Ann Am Thorac Soc. 2020 Feb 18

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Driving Pressure-Limited Strategy for Patients with Acute Respiratory Distress Syndrome
(ARDS): A Pilot Randomized Clinical Trial
Marcelo Luz Pereira Romano, MD,1 Israel Silva Maia, MD,2 Ligia Nasi Laranjeira, RT,1 Lucas
Petri Damiani, MSc,1 Denise de Moraes Paisani, PhD,1 Marcos de Carvalho Borges, MD, PhD,3
Bruno Guimarães Dantas, MD,3 Eliana Bernadete Caser, MD, PhD,4 Josué Almeida Victorino,
MD, PhD,5 Wilson de Oliveira Filho, MD,6 Marcelo Britto Passos Amato, MD, PhD,7 Alexandre
Biasi Cavalcanti, MD, PhD.1
1HCor Research Institute, São Paulo, Brazil

2 Hospital Nereu Ramos, Florianópolis, Brazil
3 Unidade de Emergência do Hospital das Clínicas da FMRP-USP, Ribeirão Preto, Brazil
4 Hospital Unimed Vitória, Vitória, Brazil
5 Hospital Cristo Redentor, Porto Alegre, Brazil
6 Hospital e Pronto-Socorro 28 de Agosto, Manaus, Brazil
7 Cardio-Pulmonary Department, Pulmonary Division, Heart Institute (Incor), University of São
Paulo, São Paulo, Brazil
Coresponding Author:
Marcelo Luz Pereira Romano, MD.
HCor Research Institute – Hospital do Coração
Rua Abílio Soares 250, 12th floor.
CEP: 04005-000 - São Paulo, SP, Brazil.
Phone: +55 (11) 30536611 EXT: 8102; FAX: +55 (11) 3886 4695
marcelo.romano@yahoo.com.br
Financial Support: HCor Research Institute – Hospital do Coração
Conflicts of Interest: None declared.
Author Contributions: All authors have met all four criteria for authorship suggested by the
International Committee of Medical Journal Editors. Study concept and design: Marcelo Luz
Pereira Romano, Israel Silva Maia, Ligia Nasi Laranjeira, Lucas Petri Damiani, Denise de Moraes
Paisani, Marcos de Carvalho Borges, Bruno Guimarães Dantas, Eliana Bernardete Caser, Josué
Almeida Vitorino, Wilson de Oliveira Filho, Marcelo Britto Passos Amato, Alexandre Biasi
Cavalcanti. Acquisition of data: Marcelo Luz Pereira Romano, Alexandre Biasi Cavalcanti,
Mariangela Pimentel Pincelli, Cassio Zandonai, Leonardo Carvalho Palma, Rosa Maria Busch,
Julia Batista de Carvalho, Betânia Silva, Daniela Correia Santos Bonomo, Juliano Martins Arruda,
ANNALSATS Articles in Press. Published February 18, 2020 as 10.1513/AnnalsATS.201907-506OC

Copyright © 2020 by the American Thoracic Society
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Luzia Noriko Takahashi, Kessy Lima Ruas, Mieko Claudia Miura, Paula Peixoto de Camargo,
Rosianne Vasconcelos, Vinícius Avellar Werneck, André Franz da Costa, Jorge Alcantara Farran.
Analysis and/or interpretation of data: Marcelo Luz Pereira Romano, Alexandre Biasi Cavalcanti,
Lucas Petri Damiani, Marcelo Britto Passos Amato, Israel Silva Maia, Ligia Nasi Laranjeira,
Denise de Moraes Paisani. Drafting of the manuscript: Marcelo Luz Pereira Romano, Israel Silva
Maia, Ligia Nasi Laranjeira, Lucas Petri Damiani, Denise de Moraes Paisani, Marcos de Carvalho
Borges, Bruno Guimarães Dantas, Eliana Bernardete Caser, Josué Almeida Vitorino, Wilson de
Oliveira Filho, Marcelo Britto Passos Amato, Alexandre Biasi Cavalcanti, Paula Peixoto de
Camargo, Rosianne Vasconcelos. Critical revision of the manuscript for important intellectual
content: Marcelo Luz Pereira Romano, Israel Silva Maia, Ligia Nasi Laranjeira, Lucas Petri
Damiani, Denise de Moraes Paisani, Marcos de Carvalho Borges, Bruno Guimarães Dantas,
Eliana Bernardete Caser, Josué Almeida Vitorino, Wilson de Oliveira Filho, Marcelo Britto Passos
Amato, Alexandre Biasi Cavalcanti. Statistical analysis: Marcelo Luz Pereira Romano, Alexandre
Biasi Cavalcanti, Lucas Petri Damiani, Ligia Nasi Laranjeira, Denise de Moraes Paisani. Study
supervision: Marcelo Luz Pereira Romano, Israel Silva Maia, Ligia Nasi Laranjeira, Lucas Petri
Damiani, Denise de Moraes Paisani, Marcos de Carvalho Borges, Bruno Guimarães Dantas,
Eliana Bernardete Caser, Josué Almeida Vitorino, Wilson de Oliveira Filho, Marcelo Britto Passos
Amato, Alexandre Biasi Cavalcanti. All authors provided final approval of the version to be
published and agreed to be accountable for all aspects of the work to ensure that questions
related to the accuracy or integrity of any part of the work are appropriately investigated and
resolved.

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Abstract
Rationale: Evidence from observational studies suggests that driving pressure is strongly
associated with pulmonary injury and mortality, regardless of positive end-expiratory pressure
(PEEP) levels, tidal volume or plateau pressure. Therefore, it is possible that targeting driving
pressure may improve the safety of ventilation strategies for ARDS patients. However, the
clinical effects of a driving pressure-limited strategy for ARDS has not been assessed
randomized controlled trials.
Objective: To evaluate the feasibility of testing a driving pressure-limited strategy in
comparison with a conventional lung protective ventilation strategy in acute respiratory
distress syndrome (ARDS) patients with baseline driving pressure of 13 cmH2O or higher.
Methods: Randomized, controlled, non-blinded, trial. Thirty-one patients with ARDS on invasive
mechanical ventilation with driving pressure of 13 cmH2O or higher. Patients allocated to the
driving pressure-limited strategy were ventilated with volume-controlled or pressure support
ventilation modes, tidal volume titrated to 4-8 mL/kg of predicted body weight (PBW), aiming a
driving pressure of 10 cmH20, or the lowest possible. Control group was ventilated according to
the ARDSNet protocol, using a tidal volume of 6 mL/kg PBW, allowing to be set down to 4
mL/kg PBW if plateau pressure was higher than 30 cmH2O.
Primary endpoint was driving pressure on days 1 to 3.
Results: Sixteen patients were randomized to the driving pressure-limited group and 15 to the
conventional strategy group. All patients were considered in analyses. Most patients had mild
ARDS with mean PaO2/FiO2 ratio of 215 (standard deviation [SD], 95). Baseline driving pressure
was 15.0 cmH2O (SD 2.6) in both groups. In comparison to the conventional strategy, driving

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pressure from the first hour to the 3th day was 4.6 cmH2O lower in the driving pressure-limited
group (95% confidence interval [CI], 6.5 to 2.8; p<0.001). From the first hour up to the third day,
tidal volume in the driving pressure-limited strategy group was kept lower than the control
group (mean difference [mL/kg of PBW], 1.3; 95% CI 1.7 to 0.9; P<0.001). We did not find
statistically significant differences in the incidence of severe acidosis (pH<7.10) within seven
days (absolute difference, -12.1; 95% CI, -41.5 to -17.3]) or any clinical secondary endpoint.
Conclusions: In ARDS patients, a trial assessing the effects of a driving pressure-limited strategy
using very low tidal volumes versus a conventional ventilation strategy on clinical outcomes is
feasible.
Clinical trial registered with ClinicalTrials.gov (NCT02365038)

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Mechanical ventilation is essential in critical care. Nevertheless, it might induce alveolar injury
and worsen ventilatory function.1,2 As extensively demonstrated, in patients with the acute
respiratory distress syndrome (ARDS), the ratio of ventilated to non-ventilated lung is reduced,
a phenomenon known as “baby lung”.3 Aerated ARDS lung has near normal intrinsic
compliance.1 Thus, considering that normal lung compliance is about 100 mL/cmH2O, the
respiratory system compliance in patients with ARDS reflects the residual baby lung size
(expressed as a percentage of the expected healthy lung volume). For example, a respiratory
system compliance of 30 mL/cmH2O indicates that the baby lung size is about 30% of the
expected healthy lung volume. Driving pressure, a variable easily measurable, is defined as the
ratio of tidal volume to the respiratory system compliance.4 Therefore, driving pressure reflects
the tidal volume adjusted for the “baby lung” size.
Evidence from observational studies suggests that driving pressure is strongly associated
with pulmonary injury and mortality, regardless of positive end-expiratory pressure (PEEP)
levels, tidal volume or plateau pressure.4-6 These findings are consistent with the fact that
cellular and tissue injury are better related to the amplitude of the recurrent stress (pressure)
that lung is exposed during ventilatory cycles.7,8 Respiratory cycles with elevated levels of
driving pressure were observed in all studies suggesting harmful effects of higher inspiratory
pressures (plateau pressure) or high pulmonary stress (high tidal volume).4
Therefore, it is possible that targeting driving pressure may improve the safety of
ventilation strategies for ARDS patients. However, the clinical effects of a driving pressure-
limited strategy for ARDS has not been assessed randomized controlled trials. The objective of
this study is to evaluate the feasibility a driving pressure-limited strategy in comparison with a

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conventional lung protective ventilation strategy (ARDSNet)9 in ARDS patients with baseline
driving pressure of 13 cmH2O or higher. Our primary aim was to determine if we would be able
to achieve a gradient of driving pressure on days 1 to 3 after randomization between the
experimental and control group.
Methods
Study Design
We conducted a pilot randomized, multicenter clinical trial, with concealed allocation of study
participants and intention to treat analysis, comparing a driving pressure-limited strategy of
mechanical ventilation versus a conventional strategy in patients with ARDS. Research Ethics
Committee of all participating institutions approved the trial (approval nº 1.197.157) and
informed consent was obtained from all patients, or next of kin, before patients were enrolled
in the trial (electronic supplementary material). The study was registered with ClinicalTrials.gov
NCT02365038. The trial was conducted in five intensive care units from tertiary general
hospitals in Brazil, including public and private health system hospitals. There were no changes
in the methods after the beginning of the study.
Patients
Patients with ARDS according to Berlin definition and receiving invasive mechanical ventilation
were considered for the study.10 Patients could be enrolled if time from the first blood gas
measurement showing hypoxemia to randomization was equal to or shorter than five days.

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We excluded patients who were younger than 18 years, those with any contraindication to
hypercapnia (e.g.: suspected or diagnosed intracranial hypertension, acute coronary
syndrome), high likelihood of death within 24 hours from initial evaluation, exclusive palliative
care, high output bronchopleural fistula, severe disturbances of thoracic compliance (e.g.:
kyphoscoliosis, tetanus) or other conditions according to the judgment of the attending
physician.
Potentially eligible patients were ventilated according to the protocol for protective
ventilation using low tidal volumes (ARDSNet)9 for three hours. After this period, ventilation
parameters were adjusted for a PEEP of 10 cmH20 and FiO2 of 100% for 30 minutes and,
subsequently, a new arterial blood sample for gas analysis was collected. For patients
ventilated with a PEEP of 16 cmH20 or higher, PEEP values were maintained. If PaO2/FiO2 was
still equal or less than 300 and driving pressure was 13 cmH2O or higher patients were eligible.
We decided to include only patients with higher values of driving pressure, and
specifically decided on the cut-off of 13 cmH2O based on three considerations. First, driving
pressure is related to mortality in ARDS, however the association is attenuated for driving
pressure values below around 14 to 15 cmH2O. Second, our mechanism to decrease driving
pressure was to adjust tidal volume down. Considering that patients started with a tidal volume
of around 6mL/kg of predicted body weight (PBW) at baseline, that we could decrease it at
most to 4 mL/kg PBW (maximal reduction of 1/3), and that driving pressure and tidal volume
are linearly related, it follows that patients with lower driving pressure would have smaller
absolute reductions on this variable. Third, the median baseline driving pressure of the patients

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randomized in a previous trial involving ARDS patients, was 13.5 cmH2O.11 Thus, we expected
that approximately 50% of ARDS patients would be eligible to our trial.
Randomization
The randomization list was generated using appropriate software with a 1:1 ratio and random
permuted blocks of four patients. In addition, randomization was stratified for age (≤55 or >55)
and site. Concealment of the randomization list was ensured by an automatized, central,
internet-based and 24-hour available system, developed by the HCor Research Institute.
Researchers entered patient information in the electronic system that provided an individual
identification number for each patient and assigned the ventilation strategy: driving pressure-
limited ventilation or ARDSNet (control group).
Interventions
Procedures employed for the driving pressure-limited strategy group and control group are
described below and in the manual of operations (detailed in the Online Supplement). There
were no special requirements regarding type of ventilator, apart from the capacity to measure
plateau pressure and PEEP. Clinicians were not blinded regarding assigned interventions
because this was not feasible.
Driving pressure-limited strategy group. Patients allocated to the driving pressure-
limited strategy were ventilated using volume-controlled or pressure support modes. The
measurement of driving pressure requires absence of spontaneous respiratory efforts.
Therefore, driving pressure cannot be assessed continuously, particularly in patients under

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pressure support mode. To overcome this barrier, we measured driving pressure once daily
with the patients sedated and, if needed paralyzed. We also assumed that respiratory system
static compliance has little variation along a 24-hour period. Then, because, driving pressure is
equal to the ratio of tidal volume to respiratory system static compliance, we based our
strategy on keeping tidal volume controlled at the level associated with a driving pressure of
10cmH2O.
Titration of tidal volume and driving pressure was conducted right after randomization,
then daily from day 1 to 7, and every other day thereafter. In cases of abrupt changes in
respiratory pressures or oxygenation, driving pressure needed to be reassessed. Patients had to
be fully sedated and not showing any respiratory movements for tidal volume titration.
Whenever necessary, we used hypnotic drugs and rapid onset neuromuscular blockers
(succinylcholine or rocuronium). Driving pressure was estimated by the difference between
plateau pressure, as measured by a 2-second inspiratory pause, and PEEP. We adjusted tidal
volume by identifying a value (between 4 and 8 mL/kg PBW) that generated a driving pressure
of 10 cmH2O. We called that the ‘target’ tidal volume of the day, which was recorded in a
plastic card hanging on patient’s bed and was supposed to be used during the whole day up to
the next titration. When the minimum allowed tidal volume (4 mL/kg PBW) generated a driving
pressure higher than 10 cmH2O, we considered this tidal volume of 4 mL/kg PBW as the target.
Similarly, when the maximum allowed tidal volume (8 mL/kg PBW) generated a driving pressure
lower than 10 cmH2O, a tidal volume of 8mL/kg PBW was maintained.
For patients who were on pressure-support mode, we briefly changed the ventilator to
volume-controlled mode after administration of rapid action sedatives and, if needed, rapid

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action neuromuscular blockers. Then, we titrated tidal volume to optimize driving pressure as
described above. As soon as patients had spontaneous efforts, they were transitioned back to
pressure support mode and we continuously adjusted the level of support to keep the target
tidal volume.
Respiratory rate was adjusted up to a maximum limit of 35 bpm to ensure pH values
between 7.30 to 7.45. When the pH was lower than 7.15, respiratory rate could be increased up
to the limit of 50 bpm, as long as auto-PEEP levels did not cross the upper limit of 3 cmH2O.
Additionally, other procedures for management of respiratory acidosis were: dead-space
reduction (replacement of the heat and moisture exchanger by active external humidifier);
treatment of hyperthermia; lipid enriched diet; adequate sedation and neuromuscular
blockade. Values of PEEP and FiO2 were set according to the low PEEP table proposed by the
ARDSNet group, aiming to keep capillary oxygen saturation between 90 and 95% or arterial
partial pressure of oxygen between 60 and 80 mmHg.
Control group. Patients allocated for the control group were ventilated using the
volume-controlled mode, applying the ARDSNet strategy,10 or pressure support mode. In both
cases, target tidal volume was 6 mL/kg PBW and plateau pressure was maintained equal or
lower than 30 cmH2O. Tidal volume was reduced to 5 or 4 mL/kg PBW if plateau pressure was
higher than 30 cmH2O. The levels of PEEP and FiO2 were set using the ARDSNet low PEEP table,
targeting a peripheral oxygen saturation between 90 and 95% or partial pressure of arterial
oxygen between 60 and 80 mmHg. Respiratory rate was adjusted to maintain pH between 7.30
and 7.45, increments being allowed up to 35 bpm. Additional procedures for management of
respiratory acidosis were like those described for the driving pressure-limited strategy group.

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Data Collection and Endpoints
Data was collected immediately before randomization (baseline data), one hour after
randomization, then every morning, starting on the day after randomization
(day 1) up to day 7, every other day from days 9 to 15, at intensive care unit (ICU) discharge,
hospital discharge and on day 28 after randomization. If patients were discharged from the
hospital before the 28th day after randomization, we contacted patients or their relatives by
telephone to obtain follow-up data.
Before randomization the following variables were collected: demographic variables;
ventilatory parameters and arterial blood gas measurements; weight; height; cause and
duration of ARDS; length of mechanical ventilation; Simplified Acute Physiologic Score (SAPS) 3;
Sequential Organ Failure Assessment (SOFA) variables; presence of septic shock, H1N1
infection, acquired immunodeficiency syndrome and previously diagnosed pulmonary disease.
Driving pressure, other mechanical ventilation variables, weight, fluid balance and
hemodynamic variables, were measured once daily on days 1 to 7, and every other day from
day 9 to 15 in the driving pressure-limited strategy group. Sedation and, if needed, short acting
neuromuscular blockers were prescribed just before measuring plateau and driving pressure.
For patients that were under pressure support ventilation, after we administered sedatives
(and if needed neuromuscular blockers), we changed to volume-controlled mode and set the
tidal volume equal to the latest value observed while the patient was on pressure-support
before collecting data on mechanical ventilation settings. In the control group, plateau
pressure was measured daily up to day 3 and thereafter only if patient did not show respiratory
movements (i.e., after day 3 we did not administer sedatives and neuromuscular blockers just

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to measure pressures and tidal volume). Vital status was determined at ICU discharge, hospital
discharge and 28 days. Additionally, we recorded the number of days under mechanical
ventilation from randomization to day 28.
The primary endpoint was driving pressure on days 1 to 3. Secondary endpoints were:
adherence to study procedures (daily adjustment of driving pressure in the driving pressure-
limited strategy group and tidal volume in the control group); rate of driving pressure equal or
lower than 13cmH2O; rate of ventilation with tidal volume within target; mean PEEP from day 1
to 7; mean tidal volume from day 1 to day 7; mean static compliance of the respiratory system
from day 1 to day 7;f mean plateau pressure from day 1 to day 7; mean driving pressure from
day 1 to day 7; mean respiratory rate from day 1 to day 7; death in the first 28 days; in-hospital
death; death in ICU; barotrauma in the first seven days; severe acidosis (pH<7.10) in the first
hour and in the first seven days; reintubation within 28 days; length of ICU and hospital stays;
days free of mechanical ventilation within 28 days. There were no changes in endpoints after
the study was commenced.
Statistical Analysis
We planned to enroll 30 patients in the trial. This sample size allowed us to detect a between-
group difference in driving pressure of 3.5 cmH2O, with a power of 80%, type I error of 5%,
using analysis of covariance (ANCOVA), assuming a standard deviation (SD) of 4.5 cmH2O in the
control group and 2 cmH2O in the experimental group, and a Pearson’s r of 0.7 between
baseline and follow-up driving pressures.

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Numerical variables were described as mean and standard deviation, or median and
interquartile range (IQR) for asymmetrical distributions. The categorical variables were
described as absolute and relative frequencies. We assessed treatment effects on the primary
outcome (driving pressure from day 1 to 3) using a linear mixed model with random intercept
parameter and interaction between treatment and time as fixed term. As a post hoc sensitivity
analysis we also considered site as random effects. In a secondary analysis, driving pressure
comparisons were done in each time point and P values were corrected with Bonferroni’s
adjustment.
The treatment effect on tidal volume was also tested with a linear mixed model with
random intercept similar to the model for the primary outcome. Categorical variables were
compared in each time with Fisher’s exact test and numerical variables were compared with
Students’t tests. Results for the linear mixed models and clinical secondary endpoints were
presented as absolute differences, 95% confidence interval (CI) and P values. We did not adjust
P values for multiple comparisons in analyses of secondary outcomes. The significance level was
0.05. There were no interim analyses. All analyses were performed using the R (R Core Team,
Vienna, Austria, 2019) software12.
Results
Patients
During the period of June, 2015, to February, 2017, 36 patients with ARDS were screened. From
these, five were not eligible. Therefore, 31 patients were randomized, with 16 allocated to the

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driving pressure-limited strategy and 15 for the control (ARDSNet) group. All randomized
patients were followed for 28 days and were included in the final analysis of the data (Figure 1).
The trial was finalized after the calculated sample size was reached.
Demographic characteristics of both groups at baseline were comparable (Table 1).
Mean age was 48.4 years (SD 16.9) and the mean SAPS3 score was 55.9 (SD 12.5) points. Fifteen
patients (48%) presented septic shock. In addition to the pulmonary dysfunction, on average
patients presented more than two organ dysfunctions. Most cases (77,4%) had pulmonary
rather than extrapulmonary ARDS.
Ventilatory and blood-gas related variables were also well balanced between groups at
the baseline. The majority of ARDS cases were mild, with a mean PaO2/FiO2 ratio of 215 (SD,
95). Only one case of severe ARDS was enrolled and assigned to the driving-pressure limited
strategy group. Baseline driving pressure was approximately 15 cmH2O (SD 2.6) in both groups,
with a tidal volume below 6mL/kg PBW, plateau pressure below 30 cmH2O and PEEP close to 10
cmH2O.
Primary Endpoint
In the driving pressure-limited strategy group, right after the first hour, a reduction of driving
pressure was observed after the adjustment of the target tidal volume for that day, dropping
from 15.3 cmH2O to 10.6 cmH2O (p<0.001) (Table 2 and Figure 2). The main analysis showed
that the mean driving pressure on the first three days was 4.6 cmH2O (95% CI, 6.5 to 2.8;
p<0.001) smaller in the driving pressure-limited strategy compared to the control group.
Inclusion of site as random effects in the post hoc model did not substantially change the

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estimate of effect of the driving-pressure limited group versus control group on driving
pressure from the first hour to the third day (mean difference, 4.7; 95% CI, 6.7 to 2.8; p<0.001).
Secondary Endpoints
Daily titration of target tidal volume to achieve a driving pressure of 10 cmH2O was done in all
cases in the first hour and on day 1 in the driving pressure-limited group (Table 2), and in all but
1 patient on days 2 and 3. Tidal volume was maintained at or below 6 mL/kg PBW in about 90%
of patients in the first 3 days in the control group, with a mean of tidal volume just under 6
ml/Kg PBW from the first hour to day 3.
In the driving pressure-limited group, all patients achieved a driving pressure equal or
lower than 13 cmH2O in the first hour, and all but one did so on days 1 to 3. Conversely, only 5
from 15 patients in the control group had a driving pressure equal or lower than 13 cmH2O, and
about half achieved those levels on days 1 to 3 (Table 2).
From the first hour up to the third day, tidal volume in the driving pressure-limited
strategy group was kept lower than the control group (mean difference [mL/kg of PBW], 1.3;
95% CI 1.7 to 0.9; P<0.001) (Table 2 and Figure E1 in the Online Supplement). Mean plateau
pressure was lower in the driving pressure-limited group vs control group in the first three days,
and in both cases below 30 cmH2O (Table 2 and Figure E1, in the Online Supplement).
Respiratory rate was higher in the driving pressure-limited group on days 2 and 3 (p=0.03 and
0.004). There were no statistically significant between-group differences in the respiratory
system static compliance PEEP in any of the first seven days (Tables E1 to E3, and figure E2 in
the Online Supplement).

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There were no statistically significant differences between groups on the clinical
secondary endpoints: death in the first 28 days; in-hospital death; death in ICU; barotrauma in
the first seven days; severe acidosis (pH<7.10) in the first hour and in the first seven days;
reintubation within 28 days; length of ICU and hospital stays; days free of mechanical
ventilation within 28 days (Table 3).
Other Endpoints
Mean PaCO2 was higher in the driving-pressure limited group on day one (59.5 vs 49.1; P= 0.04)
and day 2 (59.8 vs 49.8; P=0.03) but there was no statistically significant difference on day 3
and afterwards (Tables E1, E2, E3 in the Online Supplement). The value of pH was lower in the
driving-pressure limited group on day 1 (7.27 vs 7.39; P=0.04). No patient needed bicarbonate
administration to manage acidemia.
Other data, such as fluid balance on the first day, weight variation until the seventh day,
number of days on vasopressors (norepinephrine), number of days on neuromuscular blockers,
sedative or hypnotic drugs, were also similar in both groups (Table E4, in the Online
Supplement).
Discussion
In ARDS patients, a driving pressure-limited mechanical ventilation strategy was feasible in
comparison to the conventional strategy (ARDSNet), resulting in reductions of driving pressure
from the first hour up to the third day, without increased risk of severe adverse events, such as

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severe acidosis. There were no differences regarding clinical endpoints, but our trial was not
powered to detect effect on those endpoints.
Adherence to the trial protocol was good, as evidenced by titration of daily target tidal
volume in all cases assigned to the driving pressure-limited strategy on the first hour and on
day 1, and all but 1 case on days 2 and 3. In most patients in the control group, tidal volume
was controlled within recommended values (4 to 6mL/kg of PBW). Although we used very low
tidal volumes in the driving pressure-limited group, we did not observe between-group
statistically significant differences regarding the number of days on sedatives, hypnotic or
neuromuscular blockers.
A safety concern regarding the use of very low tidal volumes to decrease driving
pressure is the emergence of severe respiratory acidosis. In fact, previous studies that
evaluated the use of very low tidal volume (3 or 4 mL/kg PBW) added extracorporeal carbonic
dioxide removal to all patients.13,14 In our feasibility trial, the between-group PaCO2 difference
was about 10 mmHg in the first hour to first day, with smaller differences afterwards. Mean
PaCO2 and pH in the driving-pressure limited group were approximately 60mmHg and 7.27,
values that are reasonable in patient with ARDS provided severe acidosis is avoided. In this
regard, there were only 3 cases of severe acidosis (pH<7.10) in the driving pressure-limited
group and 1 case in the control group (absolute difference 12.1; 95% CI, -41.5; 17.3). These
results suggest that the driving-pressure limited strategy seems not to frequently cause severe
acidosis in ARDS patients. However, more precise estimation of the risk of severe acidosis
caused by the driving-pressure limited strategy can only be provided in larger trials. In addition,
our small sample size considered mostly patients with mild or moderated ARDS.

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In this trial we used an inspiratory pause of 2 seconds to measure plateau pressure and
to calculate driving pressure. It has been suggested that plateau pressure measured in the
pressure-time trace corresponding to the first zero flow point (P1) may reflect additional
dynamic determinants of lung lesion better than the measure after a 2 second pause.15
However, both values are highly correlated and it is unlikely that defining plateau pressure at
P1 would add value.16 Furthermore, the main study that assessed the relationship between
driving pressure and clinical outcomes considered plateau pressure measured after a 2 second
pause.4
Our strategy for reducing driving pressure was based exclusively on the adjustment of
tidal volume. Given that driving pressure is a relation between tidal volume and respiratory
system static compliance, it is possible that additional reductions would be achieved with
strategies focused on increasing the respiratory system static compliance, as for example the
optimization of PEEP. The effect of recruitment maneuver associated to PEEP titration on the
compliance of the respiratory system depends on the degree of pulmonary recruitability in
ARDS patients. However, some studies suggest that average recruitability is only modest with
substantial variability observed among different patients. Therefore, approaches that aim PEEP
optimization have better chances to present positive results if used in patients with high
pulmonary recruitability.
We have verified a reduction in driving pressure of approximately 4 cmH2O between
groups, from the first hour up to the second observation day. Results from a metanalysis of
observational data suggest that this driving pressure decrease is associated with a reduction in
the relative risk of death of approximately 20%.4 This information does not imply that actively

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ensuing maneuvers to decrease driving pressure will result in lower mortality because this was
a meta-analysis of observational data, therefore this relationship is far from being causal.
Nevertheless, this effect size may be considered when estimating sample size for future
randomized studies to evaluate the effect of driving pressure reduction on clinically-relevant
endpoints.
This study has several limitations. First, the sample size was small, resulting in low power
to evaluate the effects of driving pressure reduction strategy on patient-centered clinical
endpoints. Second, the trial was not blinded because it was not feasible to blind clinicians.
Third, most participants had mild ARDS. Therefore, our data is limited for predicting if it is
feasible to use very low tidal volumes without ECMO for patients with severe ARDS. Fourth,
driving pressure measurements were performed on an intermittent basis instead of
continuously, because absence of respiratory efforts is required. Conversely, we offered and
tested a practical approach to limit driving pressure based on controlling the tidal volume,
which is linearly related to driving pressure. Fifth, we assumed that respiratory system static
compliance varies little in a 24-hour period. Although that is a reasonable assumption for most
cases, rapid changes in static compliance may occur in critically patients. In cases of abrupt
changes in respiratory pressures or oxygenation, our protocol recommended reassessment of
driving pressure. Sixth, we did not perform esophageal pressure measurement, which limit us
to evaluate the effects of the two distinct ventilation strategies on transpulmonary pressure.
Seventh, because of resource limitations we did not evaluate any biomarkers in our population.

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Conclusions
In ARDS patients, a mechanical ventilation strategy that limits driving pressure due to the use of
very low tidal volumes is feasible in comparison to the conventional strategy. These results are
useful for the planning of a larger randomized controlled clinical trial to evaluate the effect of a
driving-pressure limited strategy on clinical endpoints

Page 21 of 71
References
1. Fan E, Del Sorbo L, Goligher EC, et al. An Official American Thoracic Society/European
Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice
Guideline: Mechanical Ventilation in Adult Patients with Acute Respiratory Distress
Syndrome. Am J Respir Crit Care Med. 2017;195(9):1253-1263.
2. Dreyfuss D, Soler P, Basset G, Saumon G. High inflation pressure pulmonary edema.
Respective effects of high airway pressure, high tidal volume, and positive end-expiratory
pressure. Am Rev Respir Dis. 1988;137(5):1159-1164.
3. Gattinoni L, Pesenti A. The concept of "baby lung". Intensive Care Med. 2005;31(6):776-784.
4. Amato MB, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute
respiratory distress syndrome. N Engl J Med. 2015;372(8):747-755.
5. Guerin C, Papazian L, Reignier J, et al. Effect of driving pressure on mortality in ARDS
patients during lung protective mechanical ventilation in two randomized controlled trials.
Crit Care. 2016;20(1):384.
6. Serpa Neto A, Schmidt M, Azevedo LC, et al. Associations between ventilator settings during
extracorporeal membrane oxygenation for refractory hypoxemia and outcome in patients
with acute respiratory distress syndrome: a pooled individual patient data analysis :
Mechanical ventilation during ECMO. Intensive Care Med. 2016;42(11):1672-1684.
7. Tschumperlin DJ, Oswari J, Margulies AS. Deformation-induced injury of alveolar epithelial
cells. Effect of frequency, duration, and amplitude. Am J Respir Crit Care Med. 2000;162(2 Pt
1):357-362.
8. Ye H, Zhan Q, Ren Y, Liu X, Yang C, Wang C. Cyclic deformation-induced injury and
differentiation of rat alveolar epithelial type II cells. Respir Physiol Neurobiol. 2012;180(2-
3):237-246.
9. Acute Respiratory Distress Syndrome N, Brower RG, Matthay MA, et al. Ventilation with
lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the
acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301-1308.
10. Force ADT, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the Berlin
Definition. JAMA. 2012;307(23):2526-2533.
11. Cavalcanti AB, Suzumura EA, Laranjeira LN, et al. Effect of Lung Recruitment and Titrated
Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute
Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2017;318(14):1335-
1345.
12. R Core Team (2019). R: A language and environment for statistical computing. R Foundation
for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/.
13. Bein T, Weber-Carstens S, Goldmann A, et al. Lower tidal volume strategy ( approximately 3
ml/kg) combined with extracorporeal CO2 removal versus 'conventional' protective

Page 22 of 71
ventilation (6 ml/kg) in severe ARDS: the prospective randomized Xtravent-study. Intensive

Care Med. 2013;39(5):847-856.
14. Fanelli V, Ranieri MV, Mancebo J, et al. Feasibility and safety of low-flow extracorporeal
carbon dioxide removal to facilitate ultra-protective ventilation in patients with moderate
acute respiratory distress sindrome. Crit Care. 2016;20:36.
15. Santini, A., Votta, E., Protti, A., Mezidi, M., & Guérin, C. (2017). Driving airway pressure:
should we use a static measure to describe a dynamic phenomenon?. Intensive care
medicine, 43(10), 1544-1545.
16. Mezidi, M., Yonis, H., Aublanc, M., Lissonde, F., Louf-Durier, A., Perinel, S., ... & Guérin, C.
(2017). Effect of end-inspiratory plateau pressure duration on driving pressure. Intensive
care medicine, 43(4), 587-589.

Page 23 of 71
Figure Legends
Figure 1. Flow of patients in the trial.
Figure 2. Driving pressure during the 7 days after randomization among patients randomized to
driving pressure-limited strategy versus control group strategy (ARDSNet).

Page 24 of 71
Table 1- Patient baseline characteristics
Driving Pressure- Conventional

Characteristics Total Limited Strategy (ARDSNet) Strategy
(n=31) (n=16) (n=15)
Age, Y, mean (SD) 48.4 (16.9) 45.1 (18.4) 51.9 (14.9)
Female sex, n (%) 10 (32.3) 6 (37.5) 4 (26.7)
SAPS 3 score, mean (SD) 55.9 (12.5) 53.5 (12.0) 58.5 (12.9)
No. of non-pulmonary organ failures, mean (SD) 2.5 (0.9) 2.4 (1.1) 2.5 (0.7)
Septic shock, n (%) 15 (48.4) 9 (56.2) 6 (40)
Cause of ARDS, n (%)

Non-pulmonary sepsis 7 (22.6) 5 (31.2) 2 (13.3)
Pneumonia 24 (77.4) 11 (68.8) 13 (86.7)
Time since onset of ARDS, hours, median [IQR] 24 [12 - 36] 24 [16.5 - 39.8] 24 [12 - 26.5]
Days intubated prior to randomization, median [IQR] 2 [1 - 3.5] 1.5 [1 - 3) 2 [1 - 4.5]
PaO2/FiO2, mean (SD) 214.7 (94.6) 218.5 (121.8) 210.6 (57.1)
Tidal volume - ml/kg predicted body weight, mean (SD) 5.8 (0.5) 5.9 (0.4) 5.7 (0.6)
Respiratory rate, breaths/min, mean (SD) 28.5 (5.8) 27.5 (5.4) 29.5 (6.3)
Minute ventilation, liters/min, mean (SD) 10.2 (2.3) 9.8 (2.0) 10.6 (2.6)
Plateau airway pressure, cmH2O, mean (SD) 24.6 (3.0) 24.2 (3.0) 25 (3.0)
Positive end-expiratory pressure, cmH2O, mean (SD) 9.6 (2.0) 9.3 (1.9) 9.9 (2.2)
Driving pressure, mmHg, mean (SD) 15 (2.6) 14.9 (2.7) 15.1 (2.5)
Respiratory system static compliance, ml/cmH2O, mean (SD) 25 (6.0) 24.6 (4.1) 25.4 (7.7)

Page 25 of 71
Table 2- Primary and secondary respiratory endpoints during the first three days
Outcome Hour 1 Day 1 Day 2 Day 3
Driving Control P Driving Control P Driving Control P Driving Control P
Pressure- Group value Pressure- Group value Pressure- Group value Pressure- Group value
Limited (N=15) Limited (N=15) Limited (N=15) Limited (N=14)
Group Group Group Group
(N=16) (N=16) (N=14) (N=12)
Primary outcome
Driving pressure, cmH2O
Mean (SD) 10.6 (1.2) 15.3 (3.0) <0,001 11 (1.5) 15 (3.5) <0,001 11.2 (2.1) 14.9 (3.2) 0.002 10.7 (2.1) 13.9 (3.6) 0.02
[Minimum – Maximum] [9 - 13] [10 - 20] - [9 – 15] [10 – 23] - [8 – 17] [9 – 19] - [7 – 14] [9 – 20] -
Secondary outcomes
Daily adjustment of driving 16 (100) - - 16 (100) - - 13 (86.6) - - 11 (91,7) - -
pressure in the driving pressure-
limited group, n. (%)
Daily adjustment of tidal volume in - 15 (100) - - 15 (100) - - 15 (100) - - 15 (100) -
the control group, no. (%)
Driving Pressure ≤ 13 cmH2O, n. (%) 16 (100) 5 (33.3) <0,001 15 (93.8) 7 (46.7) 0.006 13(92.9) 7 (46.7) 0.01 11 (91.7) 8 (57.1) 0.08
Tidal volume – mL/kg of predicted body weight
Mean (SD) 4.3 (0.5) 5.6 (0.6) <0,001 4.3 (0.5) 5.8 (0.5) <0,001 4.5 (0.5) 5.7 (0.4) <0,001 4.5 (0.6) 5.7 (0.6) <0,001
[Minimum – Maximum] [3.8 - 5.1] [4.1 - 6.1] - [3.8 - 5.1] [4.8 - 7.1] - [3.8 - 5.5] [4.8 - 6.1] - [3.8 - 5.5] [4.1 - 6.1] -
Within recommended range*, 13 (81.2) 14 (93.3) 0.64 13 (81.2) 13 (86.7) >0.99 12 (80.0) 14 (93.3) 0.60 9 (75.0) 13 (92.9) 0.48
n (%)
PEEP – cmH2O, mean (SD) 8.4 (1.9) 9.4 (1.8) 0.18 9.1 (2.0) 9.5 (1.9) 0.27 8.1 (2.5) 8.9 (2.2) 0.28 8.1 (3.4) 9.0 (2.3) 0.31
Respiratory system static 25.6 (5.3) 24.9 (7.8) 0.99 24.9 (6.4) 26.3 (8.0) 0.46 25.4 (6.4) 26.5 (9.3) 0.95 27.5 (8.9) 29.1 (11.2) 0.80
compliance – ml/ cmH2O, mean
(SD)
Plateau pressure – cmH2O, mean
(SD) 19 (2.2) 24.7 (3.2) <0,001 20.1 (3.2) 24.5 (3.8) 0.002 19.6 (3.5) 23.8 (3.5) 0.005 18.8 (4.9) 22.9 (3.8) 0.04
Respiratory rate – breaths/min,
mean (SD) 33.1 (6.4) 30.4 (5.7) 0.35 35 (6.3) 31.6 (4.2) 0.12 35.1 (8.6) 29.4 (5.1) 0.03 34.3 (4.2) 28.5 (4.7) 0.004
* Recommended range was 4 to 8 mL/kg of predicted body weight among patients in the driving pressure-limited group and 6 to 8 mL/kg PBW among patients in the control
group.

Page 26 of 71
Table 3 – Clinical outcomes

Driving Pressure- Control Group Absolute difference (95%
Outcome P value
Limited Group (n=16) (n=15) CI)
Death in the first 28 days - no. of events / total no. (%) 7 (43.8) 5 (33.3) -10.4 (-50.9; 30.1) 0.72
In-hospital Death - no. of events / total no. (%) 7 (43.8) 8 (53.3) 9.6 (-31.9; 51.1) 0.72
Death in intensive care unit - no. of events / total no. (%) 6 (37.5) 8 (53.3) 15.8 (-25.3; 56.9) 0.48
Barotrauma in the first 7 days - no. of events / total no. (%) 1 (6.2) 0 (0) -6.2 (-24.4; 11.9) >0.99
Severe acidosis in the first hour (pH<7.1) - no. of events/ total no. (%) 2 (12.5) 0 (0) -12.5 (-35.2; 10.2) 0.49
Severe acidosis in the first 7 days (pH<7.1) - no. of events/ total no. (%) 3 (18.8) 1 (6.7) -12.1 (-41.5; 17.3) 0.60
Other serious adverse events - no. of events/ total no. (%) 0 (0) 0 (0) - -
Reintubation in 28 days - no. of events/ total no. (%) 3/11 (27.3) 1/7 (14.3) -13.0 (-61.6; 35.6) >0.99
Length of intensive care unit stay – days, median [IQR] 11.4 [7.8 - 18] 15.3 [7.7 - 29.3] 3.9 (-6.9; 18.7) 0.45
Length of hospital stay – days, median [IQR] 19.3 [10.9 - 29.2] 21.4 [12.3 - 37.2] 2.0 (-10.5; 22.3) 0.55
Days free of mechanical ventilation in 28 days – days, median [IQR] 9.5 [5.2 - 11.5] 11 [6 - 27] 1.5 (-4.5; 18.5) 0.28
CI denotes confidence interval; IQR denotes interquartile range.

Page 27 of 71
Figure 1 - Patient Flow Study
260x209mm (96 x 96 DPI)

Page 28 of 71
Figure 2 - Driving Pressure X Time
162x101mm (300 x 300 DPI)

Page 29 of 71
ONLINE SUPPLEMENT: Driving Pressure-Limited Strategy

for Patients with Acute Respiratory Distress Syndrome
(ARDS): a Pilot Randomized Clinical Trial
Marcelo Luz Pereira Romano, MD,1 Israel Silva Maia, MD,2
Ligia Nasi Laranjeira, RT,1 Lucas Petri Damiani, MSc,1 Denise
de Moraes Paisani, PhD,1 Marcos de Carvalho Borges, MD,
PhD,3 Bruno Guimarães Dantas, MD,3 Eliana Bernadete Caser,
MD, PhD,4 Josué Almeida Vitorino, MD, PhD,5 Wilson de
Oliveira Filho, MD,6 Marcelo Britto Passos Amato, MD, PhD,7
Alexandre Biasi Cavalcanti, MD, PhD.1
Supplement 1: Ethics Committee Approval for the Coordinating

Center (HCor)
Supplement 2: Informed Consent (English version)
Supplement 3: Manual of Operations
Supplement 4: Tables E1, E2, E3 and E4
Supplement 5: Figure E1 and E2

Page 30 of 71
HOSPITAL DO CORAÇÃO/
ASSOCIAÇÃO DO SANATÓRIO
SÍRIO - ASS
PARECER CONSUBSTANCIADO DO CEP
DADOS DO PROJETO DE PESQUISA
Título da Pesquisa: Estudo clínico randomizado piloto avaliando ventilação mecânica com ¿driving
pressure¿ limitada em comparação a estratégia com volume corrente e pressão de
platô limitados em pacientes sem SARA e limitada em comparação a estratégia
convencional (ARDSNet) em pacientes com SARA
Pesquisador: Alexandre Biasi Cavalcanti
Área Temática:
Versão: 6
CAAE: 33167414.3.1001.0060
Instituição Proponente: Hospital do Coração/ Associação do Sanatório Sírio
Patrocinador Principal: Financiamento Próprio
DADOS DO PARECER
Número do Parecer: 1.197.157
Apresentação do Projeto:
Estudo clínico randomizado piloto avaliando ventilação mecânica com “driving pressure” limitada em
comparação a estratégia com volume corrente e pressão de platô limitados em pacientes com e sem SARA.
Objetivo da Pesquisa:
Estudo piloto para avaliar a factibilidade de testar estratégia de ventilação mecânica com “driving pressure”
limitada em comparação a estratégia com volume corrente limitado em 8mL/kg e pressão de platô 30cmH2O
em pacientes com e sem SARA. O desfecho primário para avaliação de factibilidade será a ocorrência de
gradiente de driving pressure nos dias 1 a 3 entre os grupos experimental e controle.
Avaliação dos Riscos e Benefícios:

Benefícios:
É possível que a estratégia da ventilação mecânica com limitação da pressão de distensão possa trazer
benefícios como reduzir o tempo de ventilação mecânica, prevenir lesões pulmonares e
Endereço: Rua Abrão Dib, 50 - Térreo

Bairro: Paraíso CEP: 04.004-030
UF: SP Município: SAO PAULO
Telefone: (11)3886-4688 Fax: (11)3886-4689 E-mail: etica.pesquisa@hcor.com.br
Página 01 de 04

Page 31 of 71
SÍRIO - ASS
Continuação do Parecer: 1.197.157
aumentar a chance de recuperação dos pacientes. Caso o estudo confirme que a estratégia utilizada é
benéfica ao paciente esta intervenção poderá e deverá ser aplicada amplamente nas unidades de terapia
intensiva. Caso este estudo demonstre ausência de benefício, esta resposta também será importante do
ponto de vista de mudança de conduta médica.
Riscos
A ventilação com limitação de pressão de distensão pode, em alguns casos, produzir acúmulo de gás
carbônico no sangue. Este acúmulo é bem tolerado pela maioria dos pacientes e considerado necessário
para evitar pressões ou volumes altos que danificariam mais os pulmões. Entretanto, algumas vezes o
acúmulo pode ser excessivo e trazer problemas adicionais ao paciente como queda da pressão,
desconforto, aumento da frequência cardíaca e arritmias cardíacas. É importante salientar que este estudo
prevê diversas estratégias para prevenir o problema de acúmulo de gás carbônico excessivo, de modo que
o risco de problemas como os mencionados acima deva ser baixo.
Comentários e Considerações sobre a Pesquisa:

A presente emenda apresenta alterações no protocolo, conforme justificativa anexada pelo pesquisador. A
nova versão do projeto foi reavaliada pela Comissão Científica cujo formulário também foi anexado ao
sistema e não apresentou restrições.
Considerações sobre os Termos de apresentação obrigatória:

TCLE adequado de acordo com normas vigentes.
Recomendações:
Sem recomendações.
Conclusões ou Pendências e Lista de Inadequações:
Sem pendências.
Considerações Finais a critério do CEP:
Este parecer foi elaborado baseado nos documentos abaixo relacionados:

Tipo Documento Arquivo Postagem Autor Situação
TCLE / Termos de TCLE_Com_SARA.docx 07/07/2014 Aceito

Página 02 de 04

Page 32 of 71
SÍRIO - ASS
Assentimento / TCLE_Com_SARA.docx 11:46:44 Aceito

Justificativa de
Ausência
TCLE / Termos de TCLE_Sem_SARA.doc 07/07/2014 Aceito
Assentimento / 11:46:53
Justificativa de
Ausência
Projeto Detalhado / Protocolo_Com_SARA.pdf 07/07/2014 Aceito
Brochura 11:59:47
Investigador
Projeto Detalhado / Apendice_A_Com_SARA.pdf 07/07/2014 Aceito
Brochura 11:59:57
Investigador
Projeto Detalhado / Apendice_B_Com_SARA.pdf 07/07/2014 Aceito
Brochura 12:00:06
Investigador
Projeto Detalhado / Apendice_C_Com_SARA.pdf 07/07/2014 Aceito
Brochura 12:00:17
Investigador
Projeto Detalhado / Protocolo_Sem_SARA.pdf 07/07/2014 Aceito
Brochura 12:00:34
Investigador
Projeto Detalhado / Apendice_A_Sem_SARA.pdf 07/07/2014 Aceito
Brochura 12:00:46
Investigador
Projeto Detalhado / Apendice_B_Sem_SARA.pdf 07/07/2014 Aceito
Brochura 12:00:57
Investigador
Folha de Rosto Folha_Rosto_Assinada.pdf 07/07/2014 Aceito
11:49:29
Outros Declaracao_Responsabilidades_Investig 07/07/2014 Aceito
ador.pdf 18:42:48
Outros Avaliacao_Metodologica.pdf 07/07/2014 Aceito
18:45:54
Outros Anuencia.pdf 07/07/2014 Aceito
18:50:02
Informações Básicas PB_INFORMAÇÕES_BÁSICAS_DO_P 07/07/2014 Aceito
do Projeto ROJETO_354010.pdf 18:52:55
Projeto Detalhado / Protocolo_Sem_SARA_2014_0909 09/09/2014 Aceito
Brochura (2).pdf 09:24:19
Investigador
Informações Básicas PB_INFORMAÇÕES_BÁSICAS_392611 09/09/2014 Aceito
do Projeto _E1.pdf 09:46:17

Página 03 de 04

Page 33 of 71
SÍRIO - ASS

Projeto Detalhado / Protocolo_ART_2_pilotov2_revisado.pdf 06/07/2015 Aceito
Brochura 15:57:52
Investigador
Outros ART_2_Piloto_Apendice_A_revisado.pdf 06/07/2015 Aceito
15:58:38
Outros ART_2_Piloto_Apendice_B_revisado.pdf 06/07/2015 Aceito
15:59:46
Outros Justificativa_Emenda_ART_2.pdf 06/07/2015 Aceito
16:00:05
TCLE / Termos de TCLE_Com_SARA_V2.docx 06/07/2015 Aceito
Assentimento / 16:00:51
Justificativa de
Ausência
Outros aval_metod_reavaliação.pdf 06/07/2015 Aceito
16:02:06
Situação do Parecer:
Aprovado
Necessita Apreciação da CONEP:
Não
SAO PAULO, 24 de Agosto de 2015
Assinado por:
Alberto José da Silva Duarte
(Coordenador)

Página 04 de 04

Page 34 of 71
INFORMED CONSENT FORM

Pilot randomized clinical trial evaluating limited driving pressure mechanical
ventilation compared to conventional strategy (ARDSNet) in patients with ARDS
Participant Information
As a legal representative of ________________________, we are requesting your
permission to participate in a study called “Driving Pressure in SARA” because he or she is
admitted to the ICU due to Acute Respiratory Distress Syndrome (ARDS), a disease requiring
artificial respiration through a mechanical respirator (breathing apparatus).
Participation in this study is entirely voluntary. Your relative (patient) does not necessarily
have to be part of it. If you agree to participate, consent may be withdrawn by you or the
patient at any time for any reason, without prejudice to your treatment.
A) Justification, objectives and procedures to be applied

A-1) Rationale: Why is this study being done?
The lungs, which are air-filled organs when healthy, fill with fluid and / or collapse in
patients with ARDS, impairing breathing. ARDS is a serious disease and the use of mechanical
respirators is critical to the life of patients at this stage. Artificial respiration should be
maintained until patients are able to breathe alone again. However, even with the use of
mechanical respirators, the best techniques for fitting these devices, and the best intensive
support treatments available to date, a substantial portion of patients do not survive.
Studies assessing which respirator adjustments may benefit ARDS patients have shown that
the use of small volumes of air during ventilation increases the chances of recovery and
survival. This is the best treatment available to date and is considered the standard
treatment.
More recently, some studies suggest that it would be possible to improve the care of
patients with ARDS by limiting driving pressure rather than limiting air volume. Simply put,
the distension pressure is the pressure generated in the lungs during inspiration. However,
these studies were not specifically designed to prove that limiting distension pressure is
beneficial and the results need to be supported by appropriate studies.
A-2) Objectives: What is the purpose of this study?

The aim of this study is to evaluate whether a mechanical ventilation strategy
controlling the distension pressure can improve the chances of recovery of ARDS patients
compared with the standard strategy (ARDSNet), which focuses on air volume control.
A-3) Procedures that will be performed in the study:

Participation in the survey is voluntary. If the patient is allowed to participate in this
study, he or she will be treated with either the distension pressure limitation technique or
the standard ARDSNet technique that limits air volume. The definition of the treatment
technique is made by randomization, a process equivalent to the draw. As mentioned above,
there is evidence suggesting that control of mechanical ventilation limited distension
pressure may be beneficial, but this is not yet proven and the new technique (limiting

Page 35 of 71
distension pressure) is not yet adopted in clinical practice. Therefore, it is most ethical to
choose treatment by randomization.
If the patient is randomly selected to receive the distension pressure control strategy,
adjustments will be made to the mechanical ventilation device, but there is no need to
change the device or special devices. At an early stage, regardless of the strategy being
treated (pressure limitation or ARDSNet), patients receive sedatives to allow adequate
mechanical ventilation. A few days later, with improvement, the sedative dose is decreased
or suspended, allowing the patient to wake up. When the patient is awake, if mechanical
ventilation is still needed, once a day, the distension pressure adjustment in the mechanical
ventilation device will be performed, requiring rapid action sedative administration (the
effect of which lasts a maximum of 10 minutes).
If the patient is drawn so as not to receive driving pressure-limited mechanical ventilation,
he / she will receive standard treatment (ARDSnet), which is the best treatment available to
date, consisting of volume ventilation. small of air.
The exams the patient will take are the exams they would normally take to care for their
illness. The exception is the blood dosage of inflammation markers. For this will be used
blood sample collected on the day of entry of the patient into the study, and after days 1, 3,
5 and 7. This sample will be collected together with routine examinations, avoiding
additional venipuncture.
After 28 days and 6 months, the study team will contact the patient and / or family by
telephone to inquire about the patient's health.
B) Discomforts, risks and benefits

B-1) What are the possible benefits of the study?
Regardless of the strategy your family member receives, distention pressure or
volume limitation (ARDSNet), they will be assisted with lung protection techniques and
within the best available knowledge today.
It is possible that the strategy of mechanical ventilation with distension pressure limitation
may bring benefits such as reducing the time of mechanical ventilation, preventing lung
injury and increasing the chance of recovery of patients. Given the severity of the disease
and some patients do not survive even with all the treatment available today, the potential
benefit is great. However, there is no guarantee as to which technique, distention pressure
limitation, or volume limitation is superior.
In addition, if the benefit of the controlled mechanical ventilation strategy by limiting the
distension pressure in ARDS patients is proven, it will be contributing to the fact that after
the outcome of the study, many patients like him or her have better results in your
treatment worldwide.
B-2) What are the possible risks and discomforts of the study?
Both volume-limited ventilation (ARDSNet) and distension-pressure-limited
ventilation can in many cases produce carbon dioxide accumulation in the blood. This
accumulation is well tolerated by most patients and is considered necessary to avoid high
pressures or volumes that would further damage the lungs. However, sometimes the
accumulation can be excessive and bring additional problems to the patient such as pressure
drop, discomfort, increased heart rate and cardiac arrhythmias.

Page 36 of 71
It is not yet known which of the ventilation techniques, with volume limitation (ARDSNet) or
distension pressure limitation, produces the greatest carbon dioxide accumulation. It is
possible that for patients with more severe lung disease, the distension pressure limitation
technique produces more carbon dioxide accumulation than the standard technique.
Importantly, this study provides several strategies to minimize the problem of excessive
carbon dioxide accumulation.
C) Follow-up and assistance

Other than the procedures described above, there will be no other research
influences in the form of monitoring and assistance. That is, the patient will receive all the
necessary care to treat their problems.
D) Guarantee of complete freedom to the research participant

And if I don't want to participate in the study, is there another option?
You may freely choose whether or not to consent to the patient's participation in
the study. If not, all care in the ICU and throughout the hospitalization will be offered
according to the institution's routine.
Can I give up participating in the study?
If you decide to voluntarily participate in the study, you may withdraw consent at
any time without causing harm to you. We emphasize that all care in this institution will
continue to be offered. Similarly, when the patient is able to communicate, they may also
withdraw their consent if they do not agree with their participation in the research.
E) Confidentiality and Privacy Guarantee

Will my information and exam results be confidential?
Data will only be used for study purposes and will be kept confidential. Study results
will be disseminated for academic and scientific purposes without identifying any
participating patients.
F) Guarantee that the participant will receive a copy of the Informed

Consent Form
A copy of the Consent Form will be given to you.
G) Reimbursement and Indemnity
Participation in the study involves no cost to you, the patient, or health insurance.
This way there is no refund or any kind of financial reward.

Page 37 of 71
As with any research or health care outside the research, the patient or family member is
assured of claiming damages if there is potential harm from participating in the study.
Information about the Research Ethics Committee and contact:
The CEP (Research Ethics Committee) is a body that aims to protect the welfare of the
individuals surveyed. It is responsible for the evaluation and monitoring of the ethical
aspects of all research involving human beings, aiming to ensure the dignity, rights, safety
and well-being of the research subject. Before starting, this study was evaluated and found
appropriate by the HCor Research Ethics Committee. If you have questions and / or
questions about your rights as a participant in this study, you can contact the Heart Hospital
Zip code at +55 (11) 3886-4688 or email etica.pesquisa@hcor.com.br
Contact details of the researchers responsible for the HCor study:
Marcelo Romano – +55 (11) 98102-0899

Alexandre Biasi Cavalcanti – + 55 (11) 99882-9343
You have all the necessary time to read this Informed Consent and to decide if you want
your family member (patient) to participate in this study. Feel free to discuss with other
family members, friends, or your health care team.
Consent Form
I declare that I have been informed of the above study objectives in a clear and
detailed manner and clarify my doubts. I know that at any time I can request new
information and modify my decision to participate (or my family member to participate) if I
so wish.
I declare that, after being clarified by the researcher and having understood what
has been explained to me, I agree to participate (or I agree that my family member
participates) in this study. Also, I received a copy of this IC and was given the opportunity to
clarify my doubts.
____________________________________________
Participant Name
____________________________________________
Name of Legal Representative
____________________________________________ ____ / ____ / _______

Signature of Legal Representative Date
____________________________________________
Researcher Name
________________________________________ ____ / ____ / _______

Researcher's Signature Date

Page 38 of 71
OPERATION MANUAL
Complete version
ART-2
Pilot
A randomized pilot clinical trial evaluating
mechanical ventilation with limited driving
pressure strategy compared to conventional
(ARDSNet) in patients with ARDS
Version 1 - May 2015

Version 1 – May 2015

Page 39 of 71
If in doubt, contact the coordinating

center:
Dr. Alexandre Biasi Cavalcanti

Principal Investigator
abiasi@hcor.com.br
Tel: +55 (11) 3053-6611 Ramal 8102
Cel: +55 (11) 99882-9343
Dr. Marcelo Romano

Principal Investigator
marcelo.romano@yahoo.com.br
Tel: +55 (11) 3053-6611 Ramal 1033
Cel: +55 (11) 981020899
Ligia Nasi Laranjeira

Site Manager
lnasi@hcor.com.br
Tel: +55 (11) 3053-6611 Ramal 8210
Cel: +55 (11) 96551-4949
Denise de Moraes Paisani

Data Manager
dpaisani@hcor.com.br
Tel: +55 (11) 3053-6611 Ramal 8240
Cel: +55 (11) 96578-9897
Gisele Mota Ribeiro

Regulatory Affairs
gfmribeiro@hcor.com.br
Tel: +55 (11) 3053-6611 Ramal 8222

Page 40 of 71
ART-2 OPERATION MANUAL

Pilot
INDEX – Complete Version

DRIVING PRESSURE ASSESSMENT _______________________________________________________________________
ELIGIBILITY _________________________________________________________________________________________
RANDOMIZATION ____________________________________________________________________________________
PLATEAU PRESSURE ASSESSMENT (DRIVING PRESSURE AND ARDSNET GROUPS) ________________________________
DRIVING PRESSURE STRATEGY - HOW TO CALCULATE PREDICTED BODY WEIGHT ________________________________
DRIVING PRESSURE STRATEGY – TARGET TIDAL VOLUME TITLE OF THE DAY____________________________________
DRIVING PRESSURE STRATEGY - MECHANICAL VENTILATION MEASUREMENT THE TIDAL VOLUME__________________
DRIVING PRESSURE STRATEGY - RESPIRATORY RATE ADJUSTMENT ___________________________________________
DRIVING PRESSURE STRATEGY - PEEP AND FIO2 ADJUSTMENT ________________________________________________
DRIVING PRESSURE STRATEGY - INSPIRATORY FLOW ADJUSTMENT ___________________________________________
DRIVING PRESSURE STRATEGY - REFRACTORY HYPOXEMIA __________________________________________________
ESTRATÉGIA DRIVING PRESSURE – MECHANICAL VENTILATION WEANING_______________________________________
DRIVING PRESSURE STRATEGY - SUPPORT PRESSURE WEANING ________________________________________________
ARDSNET STRATEGY - HOW TO CALCULATE PREDICTED BODY WEIGHT _________________________________________
ARDSNET STRATEGY - MAINTENANCE VENTILATION: INITIAL PARAMETERS ______________________________________
ARDSNET STRATEGY - RESPIRATORY FREQUENCY ADJUSTMENT (STRATEGY FOR: ALKALEMIA AND ACIDEMIA ) _______
ARDSNET STRATEGY - PEEP AND FIO2 ADJUSTMENT ________________________________________________________
ARDSNET STRATEGY – STRATEGY FOR REFRACTORY HYPOXEMIA ______________________________________________
ARDSNET STRATEGY - WEANING ___________________________________________________________________________
SPONTANEOUS BREATHING TEST - WHEN TO PERFORM? ___________________________________________________
SPONTANEOUS BREATHING TEST - HOW TO PERFORM? ________________________________________________________
EXTUBATION _______________________________________________________________________________________
DYSSYNCHRONY _____________________________________________________________________________________
TRACHEAL ASPIRATION, HUMIDIFIER FILTER CHANGE AND TRACH-CARE _______________________________________

INDEX

Page 41 of 71
ART-2
DRIV. PRES. ASSESSMENT

OPERATION MANUAL
Pilot
DRIVING PRESSURE ASSESSMENT
To confirm whether the patient has “driving pressure” (DP) greater than or equal to
13 cmH2O, adjust the following values only for DP measurement:
a) Check if patients is sedated and not breathing

If necessary, use the fast acting sedative; if necessary, use fast acting neuromuscular blocker
b) Mode: Assisted/Volume Controlled

c) Tidal volume: 6mL/kg predicted weight (see section “HOW TO CALCULATE
PREDICTED BODY WEIGHT”)
DRIVING PRESSURE ASSESSMENT

d) Inspirator: Expirator Ratio ( I:E) = 1:1 a 1:2
e) Inspiratory flow 60L/min. Downflow Waveform
Reduce up to 40L/min if peak pressure >45cmH2O
f) Inspiratory pause 0,5 second

Pause can be adjusted if I:E ratio is out of range 1:1 to 1:2
g) Respiratory rate to get the same minute volume

RR=minute volume/new tidal volume
h) PEEP and FiO2 maintained: no adjustment required at this time
Calculate the driving pressure:
Driving Pressure = Plateau Pressure - PEEP
If the driving pressure is greater than or equal to 13cmH2O, the patient is potentially eligible.
Confirm the other eligibility criteria in the section: "Screening"

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Pilot
ELIGIBILITY
Consider daily patients intubated and on mechanical ventilation.
ELIGIBILITY
Consider for trialparticipation ALL patients with inclusion criteria below:
1. INCLUSION CRITERIA (ALL must be present):

a) Acute installation respiratory failure Yes No
b) Bilateral pulmonary infiltrate on chest X-ray, compatible with pulmonary edema Yes No
c) Respiratory failure not fully explained by heart failure or fluid overload.

Yes No
Note: If there is no risk factor for ARDS (shock, gastric aspiration, sepsis, pneumonia, high-risk
surgery (spinal orthopedic, acute abdomen, carDayc, aortic vascular), traumatic brain injury,
smoke inhalation, near drowning, pulmonary contusion, multiple fractures, multiple
transfusions, drug or alcohol abuse) becomes mandatory objective assessment (with
echocardiogram or pulmonary artery catheter) to exclude cardiogenic edema.
d) PaO2 / FiO2 ≤ 300 mmHg with PEEP ≥5cmH2O Yes No
ELIGIBILITY
e) Intubated patients under mechanical ventilation with diagnosis of ARDS for 5 days
or less (from first blood gas analysis with PaO2/ FiO2 ≤ 300 mmHg) Yes No
f) Driving pressure > 13cmH2O with tidal volume of 6 ml/kg predicted weight Yes No
g) Consent of legal representative (Free and Informed Consent Form Yes No
signed and dated)
IF ALL INCLUSION CRITERIA ABOVE ARE FULFILLED, REGISTER PATIENT DATA IN ADMISSION AND
ELIGIBILITY FORMS.
Visit the website: https://servicos.hcor.com.br/IEP/estudoclinico/
2. EXCLUSION CRITERIA
a) Age <18 years Yes No
b) Contraindication to hypercapnia as intracranial hypertension (suspected or proven),
or acute coronary syndrome. Yes No
c) Patient out of therapeutic perspective, candidate for exclusive palliative care . Yes No
(e.g. dying patient with imminent death or cancer patient under exclusive
palliative care)
d) Patient with high output broncho-pleural fistula. Yes No
e) Patients with severe changes in chest wall compliance (e.g.severe kyphoscoliosis,
tetanus, or others at the discretion of the investigator) Yes No
f) Patient previously included (randomized) in any ART study Yes No
The patient will not be eligible for the study if they have any exclusion criteria
If the patient meets all the inclusion criteria and no exclusion criteria, he will be considered as eligible.
In this case, follow the steps in the “RANDOMIZATION” section.

Page 43 of 71

Pilot
RANDOMIZATION
RANDOMIZATION may only be done on internet.
Visit de study website:
https://servicos.hcor.com.br/iep/estudoclinico
RANDOMIZATION
Information about ADMISSION, DATA, CONTACT, and ELIGIBILITY Forms must be entered on the ART
study website to allow patient RANDOMIZATION.
To randomize:
Click on the “RANDOMIZE” button, and then the system will reveal wich group the patient
is allocated:
Driving Pressure OR ARDSNET

strategy strategy
RANDOMIZATION
If the patient is randomized to receive the Driving If the patient is randomized to receive the ARDSNET
pressure strategy, follow the steps in the section: strategy, follow the steps in the section:
DRIVING PRESSURE STRATEGY :TRITATION ARDSNET STRATEGY: MAINTENANCE

THE TARGET TIDAL VOLUME OF THE DAY VENTILATION INITIAL PARAMETERS
After randomization, attach the table corresponding to the group allocated to the patient's mechanical
ventilator. Specify patient tidal volume
Version 1 – MayArticles
ANNALSATS 2015 in Press. Published February 18, 2020 as 10.1513/AnnalsATS.201907-506OC
Page 44 of 71

Pilot
PLATEAU PRESSURE ASSESSMENT

(Driving Pressure and ARDSNet Groups)
PLATEAU PRESSURE ASSESSMENT ( Driving Pressure e ARDSNet Group)

To measure plateau pressure, make sure that the patient is sedated and without
breathing efforts
If necessary, use fast acting sedative; if necessary, use fast acting neuromuscular blocker
DRIVING PRESSURE GROUP ARDSNET GROUP

To measure plateau pressure the To measure plateau pressure the patient
patient must be without respiratory must be without respiratory effort:
effort:
PLATEAU PRESSURE
Day 0 (RANDOMIZATION Day ) Day 0 (RANDOMIZATION day)
ASSESSMENT
Day 1 Day 1
Day 2 Day 2
Day 3 Day 3
Day 4 Daily until day 7
Day 5
Day 6
Day 7
Day 9
Day11
Every 2 days
Day13
Day15
ARDSNET GROUP - On days 4, 5, 6, 7, 9, 11,
13 and 15: Record plateau pressure only if
patient is on ACV and no signs of respiratory
distress

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Pilot
DRIVING PRESSURE STRATEGY– HOW TO CALCULATE

PREDICTED BODY WEIGHT
The tidal volume should always be adjusted in relation to the predicted body weight (NEVER in relation to the actual weight).
Use de formula below
MEN: Predicted height (kg) = 50 +2,3 {[height (cm) x 0,394] – 60}
HOW TO CALCULATE PREDICTED BODY WEIGHT

WOMEN: Predicted height (kg) = 45,5 +2,3 {[ height (cm) x 0,394] – 60}
Alternatively, use the table: HEIGHT / PREDICTED WEIGHT / TIDAL VOLUME below:
MAN
Height(cm) 150 155 160 165 170 175 180 185 190 195 200
Predicted weight (kg) 48 52 57 62 66 71 75 80 84 89 93
Tidal Volume 4mL/Kg
192 210 228 246 264 282 300 319 337 355 373
DP - PREDICTED WEIGHT
predicted weight
Tidal Volume 5mL/Kg
240 262 285 308 330 353 376 398 421 444 466
predicted weight
Tidal Volume 6mL/Kg
288 315 342 369 396 424 451 478 505 532 559
predicted weight
Tidal Volume 7mL/Kg
336 364 399 434 462 497 525 560 588 623 651
predicted weight
Tidal Volume 8mL/Kg
384 416 456 496 528 568 600 640 672 712 744
predicted weight
WOMAN
Height(cm) 140 145 150 155 160 165 170 175 180 185 190
Tidal Volume 4mL/Kg
137 156 174 192 210 228 246 264 282 301 319
predicted weight
Tidal Volume 5mL/Kg
172 194 217 240 262 285 308 330 353 376 398
predicted weight
Tidal Volume 6mL/Kg
206 233 261 288 315 342 369 397 424 451 478
predicted weight
Tidal Volume 7mL/Kg
238 273 301 336 364 399 434 462 497 525 560
predicted weight
Tidal Volume 8mL/Kg
272 312 344 384 416 456 496 528 568 600 640
predicted weight

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Pilot
TRITATION THE “TARGET TITLE VOLUME OF THE DAY”

The “target tidal volume of the day” should be titrated once a day in the morning *
* It may be necessary to recalculate the “target tidal volume of the day” there are significant changes in ventilatory
mechanics.(eg rise in peak and / or plateau pressures suggesting worsening compliance; clinical events such as ventilator
disconnection with worsening pressures / oxygenation)
Instructions for titrating “target tidal volume of the day”
a) Make sure the patient is sedated and without breathing efforts

If necessary, use fast acting sedative; if necessary, use fast acting neuromuscular blocker
TRITATION THE “TARGET TITLE VOLUME OF THE DAY”

b) Mode: Assisted / Volume Controlled
c) Titration the target tidal volume of the day: Adjust tidal volume between 4 and 8
mL / kg of predicted weight until the target driving pressure (10cmH2O) is obtained.
This is the “TARGET TIDAL VOLUME OF THE DAY” and should be maintained until the
next titration.
Plateau Pressure - PEEP = Driving Pressure
(Goal = 10cmH2O)
Note: If there is severe respiratory acidosis: pH <7.15, tidal volumes greater than those calculated to generate driving
pressure of 10 cmH2O may be used (see section “driving pressure strategy - RESPIRATORY FREQUENCY ADJUSTMENT”)
d) Ratio I:E = 1:1 a 1:2
e) Inspiratory flow 60L / min. Downflow Waveform
DP - VOLUME TITLE
Reduce to up to 40L / min if peak pressure is> 45cmH2O
f) Inspiratory pause 0.5 second

The pause can be adjusted if the I: E ratio is outside the range of 1: 1 to 1: 2.
g) Respiratory rate, PEEP and FiO2: same values as before mode and tidal volume
adjustment
After the titration of “target tidal volume of the day”, adjust the other
parameters as the section “Driving Pressure Strategy - Ventilation after Titration
“the target tidal volume of the day”

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Pilot
DRIVING PRESSURE STRATEGY

MECHANICAL VENTILATION AFTER TITRATION THE TIDAL VOLUME
After titration of the “target tidal volume of the day” to obtain driving pressure of 10cmH2O
MECHANICAL VENTILATION AFTER TITRATION THE TIDAL VOLUME

a) Mode: Assist-controlled volume or pressure support
b) PEEP e FiO2 adjusted according to table to maintain SpO2 90-95% and PaO2 60 – 80mmHg
FiO2 30% 40% 40% 50% 50% 60% 70% 70% 70% 80% 90% 90% 90% 100%
PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 18-24
Note: PEEP levels on this scale represent programmed ventilator levels (No total PEEP, auto-PEEP, or intrinsic PEEP levels)
c) Other parameters according to table below
If volume assist-controlled mode If support pressure mode

Tidal “Target tidal volume of the day”* -------
Volume
Initial frequency adjustment to maintain the
Respiratory same minute volume before the study entry. -------
Rate Maximum RR: 35 / min (may reach 50 / min if
pH <7.15 - see section “RR setting”)
Flow 60 L / min in downflow wave (should be reduced if peak
pressure> 45cmH2O);
-------
Inspiratory 0.5 second (reduce or withdraw pause if I: E ratio
Break reversal);
-------
Ratio I:E 1:1 to 1:2 -------
Support Adjusted to maintain “target tidal
pressure ------- volume of the day” *
Note: No plateau pressure limit target
*Situations where driving pressure may be less than 10 cmH2O

• Patients with a tidal volume of 8mL / kg and maintaining driving pressure <10 cmH2O. In these cases, do not
increase tidal volume beyond 8mL / kg
TITRATION THE TIDAL
VENTILATION AFTER
DP - MECHANICAL
• Assisted volume-controlled patients whose tidal volume generates driving pressure less than 10cmH2O and who
VOLUME
are quite comfortable from a metabolic and respiratory standpoint (respiratory rate
E
≤20bpm, pH> 7.30 and PaCO2 <50mmHg), that current volume as “TARGET TIDAL VOLUME OF THE DAY”.
• Patients supporting pressure whose tidal volume generates driving pressure less than 10 cmH2O and who are
quite comfortable from a metabolic and respiratory standpoint (support pressure ≤15cmH2O; respiratory rate ≤
25; pH ≥ 7.30; no signs discomfort) consider thatvolume as “TARGET TIDAL VOLUME OF THE DAY”.
Version 1 - May
Version 1 –2015
May 2015

Page 48 of 71

Pilot

RESPIRATORY RATE ADJUSTMENT
Adjust respiratory rate to achieve arterial pH target
GOAL: arterial pH between 7.30 and 7.45
(Measure arterial pH when clinically indicated)
STRATEGY FOR ALKALEMIA (pH> 7.45):

Reduce respiratory rate (RR) if possible
STRATEGY LIGHT ACIDEMIA (7.15 ≤ p H <7.30):
If PaCO2≤40mmHg If PaCO2>40mmHg
RESPIRATORY RATE ADJUSTMENT

Reduce dead space (remove “windpipe”, replace
Consider bicarbonate and address HME with active external humidifier); avoid
cause of metabolic acidosis (e.g. temperature ≥37 ° C (anti-thermal time and physical
acute renal failure requiring dialysis) measures if necessary); consider lipid-rich diet and
reduce intravenous or enteral carbohydrates.
Consider adequate sedation and use neuromuscular
blocker.
Progressively increase RR to a maximum of 35 aiming
at pH> 7.30 or PaCO2 ≤40mmHg (whichever occurs
earlier). Address metabolic acidosis if associated.
If RR = 35 and pH remain between 7.15 and 7.30, do

not perform additional measurements.
STRATEGY FOR IMPORTANT ACIDEMIA (pH <7.15):
Reduce dead space (remove “windpipe”, replace HME with

Consider bicarbonate and address cause of active external humidifier); avoid temperature ≥37 ° C (anti-
metabolic acidosis (e.g. acute renal failure thermal time and physical measures if necessary); consider
requiring dialysis) lipid-rich diet and reduce intravenous or enteral carbohydrates.
Consider adequate sedation and use neuromuscular blocker.
Increase RR to maximum of 50 bpm or maximum tolerated.
Watch for signs of self PEEP * Address metabolic acidosis if
* Auto-PEEP: associated
Measure if there are auto-PEEP signals on
the flow curve or if plateau pressure rises If pH remains <7.15
If self-PEEP> 3cmH2O and patient under If RR = 50, increase the tidal volume by 1 mL / kg predicted
controlled ventilation, consider reducing weight, respecting the maximum value of 8 mL / kg predicted
frequency. weight. The driving pressure target (10cmH2O) may only be
RATE ADJUSTMENT
DP – RESPIRATORY
exceeded in this situation.
If pH remains <7.15
At medical discretion: consider use of extracorporeal

Version 1 – May 2015 membrane circuit
ANNALSATS Articles in Press. Published February 18, 2020 as for refractory severe respiratory acidosis
10.1513/AnnalsATS.201907-506OC
(Novalung)
Page 49 of 71
ART-2
DP – RESPIRATORY
PEEP AND FIO2
OPERATION MANUAL
ADJUSTMENT
Pilot

PEEP AND FiO2 ADJUSTMENT
Adjust PEEP and FiO2 to achieve target oxygenation range
PaO2: 60 - 80mmHg
Oxygenation target range: or
SpO2: 90 - 95%
Make changes in PEEP and FiO2 following the combinations established in the table:
FiO2 30% 40% 40% 50% 50% 60% 70% 70% 70% 80% 90% 90% 90% 100%
PEEP AND FiO2 ADJUSTMENT

PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 18-24
CONSIDERATIONS
When there are simultaneous measurements of PaO2 and SpO2, consider PaO2
Evaluate SpO2 or PaO2 oxygenation at least every 4 hours
When using SpO2 to assess arterial oxygenation, take the following measures to ensure accuracy:
Make sure that the SpO2 sensor is well positioned, clean, providing consistent and well-shaped
waveform measurements.
Changes in position or tracheal aspiration must have not been made within the last 10 minutes
Invasive procedures or ventilator changes should not have been performed in the last 30 minutes
Observe SpO2 values for at least one minute
Brief periods (5 minutes) of SpO2 <90% or> 95% can be tolerated without making changes.
100% FiO2 can be used for short periods (10 minutes) under the following conditions:
Transient SpO2 Falls
To prevent SpO2 from falling during procedures (e.g. tracheal aspiration or position changes)
If the PEEP and FiO2 No match is compatible with the table (e.g. after urgent FiO2 or PEEP changes),
readjust at 5-15 minute intervals until matching
If arterial oxygenation is outside the target range and FiO2 = 100%, gradually raise PEEP from 2 by 2
cmH2O to a maximum of 24 cmH2O
Attention! If SpO2> 95%, reduce PEEP and FiO2 according to table

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Pilot
DRIVING PRESSURE STRATEGY – INSPIRATORY FLOW ADJUSTMENT AND RELATION I: E

DRIVING PRESSURE STRATEGY – INSPIRATORY FLOW
ADJUSTMENT AND RELATION I: E
DP- FLOW ADJ. AND

RELATION I: E
60L / min inspiratory flow
Downflow Waveform
Reduce up to 40L / min if peak pressure is> 45cmH2O
Maintain I: E ratio from 1: 1 to 1: 2
0.5 second inspiratory pause.
The pause can be adjusted ,and even withdrawn ,if the I: E ratio is outside the 1: 1
to 1: 2 range.

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Pilot
DRIVING PRESSURE STRATEGY – REFRACTORY HYPOXEMIA
Definition of refractory hypoxemia: PaO2 <55mmHg or SpO2 <88% with FiO2 =100%
If the patient develops refractory hypoxemia, perform the following

sequence of interventions:
DRIVING PRESSURE STRATEGY – REFRACTORY HYPOXEMIA
DP – REFRACTORY
HYPOXEMIA
1) Prone Position
2) Alveolar Recruitment (as per ART study)
If not successful
3) Nitric oxide - start at 5 ppm (perform progressive increases

of 5 ppm until improvement)
If unsuccessful
or nitric oxide not
available
5) ECMO (extracorporeal membrane oxygenation)

to a to a
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Pilot
DRIVING PRESSURE STRATEGY - WEANING
PEEP AND FiO2 WEANING
Perform PEEP and FiO2 reductions as per combination table:
FiO2 30% 40% 40% 50% 50% 60% 70% 70% 70% 80% 90% 90% 90% 100%
PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 18-24
ARDSNET table of FiO2 and PEEP combinations to maintain SpO2 between 90-95% or PaO2 between 60- 80mmHg
SUPPORT PRESSURE VENTILATION

Initiate in patients alert when PEEP is ≤ 14 cmH 2O or at the discretion of the care team
STRATEGY - WEANING
DRIVING PRESSURE
Support Pressure Adjustment:
DP –WEANING
The support pressure level adjustment is adequate to achieve “target tidal
volume of the day” with a tolerance of +/- 1ml / kg predicted weight.
The minimum support pressure is 0 cmH2O, i.e. CPAP
Frequently check tidal volume and adjust support pressure “target tidal volume
of the day”
If tidal volume is> target tidal Reduce support

volume of the day pressure
If even reducing the support pressure to low values, the patient continues to
make tidal volume greater than “target tidal volume of the day”, proceed as
follows:
1. Try to ward off other factors like pain, anxiety and

delirium. Note: If there is a plan to
perform spontaneous
If unsuccessful
breathing and extubation
2. Try raising PEEP to 10 cmH2O or 12 cmH2O testing within the next 24
hours, the patient may be
If unsuccessful
kept at the lowest
3.Consider mild sedation (e.g. dexmedetomidine), possible support pressure
use of neuroleptics (haloperidol, quetiapine, until the time of
olanzapine or risperidone) and avoid opioids extubation.
.
If unsuccessful
4. Consider sedating the patient and returning to volume
controlled mode.
Daily assess the possibility of performing spontaneous ventilation testing on weaning patients (see section
“SPONTANEAN VENTILATION TEST - WHEN TO PERFORM?”)
Version 1 – May 2015 Copyright © 2020 by the American Thoracic Society
to a to a
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Pilot

SUPPORT PRESSURE WEANING
Reduce support pressure from 2 to 4 cmH2O at a time, provided RR <30
breaths / min (and No other signs of discomfort), even if tidal volume is
lower than target
DRIVING PRESSURE STRATEGY - SUPPORT PRESSURE WEANING

Driving pressure less than 10 cmH2O can be used at this stage.
Reduce PS whenever tidal volume> target tidal volume of the day
TARGETS DURING SUPPORT PRESSURE:

Support pressure ≤10cmH2O
Tidal volume ≤ “target tidal volume of the day”
RR ≤ 35
pH ≥ 7.30
No signs of respiratory distress
PRESSURE WASTE
DP –- SUPPORT
Atelectasis or stoppers: It may be necessary to increase the support
pressure to maintain the target tidal volume of the day. It should not
exceed 15cmH2O.
In these cases, search for deterioration of respiratory mechanics
In patients with signs of discomfort (e.g. respiratory rate ≥ 30 breaths / min), consider other
causes (e.g. pain or anxiety) before increasing Support Pressure.
NOTE
The support pressure not must be increased beyond the set level (which guarantees tidal
volume sufficient current for driving pressure of 10 cmH2O)
If necessary, return for assisted-controlled ventilation (volume-controlled).
Daily assess the possibility of spontaneous ventilation testing on weaning patients

(see section “SPONTANEAN VENTILATION TEST - WHEN TO PERFORM?”)
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Pilot
ARDSNET STRATEGY
– HOW TO CALCULATE PREDICTED BODY WEIGHT
ARDSNET STRATEGY-– HOW TO CALCULATE PREDICTED BODY

The tidal volume should always be adjusted in relation to the predicted body weight (NEVER in relation to the actual weight).
Use the formula below:

MEN: Predicted weight (kg) = 50 +2.3 {[height (cm) x 0.394] - 60}
WOMEN: Predicted weight (kg) = 45.5 +2.3 {[height (cm) x 0.394] - 60}
Alternatively, use the table: HEIGHT / PREDICTED WEIGHT / TIDAL VOLUME

below:
WEIGHT
Men
Height (cm) 150 155 160 165 170 175 180 185 190 195 200
Tidal volume 4mL / kg
192 210 228 246 264 282 300 319 337 355 373
predicted weight
240 262 285 308 330 353 376 398 421 444 466
predicted weight
Initial tidal volume
6mL / kg weight 288 315 342 369 396 424 451 478 505 532
559
ARDSNET CALCULATE
predicted
PREDICTED BODY
Women
Height (cm) 140 145 150 155 160 165 170 175 180 185 190
137 156 174 192 210 228 246 264 282 301 319
predicted weight
172 194 217 240 262 285 308 330 353 376 398
predicted weight
Initial tidal volume
6mL / kg weight 206 233 261 288 315 342 369 397 424 451 478
predicted
Attention! If plateau pressure> 30cmH2O, reduce tidal volume

to a to a
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Pilot
ARDSNET STRATEGY
MAINTENANCE VENTILATION - INITIAL PARAMETERS
ARDSNET STRATEGY-MAINTENANCE VENTILATION - INITIAL PARAMETERS

- VENTILAÇÃO DE MANUTENÇÃO – PARÂMETROS INICIAIS
For patients in the ARDSNET group, start maintenance ventilation immediately
after randomization. Start with the following parameters:
a) Mode: Assisted / Volume Controlled
b) Plateau pressure ≤ 30 cmH2O
c) Tidal volume: 6mL / kg predicted weight (See “HOW TO CALCULATE PREDICTED BODY WEIGHT”)
If plateau> 30cmH2O, reduce to 5mL / kg predicted weight. If plateau> 30cmH2O,

reduce to 4mL / kg predicted weight.
Minimum and maximum values are 4mL / kg and 6mL / kg predicted body weight.
d) Ratio I: E = 1: 1 to 1: 2
e) Inspiratory flow 60 L / min. Downflow Waveform

Reduce to up to 40L / min if peak pressure is> 45cmH2O
f) Inspiratory pause 0.5 second

The pause can be adjusted if the I: E ratio is outside the range of 1: 1 to 1: 2.
g) Respiratory rate: initial rate adjustment to maintain the same minute volume
before study entry, if possible
Respiratory rate = minute volume / new tidal volume
Maximum respiratory rate will be 35 / min
h) PEEP and FiO2 adjusted according to the table below to maintain SpO2 90-95% or PaO2
60-80mmHg:
Attention! If SpO2 is> 95%, it is mandatory to reduce PEEP and FiO2 according to table
ARDSNET-MAINTENANCE
VENTILATION
FiO2 30% 40% 40% 50% 50% 60% 70% 70% 70% 80% 90% 90% 90% 100%
PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 18-24

to a to a
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ARDSNET STRATEGY - RESPIRATORY RATE ADJUSTMENT(STRATEGIES FOR ALKALEMIA / ACIDEMIA)

Pilot
ARDSNET STRATEGY - RESPIRATORY RATE ADJUSTMENT

(STRATEGIES FOR ALKALEMIA / ACIDEMIA)
Adjust respiratory rate to get arterial pH target
GOAL: arterial pH between 7.30 and 7.45
(Measure arterial pH when clinically indicated)
STRATEGIES FOR ALKALEMIA (pH> 7.45):

Reduce respiratory rate (RR) if possible
STRATEGIES FOR LIGHT ACIDEMIA (7.15 ≤ p H <7.30):
Consider bicarbonate and address cause of Body temperature control (≤37 ° C). Progressively increase RR to
metabolic acidosis (e.g. acute renal failure maximum 35 targeting pH> 7.30 or PaCO2 ≤40mmHg (whichever
requiring dialysis) occurs earlier). Address metabolic acidosis if associated
If RR = 35 and pH remain between 7.15 and 7.30, Do not perform

additional measurements.
STRATEGIES FOR IMPORTANT ACIDEMIA (pH <7.15):
ARD
Consider bicarbonate and address cause of Body temperature control (≤37 ° C). Increase RR SN
metabolic acidosis (e.g. acute renal failure to 35. Address metabolic acidosis if associated ET
requiring dialysis) –
If pH remains <7.15 AJUS
If RR = 35 and pH <7.15, increase tidal volume by 1mL / kg, T
E
reaching up to 6mL / kg predicted weight. D
E
Plateau pressure may be> 30cmH2O only in this situation FR
If pH remains <7.15
If RR = 35, pH <7.15 and PaCO2 continues> 40mmHg,
adopt tidal volume of 7mL / kg predicted weight.
Tidal volume may be exceeded only under this condition.
If pH remains <7.15
If RR = 35, pH <7.15 and PaCO2 continues> 40mmHg adopt tidal

RATE ADJUSTMENT
ARDSNET - RESPIRATORY
volume of 8mL / kg predicted weight. This is the maximum tidal

volume allowed only in this condition.
If pH remains <7.15
If RR = 35, pH <7.15 and PaCO2 continues> 40mmHg exchange

passive humidifier / heater for active. At the discretion of the medical
staff: nitric oxide (if available) or ECMO (if available)
to a to a
Page 57 of 71
ART-2
ARDSNET – PEEP and FiO2

OPERATION MANUAL
ADJUSTMENTS
Pilot
ARDSNET STRATEGY - PEEP and FiO2 ADJUSTMENTS

Adjust PEEP and FiO2 to achieve target oxygenation range
PaO2: 60 - 80mmHg
ou
Oxygenation target range:
SpO2 : 90 –95%
Make changes in PEEP and FiO2 following the combinations established in the table:
ADJUSTMENTS
ARDSNET STRATEGY - PEEP and FiO2
FiO2 30% 40% 40% 50% 50% 60% 70% 70% 70% 80% 90% 90% 90% 100%
PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 18-24
CONSIDERATIONS
Attention! If SpO2 is> 95, it is mandatory to reduce PEEP and FiO2 according to table.
When there are simultaneous measurements of PaO2 and SpO2, consider PaO2
Evaluate SpO2 or PaO2 oxygenation at least every 4 hours
When using SpO2 to assess arterial oxygenation, take the following measures to ensure accuracy:
Make sure that the SpO2 sensor is well positioned, clean, providing consistent and well-shaped
waveform measurements.
Changes in position or tracheal aspiration must have not been made within the last 10 minutes
Invasive Procedures or ventilator Changes Should Not Have Been Performed in the Last 30 Minutes
Observe SpO2 values for at least one minute
Brief periods (5 minutes) of SpO2 <90% or> 95% can be tolerated without making changes.
100% FiO2 can be used for short periods (10 minutes) under the following conditions:
Transient SpO2 Falls
To prevent SpO2 from falling during procedures (e.g. tracheal aspiration or position changes)
If the PEEP and FiO2 match is not compatible with the table (e.g. after urgent FiO2 or PEEP changes),
readjust at 5-15 minute intervals until matching is achieved
If arterial oxygenation is outside the target range and plateau pressure ≥30cmH2O, then only FiO2 should
be increased until PaO2 60-80mmHg or SpO2 90-95% is obtained.
If arterial oxygenation is outside the target range and FiO2 = 100%, gradually raise PEEP from 2 by 2cmH2O to a
maximum of 24cmH2O. Under these circumstances the plateau pressure may exceed 30cmH2O
Attention: If SpO2> 95%, reduce Copyright
Version1 –May 2015
Versão 3 – Maio 2015 PEEP and©FiO2
2020according to table
by the American Thoracic Society
Page 58 of 71

Pilot
ARDSNET STRATEGY
STRATEGIES FOR REFRACTORY HYPOXEMIA
ARDSNET – CONDUCT
HYPOXEMIA
FOR REFRACTORY
Definition of refractory hypoxemia: PaO2 <55mmHg or SpO2 <88%
HYPOXEMIA
ARDSNET STRATEGY-STRATEGIES FOR REFRACTORY
with FiO2 = 100%
If the patient develops refractory hypoxemia, perform the following

sequence of interventions:
1) Raise PEEP up to 24cmH2O and keep FiO2 = 100%

(according to ARDSNET table)
If unsuccessful
2) Prone position
If unsuccessful
3) Alveolar recruitment maneuver (as

maneuver of the ART study)
If unsuccessful
4) Nitric Oxide - start at 5 ppm

(perform 5 ppm progressive increases until oxygenation
improves)
If nitric oxide not
available or unsuccessful
after 60 minutes
5) ECMO (extracorporeal membrane oxygenation)
ANNALSATS
Version 1 – May 2015 Articles in Press. Published February 18, 2020 as 10.1513/AnnalsATS.201907-506OC
Page 59 of 71
ART-2
Pilot OPERATION MANUAL
ARDSNET STARTEGY - WEANING
PEEP AND FiO2 WEANING
Perform PEEP and FiO2 reductions according to the combination table
FiO2 30% 40% 40% 50% 50% 60% 70% 70% 70% 80% 90% 90% 90% 100%
ARDSNET - WEANING
PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 18-24
ARDSNET table of FiO2 and PEEP combinations to maintain SpO2 between 90-95% or PaO2 between 60- 80mmHg
ARDSNET STARTEGY - WEANING

SUPPORT PRESSURE VENTILATION
Initiate in alert patients when PEEP is ≤ 14 cmH2O and at the discretion of the medical team
Start at 10 cmH2O of Support Pressure. Adjust to achieve tidal volume around 6mL / kg
predicted weight.
Reduce Support Pressure 2 to 4 cmH2O twice daily

As long as respiratory rate <28 breaths / min and No other signs of discomfort
OBSERVATIONS
In patients with signs of discomfort (e.g. respiratory rate ≥30 breaths / min),
consider other causes (e.g. pain or anxiety) before increasing Support Pressure.
If necessary suport pressure above 14 cmH2O, return to assisted ventilation (volume
controlled).
Daily assess the possibility of spontaneous ventilation testing in weaning patients (see section “SPONTANEAN
VENTILATION TEST - WHEN TO PERFORM?”)

Version
Version 1 -1May
– May
20152015 Copyright © 2020 by the American Thoracic Society
Page 60 of 71

Pilot
SPONTANEOUS BREATHING TEST - WHEN TO PERFORM?
WHEN DOING A SPONTANEAL BREATH TEST?
Consider the following criteria as decision-making aid

It is not necessary to meet all criteria to perform spontaneous breathing test
Some patients who do not meet all criteria may be tested and successfully extubated.
CRITERIA FOR PERFORMING SPONTANEAL BREATHING TEST
Acute process improvement (ARDS and associated conditions) that motivated

intubation and mechanical ventilation
CLINICAL EVALUATION
Alert and cooperative patient

Controlled chest pain
TO PERFORM?
SBT – WHEN
Adequate cough (moderate to high strength)
Absence of excessive tracheobronchial secretion
Absence of signs of respiratory distress:
Nose Wings
Use of accessory respiratory muscles (suprasternal and / or intercostal retraction)
Paradoxical movements of the ribcage / abdomen
Respiratory stability: oxygenation
PEEP ≤ 10 cmH2O
Support pressure ≤ 10 cmH2O
PaO2/FiO2 ≥ 150 mmHg
SpO2> 90% under FiO2≤ 40%
OBJECTIVE MEASURES
Respiratory stability:
Respiratory ratefunction
≤ 35 breaths / min
Minute volume <10 L / min
Respiratory rate / tidal volume (L) <105 breaths / min / L
Absence of significant respiratory acidosis (pH≥7.25)
Cardiovascular stability:
Heart rate <140 bpm
Systolic blood pressure> 90 and <160 mmHg
Low doses or without vasoconstrictor / inotropic drugs
Neurological Stability:
Ideally alert and cooperative patient
If the team deems the patient fit to perform the spontaneous ventilation test, see parameters for
performing the test Articles
ANNALSATS in the section
in Press.“SPONTANEOUS
Published FebruaryBREATHING TEST (SBT) - HOW TO
18, 2020 as 10.1513/AnnalsATS.201907-506OC
PERFORM?”
Version 1 - May 2015 Copyright © 2020 by the American Thoracic Society
Page 61 of 71

Pilot
SPONTANEOUS BREATH TEST - HOW TO DO IT?

The ability to discontinue mechanical ventilation should be formally assessed by spontaneous
breathing testing rather than during regular ventilatory support.
ADJUSTMENTS FOR SPONTANEOUS BREATHING TEST
ESPONTÂNEA (TRE) - COMO REALIZAR?

Mode: Pressure Pressure Support: PEEP: FiO2: keep what you
SPONTANEOUS BREATH TEST - HOW TO DO IT?

Support 5 cmH2O 5 cmH2O were before
Keep for 30 minutes
FAILURE CRITERIA ON THE SPONTANEAL BREATHING TEST
Agitation, excessive anxiety or falling level of consciousness

CLINICAL EVALUATION
Important sweating
Cyanosis
Signs of respiratory distress:
SBT- HOW TO DO IT?

Nose Wings
Use of accessory respiratory muscles (suprasternal and / or intercostal retraction)
Paradoxical movements of the ribcage / abdomen
Respiratory instability: oxygenation

SpO2<90%
Respiratory instability: function
OBJECTIVE MEASURES
Breathing rate> 35 breaths / min or increase> 10 breaths / min/L

Breathing rate / tidal volume (L)> 105 breaths / min / L
If arterial blood gas analysis is performed:
pH < 7,25
PaCO2> 50mmHg or increase> 8mmHg
Instabilidade cardiovascular:
Cardiovascular instability
 Frequência cardíaca > 140 bpm
Heart rate> 140bpm
 Pressão
Systolic blood pressure
arterial <90 <or>
sistólica 90160
oummHg
> 160 mmHg
 Onset of arrhythmias (e.g. frequent ventricular extra systoles)
Início de arritmias (p.ex. extra-sístoles ventriculares freqüentes)
If there are signs of failure during the test:

Immediately discontinue it and return mechanical ventilation parameters that were before the test and
maintain until the following morning (for rest)
Seek and treat factors that reduce weaning success (e.g. anxiety, delirium, bronchospasm,
hypophosphatemia / hypokalemia / hypomagnesemia, bloating)
If there are no signs of failure during the test, perform extubation. See recommendations in the section “EXTUBATION”.
Page 62 of 71

Pilot
EXTUBATION
Patients who pass the spontaneous breathing test may be extubated.
EXTUBATION
Pre-extubation airway permeability test (“Cuff leak test”) is optional..
Consider using systemic steroids in long-term intubated patients to prevent upper airway
obstruction after extubation.
EXTUBATION
POST-EXTUBATION INVASIVE VENTILATION
Consider noninvasive ventilation immediately after extubation for all patients.
Strongly recommended for patients at high risk of extubation failure such as:
Patients who did not meet all criteria for spontaneous ventilation test pre-extubation
(e.g. respiratory rate / tidal volume (L) ≥ 105 breaths / min / L)
Patients who failed the spontaneous ventilation test at least once.
EXTUBATION

Page 63 of 71

Pilot
DYSSYNCHRONY WITH MECHANICAL VENTILATION

If airway pressure drops below PEEP during inspiration or the ventilator often double-
breaths (> 3 / minute) due to pressure drop (or flow) below the expiration trigger level:
Consider increased respiratory rate. Check if respiratory rate is adjusted to ensure

adequate minute volume. Try to get the same volume minute before tidal volume
reduction (RR = minute volume / new tidal volume).
Consider increased inspiratory flow to 60 L / min (provided peak pressure No exceeds 45

cmH2O)
DYSSYNCHRONY WITH MECHANICAL VENTILATION

If patient is in support pressure mode, consider increasing support pressure (provided
it does not exceed 15 cmH2O)
Consider treating pain or anxiety
Consider increasing sedation level
Consider adding neuromuscular block
DYSSYNCHRONY

Version 1 - May 2015
Page 64 of 71

Pilot
TRACHEAL ASPIRATION, HUMIDIFIER FILTER CHANGE AND TRACH-CARE
Tracheal aspiration is suggested to be performed with a closed system (Trach-Care).
Change humidifier filter and Trach-Care only when there is visible dirt
TRACHEAL ASPIRATION, HUMIDIFIER FILTER CHANGE AND TRACH-CARE

Use plain-stemmed forceps and lock to occlude the endotracheal tube while changing
(e.g., strong forceps or plain Reynold forceps, with locking, protected rods)
Make the team exchange and in the shortest time possible
CHANGE AND TRACH-

ASPIRATION, FILTER
TRACHEAL
CARE
Version
Version 11- May
– May 2015
2015
Page 65 of 71

Page 66 of 71
Table E1. Respiratory and ventilatory variables during the first three days.
Hour 1 Day 1 Day 2 Day 3

Driving Pressure Driving Driving Driving ARDSNet
Variable Limited
ARDSNet P value ARDSNet P value ARDSNet P value¹ P value
Pressure Pressure Pressure
Limited Limited Limited
(N=16) (N=15) (N=16) (N=15) (N=14) (N=15) (N=14)
(N=12)
Tidal volume – mL/kg of
predicted body weight 4.3 ± 0.5 5.6 ± 0.6 <0,001 4.3 ± 0.5 5.8 ± 0.5 <0,001 4.5 ± 0.5 5.7 ± 0.4 <0,001 4.5 ± 0.6 5.7 ± 0.6 <0,001
PEEP – cmH2O 8.4 ± 1.9 9.4 ± 1.8 0.18 9.1 ± 2 9.5 ± 1.9 0.27 8.1 ± 2.5 8.9 ± 2.2 0.28 8.1 ± 3.4 9 ± 2.3 0.31
Plateau pressure – cmH2O 19 ± 2.2 24.7 ± 3.2 <0,001 20.1 ± 3.2 24.5 ± 3.8 0.002 19.6 ± 3.5 23.8 ± 3.5 0.005 18.8 ± 4.9 22.9 ± 3.8 0.04
Plateau pressure > 30 cmH2O
– no./total no. (%) 0 (0%) 0 (0%) >0,99 0 (0%) 1 (6.7%) 0.48 0 (0%) 0 (0%) >0,99 0 (0%) 0 (0%) >0,99
Respiratory rate – breaths/min 33.1 ± 6.4 30.4 ± 5.7 0.35 35 ± 6.3 31.6 ± 4.2 0.12 35.1 ± 8.6 29.4 ± 5.1 0.03 34.3 ± 4.2 28.5 ± 4.7 0.004
FiO2 (%) 47.8 ± 11.4 54 ± 12.4 0.15 51.6 ± 20 52 ± 10.8 0.33 45.3 ± 13 50 ± 12.5 0.24 45.8 ± 19.3 47.1 ± 11.4 0.42
106.7 ± 102.8 ±
PaO2 89.1 ± 23.2 115.5 ± 34.9 0.04 32.2 137.7 ± 32.9 0.02 109.1 ± 38.5 29.7 0.82 97.3 ± 42.8 98.3 ± 24.1 0.50
224.3 ± 215.6 ± 233.4 ± 219.5 ±
PaO2 : FiO2 192.4 ± 52.3 221.5 ± 70.7 0.31 76.1 272.4 ± 73.8 0.07 253.2 ± 96.5 70.6 0.25 97.5 72.8 0.66
PaCO2 – mmHg 59.5 ± 15.8 49.1 ± 15.5 0.04 59.8 ± 11.6 49.8 ± 14.5 0.03 60.3 ± 19.2 51.9 ± 11.3 0.25 59.5 ± 24.3 51.6 ± 16.3 0.64
Arterial pH 7.27 ± 0.2 7.34 ± 0.1 0.42 7.27 ± 0.18 7.39 ± 0.09 0.04 7.33 ± 0.09 7.34 ± 0.12 0.59 7.35 ± 0.14 7.4 ± 0.11 0.41
Respiratory system static
compliance – ml/ cmH2O 25.6 ± 5.3 24.9 ± 7.8 0.99 24.9 ± 6.4 26.3 ± 8 0.46 25.4 ± 6.4 26.5 ± 9.3 0.95 27.5 ± 8.9 29.1 ± 11.2 0.80
Minute ventilation - liters/min 8.7± 1.9 10.8 ± 2.4 0.02 9.1 ± 1.5 11.5 ± 1.8 0.002 9.7 ± 2.0 10.6 ± 2.0 0.506 10.4 ± 2.2 9.4 ± 1.2
Other ventilatory variables
Volume-controlled mode -
16 (100%) 15 (100%) >0.99 16 (100%) 15 (100%) >0.99 14(93,3%) 15(100%) >0,99 12 (100%) 14 (100%) >0,99
no./total no. (%)
Pressure support mode-
0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (6,7%) 0 (0%) 0 (%) 0 (0%)
no./total no. (%)
Other ventilation mode -
0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (%) 0 (0%)
no./total no. (%)
Absence of ventilatory effort
during plateau pressure
16 (100%) 15 (100%) >0.99 16 (100%) 15 (100%) >0.99 14 (93,3%) 14(93,3%) >0.99 12 (100%) 14 (100%) >0,99
measurement - no./total no.
(%)

Page 67 of 71
Table E2. Respiratory and ventilatory variables after fourth days of treatment.
Day 4 Day 5 Day 6 Day 7

Driving Driving Driving Driving
P P P
Variable Pressure ARDSNet Pressure ARDSNet Pressure ARDSNet Pressure ARDSNet P value
value value value¹
Limited Limited Limited Limited
(N=12) (N=13) (N=12) (N=12) (N=10) (N=11) (N=9) (N=10)
Tidal volume – mL/kg of predicted body
weight 4.8 ± 0.9 5.7 ± 0.6 0.03 5.2 ± 1 5.8 ± 0.6 0.23 5.5 ± 1.4 5.7 ± 0.7 0.46 5.3 ± 1.2 5.6 ± 0.5 0.84
PEEP – cmH2O 7.6 ± 3.3 8.6 ± 2 0.15 8.3 ± 3.2 7.9 ± 2.2 >0,99 7.4 ± 2.2 8.5 ± 1.5 0.30 9.1 ± 3 8.1 ± 1.4 0.31
Plateau pressure – cmH2O 18.7 ± 4.8 22.7 ± 5.6 0.05 19.3 ± 5.9 23.3 ± 5.6 0.14 19 ± 5.2 24.7 ± 4.3 0.02 19.4 ± 7.4 24.6 ± 4.4 0.07
Plateau pressure > 30 cmH2O – no./total
no. (%) 0 1 0.48 0 1 0.45 0 1 >0,99 1 0 0.46
Respiratory rate – breaths/min 32.2 ± 8.6 28.9 ± 4.5 0.33 31.3 ± 9.7 27.1 ± 6.2 0.27 31.2 ± 10.1 27.4 ± 7.5 0.50 27.7 ± 9.5 28.8 ± 5.1 0.62
FiO2 (%) 46.7 ± 22.3 46.9 ± 14.4 0.58 51.2 ± 24.9 46.7 ± 15 > 0,99 45 ± 14.3 43.6 ± 9.2 >0,99 46.7 ± 15.8 44 ± 10.7 0.82
86.4 ±
PaO2 86.3 ± 20.7 100.8 ± 38.9 0.50 90.7 ± 22.9 106.1 ± 40.7 0.40 94.9 ± 23.6 99.3 ± 41.8 0.75 110.4 ± 36.8 18.6 0.28
208.5 ± 207.2 ±
PaO2 : FiO2 68.2 223.7 ± 80 0.93 207.7 ± 82.1 247.1 ± 112.1 0.49 232.9 ± 95.2 231.6 ± 87.5 0.92 253.2 ± 86.8 66.5 0.28
55.4 ±
PaCO2 – mmHg 61.8 ± 28.7 50.2 ± 15.8 0.34 60.1 ± 20 51.1 ± 12.3 0.42 50.1 ± 19.7 59.6 ± 20.8 0.11 52.1 ± 18.4 15.4 0.49
Arterial pH 7.36 ± 0.12 7.4 ± 0.09 0.53 7.33 ± 0.13 7.4 ± 0.12 0.11 7.37 ± 0.08 7.34 ± 0.12 0.65 7.35 ± 0.15 7.37 ± 0.1 0.93
Respiratory system static compliance –
ml/ cmH2O 28.3 ± 10.4 31.4 ± 14.6 0.70 32.3 ± 16.9 27.2 ± 11.3 0.60 28.7 ± 11.4 26 ± 10.6 0.67 38.9 ± 20.2 25 ± 11.2 0.18
Other ventilatory variables
Minute ventilation - liters/min 9.2± 1.6 10.9 ± 2.0 0.02 9.5 ± 1.7 10.1 ± 2.6 0.77 9.8 ± 1.75 10.0 ± 2.6 0.72 8.7± 2.8 10.4 ± 1.9 0.24
Controlled volume mode - no./total no.
12 (100%) 12 (92,3%) 1 11 (91,7%) 10 (83,3%) 1 8 (80%) 10 (90,9%) 0,58 7 (77,8%) 9 (90%) 0,58
(%)
Pressure support mode- no./total no. (%) 0 (0%) 1 (7,7%) 1 (8,3%%) 2 (16,7%) 2 (20%) 1 (9,1%) 2 (22,2%) 1 (10%)
Other ventilation mode 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Absence of ventilatory effort during
plateau pressure measurement - 12 (100%) 11 (84,6%) 0,48 11 (91,7%) 9 (75%) 0,59 8 (80%) 9 (81,8%) 1 7 (77,8%) 8 (80%) 1
no./total no. (%)

Page 68 of 71
Table E3. Respiratory and ventilator variables between seven and nine days of treatment
Day 9 Day 11 Day 13 Day 15

Driving Driving Driving Driving
Variable Pressure ARDSNet Pressure ARDSNet Pressure ARDSNet Pressure ARDSNet
P value P value P value¹ P value
Limited (N=9) Limited (N=7) Limited (N=7) Limited (N=6)
(N=7) (N=6 (N=3) (N=3)
Tidal volume – mL/kg of
predicted body weight 5.5 ± 1.2 5.5 ± 0.8 0.79 5.7 ± 1.7 6.3 ± 1.5 0.36 5.6 ± 0.9 6.6 ± 1.6 0.52 5.6 ± 1.8 5.5 ± 0.8 > 0,99
PEEP – cmH2O 8 ± 2.2 8.8 ± 2.4 0.82 7.3 ± 2 7.4 ± 1.8 >0,99 6.7 ± 2.9 7.1 ± 1.9 0.72 6 ± 1.7 7.3 ± 2 0.34
Plateau pressure – cmH2O 20.7 ± 8.6 22.9 ± 6.1 0.22 15.6 ± 2.7 29.5 ± 0.7 0.08 16.7 ± 2.9 29 ± 1.4 0.14 17 ± 2.8 29.5 ± 0.7 0.33
Plateau pressure > 30

cmH2O – no./total no. (%) 1 (14.3%) 0 (0%) >0,99 0 (0%) 0 (0%) >0,99 0 (0%) 0 (0%) > 0,99 0 (0%) 0 (0%) >0,99
Respiratory system static

compliance – ml/ cmH2O 30.2 ± 13.3 33.5 ± 24.9 0.90 40.7 ± 20.6 14.2 ± 5.3 0.09 36.3 ± 4.5 13.8 ± 3.9 0.2 31.9 ± 5.5 13.5 ± 4.3 0.33

Page 69 of 71
Table E4. Fluid balance, weight gain and co-interventions during the first seven days of treatment
Driving Pressure Limited

ARDSNET (n=15) p
(n=16)
24-fluid balance on day 1 - mL -408.1 ± 1226 (n=16) 9.3 ± 1827.3 (n=15) 0.71
weight gain (baseline to day 1)-kg 5.4 ± 11.9 (n=8) 0 ± 1.8 (n=6) 0.37
weight gain (baseline to day 7)- kg -0.7 ± 8.9 (n=7) -3.5 ± 4.7 (n=4) 0.51
Use of vasopressor - n/total n(%) 14/16 (87.5%) 13/15 (86.7%) >0,99
Days of vasopressor use 4 [3 - 6.8] (n=14) 4 [2 - 7] (n=13) 0.82
Use of neuromuscular blockade - n/total n (%) 14/16 (87.5%) 15/15 (100%) 0.48
Days of neuromuscular blocker use 2.5 [2 - 5.5] (n=14) 4 [2 - 5] (n=15) 0.45
Use of sedative infusion- n/total n (%) 16/16 (100%) 14/15 (93.3%) 0.48
Days of sedative infusion 5.5 [3.8 - 7] (n=16) 7 [6.2 - 7] (n=14) 0.05
Use of narcotic infusion- n/total n (%) 15/16 (93.8%) 15/15 (100%) >0,99
Days of narcotic infusion 6 [4 - 7] (n=15) 6 [3 - 7] (n=15) 0.81
Alveolar recruitment maneuver 0/16 (0%) 0/15 (0%) >0,99
Inhaled nitric oxid – n (%) 0/16 (0%) 0/15 (0%) >0,99
High frequency oscillation-n (%) 0/16 (0%) 0/15 (0%) >0,99
Extracorporeal membrane oxygenation –n (%) 0/16 (0%) 0/15 (0%) >0,99

Page 70 of 71
Figure E1-Tidal Volume in Groups X Time.tiff
155x101mm (300 x 300 DPI)

Page 71 of 71
Figure E2-Compliance of the Respiratory System in Groups.tiff
162x101mm (300 x 300 DPI)


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Page 1 of 71

1HCor Research Institute, São Paulo, Brazil

Paulo, São Paulo, Brazil

Financial Support: HCor Research Institute – Hospital do Coração

Conflicts of Interest: None declared.

ANNALSATS Articles in Press. Published February 18, 2020 as 10.1513/AnnalsATS.201907-506OC

ANNALSATS Articles in Press. Published February 18, 2020 as 10.1513/AnnalsATS.201907-506OC

randomized controlled trials.

Objective: To evaluate the feasibility of testing a driving pressure-limited strategy in

comparison with a conventional lung protective ventilation strategy in acute respiratory

driving pressure-limited strategy were ventilated with volume-controlled or pressure support

mL/kg PBW if plateau pressure was higher than 30 cmH2O.

Primary endpoint was driving pressure on days 1 to 3.

ANNALSATS Articles in Press. Published February 18, 2020 as 10.1513/AnnalsATS.201907-506OC

Clinical trial registered with ClinicalTrials.gov (NCT02365038)

ANNALSATS Articles in Press. Published February 18, 2020 as 10.1513/AnnalsATS.201907-506OC

the tidal volume adjusted for the “baby lung” size.

pressures (plateau pressure) or high pulmonary stress (high tidal volume).4

ANNALSATS Articles in Press. Published February 18, 2020 as 10.1513/AnnalsATS.201907-506OC

to achieve a gradient of driving pressure on days 1 to 3 after randomization between the

experimental and control group.

participants and intention to treat analysis, comparing a driving pressure-limited strategy of

in the methods after the beginning of the study.

ANNALSATS Articles in Press. Published February 18, 2020 as 10.1513/AnnalsATS.201907-506OC

hypercapnia (e.g.: suspected or diagnosed intracranial hypertension, acute coronary

kyphoscoliosis, tetanus) or other conditions according to the judgment of the attending

ANNALSATS Articles in Press. Published February 18, 2020 as 10.1513/AnnalsATS.201907-506OC

that approximately 50% of ARDS patients would be eligible to our trial.

limited ventilation or ARDSNet (control group).

because this was not feasible.

Driving pressure-limited strategy group. Patients allocated to the driving pressure-

measurement of driving pressure requires absence of spontaneous respiratory efforts.

Therefore, driving pressure cannot be assessed continuously, particularly in patients under

ANNALSATS Articles in Press. Published February 18, 2020 as 10.1513/AnnalsATS.201907-506OC

respiratory pressures or oxygenation, driving pressure needed to be reassessed. Patients had to

(succinylcholine or rocuronium). Driving pressure was estimated by the difference between

lower than 10 cmH2O, a tidal volume of 8mL/kg PBW was maintained.

ANNALSATS Articles in Press. Published February 18, 2020 as 10.1513/AnnalsATS.201907-506OC

Respiratory rate was adjusted up to a maximum limit of 35 bpm to ensure pH values

Additionally, other procedures for management of respiratory acidosis were: dead-space

treatment of hyperthermia; lipid enriched diet; adequate sedation and neuromuscular

partial pressure of oxygen between 60 and 80 mmHg.

ANNALSATS Articles in Press. Published February 18, 2020 as 10.1513/AnnalsATS.201907-506OC

Data Collection and Endpoints

randomization, then every morning, starting on the day after randomization

telephone to obtain follow-up data.

Before randomization the following variables were collected: demographic variables;

infection, acquired immunodeficiency syndrome and previously diagnosed pulmonary disease.

ANNALSATS Articles in Press. Published February 18, 2020 as 10.1513/AnnalsATS.201907-506OC

ventilation from randomization to day 28.

the study was commenced.

baseline and follow-up driving pressures.

ANNALSATS Articles in Press. Published February 18, 2020 as 10.1513/AnnalsATS.201907-506OC

Vienna, Austria, 2019) software12.

ANNALSATS Articles in Press. Published February 18, 2020 as 10.1513/AnnalsATS.201907-506OC

Demographic characteristics of both groups at baseline were comparable (Table 1).

rather than extrapulmonary ARDS.

ANNALSATS Articles in Press. Published February 18, 2020 as 10.1513/AnnalsATS.201907-506OC

ml/Kg PBW from the first hour to day 3.

about half achieved those levels on days 1 to 3 (Table 2).

0.004). There were no statistically significant between-group differences in the respiratory

the Online Supplement).

ANNALSATS Articles in Press. Published February 18, 2020 as 10.1513/AnnalsATS.201907-506OC