DELIRIUM: DALLA DIAGNOSI
AL TRATTAMENTO
LE PROSPETTIVE DELLA RICERCA
S.Govoni
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
Delirium is an acute disorder of
attention and cognition in
elderly people that is common,
serious, costly, underrecognised, and often fatal.
Inouye SK et al. Delirium in elderly people, Lancet
2014; 383: 911–22
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
Delirium can be thought of as
acute brain failure—ie, a
multifactorial syndrome analogous
to acute heart failure—and might
provide a novel approach to
elucidation of brain functioning
and pathophysiology.
Inouye SK et al. Delirium in elderly people, Lancet
2014; 383: 911–22
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
Defining delirium pathophysiology,
is that useful?
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
Defining delirium pathophysiology,
is that useful?
Yes, in order to find:
• predictive markers
• treatment targets
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
The literature has focused the attention
mainly on two systems:
•
•
trasmitters/hormones involved in
inflammation and immune
modulation
cholinergic transmission
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
Cerejeira J. et al.
Neuroimmunomodulation
2014;21:72–78
Elevated levels of TNF-α or IL-1 (but not IL-6 or
IFN-γ) in the CNS following acute systemic
inflammation are responsible for a cluster of
transient and stereotyped changes known as
‘sickness behaviour’. This syndrome mimics the
symptoms experienced by humans during a viral
or bacterial infection and manifests with
decreased levels of social exploration, locomotor
activity and sweetened liquid or food intake. Aged
mice show enhanced production of proinflammatory cytokines in the brain after LPS
stimulation and this translates into a more severe
sickness. In contrast, the symptoms are
attenuated by IL-10.
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
TLR4
deficient
mice had
less
stressinduced
behaviour
al changes
compared
with
controls
Role of microglia
and toll-like
receptor 4 in the
pathophysiology
of delirium Jalleh
R et al. Medical
Hypotheses 79
(2012) 735–739
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
Caccialanza et al. 2012
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
Gool WA et al. Systemic infection and delirium: when
cytokines and acetylcholine collide, Lancet 2010; 375:
773–75
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
Gool WA et
al. Systemic
infection and
delirium:
when
cytokines and
acetylcholine
collide,
Lancet 2010;
375: 773–75
Hshieh et
al. J
Gerontol A
Biol Sci
Med Sci .
2008 July ;
63(7):
764–772.
Hshieh et
al. J
Gerontol A
Biol Sci
Med Sci .
2008 July ;
63(7):
764–772.
Hshieh et al. J Gerontol A Biol Sci Med Sci . 2008 July
; 63(7): 764–772.
Defining delirium pathophysiology,
is that useful?
Yes, in order to find:
• predictive markers
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
BUT…
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
van Munster BC et al., Longitudinal assessment of serum anticholinergic activity in
delirium of the elderly, Journal of Psychiatric Research 46 (2012) 1339-1345
Watne LO et al.
Anticholinergic
Activity in
Cerebrospinal Fluid
and Serum
inIndividuals with
Hip Fracture with
and without
Delirium, J Am
Geriatr Soc 62:94–
102, 2014
Other confounders
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
Thomas N Robinson, Christopher
D Raeburn, Erik M Angles, and
Marc Moss
Low Tryptophan Levels Are
Associated with Post-Operative
Delirium in the Elderly
Am J Surg. 2008; 196: 670–674.
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
Post-operative Tryptophan Levels in Elderly
Subjects with and without Delirium
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
Do nutrients play a role in delirium?
Clinicians should always be vigilant and
reflect on the possibility of nutritional
deficiencies as causal agents or
contributors to delirium and consider
testing for and treating underlying
nutritional deficiencies (B vitamins,
dehydration, hypoglycemia) or excesses
(hypertriglyceridemia, hyperglycemia).
Sanford and Flaherty, Curr Opin Clin Nutr Metab Care
2014, 17:45–50
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
Defining delirium pathophysiology,
is that useful?
Yes, in order to find:
• treatment targets
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
BUT…
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
No convincing evidence shows that
pharmacological prevention or treatment is
effective. Drug reduction for sedation and
analgesia and nonpharmacological
approaches are recommended
Inouye SK et al. Delirium in elderly people, Lancet
2014; 383: 911–22
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
Antidepressants
Methylphenidate
L-dopa
Bromocriptine
Amantadine
Stimulatory
trasmission
Neurotransmitter
specific
interventions
Afferent
information
overload
Neurodormanc
y
Baclofen
Zolpidem
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
Re-thinking delirium in clinical
practice in ICU: the difficulty to
intervene with drugs in absence of
full knowledge of delirium
physiopathology
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
Reade EC et al. N Engl J
Med 2014;370:444-54.
In conclusion, tramadol, which is a commonly
used analgesic in surgical settings, has the
potential to lead to delirium. It is important for
surgeons to have a high index of suspicion in
order to be able to recognize promptly
this uncommon but serious adverse effect of the
drug and withdraw the offending agent along with
having effective liaisoning with their psychiatric
colleagues for appropriate management.
Ghosh S. et al., Acute Delirium due to Parenteral
Tramadol, Case Reports in Emergency Medicine
2013
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
Defining delirium pathophysiology,
is that useful?
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
Inouye SK et al. Delirium in elderly people, Lancet
2014; 383: 911–22
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA
Conclusions: nothing practical,
but: avoid sedative and
anticholinergic drugs.
DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA
DEPARTMENT OF DRUG SCIENCE
- PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA