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Long-term Cognitive Impairment after Critical Illness – Definition,
Incidence, Pathophysiology and Hypothesis of Neurotrophic Treatment
Ignacio J Previgliano, 1 Bader Andres 2 and Pawel J Ciesielczyk 3
1. Head, Intensive Care Division, Hospital Fernandez, Buenos Aires, Argentina; Professor of Neurology, Maimonides University, Buenos Aires, Argentina;
2. Resident, ICU Division, Hospital Fernandez, Buenos Aires, Argentina; 3. Medical Division, EVER Neuro Pharma GmbH, Unterach, Austria
Abstract Cognitive impairment after critical illness (CIACI) is a frequent consequence of serious disease or injury that has been reported in as many
as 66 % of patients, 3 months after an illness requiring intensive care unit hospitalisation. The condition has been recognised only within the
past 15 years and its pathological mechanisms are, as yet, incompletely understood. The neurological changes and cellular and inflammatory
processes of CIACI overlap with those of stroke, traumatic brain injury and neurodegenerative disorders. Patients also show brain atrophy,
which worsens with the duration of intensive care unit stay. Risk factors associated with CIACI include depression, biomarkers of Alzheimer’s
disease (e.g. apolipoprotein E), delirium, exposure to some drugs (e.g. fentanyl, morphine and propofol) and intubation. Current strategies
to prevent or treat CIACI include treatments to reduce agitation and delirium and physical and mental rehabilitation including cognitive
therapy. Many brain diseases and injuries affect the functioning of the neurovascular unit (NVU), which constitutes the key cellular building
block of the blood–brain barrier (BBB). CIACI is believed to affect the integrity of the NVU and it is among the potential targets for therapy.
Neurotrophic factors (NTFs), such as brain-derived neurotrophic factor (BDNF) are known to play an important role in neurogenesis,
maintenance of NVU structure and neuronal repair after disease and injury. This led to the development of strategies including the
NTF-preparation (Cerebrolysin ® ), which is effective as a post-stroke therapy and has potential in the treatment of Alzheimer’s disease and
brain injury as well as CIACI. There are currently no proven treatments for CIACI; improved understanding of the condition and further
evaluation of NTFs may lead to effective treatments, which are vital to tackle this increasingly serious public health problem.
Keywords Cognitive impairment, critical illness, neurotrophic treatment
Disclosures: Ignacio J Previgliano has received honoraria as a speaker. Bader Andres has no conflicts of interest to declare. Pawel J Ciesielczyk is an employee of EVER
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation
and reproduction provided the original author(s) and source are given appropriate credit.
Acknowledgements: Editorial assistance was provided by James Gilbart, Touch Medical Media.
Received: 27 May 2015 Accepted: 29 July 2015 Citation: European Neurological Review, 2015;10(2):195–203
Correspondence: Ignacio J Previgliano, Hospital Juan A Fernández, Buenos Aires, Argentina. firstname.lastname@example.org.
Support: The publication of this article was supported by EVER Neuro Pharma. The views and opinions expressed are those of the authors and not necessarily those of
EVER Neuro Pharma.
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
relevant research and clinical data. The authors overviewed the major
clinical features of CIACI. We have also outlined the probable underlying
pathological mechanisms as well as endogenous biological defence
processing) that modify a person’s activity and social interaction. CI
is additionally defined as self- and/or informant-reported involving
decreased ability on cognitive tasks and/or preserved basic activities
of daily living/minimal impairment in complex instrumental functions.
Decline in cognitive functions can have an evolving course. The patient
has the ability to perform daily living activities, except those that require
complex cognitive instruments. 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 (decreased memory,
attention and concentration or lower mental speed) at 1 year. 1
processes that are the potential targets for novel treatments. Finally,
we overviewed current therapeutic approaches as well as proposed a
new treatment strategy based on the hypothesis that an intervention
at the neurotrophic regulation level could potentially address both
neuroprotection and neurorepair in the critical care period and beyond,
counteracting and/or preventing development of CIACI. The recently
published data indicating that delirium is an independent risk factor of
CIACI 2 suggests that this group of patients might benefit from timely
administered preventive therapies.
This article aims to outline the current knowledge of CIACI and
to present a hypothesis of novel treatment to prevent CIACI based on
In various studies, CI is has been reported as a frequent consequence
of critical illness. 3 One example was a large prospective cohort study
TOU CH MED ICA L MEDIA
Major Clinical Features of CIACI