GESTIONE DEGLI IMPIANTI DI DISTRIBUZIONE DEI GAS MEDICALI

Tecniche innovative di assistenza
vitale per pazienti critici:
la Ventilazione Liquida Totale come possibile
tecnica alternativa alla ventilazione convenzionale
per il trattamento del neonato prematuro.
Maria Laura COSTANTINO
Dipartimento di Ingegneria Strutturale
Laboratorio di Meccanica delle
Strutture Biologiche (LaBS)
Politecnico di Milano
POLITECNICO DI MILANO, 20 Maggio 2011
MOTIVATION
Vermont Oxford Network 2008 Statistics on newborns
• 5.26% preterm (Gestational Age (GA) ≤ 34 w)
• 4.6% need respiratory assistance
(mortality: 9.3%)
• 1.2% are Very Low Birth Weight
(VLBW) (GA< 28w or Birth Weight (BW) < 1000g)
• 90% VLBW need respiratory assistance
(mortality ≈25%)
Lung immaturity
+
Risks ensuing mechanical
ventilation (MV)
Surfactant deficiency
•
•
•
•
Barotrauma
Volutrauma
Impaired ventilation-perfusion matching
Dysplasia
Total Liquid Ventilation with Perfluorocarbons (PFC) stands
Need of an
alternative
ventilation
as a
valid alternative
to MV technique
M.L. Costantino
BACKGROUND
Liquid Ventilation
In the 20’s Winternitz and Smith: No pulmonary damage caused by
saline solution
1962, Kylstra: Survival of small animals immersed in hyperbarically
oxygenated saline:
•Inadequate oxygenation
•Muscular fatigue
•Need of inducing respiratory acts mechanically
1966, Clark and Gollan: proposal to use oxygenated
organic fluids (Perfluorocarbons, PFC)
Liquid Ventilation:
Liquid PFC as carriers for O2 and CO2 in the
lungs instead of a gaseous mixture
M.L. Costantino
BACKGROUND
Perfluorocarbon (PFC) characteristics
• High O2 and CO2 solubility
coefficients
• Low surface tension
• High viscosity and density
• Insoluble in water and lipids
1
Properties
at 37°C; 2 at 25°C
Air
Saline
RM-101®
FC-77
Perflubron®
1.13
1000
1770
1780
1920
0.02
1.00
1.41
1.30
2.11
17.07
1.00
0.80
0.72
1.10
Tension [N/m]
-
72·10-3
15·10-3
15·10-3
18·10-3
Solubility [ml/100ml/atm]
100
3
52
56
53
Solubility [ml/100ml/atm]
100
57
160
198
210
Diffusion Coefficient [cm2/s]
0.178
3.22·10-5
5.81·10-5
-
0.139
2.55·10-5
1.05·10-5
-
-
-
6267
8533
5600
1467
2Density
[kg/m3]
2Dynamic
Viscosity [10-3Pa s]
2Kinematic
1Surface
2O
2
2CO2
2O
2
2CO
• Highly volatile at room
temperature
• Low tissue absorption with no
ensuing toxicity
• Bio-chemically stable
2
Viscosity [10-6m2/s]
Diffusion Coefficient [cm2/s]
1Vapor
Tension [Pa]
M.L. Costantino
-
LIQUID VENTILATION TECHNIQUES
Partial Liquid Ventilation
(PLV)
• Functional residual capacity of
the lung filled with PFC
Total Liquid Ventilation
(TLV)
• Functional residual capacity of
the lung filled with PFC
• Gas Tidal Volume
• Liquid Tidal Volume
• Air + PFC in the lungs
• Air totally replaced by PFC
• Ventilation provided by means of a
• Ventilation provided by means
conventional ventilator
of a dedicate system or
• 1995 Randomized controlled
multicenter clinical trials
M.L. Costantino
“Liquid ventilator”
• Still under animal trials
TLV functional and mechanical benefits
Reduction of
surface forces
Uniform distribution in
the lungs
Exudate elimination
(Wolfson et al., 1988,
Greenspan et al., 1990)
Alveolar
collapse
decrease
Alveolar recruitment
improvement
(Fuhrman, 2000)
V/Q ratio
improvement
Lung compliance
increase
(Hirschl et al.,1996 )
Antiinflammatory
action
Decrease of
airway
pressure
necessary to
inflate alveoli
TLV is an appropriate treatment for very low birth weight newborns
(Wolfson et al. 1992)
M.L. Costantino
GRAVITY-ASSISTED VENTILATION
Used during preliminary
human trials of TLV
No active pumping system:
• Passive inspiration
• Passive expiration
Inspiratory
Reservoir
No precise control of
inspiratory and expiratory TV
• Manual maneuvers needed
• No circuit to recycle and
refresh exhausted PFC
Need of a dedicated device
M.L. Costantino
Expiratory
Reservoir
Greenspan et al. 1990
TASKS OF A LIQUID VENTILATOR
•
•
•
•
•
•
•
•
•
•
Active PFC inspiration and expiration
Oxygenate and remove carbon dioxide from PFC
Optimize PFC flow rate in the oxygenator
Filter contaminating agents (e.g. meconium)
Control the delivered and withdrawn Tidal Volume (TV)
Control inspiratory flow rate waveform
Monitor pressure in the airways
Computer-based control system
Disposable PFC contacting components
Avoid PFC evaporation (in reservoirs, tubing, etc.)
SV
OXY
Roller Heater
Pump
PC
SV
Reservoir
Curtis et al. in 1990
Different research groups proposed several circuital solutions
Wolfson et al., 1988
Tredici et al., 2004
Robert et al., 2006
M.L. Costantino
TLV VENTILATOR’ WORKING PRINCIPLE
ACTIVE PFC PUMPING
PFC REFRESH
• Bubble oxygenators
• Rotary Pumps (e.g. Roller pump)
• Silicone Membrane oxygenators
• Positive displacement pumps (e.g.
• On line (coupled) or off line (uncoupled)
Piston pump)
refresh circuit
• Active inspiratory and expiratory phase
DIFFUSIVE OXYGEN and CARBON DIOXIDE TRANSFER
• O2 and CO2 transfer between gas and PFC in the oxygenator
• O2 and CO2 transfer between PFC and blood in the lungs
Fick’s law
Oxygenator
Medical
gas
PFC
Pp
Nk
tPF C
tm

Dm DP F C
M.L. Costantino
2 VENTILATORS PROTOTYPES
In vivo trials
1- Double Rotary pumps
Since 1995: development of TLV ventilator
prototypes dedicated to very preterm newborns
(24 < Gestational age < 28 weeks)
2- Double Piston pumps
Ventilation circuit
Inspiratory
reservoir
Oxy
Expiratio
n
Inspiration
p
Animal
Corno et al., 2003
TLV
ETT
Filter
Expiratory
reservoir
Roller
pump
Refresh circuit
Exp
pump
Insp
pump
Control System
Bagnoli et al. 2005
M.L. Costantino
IN VIVO TRIALS: Experimental Protocol* (I)
Animals: 17 Preterm lambs (110 ± 5 days of gestation)
Weight: 1.3 to 6 kg
Ventilation fluid: FC-77 (Fluorinert TM, 3M, Belgium)
Medical Gases: Oxygen and Air (40%<FiO2<80 %)
Divided into two groups underwent
either gas ventilation (GV) or TLV
Monitored Parameters
• Endotracheal pressure
• Arterial and venous blood gases and pH (Radiometer
ABL 700, Copenhagen, Denmark) every 30 min and 10
min after each ventilation parameter variation
• Tissue harvesting for histo-pathological analysis at the
end of experiment after animal euthanasia
Ventilation
parameters
TV
[ml/kg]
10-15
FRC
[ml/kg]
≈20
I:E
1:2
1:3
RR
[bpm]
4-6
*Complying with the recommendations of the EEC (86/609/EEC) for the care and use of laboratory animals and approved by the animal
care committee of the University of Milan
M.L. Costantino
IN VIVO TRIALS: Experimental Protocol* (II)
Animal preparation:
• Induction of anesthesia and muscle relaxation of the mother
• Cesarean section to expose the fetus head maintaining placental circulation (EXIT)
• Fetus instrumentation: cannulation of right external jugular vein and controlateral carotid
artery for infusion of fluids and continuous blood pressure monitoring and sampling
• TLV or GV started with the lamb still connected to the umbilical cord (protective strategies)
GV group (n=6):
• Gas ventilation maintained up to 6h (FiO2=0.6, RR=35-50
breaths/min, Vmin=0.4-1.5 l/min), Inspiratory Peak
Pressure=20 cmH2O, I/E ratio 1:1, PEEP = 3-7 cmH2O)
TLV group (n=11):
• Total liquid ventilation maintained up to 6h (FiO2=0.6,
TV=10-15ml/kg,
RR=4-6
breaths/min,
I:E=1:2/1:3,
FRC≈20ml/kg)
*Complying with the recommendations of the EEC (86/609/EEC) for the care and use of laboratory animals and approved by
the animal care committee of the University of Milan.
M.L. Costantino
IN VIVO TRIALS: Results
Mean arterial and venous blood data
120
100= 60-75 mmHg
Goal: Physiologic* gas exchanges pO
2
pO2 GV
80 pCO2= 36-45 mmHg
pO2 TLV
pCO2 [mmHg]
pO 2 [mmHg]
160
80
40
60
40
pCO2 GV
20
0
pCO2 TLV
0
0
30 60 90 120 150 180 210 240 270 300 330 360
time [min]
0
30 60 90 120 150 180 210 240 270 300 330 360
time [min]
•Adequate oxygenation and blood pressure were maintained for 6 hours
• Severe hypercapnia
•Survival rate: TLV=55% (5/11; mean body weight 2.7±1.6 kg)
GV=33% (2/6; mean body weight 4.9±1.0 kg)
*G.S.Dawes. FOETAL and neonatal physiology. Glodsmith, Karotin. Assisted ventilation of the neonate
M.L. Costantino
IN VIVO TRIALS: Results
Histological analysis
TLV
TLV
GV
a)
c)
b)
d)
control
Histological analysis showed that animals in TLV group exhibited good alveolar
distention, no atelectasis and no signs of inflammation in the airways
 TLV=49.3%
Percentage open alveolar area:
 GV=38.8%
 Control=46.9%
M.L. Costantino
IN VIVO TRIALS: Results
Periodic Acid Shiff (P.A.S.) reaction
The lungs were also analyzed with P.A.S. reaction to
estimate the amount of glycogen produced by alveolar
epithelial cells (AECs) as an index for lung immaturity.
---
Larger glycogen pools (low or absent surfactant production)
in the more preterm animals. These lambs also showed
lower oxygenation with respect to the average of each group
and higher mortality.
P.A.S.
--+
# of lambs
(survived)
BW [kg]
pO2 [mmHg]
pCO2 [mmHg]
- ++
Mature
(- - -)
Preterm
(- - +)
Very preterm
(- + +)
TLV
11 (6)
1 (0)
6 (4)
4 (2)
GV
6 (2)
2 (2)
3 (0)
1 (0)
TLV
2.8±1.0
3.3±0.0
3.2±1.1
2.0±0.4
GV
3.6±1.5
4.9±1.6
3.5±0.3
1.3± 0
TLV
64±32
89±0
81±39
44±16
GV
38±45
87±17
5.3±3.7
7±0
TLV
80±17
67±0
75 ±19
90±14
GV
128±58
68 ±4
183±6
139±0
M.L. Costantino
CONCLUSIONS
• The TLV circuit proved to be able to provide adequate gas
exchange during in vivo animal trials
• Good control of functional residual capacity and tidal volume
• Good alveolar distention, no atelectasis and no signs of
inflammation in the airways
TLV seems to be feasible with ease of use, safety and reliability:
good alternative to conventional gas ventilation.
… HOWEVER works are in progress
• Development of a new TLV ventilator (3rd Prototype)
• Test of PFC interaction with the biological system
“FIRB 2008 Futuro in Ricerca”
3-years grant (2010-2013)
“Development of a novel device for Total Liquid Ventilation and evaluation of the biological and
biomechanical effects induced on the respiratory system” (Neo-Li-Ve Project)”
M.L. Costantino
Thank you for
your attention
M.L. Costantino