Cardiac function during weaning failure: the role of diastolic dysfunction
Roche‑Campo et al. Ann. Intensive Care
Cardiac function during weaning failure: the role of diastolic dysfunction
Ferran Roche‑Campo 0 2 3
Alexandre Bedet 0 1 3
Emmanuel Vivier 0 3 6
Laurent Brochard 0 3 4 5
Armand Mekontso Dessap 0 1 3
0 Service de Réanimation Médicale, DHU AT‐VB, Hôpitaux Universitaires Henri Mondor, Assistance Publique - Hôpitaux de Paris, 51 Avenue du Maréchal de Lattre de Tassigny , 94010 Créteil Cedex , France
1 Groupe de Recherche Clinique CARMAS, Institut Mondor de Recherche Biomédicale, Faculté de Médecine de Créteil, Université Paris Est Créteil , 94010 Créteil , France
2 Servei de Medicina Intensiva, Hospital Verge de la Cinta , Tortosa, Tarragona , Spain
3 Service de Réanimation Médicale, DHU AT‐VB, Hôpitaux Universitaires Henri Mondor, Assistance Publique - Hôpitaux de Paris, 51 Avenue du Maréchal de Lattre de Tassigny , 94010 Créteil Cedex , France
4 Interdepartmental Division of Critical Care Medi‐ cine, University of Toronto , Toronto , Canada
5 Keenan Research Centre and Critical Care Department, St Michael's Hospital , Toronto , Canada
6 Service de Réanimation Polyvalente, Centre hospitalier Saint‐ Joseph Saint‐Luc , Lyon , France
Background: Cardiac dysfunction is a common cause of weaning failure. Weaning shares some similarities with a cardiac stress test and may challenge active phases of the cardiac cycle‑ like ventricular contractility and relaxation. This study aimed at assessing systolic and diastolic function during the weaning process and scrutinizing their dynamics during weaning trials. Methods: Echocardiography was performed during baseline ventilator settings to assess cardiac function at the initiation of the weaning process and at the start and the end of consecutive weaning trials (performed at day‑ 1, day‑ 2, and before extubation if applicable) to explore the evolution of left ventricle contractility and relaxation in a subset of patients. Results: Among 67 patients included, weaning was prolonged (≥ 7 days) in 18 (27%) patients and short (< 7 days) in 49 (73%). Prevalence of systolic dysfunction and isolated diastolic dysfunction before the initiation of weaning process were 37 and 17%, respectively. Isolated diastolic dysfunction was more frequent in patients with prolonged weaning as compared to their counterparts. Thirty‑ one patients were explored by echocardiography during consecutive weaning trials. An increase in filling pressures with an alteration of ventricular relaxation (as assessed by a decrease in tissue Doppler early mitral diastolic wave velocity) was found during failed weaning trials. Conclusions: Isolated diastolic dysfunction was associated with a prolongation of weaning. Increased filling pressures with left ventricle relaxation impairment may be a key mechanism of weaning trial failure.
Weaning; Diastolic function; Relaxation; Diastolic reserve
Weaning from mechanical ventilation is an essential step
in the care of critically ill intubated patients, accounting
for approximately 40% of the total duration of
mechanical ventilation [
]. Given that increased time on
mechanical ventilation is associated with higher mortality rates
], it is crucial to safely wean the patient from the
ventilator as soon as possible. Pulmonary edema is one of the
main causes of weaning failure [
], and cardiovascular
dysfunction during weaning may involve systolic [
or diastolic alterations [
In healthy subjects, relaxation enhancement during
exercise blunts the increase in venous return to
maintain normal filling pressures [
]. However, an impaired
relaxation may be unmasked during exercise in patients
with mild symptoms of heart failure, irrespective of the
presence of diastolic dysfunction at rest [
weaning shares some similarities with a cardiorespiratory
stress test [
], the same pathophysiology is
conceivable to explain the increase in filling pressures during
weaning failure of cardiac origin. We hypothesized that
diastolic dysfunction at baseline or impaired diastolic
relaxation during weaning trials may mediate weaning
The present study had two primary aims: first, to assess
cardiac function at initiation of the weaning process and
evaluate its association with weaning outcomes; second,
to assess the dynamics of left ventricle (LV) contractility
and relaxation in a subgroup of patients during
consecutive weaning trials.
This ancillary study, planned a priori, was performed
in one (Henri Mondor University hospital, Creteil,
France) of the nine centers participating in the B-type
natriuretic peptide (BNP) for the fluid Management of
Weaning (BMW) trial [
]. The BMW study was a
randomized, controlled trial comparing a biomarker-guided
depletive fluid management strategy to usual care
during ventilator weaning. A detailed description of the
BMW study design (NCT00473148) has been published
]. Inclusion criteria of the BMW study
were those allowing early initiation of ventilator
weaning in patients receiving mechanical ventilation for
at least 24 h. Permanent non-inclusion criteria were:
pregnancy or lactation, age < 18 years, known allergy to
furosemide or sulfonamides, tracheostomy at inclusion,
hepatic encephalopathy, cerebral edema, acute
hydrocephalus, myasthenia gravis, acute idiopathic
polyradiculoneuropathy, decision to withdraw life support, and
prolonged cardiac arrest with a poor neurological
prognosis. The protocol was approved by our institution’s
local ethics committee (Comité de Protection des
Personnes Ile-de-France IX, approval number 06–035), and
informed consent was signed by the patient or a close
relative. The main result of the BMW trial was to show
that a BNP-driven depletive fluid management strategy
decreased the duration of weaning without increasing
adverse events [
To standardize the weaning process, patients were
ventilated using a computer-driven automated weaning
system (AWS, Evita Smart Care System, Dräger Medical,
Lubeck, Germany), which gradually decreased the
pressure support level (while maintaining the patient within
a zone of respiratory comfort), as previously described
]. When the AWS declared the patient ready for
separation, extubation was performed as soon as possible
(including during the night), provided the patient met the
other criteria required for extubation [
In a subgroup of 31 patients for whom
echocardiography availability allowed consecutive examinations,
a daily weaning trial was performed if the patient was
still ventilated with the AWS and not ready for
separation. The weaning trial lasted one hour and consisted of
a low-pressure support trial (10 cm H2O in case of
moisture humidifier or 7 cm H2O in case of heated humidifier)
with zero-PEEP [
]. Criteria for weaning trial failure
were: respiratory rate > 35 breaths/min and/or increased
accessory muscle activity, SpO2 < 90%, heart rate > 140
beats/min, systolic blood pressure > 200 or < 80 mmHg,
diaphoresis and clinical signs of distress. More
information about the study protocol is available in the data
supplement (Additional file 1: ESM Study protocol).
Classification of weaning
Successful extubation was defined as patient alive and
without reintubation 72 h after extubation. We adapted
the WIND study classification of weaning process [
the use of the AWS and further summarized this
classification into two groups as follows: short weaning
(patients successfully extubated within 6 days of AWS)
and prolonged weaning (patients still ventilated after 7
days of AWS or more). Patients who died between 1 to 6
days and after 6 days of AWS were classified as short and
prolonged weaning, respectively. This dichotomization
was driven by the need for parsimony as per the limited
sample size, and the fact that prolonged weaning
identifies a subgroup of patients at increased risk of mortality,
as compared to their counterparts [
In all included patients (n = 67), echocardiography was
performed to assess cardiac function during baseline
ventilator settings (in pressure support ventilation), just
before starting the weaning process with the AWS. In
addition, we examined in a subset of patients (n = 31)
whether weaning trials (low-pressure support with
zeroPEEP) could induce an alteration of systolic or diastolic
function, independently from their baseline function. In
this subgroup, echocardiography was performed at the
beginning and end of consecutive weaning trials
performed at day-1, day-2, and before extubation. All
echocardiographic examinations were performed by a single
trained operator (FRC, with competence in advanced
critical care echocardiography) not involved in patient
care, using a transthoracic ultrasound device (EnVisor,
Philips ultrasound, Bothell, WA). Briefly, the following
echocardiographic views were examined with the patient
in the semi-recumbent position: four-chamber and
twochamber long-axis views to assess left ventricle ejection
fraction (LVEF), computed from LV volumes using the
bi-plane Simpson method when image quality was
suitable, or visually estimated when poor image quality did
not allow sufficient identification of the endocardium;
tissue Doppler peak systolic (s′) wave at the lateral mitral
valve annulus; right ventricle size (a dilated right
ventricle was defined by an end-diastolic right ventricle/left
ventricle area ratio > 0.6) and function (using the
tricuspid annular plane systolic excursion); diastolic
function [using pulsed-wave Doppler early (E) and late (A)
diastolic wave velocities at the mitral valve, and tissue
Doppler early (e′) and late (a′) diastolic wave velocities
at the lateral mitral valve annulus]. Systolic dysfunction
was defined as LVEF < 50%. Isolated diastolic
dysfunction (with preserved LVEF) was defined using the 2016
European Society of Cardiology guidelines (LVEF ≥ 50%
with plasma BNP concentration > 35 pg/mL and [E/e′
ratio ≥ 13 or e′ < 9]) [
]. Because there is no single
widely accepted definition for diastolic dysfunction, we
also assessed, as a sensitivity analysis (available in
Additional file 2: Table 1), other definitions proposed by
scientific societies and experts, as follows: (1) LVEF ≥ 50%
and e′ < 8 cm/s [
]; (2) LVEF ≥ 50% and (E/e′ ratio > 8 or
e′/a′ ratio < 1) [
]; or (3) LVEF ≥ 50%, E/e′ ratio > 8 and
plasma BNP concentration > 200 pg/mL [
of LV contractility and relaxation during weaning trials
were assessed using the s′ and e′ waves, respectively [
]. Pulsed-wave Doppler flows were obtained below the
aortic valve to assess LV outflow tract for cardiac output
computation. Mitral and aortic regurgitation were
measured semi-quantitatively using color-flow Doppler and
were considered severe at grades III–IV .
Echocardiographic images were digitally stored, and a
computerassisted evaluation was performed off-line by two trained
operators (EV, AMD). All measures were averaged over
a minimum of three cardiac cycles (five to ten in case of
The data were analyzed using SPSS Base 20 (IBM-SPSS
Inc, Chicago, IL, USA). Categorical variables were
expressed as numbers (percentage) and continuous data
as medians (25th–75th percentiles), unless otherwise
specified. We used the Chi-squared or Fisher exact test
to compare categorical variables between groups and the
Student’s T test, Mann–Whitney test or Wilcoxon paired
test to compare continuous variables, as appropriate. A
p value of < 0.05 was considered statistically significant.
Patient population, cardiac function and weaning outcome
Among the 75 participants enrolled, we have explored
cardiac function in 67. Eight patients were excluded
because of echocardiography unavailability (Fig. 1).
Weaning was prolonged in 18 (27%) patients and short
patients admitted to the ICU and
enrolled in the BMW clinical trial
included in the ancillary study
272 excluded from the BMW clinical trial
71 without weaning criteria
93 had renal failure
20 had severe neuromuscular disease
9 had hepatic encephalopthy
8 were tracheotomised
16 consents not obtained
12 were not committed to full support
8 echocardiography unavailability
67 patients with echocardiography at day-1
31 patients with serial echocardiographies during
SAPS Simplified Acute Physiologic Score, ICU intensive care unit, MV mechanical ventilation, SOFA sequential organ failure assessment, RPP product of heart rate and
systolic arterial pressure, FiO2 fraction of inspired oxygen, BNP B‑type natriuretic peptide, LVEF left ventricle ejection fraction, E early diastolic velocity measured using
Doppler transmitral flow, A late diastolic velocity measured using Doppler transmitral flow, e′ early peak diastolic velocity of mitral annulus, a′ late peak diastolic
velocity of mitral annulus, RV right ventricular end‑ diastolic area, LV left ventricular end‑ diastolic area
a Diastolic function could not be assessed in one patient for e′ and in two patients for E/e′ ratio
b Heart valve disease is defined as a severe aortic or mitral regurgitation (grade III/IV). Data are presented as n (%) or median (1st quartile–3rd quartile)
in 49 (73%) patients. All patient characteristics were
similar between groups, except for a lower PaO2/FiO2
ratio at inclusion in patients with prolonged weaning as
compared to their counterparts (Table 1). Before
starting the weaning process, the majority of patients had
an impaired cardiac function; overall, the prevalence of
systolic dysfunction and isolated diastolic function were
37 and 17%, respectively. Isolated diastolic dysfunction
was more frequent in patients with prolonged weaning
(≥ 7 days) as compared to their counterparts (Table 1).
Tricuspid annular plane systolic excursion was also lower
in patients with prolonged weaning as compared to
others, while other echocardiographic variables were similar
between groups (Table 1). End-diastolic right ventricle/
left ventricle area ratio and pulmonary artery systolic
pressure were similar in patients with or without isolated
diastolic dysfunction: 0.59 [0.58–0.66] versus 0.56 [0.44–
0.67], p = 0.46 and 43 [
] versus 37 [
p = 0.41, respectively. Cardiovascular treatments and
weaning outcomes are reported in Table 2. Most patients
received diuretics, including all those with prolonged
weaning, but the latter group had a more positive fluid
balance during weaning as compared to the short
weaning group. In comparison with the short weaning group,
fewer patients in the prolonged weaning group received
vasodilators. Weaning duration, ICU length of stay and
Data are presented as n (%) or median (1st quartile–3rd quartile). Patient who died before day‑28 had 0 ventilator free days
ICU intensive care unit
mortality were significantly greater in the prolonged
weaning group (Table 2).
Dynamics of LV contractility and relaxation during weaning trials
Among the 67 patients included, 31 were explored
during consecutive weaning trials (Additional file 2: Table 2).
Sixteen of these patients (52%) successfully passed the
first weaning trial (day-1), whereas 15 (48%) failed. The
evolution of cardiac clinical parameters and
echocardiographic parameters during consecutive weaning
trials (day-1, day-2, and before extubation) are displayed
in Figs. 2 and 3, respectively. Failure of weaning trial was
more often associated with an increase in systolic
arterial pressure, heart rate and their product
(pressurerate product), as compared with weaning trial successes
(Fig. 2). A marked increase in LV filling pressures (as
assessed by E/e′ ratio) concomitant with an alteration of
diastolic relaxation (as assessed by e′ velocity) were found
in failed weaning trials (Fig. 3, Table 3). The e′
velocity increased in fewer (6.7%) and decreased in greater
(93.3%) number of patients who failed weaning trials, as
compared to successes (p < 0.001).
We herein report a high prevalence of cardiac
dysfunction at initiation of weaning. Prolonged weaning
was associated with a predominantly isolated diastolic
rather than systolic dysfunction in our cohort.
Echocardiographic exploration suggested that LV relaxation
impairment with increased filling pressures may be a key
mechanism of failed weaning trials.
Cardiac dysfunction before the initiation of weaning
Cardiac dysfunction plays a critical role in weaning
outcome. In patients with prolonged weaning (≥ 7 days) in
our series, systolic and isolated diastolic dysfunction
were found in 22 and 39% of patients, respectively.
Systolic dysfunction is a known risk factor for extubation
]. However, in patients with preserved LVEF,
increase in preload (volume status) and afterload (arterial
stiffness) during weaning may also impair LV compliance
and provoke pulmonary edema, especially in case of
preexisting diastolic dysfunction [
]. Our results are
consistent with some previous reports describing diastolic
dysfunction as a risk factor for weaning failure [
5, 6, 25
The heterogeneity of diastolic dysfunction definitions
may explain the variability of its incidence and
prevalence in critically ill patients [
Data are presented as median (1st quartile; 3rd quartile)
s′ peak systolic velocity at the lateral mitral valve annulus, e′ early peak diastolic velocity of mitral annulus, E early diastolic velocity measured using Doppler
a s′ could not be assessed in three patients
Cardiac dynamics during weaning
During weaning, removal of positive-pressure
ventilation increases LV preload and afterload, inducing some
physiologic changes similar to those observed during a
cardiovascular stress test. Tachycardia and
hypertension are two major determinants of diastolic dysfunction.
They were more pronounced during weaning failure in
our series and have been reported as frequent features
of weaning-induced cardiac dysfunction [
Pressurerate product was significantly increased during failed
weaning trials, as compared to successes. Tachycardia
could participate in the alteration of diastolic function by
reducing diastolic filling time and/or decreasing coronary
]. In addition, LV diastolic performance has
been shown to be strongly influenced by the hypertensive
response to exercise. Hypertension is well known to
exacerbate heart failure in patients with preserved ejection
The fall in LV pressure during relaxation is a key
determinant of diastolic function, and depends on intrinsic
(contractility, LV stiffness) and extrinsic (preload,
afterload) factors [
]. The E wave velocity of mitral inflow
assesses the early diastolic filling of LV, primarily
reflecting the driving pressure between the left atrium and the
left ventricle, and is therefore affected by preload and
relaxation. The e′ velocity, measured with tissue Doppler
at the lateral mitral valve annulus, is usually used to
correct for the effect of LV relaxation on E wave [
21, 22, 32
Thus, the E/e′ ratio is considered a reliable measure of LV
filling pressure, with minimal influence of intrinsic
relaxation or age . Although the assessment of diastolic
function with these validated Doppler indices is usually
highly reproducible [
21, 32, 34
], the detection of small
changes may be challenging for non-experts in routine
We found an increase in E/e′ ratio during weaning trial,
which is compatible with an elevation of filling pressures,
as previously demonstrated [
]. Several studies have
found an independent association between e′ and LV
22, 33, 36
]. As compared to the E wave
velocity, preload may have a minimal effect on e′ [
21, 22, 37
especially in patients with diastolic dysfunction .
Our finding that e′ velocity tends to reduce during failed
weaning trials is therefore compatible with an impaired
diastolic relaxation in these patients, although a causality
cannot be ascertained. This phenomenon is compatible
with a lack of diastolic reserve, which may prevent the
ability of LV to improve diastolic function and maintain
normal filling pressures during stress [
studies evaluated the diastolic reserve with
echocardiography in patients with heart failure and preserved
ejection fraction [
]. A decrease in e′ wave, together with
a concomitant increase in E/e′ ratio, was the strongest
markers of impaired diastolic reserve in these patients.
Similar results were found in our study during failed
weaning trials. A dynamic alteration of diastolic
function during weaning stress in patients lacking diastolic
reserve could be a possible mechanism of weaning
failure, independently from the cardiac function at baseline.
This hypothesis is in accordance with a previous work
by Moschietto et al., who suggested the evolution of the
LV relaxation rate during a spontaneous breathing trial
(SBT) as the key factor in weaning outcome. However,
the decrease in e′ velocity during failed weaning trials is
in contrast with this former study which found no
significant variation during SBT. This discrepancy may be
explained by the timing of the second echocardiography.
These authors repeated echocardiographic examination
only 10 min after starting the weaning trial, whatever its
total duration , whereas we rather assessed dynamic
changes at the end of the weaning trial. The modality of
weaning trial may also play a critical role [
The key mechanism of weaning failure did not seem
to involve systolic dysfunction in our study, as also
suggested by others [
5, 25, 35
]. Inotropic support could
hypothetically exacerbate stress-induced diastolic
dysfunction by increasing heart rate and/or myocardial
oxygen demand. Dobutamine was even used as a stress test
to diagnose heart failure with preserved ejection fraction
]. Isolated diastolic dysfunction is frequent in ICU
patients, especially in the elderly [
], and its diagnosis
may deserve a specific therapeutic management in case
of complicated weaning. Conservative and depletive fluid
management are known to decrease the duration of
ventilator support [
] and weaning [
], respectively. In our
series, we could not assess the specific role of diuretics
on SBT-induced cardiovascular burden because the vast
majority of patients in the entire cohort received
diuretics. Despite the use of diuretics in all patients with
prolonged weaning, the urine output was lower and the
fluid balance was higher in this group. The control of
volume overload during diastolic heart failure may require
higher doses of furosemide and/or the association of
thiazide-like diuretics [
]; these strategies should be
tested in future trials of fluid management during
weaning. Fewer patients with prolonged weaning were treated
with vasodilators as compared to those with short
weaning. Vasodilators may be used to blunt the hypertensive
response to weaning and expedite separation from the
]. Future trials are needed to determine the
optimal blood pressure target during ventilator weaning.
Whether aerobic exercise training in ventilated patients
could improve the diastolic reserve [
], ameliorate the
tolerance of weaning trials and fasten the weaning
process also needs to be explored in future studies.
Strengths and limitations
Strengths of our study include its prospective design
and the detailed cardiac assessment using
echocardiography. In particular, our study comprehensively assessed
diastolic function at weaning start and its dynamics
during consecutive weaning trials. Limitations include the
monocentric setting and the limited sample size, which
precluded any multivariable analysis of factors associated
with prolonged weaning. Also, only a minority of patients
explored consecutively fulfilled our definition of
diastolic dysfunction, preventing any evaluation of the
relationship between diastolic dysfunction at baseline and
relaxation dynamics during weaning trials. The lack of a
single gold standard definition of diastolic dysfunction
complicated the analysis of our data, inasmuch as there
was some patient heterogeneity concerning the changes
in diastolic indices. Last, the characterization of the
cardiac origin of weaning failure with tools like the
pulmonary artery catheter or cardiac biomarkers would have
strengthened our findings.
Isolated diastolic dysfunction is more frequent in
patients with prolonged weaning (≥ 7 days), as compared
to those with a shorter weaning. In addition, failure of
weaning trial seems associated with an elevation of
filling pressures mediated by a stress-induced impairment
of diastolic relaxation, which is compatible with a lack of
diastolic reserve. Documentation of diastolic dysfunction
as a cause of weaning failure is critical, as it may require
specific management (especially vasodilators to blunt
the hypertensive response to the weaning cardiovascular
Additional file 1. Study protocol (data supplement)
Additional file 2: Table S1. Prevalence of diastolic dysfunction using
several definitions, according to weaning category (n = 67). Table S2.
Patient characteristics and echocardiographic variables before starting the
weaning process of patients explored during consecutive weaning trials
(n = 31)
A: late diastolic velocity measured using pulsed‑ wave Doppler transmitral
flow; a′: tissue Doppler late diastolic wave velocities at the lateral mitral valve
annulus; AWS: automated weaning system; BNP: B‑type natriuretic peptide;
E: early diastolic velocity measured using pulsed‑ wave Doppler transmitral
flow; e′: tissue Doppler early diastolic wave velocities at the lateral mitral valve
annulus; ICU: intensive care unit; LV: left ventricle; LVEF: left ventricle ejection
fraction; PEEP: positive end‑ expiratory pressure; s′: tissue Doppler peak systolic
wave velocity at the lateral mitral valve annulus; SpO2: peripheral oxygen
saturation; SBT: spontaneous breathing trial.
AMD have full access to all data and take responsibility for the integrity of the
data and the accuracy of the data analysis. FRC, EV, LB and AMD contrib‑
uted to initial study design, data analysis and interpretation, drafting of the
manuscript, critical revisions for intellectual content, and final approval of the
version to be published. AB contributed to data analysis and interpretation,
drafting and critical revisions of the manuscript, and final approval of the ver‑
sion to be published. All authors read and approved the final manuscript
The authors declare that they have no competing interests.
Availability of data and materials
Clinical datasets are available from the corresponding author on personal
Ethics approval and consent to participate
The protocol was approved by our institution’s local ethics committee (Comité
de Protection des Personnes Ile‑ de‑France IX, Approval Number 06‑035), and
informed consent was signed by the patient or a close relative.
Springer Nature remains neutral with regard to jurisdictional claims in pub‑
lished maps and institutional affiliations.
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