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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.