Group Title: Critical Care
Title: Protective effect of methylprednisolone on ventilator-induced diaphragm dysfunction is dose dependent
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Title: Protective effect of methylprednisolone on ventilator-induced diaphragm dysfunction is dose dependent
Series Title: Critical Care
Physical Description: Archival
Creator: Maes,K.
Agten,A.
Smuder,A.
Powers,S. K.
Decramer,M.
Gayan-Ramirez,G.
Publication Date: 2010
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General Note: Start pageP201
General Note: M3: 10.1186/cc8433
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Bibliographic ID: UF00099888
Volume ID: VID00001
Source Institution: University of Florida
Holding Location: University of Florida
Rights Management: Open Access: http://www.biomedcentral.com/info/about/openaccess/
Resource Identifier: issn - 1364-8535
http://ccforum.com/content/14/S1/P201

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Results Between 2004 and 2009 our crew evaluated for transfer on ECMO
15 ARDS patients (10 males), age 38 + 15 years, BMI 28 + 7, APACHE II
score 26 + 9, SOFA score 9 + 4, Oxygenation Index 39 + 17. The average
distance was 133 + 124 km.Two patients improved after NO trial and were
transferred without ECMO.All of the other patients underwent venovenous
ECMO: 11 with cannulation of femoral veins, one femoral-jugular veins
and one with a DL cannula in the jugular vein. ECMO settings were
(mean + SD) BF 2.9 + 0.8, GF 3.6 1.6, GF FiO, 1. Data have been recorded
30 minutes before and I hour after ECi I i i ECMO granted a better
clearance ofpCO (75 + 20.5 vs49.7 + 7.9 mmHg, P<0.01), thus improving
the pH (7.279 + 0.10 vs 7.41 0.06, P <0.01) and mean pulmonary arterial
pressure (41 + 11 vs 31 + 5 mmHg, P <0.05) and allowing a reduction in
respiratory rate (28 + 11 vs 9 + 4, P <0.01), minute ventilation (10.2 + 4.6
vs 3.3 + 1.7 I/min, P <0.01) and mean airway pressure (26 + 6 vs 22 + 5
cmH,, P <0.01). Arterial pO, mean blood pressure and heart rate did not
show I iii ..I variations. After ECMO began, vasoconstrictor therapy
(being administered to five patients) was quickly tapered. Neither clinical
nor technical major complications were reported.
Conclusions ECMO employment at referral centers enabled long
distance, high-risk ground transportation.


P199
Effects of hypertonic saline on a pig model of acute lung injury
induced by hydrochloric acid instillation
CA Holms, DA Otsuki, M I i, .. J Noel-Morgan', C Massoco2,
DT Fantoni', P Gutierrez3, JO Auler Jr'
'Faculdade de Medicina da Universidade deSao Paulo, Brazil; 2Genoa, Sao
Paulo, Brazil; lNCOR, Sao Paulo, Brazil
Critical Care 2010,14(Suppl 1):P199 (doi: 10.1186/cc8431)

Introduction Controversy exists over the possible beneficial effects of
hypertonic saline (HS) in pulmonary inflammatory response, particularly
in neutrophil immunomodulation [1,2]. This study was designed to
investigate possible benefits of HS in the treatment of pigs submitted to
experimental acute lung injury.
Methods Twelve anesthetized, tracheotomized pigs (25 to 30 kg) were
mechanically ventilated by pressure, adjusted to 8 ml/kg tidal volume,
with FiO 50%, and submitted to intratracheal instillation of 4 ml/kg
hydrochloric acid (HCI) 0.1 N. They were then randomized to ALl group
(n = 7) or ALl + HS group (n = 5), where animals of the latter group
received 4 ml/kg intravenous hypertonic saline, 15 minutes after injury.
Hemodynamic parameters, pulmonary compliance (Cs), peak pressure
(P i plateau pressure (P and tidal volume (V) were analyzed at
i. (TBL), 15 minutes .ii HCI instillation (TALl) and hourly thereafter
for 4 hours (TO to T3). Bronchoalveolar lavage was performed at the end
of the observation period for flow cytometry analysis of neutrophil burst
activity. Postmortem histopathology of the right ii I i iii, i lung was
also performed in all animals.
Results After TALI, animals of both groups presented i iii, 11 ..I increases
in P and Ppt, and a decrease in C,,t, at all time points, when compared
,i, iI V waspreserved in both groups overtime. 1i i. 1~~1 ...i
differences between groups ALl and ALl + HS, respectively, in: central
venous pressure (TO, T1 and T2), pulmonary artery occlusion pressure
(T1 and T2) and pulmonary vascular resistance index (TALl). In the ALl
group, Ii i...11 differences related to TBL were found in mean arterial
pressure (T1), mean pulmonary artery pressure (TALI, TO,T1,T2 and T3) and
pulmonary vascular resistance index (TALl, TO, T3). In the ALl + HS group,
there were i ii i,11 ... differences related to TBL in mean arterial pressure
(TO, T1, T2), mean pulmonary artery pressure (TALl, TO, T1, T2, T3), cardiac
index (TO, T1, T2) and pulmonary vascular resistance index (T1, T2, T3). No
differences were found between groups regarding histopathology and
flow cytometry analyses.
ConclusionsHS i 1i ~ i1 i i 11 11 ii i the studied parameters
regarding the lungs, in the proposed model of ALl.
Acknowledgements Grants from FAPESP 08/55376-7 and 08/56792-4.
References


P200
Conventional mechanical ventilation can injury intact lungs in
severe trauma patients
O Ignatenko, D Protsenko, AYaroshetskiy, B Gelfand
State Medical Unversity of Russia, Moscow, Russia Federation
Critical Care 2010,14(Suppl 1):P200 (doi: 10.1186/cc8432)

Introduction Conventional mechanical ventilation (MV) may cause
additional lung injury in ALI/ARDS due to overdistention of aerated
lung regions (high Vt) and cyclic lung reopening (low PEEP level).
Hyperproduction of inflammatory mediators is one of the side effects in
these cases. This factor could delay or prevent resolution of respiratory
failure [1,2]. However, it is not clear whether conventional mechanical
ventilation damages intact lungs.The aim ofthis study was to evaluate the
effects of conventional and protective mechanical ventilation on intact
lungs in patients with severe trauma.
Methods A prospective, randomized controlled trial in trauma patients
with mechanical ventilation for extrapulmonary indications. The protocol
was approved by the local ethics committee. Seventy-eight patients were
randomized to conventional (Vt 10 to 12 ml/kg IBW, PEEP 5 cmHO n
39) or protective (Vt 5 to 6 ml/kg IBW, PEEP 10 cmHO n= 39) mechanical
ventilation. TNFa, IL-1 and IL-6 levels in plasma and BAL fluids were
measured on 1, 2, 3, 5 and 7 days of MV Frequency of ALl (AECC criteria)
and VAP were evaluated. The endpoints of this study were the length of
MV, LOS in ICU and outcome on 28 days.
Results In first 3 days ALl was revealed in 26 patients (66.6%) in the
conventional and 10 patients (26.5%) in the protective MV groups (P
0.001; OR 4.375, 95% Cl 2.227 to 8.189). ARDS occurred in four patients
(10,2%) ofthe conventional MV group (LIS >2) and no one in the protective
MV group (P <0.0001). Levels ofTNFa, IL-1p and IL6 in BAL fluids were
i i ,i11 ii.. higher in the conventional MV group from 1 to 7 days with
maximal increase on day 3 (542 + 44/91 + 11; 315 + 35/86 + 10; 1,092 +
160/111 + 18, P <0.0001). No differences were found in levels of TNFa,
IL-1p and IL-6 in plasma samples. VAP occurred in 31 patients (83.7%) of
the conventional and nine patients (23%) of the protective MV groups (P
0.0001; OR 17.2, 95% Cl 5.5 to 54.3). The length of MV was 17.4 + 6 vs 12.8
3 (P 0.0001;OR 4.2,95%CI 1.5 to 11.5), LOS in the ICU was 21.9 5.6 vs
15.75 + 2.9 (P= 0.0002; OR 2.0, 95% Cl 0.18 to 23.6). The 28-day mortality
wasn't i 1i 1i ...I different in the groups.
Conclusions Conventional MV for more than 72 hours in patients with
severe trauma and intact lungs can cause lung injury, and increase
duration of MV and LOS in the ICU.
References
1, Dreyfuss D, aumon G: Ventilator-induced lung injury: lessons from
experimental studies.AmJ Respir rit Care Med 998,157:294-323
2 Parker JC, Hernandez LA, Peevy KJ: Mechanisms of ventilator-induced lung
injury. rit CareMed 1993, 21:131 143


P201
Protective effect of methylprednisolone on ventilator-induced
diaphragm dysfunction is dose dependent
K Maes', A Agten, A Smuder2, SK Powers2, M Decramer', G Gayan-Ramirez
'KU Leuven, Belgium; 2University of Florida, Gainesville, FL, USA
Critical Care 2010, 14(Suppl 1):P201 (doi: 10.1186/cc8433)

Introduction Administration of 80 mg/kg methylprednisolone has been
shown to prevent controlled mechanical ventilation (CMV) diaphragm
dysfunction in rats, partly by inhibiting the calpain system [1].The current
experiments determined whether lower doses of corticosteroids will also
provide protection against ventilator-induced diaphragm dysfunction.
Methods Rats were assigned to a control group or to 24 hours of CMV
receiving a single injection of saline or 5 mg/kg (low MP) or 30 mg/kg
(high MP) of methylprednisolone.
Results ', 1 I ln ~ 1 force production was decreased after CMV but
Si ii ...Ii ii .. i the low MP group while similar to controls in the high
MP group. Atrophy of the type Ila fibers was only present in the low MP
group. Atrophy of the type IIx/b fibers was more severe in the low MP
group than in the CMV group while no atrophy was observed in the high
MP group. '-1 i il 1 calpain activity was increased after CMV (+93%,
P <0.05 vs C) and in the low MP group (+83%, P <0.05 vs C), while it was
similar to controls in the high MP group. Expression of calpastatin was







Critical Care 2010, Volume 14 Suppl 1
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decreased in the CMV and the low MP group (-18%, P <0.05 vs C) but its
level was preserved to control levels in the high MP group. Analysis of the
caspase-3 mediated cleavage of a -spectrin revealed that CMV induced
a i -i11 -' rise in caspase-3 activity when compared with C (+194%,
P <0.001). Caspase-3 activity was similarly increased in the MP-5 and the
MP- q i II (+96% and +78% respectively, P <0.05 vs C) but this increase
was 1~1 ...i 11i less compared with that of CMV. i ii11 ... negative
correlations were found between calpain activity and diaphragm force
(-0.50 0.57, P <0.02). i i ii ... positive correlations were observed between
calpastatin and diaphragm force (0.43 and CSA of the type Ilx/b fibers (r 0.57, P <0.02).
ConclusionsThe ability ofcorticosteroids to protect against CMV-induced
diaphragmatic contractile dysfunction and atrophy are dose dependent
with only high doses of corticosteroids providing protection.
Acknowledgements Supported by Astra Zeneca Pharmaceuticals and
FWOVlaanderen.
Reference
1 Maes etal.:AmJ Respir Crit Care Med 2008, 178:1219-1226,


P202
Alveolar recruitment with non-invasive mechanical ventilation
(C-PAP) in patients with nonobstructive respiratory failure
VTomicic, R Moreno',V F, I i i, 1 ', J Keymer, A Fuentealba',
G Hormazabal', R Perez, J Molina, J 1
'Clinica Alemana de Santiago, Chile; University ofSao Paulo, Brazil
Critical Care 2010, 14(Suppl 1):P202 (doi: 10.1186/cc8434)

Introduction Non-invasive mechanical ventilation (NIMV) is able to reduce
reintubation especially in patients with exacerbation of COPD. Results have
not been reached in critically ill patients with nonobstructive respiratory
failure (NORF). However, the NIMV in most of these studies has been applied
without making an effort to open the lung and adjusting the C-PAP after
opening up the lung using a clinical approach. Our aim was to evaluate the
effects of applying recruitment manoeuvres (RM) with C-PAP and titrate it
according to clinical decremental C-PAP trial in patients with NORF
Methods NORF patients for whom NIMV was indicated between January
2008 and July 2009 were included and submitted to the NIMV-RM protocol
when a trained team was available. Bi-PAP and a full face mask were used.
The inclusion criteria were at least two of the following: respiratory rate
(RR) >30, accessory muscle activity, saturation <90% with FiO >50% and
consolidation areas on thorax X-ray. Gradual increasing of C-PAP (2 cm H0)
was used from 10 to 20 cmH0O. Each level of C-PAP was sustained for 5
minutes according to tolerance. The C-PAP after RM was adjusted when
the maximal tidal volume (VT) was reached, pulse oximetry (PO) did not
show any substantial change and when the patient was comfortable.
Demographic data, APACHE II score and lung injury score (LIS) were
measured. Cardiac rate (CR), RR, arterial pressure (AP), PO, minute ventilation
(VE) and percentage of mask leak (PML) were recorded through the RM.
Arterial blood gases were measured pre-RM, 1, 12 and 24 hours after RM.
Variables are expressed as median (range). ANOVA by repeated measures or
Kruskal-Wallis was used, P <0.05 was considered i -Ir, ... I
Results Fourteen patients were included. Age, APACHE II and LIS were: 56
(17 to 80); 14 (4 to 21) and 2 (1.3 to 2.7).The PaO,/FiO, ratio increased from
169.1 +69.7 (basal) to 261 + 106 after I hour ofRM (P 0.02).Improvement
was preserved at 12 and 24 hours, 280 + 69 and 295 + 73, respectively. The
C-PAP level 1 hour after RM was 14.9 + 2.4, and 14.1 + 1.9 at 24 hours post
RM.The hemodynamic stability, RR, AP PML and VE did not change during
and after the RM.
Conclusions RM with gradual increments of C-PAP is safe. RM in patients
with NORF could be an alternative to rescue patients with poor outcome
with NIMV alone.


P203
N-acetylcysteine attenuates ventilator-induced diaphragm
dysfunction in rats
A Agten', K Maes', A Smuder2, SK Powers2, M Decramer',
G Gayan-Ramirez'
'KU Leuven, Belgium; 2University of Florida, Gainesville, FL, USA
Critical Care 2010, 14(Suppl 1):P203 (doi: 10.1186/cc8435)


Introduction Controlled mechanical ventilation (CMV) results in
diaphragmatic dysfunction. Oxidative stress is an important contributor
to ventilator-induced diaphragm dysfunction, since 18 hours of CMV
lead to increased protein oxidation and increased lipid peroxidation. We
hypothesized that administration of an antioxidant, N-acetylcysteine
(NAC), would restore the redox balance in the diaphragm and prevent the
deleterious effects of CMV
Methods Anesthetized rats were submitted for 24 hours to either spon
taneous breathing while receiving 150 mg/kg NAC (SBNAC) or saline
(SBSAL) or to CMV while receiving 150 mg/kg NAC (MVNAC) or saline
(MVSAL).
Results After 24 hours, diaphragm forces were i 1~i1 ...i1 lower in
MVSAL compared with all groups. Administration of NAC completely
abolished this decrease such that forces produced in the MVNAC group
were comparable with those of both SB groups. Protein oxidation was
i 1i~1i ...II increased in MVSAL (+53%, P <0.01) and was restored in
MVNAC. '*1 1i i1, i caspase-3 activity was 1 ii~ ... I increased in
MVSAL compared with SBSAL (+279%, P <0.001). Caspase-3 activity
was also increased in the MVNAC group (+158.5%, P <0.01) but to a
SI iii -,1i lesser extent compared with that of MVSAL. Calpain activity
was ii 11 ... I increased after CMV (+137%, P <0.001 vs SBSAL), while
it was similar to SB groups in the MVNAC group. I iii -ii negative
correlation was found between calpain activity and diaphragm tetanic
force (r -0.48, P 0.02).
Conclusions These data show that the administration of NAC was able to
preserve the i ii , i I from the deleterious effects of CMV NAC inhibits
the increase in oxidative stress and proteolysis and reduces the decrease
in force generating capacity of the diaphragm.


P204
In vitro muscle contraction force measurements on isolated and
entire rat diaphragms
C Armbruster, C Dassow, KGamerdinger, J Guttmann, M Schneider,
S Schumann
University Medical Center Freiburg, Germany
Critical Care 2010, 14(Suppl 1):P204 (doi: 10.1186/cc8436)

Introduction Inactivity of the diaphragmatic muscles during mechanical
ventilation leads to atrophy and contractile dysfunction. Up to now, in
vitro force measurements were performed only on single diaphragmatic
muscle strips. Our intention was to find out how mechanical and electrical
stimulation influences the condition of the diaphragm as a whole organ.
To determine the status ofthe diaphragm, muscle contraction forces were
measured on entire rat diaphragms.
Methods We used an earlier described bioreactor [1] as the cultivation
and measurement device for the whole rat ii i ,, i.. The bioreactor
consists of a pressure chamber and a supply chamber that are separated
by a very flexible and soft membrane [2]. On this membrane the sample
diaphragm is placed. By application of certain gas volumes (0 to 1.5 ml)
in the pressure chamber, diaphragms are deflected to various levels of
pretension. ', i I i 1... were electrically stimulated at each deflection
level 10 times (750 ms duty cycle, 100 ms stimulation time, 5 ms pulse
width, 200 Hz frequency). Pressure changes caused by muscle contraction
were recorded inside the pressure chamber and muscle contraction
forces were calculated. After initial force measurements, diaphragms were
exposed for 6 hours to one of four different treatments: nonstimulated
storage (control), cyclic mechanical deflection, electrical stimulation every
20 minutes, combination of cyclic deflection and electrical stimulation.
After 6 hours another force measurement was performed. Supernatants
were collected after 6 hours and investigated for IL-6 activity.
Results I i 1- i on the level of deflection of the Ii i i i' 1i muscle
contraction force increased from 0.1 N (volume 0.6 ml) to 0.7 N (volume
1.5 ml). A larger pretension of the diaphragm resulted in larger muscle
contraction force. After treatment, muscle contraction force decreased in
all groups. Muscle contraction force was smallest in the passive control
group (0.05 N), larger and similar in the electrically stimulated (0.1 N) and
combination (0.09 N) groups and largest in the mechanically deflected
group (0.15 N). IL-6 activity increased after 6 hours of treatment.
Conclusions We conclude that it is possible to perform force
measurements on whole rat diaphragms in our in vitro model. Additionally,
the diaphragms can kept alive for >6 hours to apply different stimulation




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