Positive end-expiratory pressure improves elastic working pressure in anesthetized children

Background Positive end-expiratory pressure (PEEP) has been demonstrated to decrease ventilator-induced lung injury in patients under mechanical ventilation (MV) for acute respiratory failure. Recently, some studies have proposed some beneficial effects of PEEP in ventilated patients without lung injury. The influence of PEEP on respiratory mechanics in children is not well known. Our aim was to determine the effects on respiratory mechanics of setting PEEP at 5 cmH2O in anesthetized healthy children. Methods Patients younger than 15 years old without history of lung injury scheduled for elective surgery gave informed consent and were enrolled in the study. After usual care for general anesthesia, patients were placed on volume controlled MV. Two sets of respiratory mechanics studies were performed using inspiratory and expiratory breath hold, with PEEP 0 and 5 cmH2O. The maximum inspiratory and expiratory flow (QI and QE) as well as peak inspiratory pressure (PIP), plateau pressure (PPL) and total PEEP (tPEEP) were measured. Respiratory system compliance (CRS), inspiratory and expiratory resistances (RawI and RawE) and time constants (KTI and KTE) were calculated. Data were expressed as median and interquartile range (IQR). Wilcoxon sign test and Spearman’s analysis were used. Significance was set at P < 0.05. Results We included 30 patients, median age 39 (15–61.3) months old, 60% male. When PEEP increased, PIP increased from 12 (11,14) to 15.5 (14,18), and CRS increased from 0.9 (0.9,1.2) to 1.2 (0.9,1.4) mL·kg− 1·cmH2O− 1; additionally, when PEEP increased, driving pressure decreased from 6.8 (5.9,8.1) to 5.8 (4.7,7.1) cmH2O, and QE decreased from 13.8 (11.8,18.7) to 11.7 (9.1,13.5) L·min− 1 (all P < 0.01). There were no significant changes in resistance and QI. Conclusions Analysis of respiratory mechanics in anesthetized healthy children shows that PEEP at 5 cmH2O places the respiratory system in a better position in the P/V curve. A better understanding of lung mechanics may lead to changes in the traditional ventilatory approach, limiting injury associated with MV. Electronic supplementary material The online version of this article (10.1186/s12871-018-0611-8) contains supplementary material, which is available to authorized users.


Background
There are many detrimental effects of positive pressure mechanical ventilation (MV) to the lung parenchyma, giving shape to the entity we know as ventilator induced lung injury (VILI) [1,2]. Despite that it was initially described for injured lungs [3], VILI has been recognized to affect patients with uninjured lungs, triggering many pathways of local and systemic inflammation [1][2][3][4]. Positive pressure MV can cause VILI even when applied for short periods of time, and the role of protective MV during anesthesia has become important for preventing postoperative complications [5][6][7][8][9][10]. Although the exact incidence of VILI during general anesthesia is unknown, the lungs of patients under general anesthesia are especially vulnerable to VILI, since anesthetic induction reduces the end expiratory lung volume (EELV) by 9-25% in adults and up to 46% in children [11][12][13][14][15]. Cyclic opening and collapsing of alveoli have been indicated as one of the primary mechanisms of VILI during anesthesia. Imaging studies have shown that general anesthesia induces atelectasis of dependent regions and that the use of PEEP prevents its formation [3,5,9,10,14]. Protective ventilation during general anesthesia [16,17] to limit tidal volume (6-8 ml/kg) has been widely accepted and incorporated into the operating room (OR), but PEEP use is still not a common practice for patients undergoing general anesthesia [6-10, 17, 18].
In the absence of respiratory muscle activity, working pressure of the respiratory system is the pressure needed to overcome frictional forces, elastic forces and impedance. In this way, an improvement in CRS reflects lower elastic work pressures and, therefore, a pending situation of its more favorable dynamic pressure/volume curve (P/V curve) [19]. These observations also have been described in pediatric animal models [20,21].
There is little evidence to guide MV during general anesthesia in children [18,22,23]. MV parameters are primarily dependent on anesthesiologist preferences and on the characteristics of anesthesia machines [24]. Facing this scenario, many scientific societies have pointed as priority areas of research to the pathophysiology, respiratory mechanics and practice of MV in children for improving outcomes and reducing secondary long-term lung injury [23].
With these facts in mind, we sought to compare respiratory mechanics of setting PEEP at 5 cmH 2 O compared to ZEEP (PEEP set at 0 cmH 2 O) in anesthetized children without acute pulmonary pathology undergoing elective surgery. We hypothesized that usual respiratory mechanics parameters, measured with a commercial mechanical ventilator, would identify a more protective ventilation with addition of PEEP 5 cmH 2 O. Special emphasis was placed on evaluation on respiratory work pressure, flow patterns, resistance and inspiratory and expiratory time constants.

Study design and setting
This prospective study was conducted at the Surgical Block of Centro Hospitalario Pereira Rossell located in Montevideo, Uruguay. The local ethic committee approved the study and informed consent was obtained for each patient before entering the OR.

Study population
Between February 1, 2015 and April 30, 2016, children younger than 15 years old without preexisting lung injury scheduled for elective surgery were screened for the study. For definitive selection, patients categorized as ASA I or II, requiring orotracheal intubation for the surgery according to the anesthesiologist's criteria, were considered. Patients were excluded if they had any acute condition before or during anesthesia (e.g., laryngospasm, bronchoconstriction, pneumothorax), thoracic surgery, thoracic or airway malformation and chronic lung disease with oxygen dependence. Additionally, patients with endotracheal tube air leak > 20% of tidal volume (V T ) were excluded due to possible interference with data acquisition.

Data collection
We registered demographics and clinical information at admission. All procedures before respiratory system mechanics measurements were done according to institutional protocol and anesthesiologist preferences, including anesthesia induction, orotracheal intubation and initial ventilatory settings on the anesthesia machine.

Study protocol
Patients were ventilated on a Galileo Gold® ventilator (Hamilton, Bonaduz, Switzerland) on volume control mode after verification of correct positioning of the endotracheal tube. Baseline settings were as follows: V T = 6-8 mL·kg − 1 , PEEP = 5 cmH 2 O, fraction of inspired oxygen (FiO 2 ) was adjusted to a target pulse oximetry greater than 95%, inspiratory: expiratory ratio = 1:2, and respiratory rate (RR) was adjusted to achieve an end-tidal carbon dioxide (ETCO 2 ) 40 ± 5 mmHg. Tracheal tube leak compensation was deactivated through the measurements.

Respiratory mechanics measurements
Two sets of measurements were performed, at ZEEP and PEEP 5 cmH 2 O, separated by 5 min of stability, following local protocol for respiratory mechanics measurements. This protocol is summarized in Additional file 1 [19]. All measurements were made in pre-incision surgical time.
Ventilator parameters [peak inspiratory pressure (PIP), plateau pressure (P PL ), extrinsic (set) PEEP (PEEP), total PEEP (tPEEP), intrinsic PEEP (iPEEP = tPEEP -PEEP), driving pressure (ΔP = P PL -tPEEP), mean airway pressure expiratory (Paw), V T , inspiratory time (IT), respiratory rate (RR), maximum inspiratory and expiratory flow (Q I and Q E , L·min − 1 )] were assessed. An inspiratory hold followed by an expiratory hold was performed following the protocol described in Additional file 1. Flow and pressure parameters in these quasi-static conditions at the Y piece (proximal flow sensor) were recorded in an ad hoc Microsoft Excel 2010 (Microsoft®, NY, USA) database to calculate respiratory system compliance (C RS , mL·cmH 2 O − 1 ·kg − 1 ), inspiratory and expiratory airway resistance (RawI and RawE, cmH 2 O·L − 1 ·s − 1 ), and inspiratory and expiratory time constants (K TI and K TE , s) according to formulas described in Additional file 2.

Data analysis
Data are expressed as median and interquartile range (IQR). A previous study found that changing PEEP from 0 to 12 cmH 2 0 resulted in a decrease in dynamic compliance (Cdyn) in 9.4 ml/cmH 2 O with SD 6.8 [25]. Given the fact that our protocol included a moderate modification of PEEP, from 0 to 5 ml/cmH 2 O, we expected a smaller change of Cdyn, 2/3 of previously described [25]. A sample size of 30 patients is needed to determine a variation of Cdyn by 6 ml/cmH 2 O, using chi-square test and assuming an α of 0.05 and a power of 90%. Normality was assessed with the Anderson-Darling test. Wilcoxon sign test was performed for comparisons between respiratory mechanics assessments. Spearman's analysis was used to examine correlations between changes in respiratory mechanics and age and ideal body weight. Differences were considered significant if p < 0.05. All statistical analyses were performed using SPSS 20.0 (SPSS Inc., Chicago, IL, USA). Figures were plotted with GraphPad Prism version 5.0c for Mac (GraphPad Software, La Jolla, CA, USA).

Results
Thirty patients were included in the study. Sixty percent were male, the median age was 39 months (15-61.3), and weight was 15 kg (10.6-21).
Sixty percent of patients received inhaled anesthesia and 40% mixed inhalation and intravenous anesthesia. Abdominal surgery was the most frequent (20 cases), mostly hernioplasty. Malformation of the digestive tract was the most frequent comorbidity, present in 7 patients. Table 1 shows clinical characteristics of included patients.
There were no complications related to the protocol. Table 2 shows ventilatory parameters and respiratory system mechanics for the study population with ZEEP and PEEP of 5 cmH 2 O. After setting PEEP at 5 cmH 2 O we observed an increase in PIP, P PL and Paw, with a concomitant decrease in iPEEP and ΔP. Figure 1 shows individual changes on ΔP throughout the study. No modifications were done on V T , and thus, changes on ΔP were coupled to variation on C RS .
There was a moderate correlation between age and ideal body weight and changes in Q E and changes in K TE . Additional file 3 shows the correlation between changes in respiratory parameters and age and ideal body weight. No other correlations with age and weight were found.

Discussion
In this study, we measured pulmonary mechanics in anesthetized healthy children on MV for elective surgery at ZEEP and PEEP 5 cmH 2 O using a commercially available mechanical ventilator. Setting PEEP at 5 cmH 2 O resulted in a significant decrease in ΔP and iPEEP, thereby improving C RS . Changes observed in respiratory mechanics after setting PEEP at 5 cmH 2 O are summarized in Fig. 2.
We also found a decrease in Q E when PEEP was applied. All these findings are indirect signs of lungs in a better position in dynamic P/V curve, suggesting that the addition of a low level of PEEP improves respiratory mechanics.
The effect of PEEP on patients with ARDS was described more than a decade ago, promoting recruitment of non-aerated lung volume and increasing EELV. More recently, many investigators have shown that PEEP should be incorporated to lung protective strategy during the perioperative period in patients at risk for ARDS as well as previously healthy patients [6,[8][9][10]. In this setting, hypoxemia was not associated with the reduction in EELV, and thus, hypoxemia is thought to be a poor predictor of potential injurious MV. Similar findings have been described in children. Serafini et al. described densities in dependent regions of both lungs on CT scan of 10 infants after induction of anesthesia. They observed reopening of the collapsed lung with addition of 5 cmH 2 O of PEEP for 5 min [14]. Kadini et al., in a small study of 8 anesthetized children (range between 2.5 and 6.5 years old), described that 5 cmH 2 O resulted in a significant increase of VT; thus, C RS improved [24].
Our results show that the addition of PEEP sets the respiratory system in a better position of the P/V curve, probably related to the reduction of the atelectasis in lung dependent zones after induction of anesthesia and MV with ZEEP. An increase in EELV, maintaining the same V T, denotes a reduction in global strain and, potentially, VILI [26].
ΔP has taken high priority after the recent pooled data analysis of adult patients with ARDS that showed a significant relationship with mortality [27]. ΔP represents the pressure required for the movement of inspiratory flow and depends on the lung and chest wall viscoelastic resistance [28]. Recently, Neto et al. in a meta-analysis of 2250 patients under general anesthesia found that high ΔP was the only MV parameter associated with postoperative complications [29]. Even more, they found that changes in PEEP that resulted in an increase in ΔP were associated with more postoperative pulmonary complications. It is not surprising that in these studies, ΔP was the best predictor of unfavorable outcomes. We believe that the best performance of this parameter is because it integrates the set tidal volume and the patient's compliance, thus giving a more precise idea of the individual conditions of each patient.
In our patients, we observed a 14.8% (CI95% 9.3,20.3%) reduction of ΔP when PEEP of 5 cmH 2 O was applied. The range of improvement was very wide and only one patient had a significant increase in ΔP (greater than 10%). These results are in accordance with a study by Wirth et al. They elegantly showed, with electric impedance tomography in 30 anesthetized children, that changing PEEP from 2 cmH 2 O to 5 cmH 2 O homogenizes regional lung ventilation [30]. One of our patients had a significant increase of ΔP. This a very good example that ventilatory settings need to be tailored individually, because adding 5 cmH 2 0 of PEEP probably led to overdistension in this patient. We maintained the set V T after applying PEEP of 5 cmH 2 O; thus, the reduction of ΔP was dependent on the improvement in C RS . The improvement in C RS and EELV may be seen as minor, but we believe that even these small changes may have significant consequences during and after surgery, reducing lung inflammation, alteration of gas exchange, among others. Experimental and clinical data have shown that injurious ventilatory parameters can generate detrimental effects, even when applied for short periods of time [1,2,31,32]. The prolongation of K TI and K TE with PEEP of 5 cmH 2 O probably reflects mathematical coupling of changes on C RS without modifications on airway resistance. In the same way, the observed lower expiratory flow is related to the lower ΔP. These parameters are indirect markers of improvement on respiratory system mechanics and more protective ventilation.
Our study has some limitations. Respiratory mechanics measurements were done before the surgery, after a short period of applied PEEP; thus, we cannot extrapolate these findings to other surgical timings, e.g., during pneumoperitoneum, when the effect of PEEP preventing lung collapse could be even higher. Due to small size of patients, we did not measure pleural pressure, so we could not determine the contribution of the chest wall to C RS . Included patients were heterogeneous and age range is wide, so in the absence of normal reference data, we cannot generalize these results to all pediatric patients (i.e., younger patients have higher chest compliance, being at higher risk for derecruitment of the lung on ZEEP). Finally, we have to acknowledge that setting of MV parameters can directly modify the component of the equation of motion (i.e., Q I , RR, I:E ratio), but we tried to standardize the ventilatory setting during measurements. Despite these limitations, we consider our observation of the effect of PEEP in anesthetized

Conclusion
Setting PEEP at 5 cmH 2 O in children during general anesthesia improved elastic working pressure of the respiratory system, decreasing driving pressure and intrinsic PEEP. These findings are indirect signs of lungs in a better position in pressure/volume curve, suggesting that the addition of a low level of PEEP improves respiratory mechanics. These findings may be measured with usual mechanical ventilators and anesthesia machines, analyzing respiratory system mechanics after an inspiratory and expiratory hold. Future studies in infants are needed to address respiratory mechanics during anesthesia, ideally in a specific age group and pathologies with high-risk postoperative complications. A better understanding of respiratory system mechanics in children during general anesthesia may lead to a better titration of mechanical ventilation, preventing VILI.  . PIP, P PL and Paw increased after addition of PEEP of 5 cmH 2 O (PIP', P PL ',Paw'), but dP decreased (dP'). Given the same V T , C RS , represented as the angle of the diagonal line between PEEP and P PL , increased (C RS '). All of them are sign of a more efficient working pressures of the respiratory system better position in P/V curve. On (panel b) respiratory mechanics with ZEEP was added in gray tone as reference