Dr. Lluís BlanchDr. Lluís Blanch Senior Critical CareSenior Critical CareDirector of Research and Innovation Director of Research and Innovation Corporació Sanitària Parc Taulí Corporació Sanitària Parc Taulí President of SEMICYUC. President of SEMICYUC. Member of the WFSICCM CouncilMember of the WFSICCM Council

Lung-Brain Interaction during Mechanical Ventilation

Antalya, November 13, 2014

NATURE | VOL 420 | 19/26 DECEMBER 2002

Turon M et al (submitted)

Pathophysiology of neurocognitive alterations in critically ill patients

Mechanisms of Sepsis-Associated Encephalopathy

Siami S, Annane D, Sharshar T. The encephalopathy in sepsis. Crit Care Clin 2008;24:67-82

Organ crosstalk during ALI, ARDS, and MV

Quilez M, et al. COCC 2012; Quilez M, et al. COCC 2012; 2012 Feb;18(1):23-8Lopez-Aguilar J et al. Med Intensiva 2013Lopez-Aguilar J et al. Med Intensiva 2013

Brain

Lung

European Journal of Cardio-Thoracic Surgery 25 (2004) 523-529

Intracellular vacuolesInterstitial & mitocondrial edemaDilatation in endoplasmic reticulum & GolgiChromatin desintegration in the nucleus

2h 8h 24hG5

0 500 1000 1500 2000

Time (sec)

Weight

0.0

5.0

10.0

15.0

20.0

25.0

30.0

Wei

ght (

gr)

Massive BrainMassive BrainInjuryInjury

ControlControl

Crit Care Med 2005;33:1077-83

HVT: high VTHVT: high VTMBI: massive brain injuryMBI: massive brain injuryLPS: endotoxin i.v.LPS: endotoxin i.v.

Lung mRNALung mRNA

Crit Care Med 2013; 41:1992–2001

et al.

From 2000 to 2010, 697 patients met inclusion criteria

CT scans taken at end-expiration at 240 min

Potential donors were randomized to conventional ventilatory strategy: VT 10-12 mL/kg PBW & PEEP 3-5 cmH2O or the protective ventilatory strategy: VT 6-8 mL/kg PBW & PEEP 8-10 cmH2O.

Use of a lung protective strategy in potential organ donors with brain death increased the number of eligible and harvested lungs compared with a conventional strategy.

JAMA. 2010;304(23):2620-2627

Lung

Brain

Brain Areas of Interest in Coronal Section

CeA

PVP

CX

Rts CX

CX

Hippocampus

CeA

PVP

CX

Rts CX

CX

Hippocampus

RtsCX: Retrosplenial Cortex, CeA: Central Amygdala

Cortex, Hippocampus, PVP: Paraventricular Thalamic nucleus, PVN: Paraventricular Hypothalamic Nucleus

Basal

High VT

Low VT

SpontaneousBreathing

Central AmygdalaQuilez M et al. Crit Care. 2011;15(3):R124

Functions:- motivated behaviours- emotional states- housekeeping activities

Injury:- cognitive impaiments

Basal

High VT

Low VT

SpontaneousBreathing

Retrosplenial CortexQuilez M et al. Crit Care. 2011;15(3):R124

Functions:- spatial memory- learning

Injury:- memory deficits

ThalamusQuilez M et al. Crit Care. 2011;15(3):R124

Basal

SpontaneousBreathing

Low VT

High VT

Functions:-Interpretation ofsensory information

Injury:- good or bad ???

Am J Respir Crit Care Med Vol 183. pp 471–482, 2011

Effect of vagotomy on high VT ventilation-induced ALI in mice

BALF

LungTissue

Am J Respir Crit Care Med Vol 183. pp 471–482, 2011

Effect of administration of the vagus mimetic drug, semapimod, on VILI (VT 20 ml/kg, PEEP 0)

BALF

In experimental VILI, vagotomy exacerbated while vagus stimulation attenuates lung injury in rats ventilated with either high or low volume strategies. Treatment of both mice and rats with the vagus mimetic drug, semapimod, resulted in decreased lung injury.

VAP & Position

Brain

Experimental model of VAP (72h), induced by translocation of oropharyngeal pathogens to the lung Li Bassi G. Anesthesiology 2014; 120:1205-15

Cognitive impairment

Moderate to severe cognitive impairment occur after critical illness (memory, attention, executive function) and persist months to years after hospital discharge Wilcox ME et al. Crit Care Med. 2013, 41: S81-98 Pandharipande PP et al. N Engl J Med. 2013; 369: 1306-16 Hopkins RO. Crit Care. 2013; 6;17(1):116

Prolonged trendelenburg positioning could induce neurological complications Schramm P et al. Anaesthesia. 2014; 69:58-63. Pandey R, et al. Acta Anaesthesiol Belg 2010; 61:163-6

Experimental groups

TL00.33TLn=7

5

0

PEEP (cmH2O)

SR0.7 SR-inv

n=7

VM 72h, FiO2 40%, Vt 10 ml/kg

SRn=3

SR0.33

PositionI:E

TL00.33TLn=7

5

0

PEEP (cmH2O)

SR0.7 SR-inv

n=7

VM 72h, FiO2 40%, Vt 10 ml/kg

SRn=3

SR0.33

PositionI:E

Hippocampal formationHippocampal formation

Dentate Gyrus

Microscopical evaluation of Dentate gyrus in the hippocampal formation

Dentate gyrus function

Plays an important role in learning and memory

Ability to generate new neurons on a daily basis throughout life. Under normal conditions, new cells are constantly generated in the dentate gyrus in the hippocampus

Dentate gyrus (hippocampal formation) neurodegeneration (hypereosinophilia) apoptosis

TUNEL (marker of DNA fragmentation) Caspase-3 (early marker of apoptosis)

hypereosinophilia caspase-3 TUNEL assay

Results: Pulmonary colonization

SR SR-inv TLPulmonary

colonization(log ufc/gr)

2.27 0.8* 2.31 0.4* 0.22 0.2

VAP % Incidence 66.7* 83.3* 0

p<0.05 vs TL

Results. Hemodynamics

Mean arterial Pressure

0 6 12 18 24 30 36 42 48 54 60 66 72

60

70

80

90

100

110

120 * TL vs SR* TL vs SR-inv

Time (hours)

MA

P (m

mH

g)

Central venous pressure

0 6 12 18 24 30 36 42 48 54 60 66 72

0

5

10

15

Time (hours)C

VP

SR

SR-inv

TL

Mean arterial Pressure

0 6 12 18 24 30 36 42 48 54 60 66 72

60

70

80

90

100

110

120 * TL vs SR* TL vs SR-inv

Time (hours)

MA

P (m

mH

g)

Central venous pressure

0 6 12 18 24 30 36 42 48 54 60 66 72

0

5

10

15

Time (hours)

CVP

SR

SR-inv

TL

Results: Respiratory variables

Pplateau

0 24 48 72

101112131415161718

* SR-inv vs SR* SR-inv vs TL

Time (hours)

Ppla

t (cm

H2O

)

Crs

0 24 48 72

15

20

25

30

35

* SR-inv vs TL

Time (hours)C

rs (m

l/cm

H2O

)

Mean arterial Pressure

0 6 12 18 24 30 36 42 48 54 60 66 72

60

70

80

90

100

110

120 * TL vs SR* TL vs SR-inv

Time (hours)

MA

P (m

mH

g)

Central venous pressure

0 6 12 18 24 30 36 42 48 54 60 66 72

0

5

10

15

Time (hours)

CVP

SR

SR-inv

TL

Petequial Cerebral Hemorrhage Score

SR SR-inv TR

0

1

2

3

4 **

SCO

RE

SR SR-inv TL

3 (high)

2 (moderated)

1 (low)

Macroscopic Hemorrhage ScoreRepresentative images

3 (high)

2 (moderated)

1 (low)

Macroscopic Hemorrhage ScoreRepresentative images

Results. Brain Hemorrhage score

Results. Dentate gyrus (Hippocampus)

Hypereosinophilic cells (H&E)

SR SR-inv TR

0.0

2.5

5.0

7.5

10.0

**

nº p

ositi

ve c

ells

per

fiel

d

Cleaved Caspase-3

SR SR-inv TR

0.0

2.5

5.0

7.5

10.0

12.5 *

nºpo

sitiv

e ce

lls p

er fi

eld

TUNEL

SR SR-inv TR

0.0

2.5

5.0

7.5

10.0

**

nº p

ositi

ve c

ells

per

fiel

d

Apoptosis in Dentate Gyrus (Hippocampal formation)

Hippocampal formationHippocampal formation

Dentate Gyrus

SR SR-inv TL SR SR-inv TL

SR SR-inv TL

Patients receiving MV in the ICU

O’Donnell DE et alResp Physiol Neurobiol 2009

Neurophysiologic Model of Respiratory Discomfort:

Air Hunger

Work/Effort

Tightness

J Neurophysiol 2002;88:1500-1511

Insula

Insula (Limbic System):-Perception of dyspnea, hunger, thirst-Afferents of resp. chemoreceptors-Stretch receptors project to insula-Seat of emotions-Large role in memory

Air hunger may cause severe psychological trauma

Air Hunger Increases MRI Signal in Insula (Limbic System)

Crit Care Med 2011;39:2059-65

45 patients (47%) reported dyspnea (respiratory effort in seven cases, air hunger in 15, both in 16, and neither of these in seven).

Dyspneic and nondyspneic patients did not differ in terms of age, SAPS II or indication for MV.

Dyspnea was significantly associated with anxiety (OR, 8.84; 95%CI, 3.26 –24.0), assistcontrol ventilation (OR, 4.77; 95% CI, 1.60–4.3), and heart rate (OR, 1.33 per 10 beats/min; 95% CI, 1.02–1.75).

Hours

DiscomfortDyspnea - Air Hunger - Work/Effort - TightnessAgitationRisk of Extubation

Asynchrony Report

?

Mechanical Ventilation-Induced Reverse-Triggered Breaths

Stretch receptors & vagal C fibers are responsible for the Hering-Breuer reflexes

Reverse triggering & Respiratory Entrainment

Akoumianaki E et al. Chest 2013;143:927-38.

Conclusions:• Cross-Talk exists between lung and brain

during critical illness.• Patients with ALI/ARDS & brain injury need

protection and support to both organs.• Research on this area is in its infancy but this

knowledge can benefit patients, their families and care providers.