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Natriuretic Peptide-Driven Fluid Management during Ventilator Weaning: A
Randomized Controlled Trial
Armand Mekontso Dessap (1,2,3), Ferran Roche-Campo (1,4), Achille Kouatchet (5), Vinko
Tomicic (6), Gaetan Beduneau (7), Romain Sonneville (8), Belen Cabello (4), Samir Jaber
(9), Elie Azoulay (10), Diego Castanares-Zapatero (11), Jerome Devaquet (12), François
Lellouche (13), Sandrine Katsahian (14), Laurent Brochard (1,2,3,15).
(1) AP-HP, CHU Henri Mondor, Service de Réanimation Médicale, Créteil, F-94010 France
(2) Université Paris Est Créteil, Faculté de Médecine, Créteil, F-94010, France
(3) INSERM, Unité U955, Créteil, F-94010, France
(4) Hospital de Sant Pau, Servei de Medicina Intensiva, Barcelona, Spain
(5) CHU d’Angers, Service de Réanimation Médicale, Angers, France
(6) Clinica Alemana, Departamento de Paciente Crítico, Santiago de Chile, Chile;
(7) CHU de Rouen, Service de Réanimation Médicale and UPRES-EA 3830, Rouen, France
(8) AP-HP, CHU Bichat-Claude Bernard, Service de Réanimation Médicale et des Maladies
Infectieuses, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France
(9) CHU Saint Eloi, Réanimation DAR B, INSERM U1046, Montpellier, France
(10) AP-HP, CHU Saint Louis, Service de Réanimation Médicale, Paris, France
(11) Hôpital Universitaire Saint-Luc, Service de Soins Intensifs, Bruxelles, Belgium
(12) Hôpital Foch, Service de Réanimation, Suresnes, France
(13) Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada
(14) AP-HP, CHU Henri Mondor, Unité de Recherche Clinique, Créteil, F-94010 France
(15) Intensive Care Division, University Hospital of Geneva, University of Geneva, Geneva,
Switzerland
Correspondence to:
Dr Armand Mekontso Dessap; Service de Réanimation Médicale, Centre Hospitalo-
Universitaire Henri Mondor; 51, avenue du Mal de Lattre de Tassigny 94 010 Créteil Cedex,
France ; E-mail: [email protected]; Tel: +33 149 812 391; Fax: +33 142 079 943
Running title: BNP for fluid management during ventilator weaning
Page 1 of 44 AJRCCM Articles in Press. Published on September 20, 2012 as doi:10.1164/rccm.201205-0939OC
Copyright (C) 2012 by the American Thoracic Society.
1
Contributors
AMD, FL, and LB conceived and designed the study. AMD, FRC, AK, VT, GB, RS, BC, SJ,
EA, DCZ, and JD recruited patients and collected data. SK, AMD, and LB contributed to
data analysis and interpretation. AMD, SK and LB drafted the report. All authors contributed
to review and revise the report; all of them have seen and approved the final version.
Sources of support
The project was funded and promoted by the French publicly funded hospital clinical
research program (Programme Hospitalier de Recherche Clinique). Biosite France supplied
the BNP assay devices and kits (Triage MeterPlus) for the study. Dräger Medical provided
the AWS-equipped ventilators for the study.
Descriptor number: 4.13
Word count for the body of the manuscript: 3319
Word count for the abstract: 244
At a Glance Commentary
Scientific Knowledge on the Subject:
Fluid overload is associated with difficult weaning. Recent studies have demonstrated the
usefulness of natriuretic peptides for predicting and diagnosing weaning failure of cardiac
origin, which is a common cause of ventilation prolongation.
What This Study Adds to the Field:
Our study is the first trial of fluid management during weaning from mechanical ventilation.
We show that a simple BNP-guided fluid management strategy is associated with increased
diuretic use, a more negative fluid balance, and a shorter duration of mechanical ventilation,
especially in patients with LVD.
This article has an online data supplement, which is accessible from this issue's table of
content online at www.atsjournals.org
Page 2 of 44
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ABSTRACT
Rationale:
Difficult weaning from mechanical ventilation is often associated with fluid overload. B-type
natriuretic peptide (BNP) has been proposed as a tool for predicting and detecting weaning
failure of cardiovascular origin.
Objectives:
To investigate whether fluid management guided by daily BNP plasma concentrations
improves weaning outcomes compared to empirical therapy dictated by clinical acumen.
Methods:
In a randomized controlled multicentre study, we allocated 304 patients to a BNP-driven and
a physician-driven strategy of fluid management during ventilator weaning. To standardise
the weaning process, patients in both groups were ventilated using an automatic computer-
driven weaning system. The primary end point was time to successful extubation.
Measurements and main results
In the BNP-driven group, furosemide and acetazolamide were given more often and in
higher doses than in the control group, resulting in a more negative median (interquartile
range) fluid balance during weaning (-2320 (-4735, 738) mL vs. -180 (-2556, 2832) mL,
p<0.0001). Time to successful extubation was significantly shorter with the BNP-driven
strategy (58.6 (23.3, 139.8) hours vs. 42.4 (20.8, 107.5) hours, p=0.034). The BNP-driven
strategy increased the number of ventilator-free days but did not change length of stay or
mortality. The effect on weaning time was strongest in patients with left ventricular systolic
dysfunction. The two strategies did not differ significantly regarding electrolyte imbalance,
renal failure, or shock.
Conclusions:
Our results suggest that a BNP-driven fluid management strategy decreases the duration of
weaning without increasing adverse events, especially in patients with left ventricular
systolic dysfunction.
Word count for the abstract: 244
Key words: mechanical ventilation, BNP, diuretics
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INTRODUCTION
Mechanical ventilation may give rise to complications, whose incidence increases with
the duration of respiratory support (1). The purpose of the weaning procedure is to minimise
the duration of mechanical ventilation without incurring a substantial risk of failure. As
weaning contributes at least 40% of the total duration of mechanical ventilation, optimizing
this process is the main means of shortening the duration of mechanical ventilation (2).
Numerous reports suggest that outcomes of mechanically ventilated patients in the intensive
care unit (ICU) may be improved by decreasing the pulmonary capillary wedge pressure
and/or minimizing a positive fluid balance at the time of weaning (3-6). Considerable
attention has been paid to weaning failure due to fluid overload or heart failure (7-10). It has
been shown that fluid overload can lead to weaning failure of cardiac origin (8, 11).
B-type natriuretic peptide (BNP) is a cardiac biomarker secreted by the ventricular
cardiomyocytes in response to increased wall stress. BNP levels before weaning
independently predict weaning failure (12). Recent studies have demonstrated the usefulness
of natriuretic peptides for predicting and diagnosing weaning failure of cardiac origin (13,
14).
We therefore hypothesised that, during the weaning period, fluid management guided
by daily BNP plasma concentrations would improve outcomes compared to empirical
therapy dictated by clinical acumen. We tested this hypothesis in the present international,
multicentre, randomized controlled trial. To standardise the weaning process, all patients
were ventilated using a computer-driven automated weaning system (AWS) (Evita Smart
Care System, Drager Medical, Lubeck, Germany) (15). This work has been reported
previously in abstract form (16).
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PATIENTS AND METHODS
Supplemental information on patients and methods is provided in the online data supplement
(ODS).
Patients
Patients admitted to the participating ICUs were screened daily to assess if they met
the inclusion and non-inclusion criteria. Inclusion criteria were endotracheal mechanical
ventilation for at least 24 hours, SpO2 ≥90% with FiO2≤50% and PEEP≤8 cmH2O,
haemodynamic stability without vasopressor therapy or fluid bolus (rapid infusion of at least
500 mL of colloids or 1000 mL of crystalloids) during the past 12 hours (with dopamine ≤10
γ/Kg/min and dobutamine ≤10 γ/Kg/min being allowed), sedation stopped or decreased over
the past 48 hours (analgesia possibly continued), stable neurological status with Ramsay
score ≤5, body temperature >36.0°C and <39.0°C, and informed consent signed by the
patient or a close relative. Permanent non-inclusion criteria were pregnancy or lactation, age
<18 years, known allergy to furosemide or sulphonamides, tracheostomy on inclusion,
hepatic encephalopathy, cerebral oedema, acute hydrocephalus, myasthenia gravis, acute
idiopathic polyradiculoneuropathy, decision to withdraw life support, and prolonged cardiac
arrest with a poor neurological prognosis. Temporary non-inclusion criteria were extubation
scheduled on the same day (patients having already succeeded a spontaneous breathing trial),
persistent acute right ventricular failure, renal insufficiency (defined as any of the following:
need for renal replacement therapy, plasma urea >25 mmol/L, plasma creatinine >180
µmol/L, creatinine clearance <30 mL/min, greater than 25% increase in plasma creatinine
over the past 24 hours), injection of iodinated contrast agent in the past six hours, blood
sodium >150 mEq/L, blood potassium <3.5 mEq/L, or metabolic alkalosis with arterial pH
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>7.50). When inclusion was delayed because of a temporary non-inclusion criterion,
enrolment could be performed after correction of the abnormal value.
Study protocol
Patients ventilated in volume-assist or pressure-control mode were eligible for
inclusion only if a pressure-support (PS) test was positive. The PS test consisted in changing
the ventilator mode to PS, without changing FiO2 or PEEP, as previously described (15)
(ODS p 2). In patients already ventilated with PS at the time of inclusion, the positivity
criteria of the PS test were checked. The protocol did not require performing a SBT before
enrolment. Only the PS test was asked.
Randomization and masking
Patients fulfilling the inclusion and non-inclusion criteria and having a positive PS test
were ventilated using the AWS, starting with similar PS and PEEP levels to those used
during the PS test. Patients were then immediately assigned to one of two groups (BNP-
guided fluid management or usual care based on clinical acumen) via independent web-
based centralized block randomization (available 24 hours a day, 7 days a week), with
stratification on the centre and underlying disease. Three subgroups were pre-defined for
stratification: i) presence of known chronic obstructive pulmonary disease (COPD), ii)
presence of known left ventricular systolic dysfunction (LVD, ejection fraction <45%), and
iii) absence of both disorders. Patients with both disorders were classified in the COPD
subgroup. The main purpose of stratification was to ensure a homogeneous distribution of
COPD and LVD in the two arms. Careful attention was paid to minimizing changes in
diuretic therapy practices caused by the research protocol during weaning in the control
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group. All randomized patients were ventilated using the AWS during weaning and followed
up until discharge from the hospital or day 60 after randomization.
B-type natriuretic peptide (BNP) assay
A blood sample was collected each morning for a BNP assay in all randomized
patients during the weaning phase (while ventilated using the AWS). BNP was assayed
using a rapid immunofluorescence test and a bedside measuring device (Triage BNP Test,
Biosite, Jouy-en-Josas, France, ODS p 3). Two devices were supplied per centre: the first,
which was used in the BNP-guided group, displayed the BNP result; the second did not
show the result in visual display or print form and was used in the control group.
Fluid and electrolyte management
In the control group, the clinicians were blinded to the BNP assay results, and all
treatments, including diuretics, were carried out according to usual care, with no explicit
protocol. BNP results were uploaded from the device memory at study completion. In the
BNP-guided group, on days with a BNP level ≥200 pg/mL, fluid intake was restricted
(baseline infusion ≤500 mL/24 hours, parenteral nutrition ≤1000 mL/24 hours, no saline
solutions apart from nutrition and drugs) and furosemide was administered (as intravenous
bolus doses of 10 to 30 mg every 3 hours, to achieve a target urine output of 4.5 to 9
mL/kg/3 hours) (ODS p 9). The 200 pg/mL threshold was chosen based on a previous study
showing that BNP levels were higher in patients who failed weaning from mechanical
ventilation than in successfully weaned patients (12). Fluid intake restriction and diuretic
administration (according to BNP levels on extubation day) were continued for at least 24
hours after extubation in the BNP-guided group.
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Sodium, potassium, urea, creatinine, and arterial blood gases were monitored daily in
all patients. Recommendations were given to prevent and/or treat possible adverse events
related to diuretic treatment in the BNP-guided group, as detailed in the ODS p 4-5.
Ventilatory management
During ventilation using the AWS in both groups, sedation was stopped whenever
possible, whereas analgesia could be continued, with a target Ramsay score of 2-3. The
AWS gradually decreased the PS level while maintaining the patient within a zone of
respiratory comfort, as previously described (ODS p 5) (15). When the AWS declared the
patient “ready for separation”, extubation was performed as soon as possible (including
during the night), after checking for the other required extubation criteria (ODS p 5-6).
Assist-control ventilation was resumed during ventilation using the AWS in case of
respiratory worsening with a respiratory rate >40/min or hypoxemia (FiO2 >60% and PEEP
>8 cmH2O required to obtain SpO2≥90%). The tidal volume target under assist-control
ventilation was 6 ml/kg (predicted body weight). BNP was no longer assayed in controlled
mode ventilation. When the daily PS test became positive again, the patient was switched
back to ventilation using the AWS and managed according to his or her randomization
group. The diagnosis of ventilator-associated pneumonia was based on the following usual
criteria: systemic signs of infection, new or worsening infiltrates on the chest
roentgenogram, purulent tracheal secretions, and bacteriologic evidence of pulmonary
parenchymal infection (chiefly from distal airway sampling using a protected telescoping
catheter or bronchoscopy) (17). Non-invasive ventilation was allowed after extubation if
deemed necessary by the attending physician (based on predefined criterion). In the event of
re-intubation (ODS p 6), the patient was not re-ventilated using the AWS. Last, a general
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recommendation was made to investigators to wait until day 10 after randomization before
deciding to perform tracheotomy, if at all possible.
End points
The primary end point was the time from randomization to successful extubation
(patient alive and without re-intubation 72 hours after extubation). Secondary end points
included time to first extubation, time to successful weaning from invasive and non-invasive
ventilation (defined as the time from randomization to completion of 72 hours of unassisted
spontaneous breathing without non-invasive ventilation for ≥3 hours per day), ventilator-free
days calculated as the number of days without mechanical ventilation within 60 days after
randomization (patients who died or were dependent on mechanical ventilation for more than
60 days had zero ventilator-free days), ICU and hospital lengths of stay, ICU and hospital
deaths, and mortality on day 60 after randomization.
Statistical analysis
We estimated the sample size needed to detect an at least 40% decrease in weaning duration
in the BNP-guided fluid management group compared to the control group, with an α risk of
5% and a β risk of 10% (power of 90%). In a previous multicentre trial, weaning duration in
patients ventilated using the AWS was 4.4±4.0 days (15). Assuming a slightly higher
standard deviation equal to the mean (4.4), and considering that the use of non-parametric
tests might require up to 15% additional subjects (18), a sample size of 150 patients per
group was deemed necessary. The data were analysed using SPSS Base 18 (SPSS Inc,
Chicago, IL, USA) and R 2.10.1 (The R Foundation for Statistical Computing, Vienna,
Austria). Categorical variables were expressed as percentages and continuous data were
expressed as median (25th–75th percentiles) or mean (SD). We used the chi-square or Fisher
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exact test to compare categorical variables between study groups and the Mann-Whitney test
to compare continuous variables, including the primary end point. The primary end point
was also analysed in the three predefined subgroups (COPD, LVD, and neither). We also
used the Kaplan-Meier method to assess the effect of BNP-guided fluid management on the
cumulative probability of successful extubation. Because the proportional hazards
assumption was not met during the 60-day follow-up, we used the Breslow-Gehan-Wilcoxon
test to assess differences between groups (19). This test allows weighting of time points by
the number of cases at risk at each time point (20). Lastly, the effect of BNP-guided fluid
management on the cumulative incidence of successful extubation was assessed while
considering need for continuous sedation as a competing event, according to the Gray model
(21, 22). Two-sided p values <0.05 were considered significant.
This study was registered on ClinicalTrials.gov with the number NCT00473148.
RESULTS
Enrolment and baseline characteristics
1464 patients eligible for weaning were screened for enrolment between May 2007 and
July 2009. Among them, 306 were enrolled and randomized (Figure 1) to the control group
(n=152) or BNP-guided group (n=154). Two patients (assigned to the BNP-guided group)
were excluded from the data analysis due to lack of continued consent to use their data. The
withdrawal of consent was not related to any particular aspect of the protocol. The two
groups were similar at baseline regarding demographic characteristics, reason for intubation,
severity of illness, respiratory function, duration of invasive mechanical ventilation, and
urine output before study initiation (Table 1). BNP values at randomization and the
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proportions of patients with COPD and LVD were also similar between the two groups
(Table 1). In the overall population, BNP values at randomization were higher in patients
with LVD [552 (328-990) pg/mL] than in patients with COPD [263 (115-803) pg/mL,
p=0.006] or neither disease [230 (72-485) pg/mL, p<0.0001].
Diuretics and fluid balance (Table 2)
During the weaning process, the percentage of patients with at least one daily BNP
value ≥200 pg/mL was similar in the two groups. Compared to the control group, the BNP-
guided group had a higher proportion of patients receiving diuretics, which were used in
higher doses, resulting in a significantly more negative fluid balance during the weaning
period. Fluid balance on extubation day and the day after extubation were similar between
groups.
Main endpoints
The weaning time was significantly shorter and the number of ventilator-free days
significantly higher in the BNP-guided group compared to the control group (Table 3). The
probability of successful extubation was significantly increased with the BNP-guided
strategy (p=0.022, Breslow test, Figure 2), and this difference persisted after adjustment for
need for continuous sedation as a competing event (p=0.01, Gray test). No difference was
found for length of stay, ICU mortality, or hospital mortality (Table 3). Although
stratification into three subgroups did not provide sufficient power to analyse each subgroup
separately, the differences between the two strategies in times to first extubation, to
successful extubation and to successful weaning were significant in patients with LVD,
suggesting a stronger effect of BNP-guided fluid management in this subgroup than in the
other two subgroups (Figure 3).
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Complications during weaning (Table 4)
The need for non-invasive ventilation after extubation, re-intubation rate within 72
hours after extubation, tracheostomy rate, and need for prolonged mechanical ventilation
(>14 days after randomization) were similar between groups. There were no significant
between-group differences in the percentages of patients with hypokalaemia, hypernatremia,
metabolic alkalosis, or renal failure.
During the weaning period, significantly fewer patients in the BNP-guided group
experienced clinical worsening requiring re-ventilation with assist-control ventilation,
developed ventilator-associated pneumonia, or needed continuous sedation or episodes of
fluid loading, compared to the control group.
DISCUSSION
There is currently no objective practical guide to fluid management during weaning
from mechanical ventilation. In this randomized controlled trial, a simple BNP-guided fluid
management strategy was associated with increased diuretic use, a more negative fluid
balance, and a shorter duration of mechanical ventilation, especially in patients with LVD.
There was no increase in organ failures.
Several factors may confer an advantage to BNP-guided fluid management over the
usual clinical approach during weaning. BNP guidance is probably a preventive and patient-
tailored strategy allowing more conservative fluid management in patients at high risk for
difficult weaning (12, 14). Acute heart failure is a common cause of unsuccessful weaning
from mechanical ventilation (9, 10, 13). Its pathophysiology is complex and involves
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changes in intrathoracic pressure and cardiac loading conditions, left ventricular systolic (9)
and diastolic (23) dysfunction, and fluid overload (8). Positive fluid balance is associated
with prolonged mechanical ventilation (24, 25) and extubation failure (11). In patients with
weaning-induced heart failure, successful weaning was achieved after diuretic treatment in
several open studies (8, 12). The BNP measurement acted as an incentive to consider
negative fluid balance while diuresis was managed according to a predefined protocol to
minimize bias.
Previous studies of goal-directed fluid management in mechanically ventilated
critically ill patients have shown beneficial effects with interventions aimed at lowering fluid
balance (4-6, 26). They differed from ours in terms of the protocols, patient populations, and
timing of the interventions (4-6, 26). We used BNP in patients fulfilling criteria for early
weaning, whereas they used more complex algorithms usually targeting invasive
measurements such as extravascular lung water, central venous pressure, or pulmonary
artery occlusion pressure (4-6, 26). We do not know whether driving the protocol
instructions by these invasive measurements would have modified the effect of our
intervention. Such invasive measurements are difficult to implement in practice in the
context of weaning, which is usually associated with a decrease in the overall invasiveness
of management. In addition, conventional tools used to diagnose cardiovascular dysfunction
raise technical challenges in patients who are being weaned off mechanical ventilation, due
to the large swings in intrathoracic pressures. This fact has generated interest in the use of
cardiac biomarkers during weaning. Recent data have suggested that natriuretic peptides
(BNP and NT-pro BNP) may predict the weaning outcome and help to determine whether
weaning failure is caused by cardiovascular dysfunction (12-14).
Better outcomes have been shown with explicit BNP-guided pharmacotherapy
compared to empirical therapy dictated by clinical acumen in circumstances other than
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weaning from mechanical ventilation, especially in outpatients with chronic heart failure
(27) and in patients presenting to emergency department with acute dyspnoea (28). In our
study, although the BNP-guided strategy induced significant benefits in the overall
intervention group, patients with LVD showed the strongest effect, whereas those with
COPD seemed less likely to benefit. Natriuretic peptides are secreted primarily by the left
ventricle in response to changes in left ventricular wall stretch, and their concentrations
correlate closely with filling pressures in patients with LVD (29). LVD is a risk factor for
weaning failure of cardiovascular origin (9). In patients with LVD, high-pressure pulmonary
oedema and an inadequate cardiac output may constitute major obstacles to weaning from
mechanical ventilation (30). By contrast, weaning difficulties in other groups of patients may
be due to other factors such as poor respiratory mechanics, elevated work of breathing, or
CO2 retention in patients with COPD (31). In addition, elevated BNP in patients with COPD
may be partly related to pulmonary hypertension and increased right ventricle afterload (32),
a form of cardiac dysfunction that may not always respond well to diuretics.
Possible explanations for the lower rate of ventilator-associated pneumonia in the
BNP-guided fluid management group may include decreased risk exposure (earlier
separation from the ventilator) and a direct effect of fluid balance on bacterial colonisation
and infectivity. Conceivably, respiratory symptom worsening due to pulmonary oedema may
have been mistaken for pneumonia in some patients, although the strict criteria used to
diagnose pneumonia limited this possibility. There were more episodes of worsening and
need for sedation in the control group, and our analysis adjusted on sedation suggests that
this may be a consequence of a less aggressive reduction of fluid balance in the control
group.
The BNP-guided strategy had no adverse consequences on haemodynamic or renal
function. Arterial pressure, vasopressor requirements, blood urea nitrogen, and creatinine
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level were similar in the two groups. The protocols were designed to minimise risks, and
diuretic therapy was titrated based on the patient’s response and was avoided in patients with
worsening renal function. Frequent use of acetazolamide was a necessary part of the protocol
in order to avoid alkalemia. Electrolyte levels were monitored closely during diuretic therapy
and were comparable between groups.
Since we tested specific management strategies that used several safeguards, we do
not know whether the BNP-guided fluid management strategy would be as safe and as
beneficial when using the simplified target of a zero fluid balance or zero weight gain. In
addition, departures from the specific inclusion and non-inclusion criteria used in this trial
may lead to clinical outcomes that differ from those observed in this study. This point may
affect the generalizability of our study, i.e., its external validity, which may also be
influenced by the general fluid balance policy of a given ICU. Although cardiac dysfunction
is the most important source of BNP variations in critically ill patients, other major factors
include sepsis and renal failure. We did not include patients with renal failure, because of the
influence of renal function on BNP levels.
The weaning procedure was relatively brief in the control group. This finding may
be related to our selection criteria and/or to the use of the AWS (15). Using the AWS,
however, allowed optimal standardisation of the weaning procedure. Because the study was
not blinded and all participating physicians were aware of the study question, diuretics may
have been used more widely than usual in the control group, which would tend to minimise
the difference in weaning duration between the groups. Although a greater clinician
presence, assessment, and involvement in the BNP-guided group as compared to the usual
care group cannot be excluded, the use of a strict protocol for diuresis and of AWS allowed
us to make the weaning process relatively independent from physician care.
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In conclusion, we found that the use of a BNP-driven fluid management protocol
during weaning from mechanical ventilation decreased the fluid balance and duration of
weaning without increasing adverse events, compared with physician-guided fluid
management, especially in patients with LVD. We detected no significant differences in
mortality rate or length of stay between the two approaches.
ACKNOWLEDGMENTS
None
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FIGURE LEGENDS
Figure 1. Study flow-chart.
Figure 2. Probability of successful extubation within 60 days after randomization
Figure 3. Mean and standard deviation for time to first extubation, time to successful
extubation, and time to successful weaning from invasive and non-invasive ventilation in
patients with chronic obstructive pulmonary disease, left ventricular systolic dysfunction, or
neither. COPD, chronic obstructive pulmonary disease; LVD, left ventricular systolic
dysfunction; neither, no COPD or LVD; * denotes p<0.05 between the usual care and BNP-
guided groups (Mann-Whitney test)
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Table 1. Baseline characteristics
Usual care group
(n=152)
BNP-guided group
(n=152)
Age (years) 65 (52-74) 66 (55-76)
Sex (male) 102 (67.1%) 93 (61.2%)
McCabe class
0 96 (63.2%) 93 (61.2%)
1 48 (31.6%) 42 (27.6%)
2 8 (5.3%) 17 (11.2%)
SAPS II at ICU admission 44 (34-56) 43 (34-54)
SOFA score at ICU admission 7 (4-9) 7 (4-9)
Reason for intubation
Coma 22 (14.5%) 15 (9.9%)
Septic shock 18 (11.8%) 21 (13.8%)
COPD exacerbation 10 (6.6%) 15 (9.9%)
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Cardiogenic pulmonary oedema 19 (12.5%) 14 (9.2%)
Pneumonia 40 (26.3%) 50 (32.9%)
Cardiac arrest 10 (6.6%) 6 (3.9%)
Surgery 19 (12.5%) 23 (15.1%)
Others 14 (9.2%) 8 (5.3%)
Events between ICU admission and randomization
Septic shock* 61 (40.1%) 70 (46.1%)
Ventilator-associated pneumonia 32 (21.1%) 25 (16.4%)
Acute respiratory distress syndrome* 55 (36.2%) 53 (34.9%)
Use of neuromuscular blockers 35 (23.0%) 32 (21.1%)
Steroid treatment 53 (34.9%) 60 (39.5%)
Duration of invasive mechanical ventilation before inclusion
(days)
Median (IQR) 4.4 (2.7-7.8) 5.0 (3.0-9.1)
Mean (SD) 6.5 (5.7) 7.5 (7.6)
Diuretic treatment on the day before randomization 64 (42.1%) 64 (42.1%)
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Urine output on the day before randomization (mL) 1925 (1400-2750) 1928 (1200-3080)
Pressure support test at inclusion
Pressure support level (cmH2O) 14 (10-15) 13 (10-15)
PEEP level (cmH2O) 5 (5-8) 5 (5-6)
FiO2 level 40 (35-50) 40 (30-50)
Cardiopulmonary disease at randomization
COPD 38 (25.0%) 41 (27.0%)
LVD 24 (15.8%) 20 (13.2%)
Neither 90 (59.2%) 91 (59.9%)
SOFA score at randomization 4 (2-6) 4 (3-5)
Arterial blood gases at randomization
pH 7.43 (7.39-7.48) 7.43 (7.40-7.46)
PaCO2 (mmHg) 40 (34-45) 41 (37-47)
PaO2/FiO2 ratio (mmHg) 218 (176-266) 225 (174-297)
BNP values at randomization (pg/mL) 296 (113-555) 256 (91-700)
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Data are n (%) or median (IQR). SAPS II, Simplified Acute Physiology Score II; SOFA, Sequential Organ Failure Assessment; PEEP, positive
end-expiratory pressure; FiO2, fraction of inspired oxygen; COPD, chronic obstructive pulmonary disease; LVD, left ventricular systolic
dysfunction. *: at admission or later during the ICU stay
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Table 2. Fluid management during weaning
Usual care group
(n=152)
BNP-guided group
(n=152)
p value
Patients with at least one daily BNP value ≥200 pg/mL during weaning, n (%) 105 (69.1%) 100 (65.8%) 0.541
Patients treated at least once with furosemide during weaning, n (%) 108 (71.1%) 124 (81.6%) 0.031
Patients treated at least once with acetazolamide during weaning, n (%) 33 (21.7%) 65 (42.8%) < 0.0001
Patients treated at least once with any diuretic during weaning, n (%) 110 (72.4%) 127 (83.6%) 0.019
Cumulative furosemide dose during weaning (mg) 0.003
Median (IQR) 70 (0-160) 118 (23-229)
Mean (SD) 180 (544) 180 (231)
Average daily furosemide dose during weaning (mg) < 0.0001
Median (IQR) 14 (0-40) 40 (9-78)
Mean (SD) 30 (50) 47 (41)
Cumulative fluid balance during weaning (mL) < 0.0001
Median (IQR) -180 (-2556 to 2832) -2320 (-4735 to 738)
Mean (SD) 847 (6569) -1402 (5818)
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Average daily fluid balance during weaning (mL) < 0.0001
Median (IQR) -37 (-731 to 586) -640 (-1811 to 225)
Mean (SD) -136 (1312) -852 (1456)
Average daily fluid intake during weaning (mL) 0.105
Median (IQR) 2226 (1758 to 2730) 2040 (1650 to 2629)
Mean (SD) 2324 (876) 2188 (774)
Average daily urine output during weaning (mL)
Median (IQR) 2273 (1838 to 2973) 2836 (2057 to 3905) < 0.0001
Mean (SD) 2461 (1039) 3044 (1240)
Fluid balance on extubation day* (mL) 0.318
Median (IQR) -1180 (-2124 to 42) -1047 (-2540 to -350)
Mean (SD) -1078 (1639) -1263 (1759)
Fluid balance the day after extubation* (mL) 0.223
Median (IQR) -715 (-1526 to 30) -479 (-1360 to 277)
Mean (SD) 751 (1339) -646 (1469)
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Negative fluid balance was defined as urine output exceeding fluid intake; *fluid balance on extubation day and the day after extubation were
available in 274 and 229 patients respectively.
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Table 3. Main outcomes
Usual care group
(n=152)
BNP-guided group
(n=152)
p value
Time to first extubation (hours)
Median (IQR) 47.7 (22.9-124.8) 39.8 (20.0-72.4) 0.019
Mean (SD) 92.8 (110.2) 70.6 (106.8)
Time to successful extubation (hours)
Median (IQR) 58.6 (23.3-139.8) 42.4 (20.8-107.5) 0.034
Mean (SD) 112.2 (147.1) 86.2 (127.9)
Time to successful weaning from
invasive and non-invasive ventilation (hours)
Median (IQR) 74.4 (31.7-160.5) 49.3 (21.9-140.6) 0.051
Mean (SD) 134.3 (187.6) 107.1 (141.0)
Ventilator-free days from randomization to day 14 (days)
Median (IQR) 9.7 (2.3-12.9) 12.0 (6.5-13.1) 0.026
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Mean (SD) 8.2 (5.2) 9.3 (4.9)
Ventilator-free days from randomization to day 28 (days)
Median (IQR) 23.3 (14.7-26.7) 25.9 (19.3-27.1) 0.038
Mean (SD) 18.9 (10.4) 20.3 (10.4)
Ventilator-free days from randomization to day 60 (days)
Median (IQR) 54.9 (38.7-58.3) 57.9 (50.4-59.1) 0.015
Mean (SD) 42.8 (23.7) 45.7 (22.7)
ICU stay length (days)
Median (IQR) 8.0 (4.0-13.0) 8.0 (4.0-14.0) 0.995
Mean (SD) 11.6 (12.3) 11.4 (11.2)
Hospital stay length (days)
Median (IQR) 20.0 (12.0-33.0) 20.0 (13.0-33.0) 0.796
Mean (SD) 27.3 (37.3) 24.0 (14.2)
ICU mortality 19 (12.5%) 18 (11.8%) 0.861
Hospital mortality 25 (16.4%) 20 (13.2%) 0.433
Day-60 mortality 28 (18.4%) 21 (13.8%) 0.275
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Table 4. Complications during weaning
Usual care group
(n=152)
BNP-guided group
(n=152)
p value
Respiratory function
Clinical worsening requiring a return to assist-control ventilation 66 (43.4%) 42 (27.6%) 0.004
Ventilator-associated pneumonia 27 (17.8%) 14 (9.2%) 0.029
Need for non-invasive ventilation after extubation 49/138 (35.5%) 53/142 (37.3%) 0.752
Re-intubation within 72 hours after extubation 17/138 (12.3%) 23/144 (16.0%) 0.379
Tracheostomy 13 (8.6%) 21 (13.8%) 0.145
Mechanical ventilation for >14 days after randomization 20 (13.2%) 20 (13.2%) > 0.999
Cardiovascular function
Supraventricular arrhythmia 18 (11.8%) 17 (11.2%) 0.857
Ventricular arrhythmia 4 (2.6%) 1 (0.7%) 0.216
Systolic arterial pressure <90 mmHg 49 (32.2%) 40 (26.3%) 0.257
Need for fluid loading 53 (34.9%) 36 (23.7%) 0.032
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Need for catecholamine infusion 40 (26.3%) 39 (25.7%) 0.896
Neurologic function
Need for continuous sedation because of clinical worsening 80 (52.6%) 61 (40.1%) 0.029
Need for continuous analgesia 70 (46.1%) 61 (40.1%) 0.297
Renal and metabolic functions
Arterial pH >7.50 31 (20.4%) 20 (13.2%) 0.09
Blood potassium < 3.5 mEq/L 58 (38.2%) 70 (46.1%) 0.163
Blood sodium >150 mEq/L 7 (4.6%) 3 (2.0%) 0.198
Plasma creatinine >150 micromol/L 13 (8.6%) 10 (6.6%) 0.515
Plasma creatinine >180 micromol/L 3 (2.0%) 6 (3.9%) 0.501
Blood urea nitrogen >15 mmol/L 36 (23.7%) 32 (21.1%) 0.582
Blood urea nitrogen >25 mmol/L 7 (4.6%) 8 (5.3%) 0.791
Need for dialysis 0 (0%) 0 (0%) > 0.999
Data are n (%)
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Figure 1. Study flow chart
3709 patients under mechanical ventilation
1445 without weaning criteria 494 needed sedatives or had unstable neurological status 488 needed FiO2>50% or PEEP>8 cmH2O 460 were haemodynamically unstable 3 had fever or hypothermia
800 had received mechanical ventilation for less than 24 hours or were expected to be extubated within 24 h
152 analyzed
0 excluded from the analysis 0 lost to follow-up
152 allocated to usual fluid management
2 excluded from the analysis (consent withdrawal) 0 lost to follow-up
154 allocated to BNP-driven fluid management
152 analyzed
306 randomized and ventilated using the Automated Weaning System
1464 eligible for weaning
1158 excluded 297 for temporary non-inclusion criteria
291 had renal failure or metabolic abnormalities 6 had acute right ventricle failure
705 for permanent non-inclusion criteria 224 had increased intracranial pressure or hepatic encephalopathy 192 were tracheostomised 171 were not committed to full support 67 had prolonged cardiac arrest with a poor neurological prognosis 41 had severe neuromuscular disease 6 aged less than 18 years 4 pregnant
156 for non-clinical reasons 74 consents not obtained 72 were enrolled in another trial 10 had no health insurance
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Figure 2. Probability of successful extubation within 60 days after randomization
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Figure 3. Mean and standard deviation for time to first extubation, time to successful
extubation, and time to successful weaning from invasive and non-invasive ventilation in
patients with chronic obstructive pulmonary disease, left ventricular systolic dysfunction, or
neither
Time to first extubation (hours)
COPD LVD Neither0
50
100
150
200
250
300
350Standard weaning
BNP-guided weaning*
SUBGROUP
Time to successful extubation (hours)
COPD LVD Neither0
100
200
300
400
500Standard weaning
BNP-guided weaning*
SUBGROUP
Time to successful weaning from invasiveand non-invasive ventilation (hours)
COPD LVD Neither0
100
200
300
400
500Standard weaning
BNP-guided weaning*
SUBGROUP
Page 31 of 44
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1
Natriuretic Peptide-Driven Fluid Management during Ventilator Weaning: A
Randomized Controlled Trial
Armand Mekontso Dessap, Ferran Roche-Campo, Achille Kouatchet, Vinko Tomicic,
Gaetan Beduneau, Romain Sonneville, Belen Cabello, Samir Jaber, Elie Azoulay, Diego
Castanares-Zapatero, Jerome Devaquet, François Lellouche, Sandrine Katsahian, Laurent
Brochard .
ONLINE DATA SUPPLEMENT
PATIENTS AND METHODS
Patients
Patients admitted to the participating ICUs were screened daily to see if they met the
inclusion and non-inclusion criteria. Inclusion criteria were endotracheal mechanical
ventilation for at least the past 24 hours, SpO2 ≥90% with FiO2≤50% and PEEP≤8 cmH2O,
haemodynamic stability without vasopressor therapy or fluid bolus (rapid infusion of at least
500 mL of macromolecules or 1000 mL of saline) during the past 12 hours (with dopamine
≤10 γ/Kg/min and dobutamine ≤10 γ/Kg/min being allowed), sedation stopped or decreased
over the past 48 hours (analgesia possibly continued), stable neurological status with
Ramsay score ≤5, body temperature >36.0°C and <39.0°C, and informed consent signed by
the patient or a close relative. Permanent non-inclusion criteria were pregnancy or lactation,
age <18 years, known allergy to furosemide or sulphonamides, tracheostomy on inclusion,
hepatic encephalopathy, cerebral oedema, acute hydrocephalus, myasthenia gravis, acute
idiopathic polyradiculoneuropathy, decision to withdraw life support, and prolonged cardiac
arrest with a poor neurological prognosis. Temporary non-inclusion criteria were extubation
Page 34 of 44
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scheduled on the same day, persistent acute right ventricular failure [as defined by a dilated
right ventricle (end diastolic right ventricle / left ventricle area ratio >0.6) associated with
septal dyskinesia using echocardiography (E1) or the concomitant presence of a mean
pulmonary artery pressure > 25 mmHg, a central venous pressure higher than pulmonary
artery occlusion pressure and a stroke volume index < 30 mL/m2 using pulmonary artery
catheter (E2)], renal insufficiency (defined as any of the following: need for renal
replacement therapy, plasma urea >25 mmol/L, plasma creatinine >180 µmol/L, creatinine
clearance <30 mL/min, greater than 25% increase in plasma creatinine over the past 24
hours), injection of iodinated contrast agent in the past six hours, blood sodium >150 mEq/L,
blood potassium <3.5 mEq/L, or metabolic alkalosis with arterial pH >7.50). When inclusion
was delayed because of a temporary non-inclusion criterion, enrolment could be performed
after correction of the abnormal value.
Study protocol
Patients ventilated in volume-assist or pressure-control mode were eligible for
inclusion only if a pressure-support (PS) test was positive. The PS test consisted in changing
the ventilator mode to PS, without changing FiO2 or PEEP. PS was set at ≥10 cmH2O
initially then adjusted to obtain an expired tidal volume ≥6 mL/Kg of predicted body weight
and a respiratory rate ≤35/min. The maximum inspiratory pressure (PS level plus PEEP)
allowed to reach these objectives was 30 cmH2O. The test was stopped in the event of
respiratory distress or haemodynamic instability (heart rate increase >30/min versus
baseline, systolic blood pressure <80 mmHg or >160 mmHg, respiratory rate >40/min). The
test was considered positive if, after 30 minutes with no change in the inspiratory pressure
level, the patient remained clinically stable with a respiratory rate ≤35/min and an expired
tidal volume ≥6 mL/Kg of predicted body weight, without desaturation (SpO2≥90% with
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3
FiO2≤50% and PEEP ≤8 cmH2O). In patients already ventilated with PS at the time of
inclusion, the positivity criteria of the PS test were checked.
Randomisation and masking
Patients fulfilling the inclusion and non-inclusion criteria and having a positive PS test
were ventilated using the AWS, starting with similar PS and PEEP levels to those used
during the PS test. Patients were then immediately assigned to one of two groups (BNP-
guided fluid management or standard management based on clinical acumen) via
independent centralised block randomisation, with stratification on the centre and underlying
disease. Three subgroups were pre-defined for stratification: i) presence of known chronic
obstructive pulmonary disease (COPD), ii) presence of known left ventricular systolic
dysfunction (LVD, ejection fraction <45%), and iii) absence of both disorders. Patients with
both disorders were classified in the COPD subgroup. The main purpose of stratification was
to ensure a homogeneous distribution of COPD and LVD in the two arms. Careful attention
was paid to minimising changes in diuretic therapy practices caused by the research protocol
during weaning in the control group. All randomised patients were ventilated using the AWS
during weaning and followed up until discharge from the hospital or day 60 after
randomisation.
B-type natriuretic peptide (BNP) assay
A blood sample was collected each morning for a BNP assay in all randomised
patients ventilated using the AWS. BNP was assayed using a rapid immunofluorescence test
and a bedside measuring device (Triage BNP Test, Biosite, Jouy-en-Josas, France). To
ensure reliability of the assay, i) device calibration was checked daily; ii) the assay cassette
was removed from the refrigerator at least one hour before blood collection; and iii) the
Page 36 of 44
4
assay was carried out immediately after blood sample collection. Two devices were supplied
per centre: the first, which was used in the BNP-guided group, displayed the BNP result; the
second did not show the result in visual display or print form and was used in the control
group. All BNP devices were calibrated weekly using a quality control, as recommended by
the manufacturer.
Fluid and electrolyte management
In the control group, the clinicians were blinded to the BNP assay results, and all
treatments, including diuretics, were carried out according to standard practice. BNP results
were uploaded from the device memory at study completion. In the BNP-guided group, on
days with a BNP level ≥200 pg/mL, fluid intake was restricted (baseline infusion ≤500
mL/24 hours, parenteral nutrition ≤1000 mL/24 hours, no saline solutions apart from
nutrition and drugs) and furosemide was administered (as intravenous bolus doses of 0 to 30
mg every 3 hours, to achieve a target urine output of 4.5 to 9 mL/Kg/3 hours) (see appendix).
The 200 pg/mL threshold was chosen based on a previous study showing that BNP levels
were higher in patients who failed weaning from mechanical ventilation than in successfully
weaned patients.(E3) Fluid intake restriction and diuretic administration according to BNP
levels were continued for at least 24 hours after extubation in the BNP-guided group.
Sodium, potassium, urea, creatinine, and arterial blood gases were monitored daily in
all patients. Recommendations were given to prevent and/or treat possible adverse events
related to diuretic treatment in the BNP-guided group, as detailed hereafter. When urine
output exceeded 36 mL/Kg/12 hours or blood potassium was <4.0 mEq/L while receiving
diuretics, blood electrolytes were checked within the next 12 hours. In the event of metabolic
alkalosis with furosemide, acetazolamide was added (250 mg every 8 hours if pH >7.45 or
500 mg every 8 hours if pH >7.50) in the absence of contraindications (history of
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5
hypersensitivity to acetazolamide or sulphonamides; severe hepatic, renal, or adrenal
insufficiency; or history of renal lithiasis). If blood potassium was <4.5 mEq/L during
diuretic therapy, supplemental potassium was given (≥4 g/day if blood potassium was <4·0
mEq/L or ≥3 g/day if blood potassium was between 4.0 and 4.4 mEq/L). Magnesium
supplements (≥1.5 g/day) were given routinely during diuretic treatment. If plasma urea
doubled during diuretic treatment, the diuretic was suspended. In this case or in the event of
oliguria (urine output <6 mL/kg/12 hours) despite maximum-dose diuretic therapy,
echocardiography was considered to enable dobutamine therapy (starting at 5
micrograms/Kg/min) in the event of LVD (ejection fraction <45%). An additional increase
in the diuretic dosage was considered only in the absence of renal function deterioration
(need for renal replacement therapy, greater than 50% plasma creatinine increase, or
doubling of plasma urea). If blood sodium exceeded 150 mEq/L, hypotonic solutions could
be given to increase the daily fluid intake above 500 mL (no salt intake). If iodinated
contrast agent injection was expected to be needed, an infusion of 500 mL or more of 0.9%
saline was recommended and diuretic administration was suspended six hours before and six
hours after the infusion. The other conditions requiring furosemide discontinuation were as
follows: metabolic alkalosis with arterial pH >7.55, blood potassium <3.0 mEq/L, blood
sodium >155 mEq/L, renal function deterioration (same definition as above), urine output >
9 mL/kg/3 hours, and hypotension requiring fluid bolus or vasopressor therapy. When
diuretic treatment was stopped because of one of these abnormal findings, it could be re-
instituted after correction of the abnormal value, in accordance with the inclusion and non-
inclusion criteria. The first furosemide dose after re-institution was half the last dose
administered.
Ventilatory management
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6
During ventilation using the AWS, sedation was stopped whenever possible, whereas
analgesia could be continued, with a target Ramsay score of 2–3. The AWS (SmartCareTM
)
has been described elsewhere (E4-8). Briefly, it is a closed-loop knowledge-based system
that interprets clinical data in real time and provides continuous adjustment of the level of PS
delivered to intubated patients, with the goal of keeping the patient within a zone of
“respiratory comfort”. Respiratory comfort is defined primarily as a respiratory rate within
the range of 15 to 30 breaths/min (up to 34 in patients with neurologic disease), a tidal
volume above a minimum threshold (250 or 300 ml depending on the weight), and an end-
tidal CO2 level below a maximum threshold (55 or 65 mmHg depending on the presence of
COPD). Average measurements of these parameters are made every 2 to 5 minutes and the
level of PS is periodically adapted by the system in steps of 2 to 4 cm of water. The system
automatically tries to reduce the PS level to a minimal value and initiates the equivalent of a
spontaneous breathing trial when predetermined thresholds of PS are reached in a state of
normal ventilation with PEEEP ≤ 5 cm H2O. Upon successful completion of the equivalent
of a spontaneous breathing trial, the ventilator issues a directive stating that the patient is
"ready for separation from ventilator".
If the PEEP level at AWS initiation was >5 cmH2O, the level was set manually to no
more than 5 cmH2O as soon as possible, to allow the system to perform separation trials.(E8)
If the PEEP decrease caused SpO2 to drop below 90%, the adjustment was postponed then
re-attempted every 12 hours. When the AWS declared the patient “ready for separation”,
extubation was performed as soon as possible, after checking for the other required
extubation criteria, namely, SpO2 ≥90% with FiO2 ≤40% and PEEP ≤5 cmH2O,
haemodynamic stability, Ramsay Score ≤3 with continuous sedation stopped or minimal
(analgesic medication could be continued), audible cough (spontaneously or during
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7
aspiration), need for fewer than three endotracheal suctionings during the last four hours, and
no scheduled procedure requiring sedation or scheduled surgery.
Assist-control ventilation was resumed during ventilation using the AWS in case of
respiratory worsening with a respiratory rate >40/min or hypoxaemia (FiO2 >60% and PEEP
>8 cmH2O required to obtain SpO2≥90%). BNP was no longer assayed in controlled mode
ventilation. When the daily PS test became positive again, the patient was switched back to
ventilation using the AWS and managed according to his or her randomisation group. The
diagnosis of ventilator-associated pneumonia was based on the following usual criteria:
systemic signs of infection, new or worsening infiltrates on the chest roentgenogram,
purulent tracheal secretions, and bacteriologic evidence of pulmonary parenchymal infection
(chiefly from distal airway sampling using a protected telescoping catheter or
bronchoscopy).(E9) Non-invasive ventilation was allowed after extubation if deemed
necessary by the attending physician. Re-intubation criteria were as follows: respiratory
distress (with SpO2<85%, respiratory rate >35/min or pH<7.30), shock (systolic blood
pressure<90 mmHg despite ≥1000 mL fluid bolus, or requirement for vasopressor therapy),
or coma (Glasgow Coma Scale <8 or having decreased by ≥2 points compared to the score
immediately after extubation). In the event of respiratory distress requiring re-intubation, the
patient was not re-ventilated using the AWS. Last, a general recommendation was made to
investigators to wait until day 10 after randomisation before deciding to perform
tracheotomy, if at all possible.
End points
The primary end point was the time from randomisation to successful extubation
(patient alive and without re-intubation 72 hours after extubation). Secondary end points
included time to first extubation, time to successful weaning from invasive and non-invasive
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8
ventilation (defined as the time from randomisation to completion of 72 hours of unassisted
spontaneous breathing without non-invasive ventilation for ≥3 hours per day), ventilator-free
days calculated as the number of days without mechanical ventilation within 60 days after
randomisation (patients who died or were dependent on mechanical ventilation for more than
60 days had zero ventilator-free days), ICU and hospital lengths of stay, ICU and hospital
deaths, and mortality on day 60 after randomisation.
Statistical analysis
We estimated the sample size needed to detect an at least 40% decrease in weaning
duration in the BNP-guided fluid management group compared to the control group, with an
α risk of 5% and a β risk of 10% (power of 90%). In a previous multicentre trial, weaning
duration in patients ventilated using the AWS was 4·4±4·0 days.(E8) Assuming a slightly
higher standard deviation equal to the mean (4·4), and considering that the use of non-
parametric tests might require up to 15% additional subjects,(E10) a sample size of 150
patients per group was deemed necessary. The data were analysed using SPSS Base 18
(SPSS Inc, Chicago, IL, USA) and R 2.10.1 (The R Foundation for Statistical Computing,
Vienna, Austria). We used the chi-square or Fisher exact test to compare categorical
variables between study groups and the Mann-Whitney test to compare continuous variables,
including the primary end point. The primary end point was also analysed in the three
predefined subgroups (COPD, LVD, and neither). We also used the Kaplan-Meier method to
assess the effect of BNP-guided fluid management on the cumulative probability of
successful extubation. Because the proportional hazards assumption was not met during the
60-day follow-up, we used the Breslow-Gehan-Wilcoxon test to assess differences between
groups (E11). This test allows weighting of time points by the number of cases at risk at
each time point (E12). Lastly, the effect of BNP-guided fluid management on the cumulative
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9
incidence of successful extubation was assessed while considering need for continuous
sedation as a competing event, according to the Gray model (E13, 14). Two-sided p values
<0.05 were considered significant.
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10
Table E1: Algorithm for dosing diuretics according to BNP levels in the intervention
group
Initial dose of furosemide
(mg)
Urine output
(ml/kg/3 hours)
Subsequent doses of furosemide
(mg)
20
< 4.5 30
4.5–6 20
6–7.5 15
7.5–9 10
>9 0
Example for a patient of 70 kg
Initial dose of furosemide
(mg)
3-hour urine output
(ml)
Subsequent doses of furosemide
(mg)
20
< 315 30
315–419 20
420–524 15
525–630 10
>630 0
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11
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