DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA DEPARTMENT OF DRUG SCIENCE - PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA

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

Inouye SK et al. Delirium in elderly people, Lancet 2014; 383: 911–22

Delirium is an acute disorder of attention and cognition in elderly people that is common, serious, costly, under-recognised, and often fatal.

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

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.

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

Cere

jeira J

. et

al.

Neuro

imm

unom

odula

tion

2014;2

1:7

2–78

DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA DEPARTMENT OF DRUG SCIENCE - PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA

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 pro-inflammatory cytokines in the brain after LPS stimulation and this translates into a more severe sickness. In contrast, the symptoms are attenuated by IL-10.

Role of microglia and toll-like receptor 4 in the pathophysiology of delirium Jalleh R et al. Medical Hypotheses 79 (2012) 735–739

TLR4 deficient mice had less stress-induced behavioural changes compared with controls

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

Caccia

lanza e

t al. 2

012

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

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.

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

DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA DEPARTMENT OF DRUG SCIENCE - PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA

BUT…

van M

unste

r BC e

t al.,

Longitudin

al assessm

ent

of

seru

m a

nticholinerg

ic a

ctivity in

delirium

of

the e

lderly,

Journ

al of

Psychia

tric

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h 4

6 (

2012)

1339-1

345

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

DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA DEPARTMENT OF DRUG SCIENCE - PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA

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

Inouye SK et al. Delirium in elderly people, Lancet 2014; 383: 911–22

No convincing evidence shows that pharmacological prevention or treatment is effective. Drug reduction for sedation and analgesia and nonpharmacological approaches are recommended

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

Neurodormancy

Afferent information overload

Neurotransmitter specific

interventions

Stimulatory trasmission

L-dopa Bromocriptine Amantadine

Antidepressants Methylphenidate

Zolpidem

Baclofen

DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA DEPARTMENT OF DRUG SCIENCE - PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA

Re-thinking delirium in clinical practice in ICU: the difficulty to

intervene with drugs in absence of full knowledge of delirium

physiopathology

Reade E

C e

t al. N

Engl J

Med 2

014;3

70:4

44-5

4.

DIPARTIMENTO DI FARMACOLOGIA SPERIMENTALE ED APPLICATA FACOLTA’ DI FARMACIA DELL’UNIVERSITA’ DI PAVIA DEPARTMENT OF DRUG SCIENCE - PHARMACOLOGY SECTION, UNIVERSITY OF PAVIA

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.