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PHYSIOLOGICAL EFFECTS OF AN “OPEN LUNG”
VENTILATORY STRATEGY TITRATED ON ELASTANCEDERIVED END-INSPIRATORY TRANSPULMONARY
PRESSURE: study in a pig model
Francesco Staffieri, Tania Stripoli, Valentina De Monte, Antonio Crovace, Marianna Sacchi,
Michele de Michele, Paolo Trerotoli, Pierpaolo Terragni, V. Marco Ranieri, Salvatore Grasso
Online data supplement
ANIMAL PREPARATION
Anesthesia: eight certified healthy mixed breed domestic pigs (body weight 35 ± 3. 4 kg,
24-28 weeks old) were studied. Animals were starved for 24 h prior to beginning the experiment.
After intramuscular premedication with Telazol® (Tiletamine + Zolazepam) 4-5 mg/kg and atropine
0.04 mg/kg in order to achieve an adequate level of sedation, an intravenous (IV) catheter was
placed into the auricular vein of the right ear and Lactated Ringer’s solution (LRS; 10 ml•kg-1•h-1)
was infused. General anesthesia was subsequently induced with IV fentanyl (5 µg/kg) and propofol
(3-5 mg/kg to effect) and maintained with a constant rate infusion of propofol (5-8 mg•kg-1•h-1),
fentanyl (10 µg•kg-1•h-1) and an IV dose of pancuronium bromide (2.5 mg) every hour. Additional
boluses of fentanyl and pancuronium bromide were given as needed. Following induction of
anesthesia, the animals were immediately endotracheally intubated using a cuffed tube.
Instrumentation: After surgical exposition, an 18-gauge catheter was inserted into the left
carotid artery for arterial blood sampling and systemic blood pressure measurement. A triple lumen
16-gauge central venous catheter was advanced into the left jugular vein for drug and LRS
administration and recording of central venous pressure (right atrial pressure, RAP).
Gas exchange: Arterial blood gas (ABG) samples were analyzed with an automated ABG
analyzer (Ometech OPTI™ CCA-TS blood gas analyzer, AVL Scientific Inc., Rosswell, GA, USA)
using an analyzer specific cartridge (Ometech OPTI™ CCA-Cassettes, Osmetech Inc., Rosswell,
GA, USA). The ABG analyzer was calibrated daily following the instructions of the manufacturer.
All ABG values were corrected by the analyzer for the body temperature of the animal measured at
the time of sampling.
MEASUREMENTS OF RESPIRATORY MECHANICS
All pigs were mechanically ventilated using a Siemens Servo 300 ventilator (Maquet, Solna,
Sweden).
Flow was measured through a heated pneumotachograph (Fleisch No. 2; Fleisch,
Lausanne, Switzerland) connected to a differential pressure transducer (Diff-Cap, Special
Instruments, Nordlingen, Germany) placed inbetween the Y-piece of the ventilator circuit and the
endotracheal tube. The pneumotachograph was linear over the experimental range of flows. The
tidal volume (VT) was recorded by numerical integration of the flow signal. The airway opening
pressure (PAO) was measured proximally to the endotracheal tube with a pressure transducer
(Special Instruments Digima-Clic  100 cmH2O; Nordlingen, Germany).
The intra-thoracic and intra-abdominal pressures were estimated using esophageal pressure
(PES) [1, 2] and gastric pressure (PGA) [3] as surrogates, respectively. PES and PGA were measured
through a polyfunctional catheter (Nutrivent-Sidam, Mirandola, Italy) that consists of a polyuretane
nasogastric tube (107 cm long, external diameter 4,7 mm) that incorporates in the lower part two
thin walled polyethilene balloons (each 10 cm long and 15 mm diameter). The device has been
recently validated in humans for the measurement of esophageal pressure and gastric pressures [4].
According to that validation study, the balloons were filled with 4 cml of air [4]. Each balloon was
connected to a pressure transducer (Special Instruments Digima-Clic  cmH2O; Nordlingen,
Germany). Correct positioning of the esophageal balloon was verified as follows: infusion of
paralytic agents was suspended and as soon as spontaneous inspiratory efforts were recorded airway
opening was occluded and the Baydur test was performed, verifying that pressure deflection in PAO
and PES were equal [5]. The position of the esophageal balloon was further verified by the presence
of cardiac pulsation in the trace and by the adequateness of waveforms shape during mechanical
ventilation [6, 7].
All described variables were displayed and collected for further data analysis on a personal
computer through a 12-bit analog-to-digital converter board (National Instrument DAQCard 700;
Austin, TX, USA) at a sampling rate of 200 Hz (ICU Lab, KleisTEK Engineering, Bari, Italy).
The difference between the level of positive end-expiratory pressure (PEEP) set on the
ventilator (read as the PAO value at the end of a regular breath) and the plateau pressure in PAO
during a 3-5 s end-expiratory occlusion (PEEPTOT) was measured and regarded as the static intrinsic
PEEP (PEEPi,st) value, according to Pepe and coworkers [8]. The end-inspiratory occlusions were
produced by operating the appropriate control on the Servo 300 ventilator that closes both
inspiratory and expiratory branches of the circuit system at the end of a standard expiration. The
PEEPTOT of the chest wall (PEEPTOT,CW) was measured as the plateau pressure PES during the endexpiratory occlusion with its value at the elastic equilibrium point of the respiratory system serving
as a reference. The PEEPTOT applied to the lung (PEEPTOT,L) was determined as PEEPTOT,L=
PEEPTOT - PEEPTOT,CW. Static elastance of the respiratory system (ERS) was calculated as:
ERS = PAO,PLAT - PEEPTOT /VT
where PAO,PLAT is the value of PAO after an end-inspiratory occlusion of 3-5 s, produced by
operating the appropriate control on the Servo 300 ventilator that closes both inspiratory and
expiratory branches of the circuit system at the end of a standard inspiration. Static elastance of the
chest wall (ECW) was calculated as:
ECW = PES,PLAT - PEEPTOT,CW/ VT
where PES,PLAT is the value of PES after an end-inspiratory occlusion of 3-5 s, with its value at the
elastic equilibrium point of the respiratory system serving as a reference. Static elastance of the
lung (EL) was calculated as ERS – ECW
The elastance-derived PL was calculated, according to Gattinoni et al (13, 23). This method
assumes that the ratio between EL and ECW determines how the pressure applied to the entire
respiratory system (i.e. PAO) is partitioned between the lung (determining PL) and the chest wall
(determining PPL). For example, if EL and ECW contribute for 80% and 20% respectively to ERS, in a
passive patient 30 cmH2O applied at the airway opening will generate a elastance-derived PL of 24
cmH2O (80% of PAO) and a elastance-derived PPL of 6 cmH2O (20% of PAO), respectively (13).
The elastance-derived PL represents the average transpulmonary pressure that, if applied to the
whole lung, would result in the observed lung volume in static conditions. By definition, it must be
equal to zero at functional residual capacity (i.e. at zero PAO), otherwise the lung would further
empty (for a PL lower than zero) or would further inflate (for a P L higher than zero). Accordingly,
also the elastance-derived PPL (PPL = PL – PAO) must be zero at functional residual capacity. Based
on this background, the Gattinoni method (13) allows calculating the elastance-derived PPL in static
conditions in a passive patient submitted to positive pressure ventilation as follows:
( PPL/V) / ( PAO/V) = ECW / E RS
(equation 1)
and hence
 PPL/ PAO = ECW / ERS
(equation 2)
By definition, the elastance-derived PPL - PAO relationship described by equation 2 (whose slope is
defined by the ECW / ERS ratio) must originate from zero at functional residual capacity, being PPL
and PAO both equal to zero. Therefore, equation 2 can be rearranged as:
PPL = PAO * ECW /ERS
Equation 3
In summary, in this study we used tidal PES excursion to calculate ECW (22) and the equation 3 to
calculate the elastance-derived absolute PPL at end expiration (PPL,EXP) and at end inspiration
(PPL,PLAT). The elastance-derived PL was finally calculated at end-expiration (PL,EXP = PEEPTOT PPL,EXP ) and at end-inspiration (PL,PLAT = PAO,PLAT - PPL,PLAT).
MEASUREMENT OF HEMODYNAMIC PARAMETERS AND GAS EXCHANGE
Pressure transducers were zeroed against atmosphere at mid thorax level. A standard
intensive care monitor showed pressure and electrocardiogram traces for heart rate determination.
Cardiac output (CO) was determined through the trans-pulmonary thermodiluition technique
(PiCCO®, Pulsion Medical Systems, Munich, Germany). Briefly, this technique uses a transpulmonary bolus of cold saline (10 ml at 0-6 °) injected via the central venous catheter and a 5
French thermistor tipped catheter sited in the right carotid artery for the determination of the
thermodiluition curve (PV20L15, Pulsion Medical Systems, Munich, Germany). CO is then
calculated through a modified Stewart-Hamilton equation [14]. Several studies have validated this
system against the gold standard one represented by the pulmonary thermodiluition technique (i.e.
by the injection of the cold bolus in the right atrium and measurement in the pulmonary artery) [15].
In addition the PiCCO system calculates both intrathoracic blood volume (ITBV), a parameter
shown to be a predictor of the preload state of the heart in various clinical situations and extra
vascular lung water (EVLW), a parameter that reflects the volume of lung water outside of the
vascular system [14]. Sakka and coworkers validated the algorithms used for obtaining ITBV and
EVLW based on the single thermodiluition technique [16]. Following thermodiluition, the system
calibrates the arterial waveform analysis according the CO value, providing continuous CO
estimation through the pulse contour analysis method. Since changes in arterial tree compliance
and damping of the arterial pressure transducer system cause measurement errors, the system was
calibrated (thermodiluition method) before each experimental measurement. Cold fluid boluses (5
mL, temperature 0 - 10 °C) were administered in triplicate and the average of three measurements
was collected for each parameter. Systemic vascular resistance (SVR) and stroke volume (SV)
were calculated through standard formulae:
SVR (dyne sec/cm5) = (MAP – RAP)/CO x 80
SV (mL) = CO/HR
where HR is heart rate
ARDS MODEL
The hydrochloride instillation model was employed in this study to cause an ARDS-like
lung injury. Briefly, a 5-Fr feeding tube was inserted through the endotracheal tube and 4 ml/kg of
0.05 N HCl were injected at the level of the carina over 3 min [17]. In order to achieve uniform
lung injury, half of the dose (2 ml/kg) was instilled with the animal in the dorsal (supine) position
while one quarter of the dose (1 ml/kg) was instilled with the animal in right and left lateral
recumbency, respectively.
THORACIC CT SCAN
Frontal tomogram and helical computed tomogram (CT) scans of the chest were obtained in
the dorsal position (GE ProSpeed SX, General Electric Co, Milwaukee, WI, USA), using a 512 x
512 matrix, 120 kV, 200 mA, scanning time of 0.75 s, pitch of 1.0 and collimation of 5 mm. All
images were observed and photographed at a window width of 1600 Hounsfield Units (HU) and a
window level of – 600 HU. During acquisition of the CT scans particular attention was paid to
avoid any change in pig positioning between the different experimental manipulations. Images were
analyzed using Maluna 2 software (Mannheimer lung analyzer tool, University of Mannheim,
Germany) and OsiriX image processing software (http://www.osirixfoundation.com, Geneva,
Switzerland). For each CT scan slice, the entire left and right lungs were chosen as region of
interest by manually drawing the outer boundary along the inside of the ribs and the inner boundary
along the mediastinal organs. The total volume of the selected region of interest consists of a finite
number of voxels, with each voxel being a parallelogram with a 0.59 mm side squared base (pixel)
and an height corresponding to the CT section thickness (5 mm). The volume of the voxel was
hence calculated as the area of the pixel times the CT section thickness. The x-ray attenuation of
each voxel, expressed in “CT numbers” or Hounsfield units (HU), was obtained by determining the
percentage of radiation adsorbed by that voxel. The attenuation scale arbitrarily assigns to bone a
value of 1000 HU (complete absorption), to air a value of -1000 HU (no absorption) and to water a
value of 0 HU; blood and lung tissue have a density ranging between 20 and 40 HU. According to
previous studies [13, 18-22], we identified the following lung compartments: hyperinflated,
composed by voxels with CT numbers between -1000 and -900 HU; normally aerated composed by
voxels with CT numbers between -900 and -500 HU; poorly aerated composed by voxels with CT
numbers between -500 and -100 HU; non-aerated composed by voxels with CT numbers between 100 and +100 HU.
Each voxel is composed by gas and tissue. For each compartment, the weight of lung tissue
was measured considering the close correlation between CT attenuation (expressed in CT numbers)
and physical density, as previously described [23]. Briefly, assuming the specific lung weight equal
to 1, lung tissue weight of each voxel was calculated based on the “CT number” as follows:
Weight [voxel] = Volume [voxel] * (1 – (CT [voxel] / -1000))
where Volume [voxel] is the volume and CT [voxel] is the “CT number” of each voxel.
The total weight of each compartment was calculated as sum of the weight of the single voxel
forming the considered compartment.
PERIANESTHETIC ANIMAL MANAGEMENT
A veterinary anesthetist not directly involved in the study per se was always present to
provide care for the animals during experimentation and to ensure that the pigs were maintained at
an adequate level of anesthesia using parameters such as hemodynamic responses to physical and
surgical manipulations or to noxious stimulation (toe clamp) as indicators of anesthetic depth. Fluid
management was standardized throughout the study period: animals received a continuous infusion
of maintenance fluid (lactated Ringer’s solution, 10 ml/Kg/h). In order to standardize the
hemodynamic management, no further fluid administration or catecholamine infusion were
allowed. In-line suction catheters were used to avoid any unnecessary disconnection of the
ventilator circuit from the endotracheal tube.
At the end of the study all experimental animals were euthanized by IV administration of an
overdose of saturated KCl solution without regaining consciousness.
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