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Comparative effects of proportional assist and variable pressure support ventilation on
lung function and damage in experimental lung injury
Peter M. Spieth1, Andreas Güldner1, Alessandro Beda1,2, Nadja Carvalho1, Thomas Nowack1,
Anke Krause1, Ines Rentzsch1, Sabina Suchantke1, Serge Thal3, Kristin Engelhard3, Michael
Kasper4, Thea Koch1, Paolo Pelosi5, Marcelo Gama de Abreu1
1
Pulmonary Engineering Group, Department of Anesthesiology and Intensive Care Therapy,
University Hospital Dresden, Germany;
2
Postgraduate Electrical Engineering Program,
Federal University of Pará, Brazil; 3Department of Anesthesiology, University Hospital
Mainz, Germany; 4Institute of Anatomy, University of Dresden, Germany; 5Department of
Surgical Sciences and Integrated Diagnostics, University of Genoa, Italy
Drs. Spieth, Güldner and Beda equally contributed to this manuscript.
This work was supported, in part, by a research grant of the Medical Faculty Carl Gustav
Carus, Technical University of Dresden, Germany (MeDDrive Programme).
Disclosure statement: Drs. Gama de Abreu, Spieth and Koch were granted a patent on the
variable pressure support ventilation mode of assisted ventilation (noisy PSV), which has
been licensed to Dräger Medical AG (Lübeck, Germany).
Address reprints requests to Dr. M. Gama de Abreu: Pulmonary Engineering Group,
Department of Anesthesiology and Intensive Care Medicine, University Hospital Carl Gustav
Carus, Technical University Dresden, Fetscherstr. 74, 01307 Dresden, Germany. Phone: ++
49 351 458 2785, Fax: ++ 49 351 458 4336. Address electronic mail to: mgabreu@aol.com.
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Detailed description of experimental methods
Animals were intramuscularly premedicated with ketamine (10 mg/kg) and midazolam (1
mg/kg). Anesthesia was induced by intravenous boli of ketamine and midazolam and
maintained by continuous infusion (12-18 mg.kg-1.h-1 ketamine and 2 mg.kg-1.h-1 midazolam).
Muscle paralysis was achieved by infusion of atracurium (0.5 mg.kg-1.h-1) and controlled by
relaxometry (train of four ratio) during controlled mechanical ventilation. Animals were
orotracheally intubated with an 8.0 ID endotracheal tube. Mechanical ventilation was
performed in volume-controlled mode (EVITA XL, Dräger Medical, Lübeck, Germany).
Anesthesia and ventilator settings are summarized in Table E1. Fluid balance was maintained
by infusion of a crystalloid solution (E153, Serumwerke Bernburg, Bernburg, Germany, 10
mL.kg-1.h-1) and adjusted according pulmonary capillary wedge pressure if appropriate.
Animals were kept in supine position during the entire experiment. Baseline 1 measurements
were obtained after a 15 minute stabilization period following the instrumentation.
Instrumentation and induction of acute lung injury
Both, external jugular vein and internal carotid artery were cannulated with 8.5 Fr.
sheaths. The arterial line was used for continuous blood pressure measurements and blood
sampling. A 7.5 Fr. thermodilution catheter was advanced through the venous sheath into the
pulmonary artery for continuous measurement of pulmonary arterial blood pressure, mixed
venous blood sampling and cardiac output measurements. A heated pneumotachograph
(Fleisch No. 2, Lausanne, Switzerland) connected to a differential pressure transducer was
introduced between the endotracheal tube and the Y-piece of the ventilator tubes to measure
airway flow. Airway pressure (Paw) was monitored by a second pressure transducer at the
endotracheal tube. An esophageal balloon catheter was introduced at mid-chest level via
direct laryngoscopy to measure esophageal pressure (Pes). All respiratory signals were
recorded using a LabView based data acquisition system as described previously (1). A
flexible belt equipped with 16 electrodes was mounted at the xiphoid level around the thorax
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to perform electric impedance tomography (EIT - EIT Evaluation Kit 2, Dräger Medical).
ALI was induced by repetitive lavage with warm 0.9% saline solution (30 mL/kg; 39°C) until
PaO2/FIO2 fell and remained below 200 mmHg for 30 minutes (2). Afterwards, all
measurements for the time point Injury were performed.
Resuming of spontaneous breathing
After induction of lung injury, PEEP was increased to 10 cmH2O and FIO2 decreased
to 0.5 in all animals. Such settings were maintained throughout the experiments. Sedation was
reduced (10 mg.kg-1.h-1 ketamine; 1.5 mg.kg-1.h-1 midazolam) and muscle paralysis stopped to
resume spontaneous breathing. Animals were then ventilated with airway pressure release
ventilation (APRV with inspiratory:expiratory ratio = 1:1, RR = 15). As soon as spontaneous
breathing exceeded 20% of the total minute ventilation the ventilatory mode was changed to
pressure support ventilation (PSV, for detailed settings see Table E1). Following that,
Baseline 2 measurements were obtained and animals were randomly assigned to assisted
ventilation with noisy PSV, PAV or PSV.
Mechanical ventilator settings for assisted ventilation
During PSV and noisy PSV the mean pressure support was set to achieve the same
mean VT (6 mL/kg). Noisy PSV was performed by external remote control of the ventilator,
which applied randomly pressure support levels (normal distribution, coefficient of variation
= 30%), as described in detail by our group elsewhere (3). During PAV, which in the EVITA
XL is termed proportional pressure support, the flow assist was fixed at 60% and the volume
assist adjusted every 10 min to achieve the target mean VT of 6 mL/kg. After randomization,
animals were ventilated for 6 hours in the respective mode (Time 1 - Time 6).
Gas exchange and hemodynamics
Arterial and mixed venous blood samples were analyzed using an ABL 505
(Radiometer, Copenhagen, Denmark). Oxygen saturation and hemoglobin concentration were
analyzed by an OSM 3 Hemoximeter (Radiometer) calibrated for swine blood. Heart rate
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(HR), mean arterial (MAP) and pulmonary arterial (MPAP) blood pressure were obtained
from a hemodynamic monitor system (CMS, Agilent, Böblingen, Germany). Cardiac output
(CO) was measured by conventional thermodilution method. Venous admixture was
calculated using standard formulae.
Respiratory parameters and breathing pattern
Calculation of respiratory parameters was performed offline from five-minute
recordings of airway flow, Paw and Pes as previously described (4)(5). The pressure time
product (PTP) was calculated by numerical integration of Pes over time during inspiration,
taking the Pes value at end-expiration as offset. The mean transpulmonary pressure (Ptrans) was
calculated as the mean value of Paw - Pes during the acquisition period. Intrinsic PEEP (PEEPi)
was computed as the difference between Pes at beginning of inspiratory effort and the onset of
inspiration (airway flow = 0). Respiratory parameters were averaged throughout acquisition
periods. The so-called alpha-coefficient of the pattern of variability of VT was calculated by
detrended fluctuation analysis (6) from flow signals acquired during 45 min of the last
observation period hour, i.e. close to Time 6, in 4 animals of the PAV, and 5 animals of the
noisy PSV group, respectively. According to this analysis, a stochastic pattern, i.e. with
random variability, is associated with an alpha-coefficient ≈ 0.5, while a deterministic pattern,
i.e. characterized by self-organized or natural variability, is associated with an alphacoefficient near to 1.0.
The degree of subject-ventilator asynchrony was computed as the number of
breaths/min that did not effectively trigger the ventilator (missed breaths). Also, the rate of
double triggering of the mechanical ventilator was measured.
Relative changes in electrical thoracic impedance (EIT) were measured with 16
electrodes, embedded in an elastic silicon belt, placed around the thorax below the axils
(approximately the hilum position) and used to determine the spatial distribution of
ventilation as described in detail elsewhere (7). Briefly, EIT images were acquired at 50
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frames/second with a resolution of 32x32 pixels for 5 minutes. For the analysis, only a
circular region of interest with radius 7.5 pixels was considered. For each respiratory cycle,
the acquisition frame corresponding to the end of inspiration was split into 3 regions (dorsal
or dependent, central or middle, and ventral or non-dependent), and the fraction of the total
impedance of each region was calculated with software (EITa!) developed by one of the
authors (AB). Average values of regional impedance calculated over all respiratory cycles
were taken for analysis.
Post-mortems
Diffuse alveolar damage (DAD) was quantified by an expert in lung pathology blinded
to the experimental protocol and therapy groups using a weighted scoring system, as
previously described (8). mRNA expression of interleukin (IL)-1, IL-6, IL-8, tumor necrosis
factor (TNF)-α, transforming growth factor (TGF)-ß, amphiregulin (AREG) and tenascin-c
(TNC) was analyzed in lung tissue using quantitative real-time PCR (Lightcycler 480 PCR
System, Roche Applied Science, Mannheim, Germany). The absolute copy numbers of the
target genes were normalized against the absolute copy numbers of cyclophilin A as control
gene. Protein levels of cytokines were measured using commercial ELISA kits (R&D
Systems Minneapolis, MN, USA) in lung tissue (TNF-α, IL-6, IL-8), BAL (IL-8) and plasma
(TNF-α). Lung wet/dry ratio was obtained weighing the right middle lobe immediately after
removal (wet) and after drying (dry), by exposing it to CPAP of 25cm H2O for seven days.
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References:
1.
de Abreu MG, Quelhas AD, Spieth P, et al.: Comparative effects of vaporized
perfluorohexane and partial liquid ventilation in oleic acid-induced lung injury.
Anesthesiology 2006; 104:278-289
2.
Lachmann B, Robertson B, Vogel J: In vivo lung lavage as an experimental model of the
respiratory distress syndrome. Acta Anaesthesiol Scand 1980; 24:231-236
3.
Spieth PM, Carvalho AR, Güldner A, et al.: Effects of different levels of pressure
support variability in experimental lung injury. Anesthesiology 2009; 110:342-350
4.
Spieth PM, Carvalho AR, Güldner A, et al.: Pressure support improves oxygenation and
lung protection compared to pressure-controlled ventilation and is further improved by
random variation of pressure support. Crit Care Med 2011;
5.
Carvalho AR, Spieth PM, Güldner A, et al.: Distribution of regional lung aeration and
perfusion during conventional and noisy pressure support ventilation in experimental
lung injury. Journal of Applied Physiology 2011; 110:1083-1092
6.
Peng CK, Mietus JE, Liu Y, et al.: Quantifying fractal dynamics of human respiration:
age and gender effects. Annals of biomedical engineering 2002; 30:683-692
7.
Meier T, Leibecke T, Eckmann C, et al.: Electrical impedance tomography: changes in
distribution of pulmonary ventilation during laparoscopic surgery in a porcine model.
Langenbecks Arch Surg 2006; 391:383-389
8.
Spieth PM, Knels L, Kasper M, et al.: Effects of vaporized perfluorohexane and partial
liquid ventilation on regional distribution of alveolar damage in experimental lung
injury. Intensive care medicine 2007; 33:308-314
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Table E1 - Anesthesia and ventilator settings
VCV
(Baseline 1;
Injury)
PSV
(Baseline 2)
PSV
PAV
noisy PSV
Fluids
Midazolam
Ketamine
Atracurium
VT
10 ml/kg/h
2 mg/kg/h
12-18 mg/kg/h
0.5 mg/kg/h
8 mL/kg
10 ml/kg/h
1.5 mg/kg/h
10 mg/kg/h
N/A
Pinsp set to reach ~ 6 mL/kg
10 ml/kg/h
1.5 mg/kg/h
10 mg/kg/h
N/A
Pinsp set to reach ~ 6 mL/kg
RR
Spontaneous
Spontaneous
10 ml/kg/h
1.5 mg/kg/h
10 mg/kg/h
N/A
Mean Pinsp set to achieve
mean VT ~ 6 mL/kg
Spontaneous
PEEP
FIO2
I:E
To achieve paCO2 of
35-45 mmHg
5 cmH2O
1.0
1:1
10 ml/kg/h
1.5 mg/kg/h
10 mg/kg/h
N/A
Volume Assist set to reach ~
6 mL/kg
Spontaneous
N/A
N/A
10 cmH2O
0.5
Cycling off 25% of
inspiratory peak flow
3 L/min
N/A
10 cmH2O
0.5
N/A
Flow Trigger
Flow Assist
10 cmH2O
0.5
Cycling off 25% of
inspiratory peak flow
3 L/min
N/A
10 cmH2O
0.5
Cycling off 25% of
inspiratory peak flow
3 L/min
N/A
Volume Assist
N/A
N/A
N/A
N/A
Fixed to 60 % of initial
resistance
Evaluated every 10 minutes;
set to reach VT ~ 6 mL/kg
N/A
VCV, volume controlled ventilation; PSV, pressure support ventilation, PAV, proportional assist ventilation; noisy PSV, variable pressure support ventilation, VT, tidal volume;
RR, respiratory rate; FIO2, Fraction of inspired oxygen; I:E, inspiratory to expiratory time.
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