
to diagnose influenza infection, to stratify high-risk patients and to prognosticate
clinical outcomes has also improved thanks to recent advances in genomic science. Importantly, a large number of novel therapeutic agents are currently under
investigation. These novel agents target multiple critical points of the host response
pathway. Agents that modulate the host response hold particularly great promise
since dysregulated immunity is the main driver towards more severe infection. In
the future, clinical trials will be an important next step to demonstrate the efficacy
of these novel agents.

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Implementing Antimicrobial Stewardship
in Critical Care: A Practical Guide
J. Schouten and J. J. De Waele

Management of infections is an important issue in many health care settings, but
severe infections are most prevalent and antimicrobial use is most abundant in the
intensive care unit (ICU). Not surprisingly, antimicrobial resistance has emerged
primarily in the intensive care setting, where multiple facilitators for the development of resistance are present: high antibiotic pressure, loss of physiological barriers and high transmission risk. ‘Intensive care’ had higher proportions of treated
patients, combination therapy, hospital-acquired infections and parenteral administration of antibiotics in a point prevalence survey on antimicrobial prescription by
the ESAC (European Surveillance of Antimicrobial Consumption) in 172 European
hospitals across 25 countries [1].
Antimicrobial prescription is a complex process influenced by many factors. The
appropriateness of antimicrobial use in hospitals varies among physicians, hospitals
and countries due to differences in professional background, clinical experience,
knowledge, attitudes, hospital antibiotic policies, collaboration and communication
among professionals, care coordination and teamwork, care logistics, and differences in sociocultural and socioeconomic factors [2].
One can imagine that changing professional practice is a major challenge. The
scientific literature is full of examples from which it would appear that patients
are not given the care that, according to recent scientific or professional insight as
summarized in guidelines, is desirable. A multitude of studies has shown that 30–
J. Schouten ( )
Dept. of Intensive Care Medicine, Canisius Wilhelmina Ziekenhuis
Weg door Jonkerbos 100, 6532 SZ Nijmegen, Netherlands
IQ healthcare, Radboud University Medical Center
Nijmegen, Netherlands
e-mail: j.schouten@cwz.nl
J. J. De Waele
Dept. of Intensive Care Medicine, University Hospital Gent
9000 Gent, Belgium
© Springer International Publishing AG 2017
J.-L. Vincent (ed.), Annual Update in Intensive Care and Emergency Medicine 2017,
DOI 10.1007/978-3-319-51908-1_2



J. Schouten and J. J. De Waele

40% of patients do not receive care according to guidelines and the findings for
antimicrobial prescribing are similar [3]. This renders changing ICU antimicrobial
use into a challenge of formidable complexity. Given that many influencing factors
play a part, the measures or strategies undertaken to improve antimicrobial use need
to be equally diverse.
Many interventions and programs have been designed to improve appropriate
antimicrobial use in terms of choice of drugs, dosing, timing, de-escalation and
discontinuation. Such interventions are collectively known as antimicrobial stewardship programs. An ICU antimicrobial stewardship program can be thought of as
a menu of interventions that is adapted and customized to fit the infrastructure and
organization of ICUs [4].
In this chapter, we will review the rationale for antimicrobial stewardship programs and take a step by step approach on how to implement such programs in the
critical care setting and how to optimize compliance to relevant antibiotic stewardship recommendations in the ICU.

Rationale for Antibiotic Stewardship in Critical Care
Health care institutions have adopted antimicrobial stewardship programs as
a mechanism to ensure more appropriate antimicrobial use. Antimicrobial stewardship programs can have a significant impact in the ICU, leading to improved
antimicrobial use and resistance patterns and decreased infection rates and costs,
due to the inherent nature of infections encountered and the high and often inappropriate antibiotic utilization in the ICU setting.
Stewardship programs are composed of two intrinsically different sets of interventions (Table 1). A first set of interventions describes recommended professional
care interventions that define appropriate antimicrobial use in individual patients,
regarding indication, choice of drug, dose, route or duration of treatment. For example, these may address ‘de-escalation of therapy’ in individual ICU patients. A second set of interventions describes recommended strategies to ensure that professionals apply these professional care interventions in daily practice. These include both
restrictive (e. g., formulary restriction) and persuasive (e. g., education, feedback)
strategies to improve appropriate antimicrobial use in patient care. The second set of
interventions is therefore used to ensure that the first set of interventions is appropriately applied in patients [5]. These behavioral change interventions either directly or
indirectly (through interventions targeting the system/organization) target the professional and, overall, restrict or guide towards the more effective professional use
of antimicrobials.
The literature shows that in the ICU both restrictive and persuasive antimicrobial
stewardship interventions – or improvement strategies – can ensure that professionals appropriately use antibiotics [6]. The evidence for antimicrobial stewardship
programs in the ICU setting is, however, mostly based on quasi-experimental studies with or without times-series analysis and/or control groups and – with the exception of studies on procalcitonin (PCT) – there are no randomized controlled trials

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