2021 Article 3686
2021 Article 3686
2021 Article 3686
Abstract
A personalized mechanical ventilation approach for patients with adult respiratory distress syndrome (ARDS) based
on lung physiology and morphology, ARDS etiology, lung imaging, and biological phenotypes may improve ventila-
tion practice and outcome. However, additional research is warranted before personalized mechanical ventilation
strategies can be applied at the bedside. Ventilatory parameters should be titrated based on close monitoring of
targeted physiologic variables and individualized goals. Although low tidal volume (VT) is a standard of care, further
individualization of VT may necessitate the evaluation of lung volume reserve (e.g., inspiratory capacity). Low driving
pressures provide a target for clinicians to adjust VT and possibly to optimize positive end-expiratory pressure (PEEP),
while maintaining plateau pressures below safety thresholds. Esophageal pressure monitoring allows estimation of
transpulmonary pressure, but its use requires technical skill and correct physiologic interpretation for clinical applica-
tion at the bedside. Mechanical power considers ventilatory parameters as a whole in the optimization of ventilation
setting, but further studies are necessary to assess its clinical relevance. The identification of recruitability in patients
with ARDS is essential to titrate and individualize PEEP. To define gas-exchange targets for individual patients, clini-
cians should consider issues related to oxygen transport and dead space. In this review, we discuss the rationale for
personalized approaches to mechanical ventilation for patients with ARDS, the role of lung imaging, phenotype iden-
tification, physiologically based individualized approaches to ventilation, and a future research agenda.
Keywords: Tidal volume, Driving pressure, Transpulmonary pressure, Phenotype, Biomarkers, Chest computed
tomography scan
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Pelosi et al. Crit Care (2021) 25:250 Page 2 of 10
Fig. 1 Summary of recommendations. VT: tidal volume; ΔP: driving pressure; PEEP: positive end-expiratory pressure; EELV: end-expiratory lung
volume; IC: inspiratory capacity; AI: artificial intelligence; PPLAT: plateau pressure; VILI: ventilator-induced lung injury
of interventions and strategies have been combined into mechanical ventilation based on lung physiology and
meta-analyses to provide summary estimates of treat- response has laid the foundation to develop and inform
ment effect to inform clinical practice and provide a “smarter” ventilation practices.
starting point for a safe individualized approaches to Suggestion 1 Regulate the components of the ventila-
mechanical ventilation [6]. Outcome studies that set tory prescription based on close monitoring of targeted
thresholds for ventilatory variables based on mortality physiologic variables, intervention responses, and trends
risk have not established a definitive causal link between relevant to the integrated goals of treatment for the indi-
the applied pattern, ventilator-induced lung injury vidual patient.
(VILI), or death. At the bedside, clinicians seek to imple-
ment this evidence and adjust this “powerful instrument” Targeting tidal volume
by understanding physiologic mechanisms and possi- Lung protective ventilation [targeting tidal volume (VT)
ble consequences of ventilatory interventions [7]. Key of 4–6 mL/kg predicted body weight (PBW) to keep pla-
goals are to relieve excessive workload of breathing and teau pressure (PPLAT) below 30 cmH2O] is the current
improve gas exchange, without impairing hemodynamics standard of care [10]. In healthy lungs, VT can be titrated
or incurring iatrogenic injury from intolerable pressures to PBW, since lung volumes are correlated with the PBW.
or inspired oxygen [8]. Notwithstanding, selective target- By contrast in ARDS patients, lung volumes do not corre-
ing of one of these objectives may collide with goals of late closely with PBW due to heterogeneous distribution
another [9]. While using inflexible numerical ventilatory of lung disease. Thus, VT should ideally be set accord-
targets throughout all phases of ARDS is nonsensical, ing to end-expiratory lung volume (EELV) or inspiratory
tailored ventilation based on careful functional moni- capacity (IC) measured at 30 cmH2O. At higher PEEP,
toring and mechanistic understanding seems to be both EELV may change with respiratory system compliance
more desirable and justified. Therefore, personalized
Pelosi et al. Crit Care (2021) 25:250 Page 3 of 10
(CRS), and setting of VT according to EELV is not reliable. and VT utilized [19]. Specific numerical values, how-
Higher PEEP may not affect or even reduce IC, thus lim- ever, may not apply to or be relevant for individual
iting further increases in VT. At lower PEEP, IC correlates patients [20]. Additionally, the concept of transpulmo-
more closely with EELV, and VT may be set by either IC nary ΔP during tidal ventilation has been gaining rel-
or EELV [11]. Nevertheless, IC is easier for clinicians to evance recently and appears to hold potential for better
measure at bedside compared to EELV [12]. The relation- guidance of protective mechanical ventilation.
ship between VT and mortality is stronger in patients Suggestion 3 For most patients, ΔP should be targeted
with lower CRS, suggesting the importance of targeting VT below 13 c mH2O. Although ΔP may help “individualize”
in each patient according to the amount of aeration [3]. VT and PEEP settings, it is not clear whether ΔP is supe-
Processors within ventilators may automatically calculate rior to other methods to set PEEP. Whenever possible,
the best VT, within safety ranges. For example, adaptive clinicians should aim to keep PPLAT < 27 cmH2O.
support ventilation, an automated closed-loop mode of
ventilation, provides the best combination of VT and res- Targeting transpulmonary pressure
piratory rate (RR), to achieve the lowest work of breath- Transpulmonary pressure (PL), the distending force of
ing combined with the lowest driving pressure (ΔP) and the lung, is the difference between airway (PAW) and
may outperform healthcare professionals with respect to pleural pressure (PPL), with PPL estimated by esophageal
VT titration [13]. Finally, the use of artificial intelligence pressure (PES) [21, 22]. During controlled mechanical
to develop a personalized clinical decision support tool ventilation, PPL varies from non-dependent to depend-
could provide needed support to bedside clinicians [14]. ent lung regions of the lung [23]. The absolute PL gra-
Suggestion 2 Low VT (4–6 ml/kg PBW) has become a dient in the supine position primarily depends on lung
standard of care. The personalized targeting of VT may weight as well as shape and mechanical properties of
necessitate the evaluation of EELV or IC. Automated lung and chest wall. PES is a reasonable estimate of PPL
systems and artificial intelligence may enable better in the zone between the non-dependent and depend-
selection, monitoring, and control of optimal VT. ent lung regions. In ARDS, the superimposed pressure
from non-dependent to dependent lung regions is 10
cmH2O, on average [24]; thus, PPL is roughly PES + 5
Targeting driving and plateau pressure cmH2O in dependent lung regions and PES-5 cmH2O
Driving pressure (ΔP = VT/CRS) estimates VT adjusted in non-dependent lung regions. When interpreting PL
to functional lung size and has been associated with from PES measurements, the absolute difference (not
mortality [15]. Recent studies suggest the impor- corrected) between PAW and PES at end-inspiration or
tance of using ΔP to titrate VT and/or PEEP in ARDS end-expiration represents the P L in the middle lung,
patients [16]. Assuming similar CRS, ΔP is directly cor- and the difference between end-inspiration and end-
related with VT. At low CRS, a reduced VT is required expiration in PPL (ΔPPL) approximates ΔPES. Elastance
to maintain ΔP within a safe range (< 13 c mH2O). Driv- of respiratory system and chest wall may vary unpre-
ing pressure may also be used to set PEEP since the dictably and with changes in PEEP. In obese patients
best compromise between overinflation and recruit- or those with increased intraabdominal pressure
ment is determined at the lowest ΔP [17]. A study (PPLAT above 27 cmH2O), a simplified formula may
analyzing two randomized ARDS trials found that a help estimate the required correction of PPLAT: PPLAT
decrease in ΔP was associated with lower mortality target + (intraabdominal pressure-13 cmH2O)/2 [25,
compared to increased P aO2/FiO2 [18]. Several con- 26]. In mechanically ventilated non-obese patients,
cerns exist regarding PEEP titration according to ΔP the average intraabdominal pressure is 13 cmH2O and
including (1) depending on the VT used, the lowest ΔP half of intraabdominal pressure is transmitted to the
may be achieved at different PEEP levels, (2) at higher thoracic cavity [27]. The following parameters have
CRS, compared to lower CRS, higher PEEP levels may been suggested as potential targets for individual-
achieve a lower ΔP, (3) the decrease in ΔP with PEEP ized mechanical ventilation when using PL [28, 29]:
may be associated with greater intratidal recruitment, (1) end-inspiratory PL (non-dependent lung) below
(4) changes in chest wall compliance may affect the 15–20 cmH2O; (2) ΔPL below 10–15 c mH2O; (3) PEEP
ΔP measurement, and (5) the presence of airway clo- set at end-expiratory PL (dependent lung) equal to 0–6
sure may confound the relationship between ΔP and cmH2O; and (4) PL during recruitment maneuvers not
PEEP. Although a causal effect has not been demon- to exceed 25 cmH2O [29, 30]. To date, RCTs evaluat-
strated, PPLAT > 29 cmH2O and ΔP > 19 cmH2O in mod- ing the role of individualized PEEP set according to PL
erate/severe ARDS patients have been associated with at end-expiration and compared with low or high PaO2/
increased hospital mortality, irrespective of the PEEP
Pelosi et al. Crit Care (2021) 25:250 Page 4 of 10
FiO2 table have not shown beneficial effects on out- at the bedside, its value in VILI prediction remains con-
comes [31, 32]. troversial [40–42].
Suggestion 4 In patients with increased intraabdomi- Suggestion 5 Mechanical power is a summary construct
nal pressure or morbid obesity, PL, may assist with indi- that includes all of the important and well-recognized
vidualizing ventilatory settings. The measurement of PES determinants of VILI. The same mechanical power value
requires technical skills and physiologic interpretation to can be reached with different combinations of the above
be applied by bedside clinicians. variables.
set according to EIT, may aid in optimizing lung recruit- correctly. Care must be taken to refrain from prema-
ment and homogeneity of ventilation [73]. Technologi- turely positive interpretations of secondary analyses of
cal development by EIT may also quantitatively estimate previously collected data, which have not been validated
regional lung perfusion based on first-pass kinetics of in prospective cohorts or RCTs. To date, no mechanical
a bolus of hypertonic saline contrast [74, 75]. To evalu- ventilation guidelines have included statements regarding
ate lung morphology and the potential for recruitment, different ARDS phenotypes.
ARDS patients should ideally undergo chest or lung Suggestion 9 The stratification of ARDS patients
imaging at different pressures. according to different phenotypes is promising but awaits
Suggestion 8 Imaging techniques may help to better clinical confirmation before it can be translated into to
identify different lung morphology and response to ven- the clinical setting.
tilation strategies. Chest CT allows detailed and quanti-
tative analysis of overdistended lung: normally aerated,
poorly aerated and non-aerated tissue, as well as con- The seduction of short‑term physiological gains
solidated and atelectatic components. LUS and EIT are In daily practice, critical care physicians use physi-
promising tools for clinicians to use at the bedside. ological data to aid them in guiding and adjusting ther-
apies. However, clinicians are not able to accurately
Targeting biological phenotypes predict the medium- or long-term consequences of
ARDS is characterized by different pathogenetic path- physiologically based therapy on patient-centered out-
ways leading to similar clinical presentations postulated comes. Clinicians often fall prey to celebrating immedi-
to represent distinct phenotypes, which may enable pre- ate physiological gains under the pretense that they will
cision therapy. To date, two different ARDS phenotypes translate into improvements in desired outcomes. In
(hyperinflammatory and hypoinflammatory) have been this regard, physiological gains can be seductive. When
identified that differ in response to therapy and outcomes. these gains are achieved, clinicians feel validated (imme-
Post hoc latent class analysis of a panel of blood biomark- diacy bias) regardless of the downstream future effects
ers for inflammation, endothelial injury, and coagulopa- which are unknown. When anticipated gains are not
thy combined with clinical variables has revealed two achieved, clinicians engage in attribution bias-blaming
phenotypes in 5 RCTs [76–80]. Similarly, post hoc cluster severe and unresponsive illness. Short-term physiologi-
analysis of a set of biomarkers for inflammation, endothe- cal gains are an elusive concept. For example, in an ARDS
lial injury and coagulopathy without clinical variables patient on PEEP = 8 cmH2O and FiO2 = 0.6 to maintain
also revealed two phenotypes in an observational study a PaO2 = 60 mmHg, increasing PEEP to 14 cmH2O may
[81]. Of interest, the phenotypes had a differential or achieve the same PaO2 at an FiO2 = 0.5. Some clinicians
even opposite response to PEEP, fluid management, and may see that as physiological success. However, appor-
simvastatin treatment [76–78, 80]. Recently, point-of- tioning “value” to this increase in PEEP prioritizes lung
care breath testing introduced the possibility for targeted mechanics and lung physiology because they can be
exhaled breath analysis to be used as a bedside test and measured. However, the impact of the increased PEEP
potentially a diagnostic tool for timely ARDS detection on renal function, gastrointestinal permeability, or the
[82]. Genome-wide association studies sequencing of brain typically remains unmeasured and unknown. This
hundreds-of-thousands to millions of DNA variants (sin- is a fundamental problem with physiology: it measures
gle nucleotide polymorphisms) may help to identify indi- whether a specific intervention affects a specific set of
vidual patients who display a phenotype or trait that may physiological parameters. However, it does not assess
be more or less amenable to a specific treatments [83]. “other” unmeasured or unintended physiological con-
The personalized approach to treatment based on iden- sequences. Thus, physiologically based personalized
tification of phenotypes according to different biomark- therapy, although clearly important at the extremes of ill-
ers is based on two main assumptions: (1) the patient’s ness, become problematic at intermediate levels of illness
phenotype can be correctly identified and (2) treatment where safety has typically been established. Historically,
needs to be individually targeted and effective for spe- the pursuit of perceived physiological success in the belief
cific phenotypes. However, the personalized approach to that it would lead to subsequent clinical success has often
treatment based on phenotypes may be associated with proved to be disappointing with notable examples includ-
better outcomes in diseases with a single identifiable fac- ing intensive insulin therapy to normalize glycemia [84];
tor or etiology, such as cancer. Conversely, in ARDS, the drotrecogin alpha to normalize activated protein C levels
disease etiology and progression may be linked to mul- [85]; colloid resuscitation to increase intravascular vol-
tiple factors. Thus, the efficacy of a specific treatment is ume [86]; decompressive craniectomy to lower intracra-
not assured even if individual phenotypes are identified nial pressure in diffuse cerebral injury [87]; hypothermia
Pelosi et al. Crit Care (2021) 25:250 Page 7 of 10
for out of hospital cardiac arrest [88], early parenteral or Authors’ contributions
PP and PRMR designed this review. All authors contributed equally to litera-
enteral nutrition to achieve early full caloric intake [89]; ture revision and manuscript writing. All authors revised and approved the
glutamine therapy to correct glutamine deficiency [90]; final version of the manuscript.
fluid bolus resuscitation in septic African children [91].
Funding
All this does not imply that physiology should not be None.
used to guide therapies in patients with ARDS. However,
clinicians should be aware that improvement in physi- Availability of data and materials
Not applicable.
ological variables during individualized targeted therapy
does not necessarily imply clinical safety or improved
outcomes. Declarations
Suggestion 10 When applying physiological manipu- Ethics approval and consent to participate
lations, clinicians should consider the uncertainty sur- Not applicable.
rounding their subsequent effect on patient-centered Consent for publication
outcomes. Not applicable.
Competing interests
JL discloses consultancy fees for Baxter and GlaxoSmithKline. JLT is member
Future research agenda of the medical advisory board of Getinge. KB holds a Physician Services
Personalized mechanical ventilation in ARDS merits Incorporated Mid-Career Award. MJS has received speaker-fees from Hamilton
further research on specific targets: (1) characterize bio- Medical. JL has received consultancy fees from Baxter and Glaxosmithkline. All
other authors declare no conflict of interest.
markers profiles and responses to specific treatments
associated with pulmonary or extrapulmonary insults, Author details
1
pulmonary inflammation, and lung physiology; (2) the Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS
for Oncology and Neuroscience, Genoa, Italy. 2 Department of Surgical Sci-
use of mechanical power and PL; and (3) identification of ences and Integrated Diagnostic (DISC), University of Genoa, Viale Benedetto
patient’s phenotype according to the biomarkers of epi- XV 16, Genoa, Italy. 3 Pneumology and Intensive Care Medicine, University
thelial and endothelial cell damage, inflammation, and of São Paulo, São Paulo, Brazil. 4 Adult Intensive Care Unit, Albert Einstein
Hospital, São Paulo, Brazil. 5 Department of Intensive Care, Austin Hospital,
extracellular matrix. The investment of personalized Melbourne, VIC, Australia. 6 Department of Epidemiology and Preventive Medi-
mechanical ventilation is high and will require invest- cine, Australian and New Zealand Intensive Care Research Centre, Monash
ment of both personnel and resources, including experi- University, Melbourne, VIC, Australia. 7 Data Analytics Research and Evaluation
Centre, The University of Melbourne and Austin Hospital, Melbourne, Australia.
mental and clinical trials. 8
Department of Intensive Care, Royal Melbourne Hospital, Melbourne, VIC,
Australia. 9 Department of Critical Care, The University of Melbourne, Mel-
bourne, Australia. 10 Interdepartmental Division of Critical Care Medicine, Uni-
Conclusions versity of Toronto, Toronto, ON, Canada. 11 Unity Health Toronto‑St. Michael’s
Hospital, Li Ka Shing Knowledge Institute, Toronto, ON, Canada. 12 Intensive
A personalized mechanical ventilation approach based Care Unit of the Shaare Zedek Medical Medical Centre, Hebrew University
on lung physiology and morphology, ARDS etiology, lung Faculty of Medicine, Jerusalem, Israel. 13 Department of Anaesthesiology,
imaging as well as identification of biological phenotypes Emergency, and Intensive Care Medicine, University of Göttingen, Göttingen,
Germany. 14 Anaesthesia and Intensive Care Medicine, University Hospital
may improve and individualize future mechanical venti- Galway, and School of Medicine, National University of Ireland, Galway, Ireland.
lation practice. Additional research is warranted before 15
University of Minnesota and Regions Hospital, St. Paul, MN, USA. 16 Depart-
personalized mechanical ventilation strategies can be ment of Anaesthesiology, Critical Care and Pain, Tata Memorial Hospital, Homi
Bhabha National Institute, Mumbai, India. 17 Mahidol Oxford Tropical Medicine
applied at the bedside of ARDS patients. Research Unit (MORU), Mahidol University, Bangkok, Thailand. 18 Service de
Médecine Intensive‑Réanimation, Hôpital Bicêtre, Inserm UMR S_999, AP-HP
Université Paris-Saclay, Le Kremlin‑Bicêtre, France. 19 Laboratory of Pulmonary
Abbreviations Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University
ARDS: Acute respiratory distress syndrome; RCT: Randomized clinical trial; VILI: of Rio de Janeiro, Rio de Janeiro, Brazil. 20 Department of Intensive Care,
Ventilator induced lung injury; VT: Tidal volume; PBW: Predicted body weight; Amsterdam University Medical Centers, Amsterdam, The Netherlands. 21 Nuf-
PPLAT: Plateau pressure heterogeneous distribution of lung disease; EELV: End- field Department of Medicine, University of Oxford, Oxford, UK.
expiratory lung volume; IC: Inspiratory capacity; PEEP: Positive end-expiratory
pressure; CRS: Respiratory system compliance; RR: Respiratory rate; ΔP: Driving Received: 2 July 2021 Accepted: 8 July 2021
pressure; PL: Transpulmonary pressure; PAW: Airway pressure; PPL: Pleural pres-
sure; PES: Esophageal pressure regions; ΔPL: Transpulmonary driving pressure;
PRS: Respiratory system pressure; V̇ : Inspiratory flow; Raw: Airway resistance;
RM: Recruitment maneuver; FiO2: Inspired oxygen fraction; CO: Cardiac output;
VO2: Oxygen consumption; DO2: Oxygen delivery; ScvO2: Central venous References
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