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Mechanical ventilation in septic shock

Article  in  Current Opinion in Anaesthesiology · January 2021

DOI: 10.1097/ACO.0000000000000955

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Bruno Adler Maccagnan Pinheiro Besen Bruno Tomazini

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REVIEW

CURRENT
OPINION Mechanical ventilation in septic shock
Bruno Adler Maccagnan Pinheiro Besen a,
Bruno Martins Tomazini b, and Luciano Cesar Pontes Azevedo a,b

Purpose of review
The aim of this study was to review the most recent literature on mechanical ventilation strategies in patients
with septic shock.
Recent findings
Indirect clinical trial evidence has refined the use of neuromuscular blocking agents, positive end-expiratory
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pressure (PEEP) and recruitment manoeuvres in septic shock patients with acute respiratory distress syndrome.
Weaning strategies and devices have also been recently evaluated. The role of lung protective ventilation in
patients with healthy lungs, while recognized, still needs to be further refined. The possible detrimental effects
of spontaneous breathing in patients who develop acute respiratory distress syndrome is increasingly
recognized, but clinical trial evidence is still lacking to confirm this hypothesis. A new concept of lung and
diaphragm protective is emerging in the critical care literature, but its application will need a complex
intervention implementation approach to allow adequate scrutiny of this concept and uptake by clinicians.
Summary
Many advances in the management of the mechanically ventilated patient with sepsis and septic shock
have occurred in recent years, but clinical trial evidence is still necessary to translate new hypotheses to the
bedside and find the right balance between benefits and risks of these new strategies.
Keywords
acute respiratory distress syndrome, mechanical ventilation, sepsis, septic shock

INTRODUCTION ARDS. However, specific recommendations for inva-

Invasive mechanical ventilation is a lifesaving
organ support used for patients with sepsis or septic
shock. Reasons to institute invasive mechanical
ventilation include, but are not limited to reduced
level of consciousness secondary to septic enceph-
alopathy or as manifestation of hypoperfusion;
acute respiratory failure either from primary lung
injury from pneumonia or secondary acute respira-
tory distress syndrome (ARDS) from sepsis itself;
and intubation due to a perceived risk of clinical
worsening to allow for a timely intubation [1]. All
organ support strategies may come with its own
downsides, though, either because of its precise
and specific adjustments or, in the case of mechan-
ical ventilation, due to downstream consequences,
such as sedation, paralysis, immobility, infection
and other issues.
In this review, we present recent developments
in the management of septic shock patients who
need invasive mechanical ventilation at some point
during the disease course. Septic shock is the most
common cause of shock in critical care units and
emergency departments and infections, pulmonary
or not, are common reasons for a patient to develop
sive mechanical ventilation in septic shock are usu-
ally not available and the evidence comes mostly
from clinical trials in critically ill patients, which are
usually applicable to septic shock.
MECHANICAL VENTILATION IN SEPSIS
WITHOUT ACUTE RESPIRATORY
DISTRESS SYNDROME
Many septic shock patients undergo invasive
mechanical ventilation for reasons other than respi-
ratory failure and ARDS, such as decreased level of
consciousness. In these patients, a meta-analysis
showed that lung protective ventilation is associ-
ated with lower odds of mortality with an apparent
a
Medical Intensive Care Unit, Disciplina de Emergências Clı́nicas, Hos-
pital das Clı́nicas HCFMUSP, Faculdade de Medicina, Universidade de
São Paulo and bHospital Sı́rio Libanês, São Paulo (SP), Brazil
Correspondence to Luciano Cesar Pontes Azevedo, Hospital Sirio-
Libanes, Rua Prof. Daher Cutait, 69, São Paulo 01308 060, Brazil.
Tel: +55 (11) 3394 5739; e-mail: luciano.azevedo@hsl.org.br
Curr Opin Anesthesiol 2021, 33:000–000
DOI:10.1097/ACO.0000000000000955

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Intensive care and resuscitation
KEY POINTS
 Patients with septic shock without acute respiratory
distress syndrome (ARDS) should undergo low tidal
volume ventilation, although forceful reduction of tidal
volumes is sometimes not achievable and neither
desired in patients with acidosis or a higher
respiratory drive.
 The best standards for mechanical ventilation of septic
shock with ARDS include low tidal volume ventilation
limiting plateau pressure (with as needed short-term
neuromuscular blockade to achieve the desired targets),
titrated high positive end-expiratory pressures (for
paO2/FIO2 ratios < 200 mmHg), prone positioning (for
paO2/FIO2 <150 mmHg after a 12-h stabilization
period) and extracorporeal membrane oxygenation for
refractory cases in experienced centres.
 Side effects of ventilation strategies should be
considered in all patients with septic shock, especially
the effects of low tidal volume ventilation on blood pH
and the effects of high PEEP and recruitment
manoeuvres on the venous return and right
ventricular dysfunction.
 Airway driving pressure is a promising target of
mechanical ventilation under intense scrutiny, but head-
to-head comparisons to the current standards of care
are still warranted before its widespread
recommendation as the main target of lung
protective ventilation.
 Spontaneous breathing is increasingly recognized as a
potential mediator of lung injury, but the risk-benefit
profile of strategies to blunt spontaneous breathing is
still uncertain and the concept of lung and diaphragm
protective ventilation is emerging in the literature to
address this important research question.
dose-response relationship [2]. The PReVENT trial
addressed the question whether low tidal volume
ventilation would benefit patients intubated with
normal lungs [3]. In this trial, 961 patients were
randomized, of whom 25% had pneumonia or sep-
sis. To allow physiological separation, the authors
aimed to achieve 6 ml/kg target of tidal volume in
the intervention group and 10 ml/kg target of tidal
volume in the control group, with ventilatory
adjustments to ensure plateau pressures were not
excessive in the control and that the level of support
was not low in the intervention group. Under con-
trolled mechanical ventilation, physiological sepa-
ration in the tidal volume was possible, but under
pressure support ventilation, reductions of tidal vol-
ume were harder to achieve, and physiological sep-
aration was small. Ultimately, the trial did not show
beneficial clinical effects of one strategy over
another, although the risk of acute respiratory
2 www.co-anesthesiology.com
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acidosis was higher in the low tidal volume group.
These results are somewhat expected and underpin
the complex physiology behind minute-volume and
respiratory drive regulation in clinical practice and
highlight the need to update the causal model
behind these hypotheses.
The translation of these results to patients with
septic shock without ARDS requires an important
consideration: one must be cautious of applying
lung protective ventilation at any cost to patients
without ARDS in the context of metabolic acidosis.
In these patients, the best compromise may be to use
slightly higher tidal volumes and respiratory rates
while measures are taken to correct the metabolic
acidosis (such as resuscitation, bicarbonate or renal
replacement therapy). For patients who are not
mechanically ventilated, not accounting for this risk
may lead to the unwanted outcome of peri-intuba-
tion cardiac arrest [4], which is strongly associated
with worse outcomes.
MECHANICAL VENTILATION IN SEPSIS
WITH ACUTE RESPIRATORY DISTRESS
SYNDROME
The institution of invasive mechanical ventilation
in patients with septic shock and ARDS should aim
for low tidal volume ventilation, which is the stan-
dard of care for ARDS for nearly two decades now.
Low tidal volume ventilation is characterized by a
tidal volume of 4–8 ml/kg while limiting the plateau
pressure at 30 cmH2O [5]. This strategy requires
increased respiratory rates, initially in the range of
25–30 bpm to maintain adequate minute-volumes,
avoiding respiratory acidosis. For those patients
with ratio of arterial oxygen partial pressure to
fractional inspired oxygen ( paO2/FIO2) below
150 mmHg for more than 12 h (with a need of
>60% inspired oxygen), early institution of prone
positioning for at least 16 h is recommended [5,6].
Furthermore, where severe hypoxemia ensues, pro-
vided adequate patient selection, venous-venous
extracorporeal membrane oxygenation (VV-ECMO)
is now part of the standard-of-care in centres with
sufficient expertise [7,8].
Many advances in the understanding of the
ventilatory management in patients with ARDS
have been done, but these advances are still in
different phases of translation to clinical practice,
and many have yet to prove their efficacy in prop-
erly designed and adequately powered clinical trials.
Driving pressure
Airway driving pressure [DP, i.e. plateau pressure
(PPL) minus positive end-expiratory pressure (PEEP)]
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has become another potential target of lung protec-
tive ventilation since the publication of a reanalysis
of ARDS trials [9]. A mediation analysis suggested
that DP was the major mediator of outcome, instead
of low tidal volumes and PPL themselves. Lowering
the DP below a specific threshold can be achieved
through PEEP titration – and recruitment – while
maintaining the same tidal volume, which we will
discuss later. Another way to control airway driving
pressure is to further reduce tidal volumes with the
DP being the main target of ventilation instead of
blood pH (within the tidal volume and PPL con-
straints). Although lowering driving pressure below
a specific threshold may improve lung protection, its
effects on other highly correlated variables still need
further evaluation. Recently, a pilot study compared
a driving-pressure limiting strategy to a usual low
tidal volume ventilation strategy in patients with
ARDS. They included 31 patients and the authors
could achieve physiological separation between
groups (4.5 cmH2O mean difference on DP between
groups), suggesting that a larger trial would be feasi-
&
ble [10 ]. The main side effect of a driving pressure
limiting strategy was an increase in respiratory rate,
which did not fully compensate for paCO2 and lead to
higher paCO2 levels, although the risk of severe acute
respiratory acidosis (defined as pH < 7.1) was not
different between groups. This highlights the need
for a larger trial comparing these strategies before
widespread use of DP as a target in clinical settings.
Positive end-expiratory pressure titration
Current recommendations are that high PEEP levels
should be generally applied to patients with moder-
ate-to-severe ARDS [5,11]. However, how to best
achieve this high PEEP strategy is a matter of debate.
Without advanced respiratory monitoring, one can
titrate PEEP based on FIO2 levels only (using PEEP/
FIO2 tables). Although this is probably well toler-
ated, the driving pressure reanalysis suggests that
PEEP could be titrated based on its effects on respi-
ratory system compliance [9]. Uptitration of PEEP
resulting in a lower DP may be beneficial; on the
contrary, some patients will increase the DP with
PEEP increments and this is probably harmful.
Finally, some patients will sustain the same DP while
increasing PEEP, which could be desired or not
depending on the observed effects on oxygenation
and haemodynamics. In any scenario, however,
especially when translating these results to patients
with septic shock, the haemodynamic effects of
high PEEP levels should be monitored for tolerance.
High PEEP levels might lead to hypotension or
increased vasopressor use and most trial protocols
suggest a reduction in PEEP in such cases [12–14]. In
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Mechanical ventilation in septic shock Besen et al.
septic shock, this is specifically relevant, as patients
who have an impaired venous return may have a
detrimental effect of high PEEP. Furthermore, right
ventricular dysfunction as a manifestation of septic
myocardial dysfunction [15] may be worsened by
the PEEP titration strategy.
Advanced monitoring techniques can also be
used for PEEP titration. Oesophageal pressure meas-
urements can provide an estimate of pleural pressure
and therefore separate lung and chest wall mechan-
ics, which may contribute differently to compliance
in different patients. The EPVent-2 study tested the
hypothesis that an oesophageal pressure PEEP titra-
tion strategy (to avoid negative pleural pressures)
would be beneficial when compared with a usual
&
high PEEP/FIO2 table strategy [16 ]. The trial did not
show any beneficial effect of this strategy, either in
primary or secondary outcomes. Electrical imped-
ance tomography (EIT) could also allow individual-
ized PEEP titration through directly observing
overdistension and lung collapse, but clinical trials
are still needed to translate this technique to
clinical practice.
Recruitment manoeuvres
Recruitment manoeuvres have been widely used in
patients with ARDS with moderate to severe hypox-
emia. Of the trials of PEEP titrating strategies, the
LOVS trial used short recruitment manoeuvres (sus-
tained inflation to 40 cmH2O for 40 s) and did not
show deleterious effects of the strategy [12]. The ART
trial included 1010 patients and it showed that,
compared with standard lung protective mechanical
ventilation strategies, the open lung approach with
recruitment manoeuvres and staircase decremental
PEEP titration resulted in lower survival (hazard
ratio 1.2; 95% CI 1.01–1.42, P ¼ 0.041) [17].
Recently, results of the phase II PHARLAP trial were
published. The trial was prematurely interrupted
after the results of ART were published with only
115 of a planned 340 patients included [18]. There
was no difference in mortality or barotrauma, but
the authors showed a decreased need of adjuvant
therapies for hypoxemia and a higher incidence of
arrhythmias. A subsequent analysis of the ART trial
also showed that a cluster of patients characterized
by pneumonia as the cause of ARDS and requiring
vasopressors was responsible for the deleterious
effects observed in the trial; furthermore, no benefi-
cial effect on survival was observed in the other
&&
clusters of patients [19 ]. This evidence is important
in treating patients with septic shock, as this type of
recruitment manoeuvre (staircase decremental)
should be avoided in this population, especially in
patients with pneumonia. A possible strategy is to
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Intensive care and resuscitation
use short-term recruitment manoeuvres, but
this should be reserved for cases of refractory hyp-
oxemia.
Neuromuscular blockade
Since the publication of the ACURASYS trial [20],
the routine early use of neuromuscular blockade
(NMB) in patients with moderate-to-severe ARDS
became a centrepiece in treatment. However, the
ACURASYS trial was the only trial showing a
mortality benefit on the use of NMBs. The PETAL
network designed and conducted the ROSE trial,
which was prematurely stopped for futility after
&&
1006 patients were included [21 ]. The trial
objective was to reevaluate the beneficial effect
of routine use of NMBs in moderate-to-severe
ARDS. In the ROSE trial, patients in the control
group were exposed to a high PEEP strategy,
known for its beneficial effects in patients with
spontaneous breathing. NMBs were allowed in
cases of nonprotective ventilation or severe asyn-
chrony. With this design, 17% of patients in the
control group used NMBs compared with 97.4%
in the intervention group. Ultimately, there was
no difference in mortality, but patients in the
control group had higher time under light seda-
tion, especially during the first 48 h. The risk of
acquired weakness was not statistically signifi-
cantly different between groups. ROSE is the larg-
est trial addressing the NMBs in ARDS question,
but it is subject to some limitations and contro-
versy, especially because 655 patients were
excluded from the trial due to previous use of
continuous infusion of NMBs.
After these results, the use of NMBs should
probably be considered on each case basis, instead
of routine utilization. NMBs should be reserved for
patients with moderate-to-severe hypoxemia ( paO2/
FIO2 < 150 mmHg) who after deep sedation cannot
achieve lung protective ventilation parameters
(tidal volume  8 ml/kg or plateau pressures
30 cmH2O) or who present with severe asynchrony
such as breath stacking [22].
Further trials are desired in this scenario to
address the duration of NMB, whether it should
be fixed or stopped upon hypoxemia improvement
and a maximum duration of its use. The finding of
good functional outcome with few adverse events
during ICU stay in patients using it for up to 48 h
certainly should not be generalized for longer peri-
ods of time, for which the side effects could be more
common and change the risk-benefit profile of the
intervention. Furthermore, as septic shock is a risk
factor for the development of ICU-acquired weak-
ness, further studies in this subpopulation are
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warranted to achieve effect estimates appropriate
to this patient population.
Sedation and paralysis monitoring under
neuromuscular blockade
Monitoring NMB is also a matter of discussion.
Recently, a single-centre study compared train-of-
four (TOF) monitoring to clinical monitoring in
patients with ARDS. Clinical monitoring was as
efficacious as TOF to provide the desired ventilator
adjustment but resulted in lower use of atracurium
&
(roughly 25% reduction) [23 ]. Another commonly
used monitor for patients undergoing NMB is the
bispectral index, which may be inaccurate to moni-
tor sedation depth in this scenario [24]. Caution
should be exercised if one relies on its values alone
to avoid awareness.
Spontaneous breathing
Spontaneous breathing in patients with ARDS is
currently a highly active line of investigation. Many
researchers have shown the potential deleterious
effects of strong spontaneous efforts, mainly in
experimental models [25]. However, experimental
clinical trial evidence in humans so far is scarce and
an analysis of the LUNG-SAFE cohort has shown
that spontaneous breathing was not associated with
higher mortality; on the contrary, it was associated
with hastened liberation from mechanical ventila-
tion [26]. Although spontaneous breathing may be
deleterious to the lungs, the only current treatment
that can overcome spontaneous breathing is the use
of NMBs. Although its short-term use has been
shown to be well tolerated within reasonable clini-
cal grounds, prolonged NMB (i.e. more than 48–
72 h) comes with many downsides: the need for
prolonged deep sedation, commonly with benzo-
diazepines and inherently associated with a high
risk of Delirium and immobility, with their known
long-term consequences for survivors of critical ill-
ness. Therefore, the best course of action in patients
with low compliant lungs and strong spontaneous
efforts after the first 48–72 h of deep sedation and
paralysis is a matter of debate and clinical trials in
this scenario are urgently needed.
Lung and diaphragm protective ventilation
The concept of lung and diaphragm protective
ventilation stemmed from the literature on the
possible harms of spontaneous breathing together
with observations of diaphragm dysfunction in
the critically ill, both from over assistance and
under assistance [27]. This led to renewed interest
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in the evaluation of respiratory system mechanics
in spontaneously breathing patients (such as PPL
and DP analysis) [28] and also to interest in respi-
ratory drive and patient effort evaluations,
such as P0.1, pressure-muscle index (PMI) and
negative pressure swings during expiratory pauses
[29]. This concept is still in development and its
translation to clinical practice will need further
studies [30].
WEANING
Mechanical ventilation weaning has also experi-
enced many advances recently. Although noninva-
sive ventilation (NIV) has been a standard of care for
high-risk extubations, high-flow nasal cannula has
shown to reduce extubation failure in combination
with NIV in high-risk patients too [31–33]. The
recently published BREATHE trial aimed to compare
whether extubation to NIV compared with invasive
weaning in patients who failed a spontaneous
breathing trial (SBT) was associated with a reduced
duration of mechanical ventilation [34]. The trial
did not show beneficial effects on total mechanical
ventilation duration or survival. Nevertheless, it has
since challenged the belief that coping with a SBT is
always necessary before extubation during the
weaning process.
CONCLUSION
Much new evidence has been published recently in
patients under mechanical ventilation, of which
sepsis and septic shock are the most common rea-
sons of inclusion in these trials. We now have a
better understanding of how to ventilate healthy
lungs. Traditional lung protective ventilation,
prone positioning and ECMO, the current stand-
ards of care for progressively severe ARDS, are being
more and more refined to allow better PEEP titra-
tion, definition of the role of lung recruitment
manoeuvres and the role of many monitoring strat-
egies. The recent developments on the potential
harms of spontaneous breathing led to the concept
of lung and diaphragm protective ventilation,
which still needs more trials and refinements to
bedside application, and a suitable alternative other
than prolonged NMB to blunt strong spontaneous
efforts.
Acknowledgements
None.
Financial support and sponsorship
This work was supported by Hospital Sirio-Libanes.
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Mechanical ventilation in septic shock Besen et al.
Conflicts of interest
BMT and LCPA received research grants from Aché
Laboratorios Farmaceuticos. LCPA received speaker fees
from Baxter and Pfizer outside the submitted work.
BAMPB has no conflicts of interest.
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