1. in a Porcine Model of Mechanical Ventilation
Remote Ischemic Preconditioning increases Oxygenation but also Alveolar Damage
in a Porcine Model of Mechanical Ventilation
Alf Kozian, M.D., Ph.D.,*^; Thomas Schilling, M.D., Ph.D., D.E.A.A.*^; Christian Breitling, M.D.*; Dörthe Jechorek, M.D.§;
Astrid Bergmann, M.D.*; Th. Hachenberg, M.D., Ph.D.*; G. Hedenstierna, M.D., Ph.D.^; A. Larsson, M.D., Ph.D., D.E.A.A. #
* Department of Anesthesiology and Intensive Care, Otto-von-Guericke-University Magdeburg, Germany; # Department of Surgical Sciences, Anesthesia and Intensive Care;
^ Department of Medical Sciences, Hedenstierna Laboratory, Uppsala University, Uppsala, Sweden and § Institute of Pathology, Otto-von-Guericke-University Magdeburg, Germany.
UPPSALA
UNIVERSITY
BACKGROUND
One-lung ventilation (OLV) results in alveolar injury due to increased mechanical stress, atelectasis formation, and tidal recruitment [1]. As a result, an inflammatory response in the ventilated lung characterized by leukocyte recruitment and neutrophil dependent tissue destruction is induced. Remote ischemic preconditioning (RIP), in which short episodes of ischemia are repeatedly applied to one limb, is expected to protect remote organs, i.e. the lungs. The aim of this randomized, controlled, animal experiment was to evaluate the effects of RIP on pulmonary function, i.e. arterial oxygenation, and alveolar injuries indicated by leukocyte recruitment and diffuse alveolar damage (DAD) after mechanical ventilation (MV) including OLV. Animal use has been approved by the Animal Care and Use Committee of Uppsala University.
RESULTS
RIP-pigs revealed increased paO2 values after OLV (table, figure)
Fewer leukocytes were observed in BAL fluid of the ventilated lung after RIP (figure)
MV and OLV (120min) increased DAD-scores (indicated by alveolar and interstitial edema, neutrophil infiltration, alveolar overdistension, microhemorrhage and microatelectasis)
DAD was homogeneously distributed from subpleural to parahilar lung regions without differences between ventilated right, or non-ventilated left lung (figure)
Alveolar edema and microhemorrhage were increased in the ventilated lungs of RIP-pigs (figure)
Ventilation variables, cardiac output and shunt were not different between both groups over time (table)
The data indicate that MV and OLV result in significant injury of the ventilated lungs
RIP before OLV increases oxygenation and reduces alveolar leukocyte recruitment but has no global effects on alveolar damage
RIP even increases alveolar edema and microhemorrhage in the ventilated lung
Group / variable
Baseline
after RiP
120min OLV
End
Controls
RIP
Hemodynamics
MAP
[mmHg]
79±9
88±12
62±5
76±11*
71±3
80±10*
73±6
82±12*
MPAP
15±2
17±1
15±1
21±2
20±1
19±3
19±2
SVR
[dyn×sec×cm−5]
2374
±862
2711
±802
1843
±292
2582
±412*
2043
±415
2476
±587*
2051
±231
2744
±699*
PVR
257±85
319±82
254±63
325±27
430±75
459±55
341±83
379±45 CO
[l/min]
2.8±0.5
2.7±0.6
2.5±0.5
2.2±0.1
2.6±0.5
2.4±0.4
2.3±0.3
SvO2
[%]
53.9±6.4
59.0±3.1
49.2±5.5
57.4±7.0
43.3±4.5
50.5±4.0
44.6±9.0
52.5±4.2
Qs/Qt
3.4±0.7
2.9±0.7
3.2±0.7
3.0±0.4
4.5±0.9
4.3±1.3
7.1±2.3
8.5±1.9
Gas exchange
paO2
[kpa]
24.9±1.3
25.9±0.8
23.1±1.7
24.8±0.9
18.7±2.2
20.7±2.8
20.7±1.4
24.1±1.4*
paCO2
5.1±0.2
5.0±0.3
5.1±0.1
5.1±0.4
5.3±0.2
5.2±0.2
5.0±0.4
Ventilation
PAW Peak
18.2±1.7
17.0±0.0
18.9±1.1
18.7±1.9
24.2±1.7
24.3±2.2
20.5±1.3
19.4±1.6
AZV
[ml]
262±12
254±12
260±8
258±13
256±8
257±14
258±9
258±14
AZV/kg [ml/kg]
10.7±0.4
10.5±0.2
10.7±0.1
10.6±0.2
10.6±0.3
10.7±0.2
Compliance [ml/mmHg]
19.9±2.2
21.1±1.0
19.0±1.1
19.0±2.0
13.5±1.0
13.5±1.1
17.5±1.1
18.0±1.3
DAD
FEATURES
Alveolar Edema
BAL
RIP 4×5min
BAL
BAL
Anesthesia
Tracheotomy
Preparation
Recovery
PIP-TLV (n=7)
VT=10ml/kg
PEEP 5mbar
RIP / no RIP
TLV (n=14)
VT=10ml/kg
PEEP 5mbar
RIP-OLV (n=7)
VT=10ml/kg
PEEP 5mbar
RIP / no RIP
TLV (n=14)
VT=10ml/kg
PEEP 5mbar
Tissue samples
End Protocol
Microhemorrhage
no RIP-TLV (n=7)
VT=10ml/kg
PEEP 5mbar
no RIP-OLV (n=7)
VT=10ml/kg
PEEP 5mbar
paO2 at time points / RIP-pigs vs. controls
Cells in BAL / RIP-pigs vs. controls
60min
45min
60min
120min
60min
Time
Neutrophil Infiltation
STUDY TIMELINE
Randomization: RIP / no RIP
MATERIAL AND METHODS
Piglets: n=14, 2-3 month old, weight 26±2kg, Yorkshire/Norwegian country breeds
General anesthesia and tracheotomy
Mechanical ventilation: VT=10ml/kg, respiratory rate adjusted to normal paCO2, FIO2=0.40 in air, PEEP=5cmH2O
OLV: 2h period, lung separation by bronchial blocker, VT=10ml∙kg-1 Randomization: control group (n=7), RIP group (n=7)
RIP pigs: blood pressure cuff at left hind limb, inflated up to 200mmHg for 5min followed by 5min of reperfusion after deflating the cuff, repeated for 4 times
Measurements: hemodynamic data recorded continuously; blood samples; bronchoalveolar lavage (BAL) of both lungs (left non-ventilated, right ventilated)
Timepoints: baseline, after RIP, and prior to and after OLV
Cells: counted from BAL fluid by light microscopy
Lung tissue samples: (after killing the pigs) subpleural, intermediate and parahilar locations of the lungs largest diameters, fixated and stained for histological examination
Lung injury: quantified by DAD score, calculated by summarizing the products of severity and extent of alveolar edema, interstitial edema, microhemorrhage, neutrophil infiltration, microatelectasis, and alveolar overdistension
Statistics: Data were analyzed by ANOVA and non-parametric tests as indicated
Interstitial Edema
CONCLUSIONS
Mechanical ventilation results in pulmonary tissue damage indicated by increased diffuse alveolar damage scores.
Remote ischemic preconditioning decreases leukocyte recruitment into the ventilated lung and increases arterial oxygenation despite higher alveolar edema and microhemorrhage.
Whether RIP only benefits oxygenation but has contrary effects on alveolar injury remains to be studied.
At least pulmonary tissue damage is not affected by or is even increased after RIP.
[1] Kozian et al., J Cardiothorac Vasc Anesth Aug;24(4):617-23
DAD scores/ RIP-pigs vs. controls
AE and MH / RIP-pigs vs. controls
Microatelectasis
Alv. Overdistensionn