Effects of Sigh on regional lung strain and ventilation heterogeneity in acute
respiratory failure patients undergoing assisted mechanical ventilation
Tommaso Mauri MD, Nilde Eronia MD, Chiara Abbruzzese MD, Roberto Marcolin MD,
Andrea Coppadoro MD, Savino Spadaro MD, Nicolo’ Patroniti MD, Giacomo Bellani MD
PhD, Antonio Pesenti MD.
Supplemental digital content
1
DETAILED METHODS
Study population. We conducted a prospective randomized cross-over study on
20 intubated acute respiratory failure patients admitted to the general Intensive Care
Unit (ICU) of the university-affiliated San Gerardo Hospital, Monza, Italy, between
January 2012 and February 2013. Inclusion criteria were: intubated patients with
PaO2/FiO2 ratio ≤300 mmHg and positive end expiratory pressure (PEEP) ≥5 cmH2O
undergoing pressure support ventilation (PSV) for less than 72 hours as per clinical
decision. Exclusion criteria were: age <18 years, pregnancy, severe hemodynamic
instability, presence of pneumothorax, history of chronic obstructive pulmonary disease
(COPD), contraindications to the use of EIT (e.g., presence of pacemaker or automatic
implantable cardioverter defibrillator), inability to place the EIT belt in the right
position (e.g., presence of surgical wounds dressing), impossibility to perform offline
EIT tracings analysis (e.g., extremely poor quality of tracings). Institutional ethical
committee approved the study and informed consent was obtained for each patient
according to local regulations.
Clinical data. At enrollment, we collected: sex, age, predicted body weight, body
mass index (BMI), Simplified Acute Physiology Score II (SAPS II) value at ICU admission,
infectious (e.g., pneumonia) vs. non-infectious (e.g., vasculitis) and primary (i.e.,
aspiration pneumonia) vs. secondary (e.g., septic shock) etiology of acute respiratory
failure, diagnosis of acute respiratory distress syndrome (ARDS), Lung Injury Score (LIS)
(E1) and days of intubation. In-hospital mortality was recorded, too.
EIT monitoring. Patients were positioned in the semi-recumbent position during
all study phases. We placed an EIT dedicated belt containing 16 electrodes around the
patient's chest at the fifth or sixth intercostal space, and connected it to a commercial
EIT monitor (PulmoVista® 500, Dräger Medical GmbH, Lübeck, Germany). During all
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study phases, EIT data were generated by application of small alternate electrical
currents rotating around patient’s thorax, registered at 20 Hz and stored for offline
analysis, as previously described (E2-E4). Airway pressure, flow and volume tracings
were continuously recorded by means of a serial connector between the EIT monitor
and the patients’ ventilator.
Study protocol. Sedation drugs were titrated to target Richmond agitation
sedation scale values of -1 to 0. Patients were connected to an Evita 4, Evita XL or Evita
Infinity V500 ventilator (Dräger Medical GmbH, Lübeck, Germany) and PSV was set as
follows: support level to obtain Vt ≈6-8 mL/kg ideal body weight (IBW) with peak
inspiratory pressure <25 cmH2O and respiratory rate <30 breaths/min; inspiratory
flow-based trigger (2-4 L/min); expiratory trigger at 25-30% of peak inspiratory flow;
clinically set PEEP; FiO2 to obtain partial arterial oxygen tension between 70 and 100
mmHg. After baseline PSV was set and patient’s physiological parameters remained
stable for 20-30 minutes, Sigh was introduced as a 35-cmH2O continuous positive
airway pressure (CPAP) time period, lasting 3-4 seconds (according to the patient’s
tolerability). To deliver Sigh, ventilators were switched to biphasic positive airway
pressure + PSV (BiPAP+ASB on Dräger ventilators) and Sighs were performed by means
of the higher BiPAP pressure level, as previously described (E5).
The study consisted of four cross-over randomized phases lasting 20 minutes
each, during which PSV settings were left unchanged and Sigh rate was set as follows:

baseline PSV, no sigh (phase Sigh0);

baseline PSV + one sigh every two minutes (Sigh0.5);

baseline PSV + one sigh per minute (Sigh1);

baseline PSV + one sigh every 30 seconds (Sigh2).
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In summary, PSV was compared vs. PSV + BiPAP set with a 3-4 second inspiratory
time and then 120, 60 and 30 second expiratory times to generate the Sigh0.5, Sigh1 and
Sigh2 patterns, respectively.
Gas exchange, hemodynamics and ventilation data. At the end of each phase,
we collected arterial and central venous blood gases, we assessed hemodynamics and
we performed end-inspiratory and end-expiratory occlusions between two Sighs, while
assuring for patients’ relaxation. Acceptable pauses were obtained in 16 patients (80%),
while 4 patients required additional sedation by short-acting drugs (e.g., Propofol 0.10.2 mg/kg IBW). Then, from offline analysis of ventilation tracings, we registered:
spontaneous respiratory rate (RRspont), global Vt (obtained as average value of 5-10
representative inter-Sigh PSV breaths before occlusions, see below), total minute
ventilation (MVtot: the amount of air expired by the patient after both PSV breaths and
Sighs over a minute), Sigh volume, MV generated by Sighs (MVSigh: the amount of air
expired by the patient only after Sighs over a minute), mean airway pressure (mean
Paw), end-inspiratory plateau pressure (Pplat, measured during occlusions), Pmusc
Index (PMI, an estimate of patients’ inspiratory effort) calculated as
PMI = [Pplat - PSV - PEEP] (E6),
total PEEP and respiratory system static compliance (Crs) calculated as
Crs = Vt during occlusion/[Pplat - total PEEP].
Regional EIT data. All EIT data analyses were performed after identification of a
sequence of 5-10 breaths deemed as representative (i.e., stable Vt, RR and EELV) and
recognized between two Sighs at the end of each phase. First, we defined two same-size
contiguous regions of interests (ROI) from halfway up and down of the imaging field
(non-dependent [non-dep] and dependent [dep], respectively) (E4). Then, from offline
analyses of average raw EIT data of the selected breaths, we measured:
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1.
Changes in global and regional end expiratory lung volume (EELVgl,
EELVnon-dep and EELVdep, respectively), defined as the global and regional change in endexpiratory impedance, considering Sigh0 as baseline, multiplied by the ratio between Vt
measured by the ventilator spirometer and the global impedance change between endexpiration and end inspiration, both taken at Sigh0 (E2, E7). As, during this study, PEEP
wasn’t modified and Sigh affected mean Paw by 1-2 cmH2O, we reasoned that, in our
patients, changes of global and regional EELV induced by Sigh corresponded to reaeration of previously collapsed lung areas (i.e., alveolar recruitment). Thus, patients
with average EELVgl change over the three Sigh phases above the median value were
defined as having a higher potential for lung recruitment;
2.
The relative (expressed as percentage) and absolute (expressed in mL)
values of Vt reaching non-dependent and dependent lung regions (Vt%non-dep and
Vt%dep; Vtnon-dep and Vtdep; respectively);
3.
The regional Crs values, measured as Vtnon-dep or Vtdep divided by the
difference between end-inspiratory Pplat and total PEEP (Crsnon-dep and Crsdep,
respectively). Crsnon-dep was measured also during Sigh, as the gas volume introduced by
Sigh into non-dependent region divided by the end-inspiratory Sigh pressure (i.e. 35
cmH2O) minus total PEEP (Crs-Sighnon-dep). In fact, within each study phase, Crs-Sighnondep
values lower than Crsnon-dep measured during tidal breathing could be interpreted as a
sign of alveolar over-distension induced by Sigh (E8);
4.
The cumulated lung hyperdistension, as described by Costa and colleagues
(E9). Briefly, we considered baseline compliance for each pixel the one obtained during
the Sigh0 phase. Then, pixel-level hyperdistension for tidal PSV breaths during each
phase was calculated as follow:
5
Hyperdistensionpixel (%) =
(Sigh0 Compliancepixel − Current phase Compliancepixel ) x 100
⁄
Sigh0 Compliancepixel
Finally, cumulated hyperdistension for the whole imaging field was computed as:
Cumulated hyperdistension (%) =
∑1024
Pixel=1(Hyperdistensionpixel x Sigh0 Compliancepixel )
⁄ 1024
∑Pixel=1 Sigh0 Compliancepixel
5.
The heterogeneity of the dynamic regional distribution of tidal ventilation
along inspiration (intra-tidal ventilation heterogeneity: VtHit). In this study, we defined
VtHit as the average value of the Vtnon-dep/Vtdep ratios along inspiration when Vt was
divided into 8 equal-volume parts, as previously described (E10, E11). Briefly, at first, Vt
insufflation was divided into eight parts of equal volume (Vt1/8); then, we measured the
ratio between Vt1/8, non-dep/Vt1/8, dep for each of the eight Vt parts and, in this way, we
obtained 8 consecutive values of ventilation heterogeneity along inspiration for each
patient. Finally, the average value of all Vt1/8, non-dep/Vt1/8, dep ratios was calculated for
each patient, representing the VtHit of that study phase for that patient.
Statistical analysis. Sample size was chosen to detect an EELVgl increase of
100±150 mL (14-15) between Sigh0 and Sigh0.5 phases, with power of 0.8 and alpha
0.05. Comparisons between two groups of normally distributed variables were
performed by independent samples t-test, while non-normally distributed variables
were compared by Mann-Whitney U test. Differences between variables obtained during
each study phase were tested by one-way analysis of variance (ANOVA) for repeated
measures, or by one-way repeated measures ANOVA on ranks for non-normally
distributed variables; post-hoc comparisons were carried out by Dunnet method, with
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Sigh0 phase as reference. Association between two variables was assessed by linear
regression. Multivariate backward stepwise regression was performed to identify
independent predictors of mortality including only variables significantly different at
the univariate analysis (i.e., PaO2/FiO2 and VtHit). A level of p<0.05 (two-tailed) was
considered as statistically significant. Normally distributed data are indicated as mean ±
standard deviation, while median and interquartile range [IQR] are used to report nonnormally distributed variables. Statistical analyses were performed by SigmaPlot 11.0
(Systat Software Inc., San Jose, CA).
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ADDITIONAL RESULTS
Physiological effects of Sigh. No changes in hemodynamic parameters were
observed during the three Sigh phases in comparison to Sigh0 baseline values (Table 3).
Baseline variables associated with higher potential for lung recruitment.
Patients with higher potential for lung recruitment (i.e., with mean EELVgl change over
the three Sigh phases >237 mL, see Methods section) had significantly lower PaO2/FiO2
ratios during baseline Sigh0 in comparison to patients with lower potential (162±35
mmHg vs. 197±39 mmHg, p<0.05).
Variables associated with patients’ outcome. Patients who ultimately died
presented lower PaO2/FiO2 ratios (150±24 mmHg vs. 196±38 mmHg, p=0.01) and
greater VtHit values (p<0.05; Figure 5) during baseline Sigh0 phase. Interestingly, VtHit
didn’t differ between ARDS patients vs. patients without ARDS (p>0.05, data not shown)
and, in fact, both PaO2/Fio2 and VtHit values were independent predictor of mortality at
multivariate regression analysis (β=-0.511 with SE=0.002, p=0.01 and β=0.393 with
SE=0.006, p=0.04, respectively)(Figure 5).
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STUDY LIMITATIONS
This study has few important limitations: 1. EIT measurement just covers a crosssectional slice of roughly half the chest width and the behaviour of all other lung areas
can only be inferred. However, previous studies showed that the measurement of lung
volumes and regional distribution of tidal volume by EIT are correlated with other
validated methods (E2, E7). Albeit characterized by higher spatial resolution,
computerized tomography (CT) scan studies that analysed ventilation heterogeneity
were performed by single-slice approach (E13), which approximates the whole lung
behaviour to an imaged portion smaller than the one visualized by EIT. Finally, in
comparison to CT scan, EIT is unique in providing dynamic measures of lung volume
changes along the respiratory cycle and this enabled us to disclose interesting results
(i.e., the reduction of VtHit) that couldn’t be analysed in a CT scan study; 2. EIT measures
lung re-aeration rather than directly assessing recruitment. However, in this study, Sigh
was added without changing PEEP and it affected mean Paw by 1-2 cmH2O: given these
conditions, recruitment should correspond to re-aeration. Another possibility is that
EELV change measured by EIT was due to over-inflation: however, EELV increase was
sudden and stable over time (Figure 2) and was inversely correlated with patients’
respiratory rate (Table 2 and 3); 3. Study phases lasted only 20 minutes. However, in
this way, we could compare four Sigh rates within a reasonable amount of time (≈2
hours) that could assure patients’ stability, especially from a hemodynamic point of
view; 4. Although interesting and physiologically sound, the correlation between intratidal heterogeneity and mortality needs further validation because of the small sample
size; 5. Recent studies showed potential risks related to use of Sigh in mechanically
ventilated animal models of ARDS (E14-E15), as Sigh represents a very high gas volume
cyclically reaching diseased alveoli. However, we showed that, when Sigh is delivered at
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35 cmH2O, alveolar hyperdistension seems unchanged, if not reduced. Moreover, no
relevant complication was reported in any of the published studies that applied Sigh in
ventilated critically ill patients. However, longer studies specifically addressing Sigh
safety seem warranted; 6. Acceptable pauses were obtained in 16 patients, while extrasedation was needed in 4 patients, which might have led to underestimation of PMI
value. However, the significant decrease of PMI by introduction of Sigh was confirmed
when we analysed only the data from the 16 patients not requiring additional sedation
(p<0.05, data not shown); 7. We used the same Sigh pressure for all patients (i.e., 35
cmH2O), as this value seemed a fair compromise between efficacy and safety. However,
in patients with stiff chest wall, higher Sigh pressure might further enhance lung
recruitment without additional risks. Indeed, in this study, the average increase in
EELVgl obtained by Sigh in the two patients with BMI > 40 Kg/m2 was lower than in the
others (138 [82-193] mL vs. 240 [149-326] mL, p=0.115); 8. In the present study, the
definition of acute respiratory failure was quite broad and could have introduced some
heterogeneity. However, lung collapse and heterogeneity characterize most of critically
ill intubated patients and not only the most severe with ARDS. Still, we enrolled
intubated patients with arterial pO2 below 300 mmHg measured with PEEP equal or
above 5 cmH2O to improve our accuracy in recruiting patients with significant degree of
collapse (E16) and who could benefit from Sigh.
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