- Question: Does individualized positive end-expiratory pressure (PEEP) based on minimum driving pressure reduce the incidence of postoperative pulmonary complications (PPCs) after major upper abdominal surgery?
- Findings: Driving pressure–guided PEEP titration reduced the incidence of clinically significant PPCs in patients undergoing open upper abdominal surgery.
- Meaning: Driving pressure–guided PEEP individualization may be a promising technique in PEEP setting.
Postoperative pulmonary complications (PPCs) are common, associated with potentially preventable morbidity and mortality.1 Protective ventilation strategies, initially used in an intensive care unit (ICU), then adopted in surgical settings, has been shown to minimize ventilator-induced lung injury, reducing PPCs in high-risk patients.2,3 The use of low tidal volumes, positive end-expiratory pressure (PEEP), and recruitment maneuvers are the key components of intraoperative lung-protective ventilation. While the protective role of low tidal volume is widely accepted, the benefits of high or low PEEP as well as the optimal way to set the PEEP are continually debated.3–5 Selecting the optimal PEEP level requires individualization according to patients’ respiratory and other competing physiologies.6,7 Although extensive research has been performed on optimizing PEEP level utilizing pulse oximetry,8 transpulmonary pressure,9 electrical impedance tomography (EIT),10,11 pulmonary compliance,12 and dead-space fraction,13 the ideal way of identifying the optimal patient-specific PEEP remains unclear.
Recent evidence suggests that driving pressure is an important independent risk factor for mortality in patients with acute respiratory distress syndrome (ARDS),14 and a lower intraoperative driving pressure may help to prevent PPCs.15,16 Driving pressure, as equal to the tidal volume divided by respiratory system compliance, also represented as the difference between plateau pressure and PEEP, comprehensively reflects respiratory system mechanics and ventilation settings. The interdependent relationship between PEEP and driving pressure implies that the beneficial effect of PEEP may depend on the level of driving pressure. Therefore, it could conceivably be hypothesized that individualization of PEEP by minimizing driving pressure could decrease the incidence of clinically significant PPCs.
This study set out to investigate the benefits of individualized intraoperative PEEP guided by minimum driving pressure in patients undergoing major open upper abdominal surgery with an intermediate-to-high risk of PPCs. It is hoped that this research will determine the validity of minimizing driving pressure in a PEEP setting and further clarify the benefits an individualized PEEP can offer to an empiric one.
This prospective, randomized, patient- and assessor-blinded parallel study was conducted at Xinhua Hospital, affiliated with the Shanghai Jiaotong University School of Medicine. It was approved by the local ethics committee (XHEC-D-2016-037) and registered before patient enrollment in the Chinese Clinical Trial Registry (ChiCTR-IOR-16008900, principal investigator: X.S.; date of registration: July 25, 2016). Written informed consent was obtained from all eligible participants. This study adhered to the applicable Consolidated Standards Of Reporting Trials (CONSORT) guidelines.
Participants were recruited from patients who were scheduled for open upper abdominal surgery that would last for at least 2 hours under general anesthesia, with an intermediate-to-high risk of PPCs using the Assess Respiratory Risk in Surgical Patients in Catalonia (ARISCAT) score.17 Recruitment was ceased when the target sample size was reached.
Other inclusion criteria were as follows: being between 18 and 80 years of age; being classified as American Society of Anesthesiologists (ASA) physical status II and III; and having a body mass index <35 kg/m2. Patients with the following conditions were excluded: a history of upper respiratory tract or pulmonary infection within the previous 4 weeks; pleural effusion; chest diseases; neuromuscular dysfunction; and serious cardiovascular, lung, kidney, or hematopoietic diseases, such as renal failure, leukemia, congenital heart diseases, etc. Withdrawal of consent, unable to complete required study protocol, severe hypotension due to intraoperative hemorrhage or life-threatening complications would be considered as dropout.
Randomization and Blinding
A computer-generated sequence (by C.Z.) was used to assign the participants in a blocked randomization approach (block size of 4, 1:1). Sealed opaque envelopes containing group identification cards, prepared to maintain allocation concealment, were opened before the induction of anesthesia. The attending anesthesiologist who performed the PEEP titration protocol, provided care for the participant, and collected intraoperative data was aware of the group assignment and therefore not blinded. Physiologic parameters in the postanesthetic care unit (PACU) were collected by an anesthesiologist who was also not blinded. Data collection in the postoperative period and the following analyses were performed by blinded investigators.
Intervention and Ventilation Protocol
Perioperative management in all participants was in compliance with enhanced recovery after surgery (ERAS) principles. Details can be found in Supplemental Digital Content 1, Methods, https://links.lww.com/AA/D553.
Recruitment maneuver was performed by sustaining the inspiratory pressure at 40 cm H2O for 10 to 15 seconds after the induction of anesthesia, using a reservoir bag (1 L) in the anesthesia machine and mixtures of oxygen (30%) and air (70%) at 10 L/min, with the adjustable pressure-limiting valve set at 40 cm H2O. After that, the volume-controlled ventilation mode was utilized (tidal volume of 6 mL/kg of ideal body weight, inspired oxygen fraction [Fio2] of 0.30, inspiratory pause of 30%, inspiration-to-expiration ratio of 1:2, PEEP of 6 cm H2O, and flow of 3 L/min). The respiratory rate was set to 12 breaths/min in the beginning and then adjusted (within 10–20 breaths/min) to maintain the Etco2 between 35 and 45 mm Hg.
The following interventions were performed after surgical incision: in the fixed PEEP group, the PEEP was set to 6 cm H2O throughout the surgery; and in the individualized PEEP group, an incremental PEEP titration protocol (an increment of 2 cm H2O for every 8 minutes from 0 to 14 cm H2O) was performed to identify the optimal individualized PEEP that resulted in minimum driving pressure (calculated as plateau pressure − PEEP), indicating maximum respiratory compliance. Subsequently, this optimal individualized PEEP was maintained throughout the procedure.
The incidence and severity of PPCs were adjudicated by an assessor masked to group allocation and not involved in perioperative management with a definition from previous studies on a scale of 0 to 5 (Table 1).18,19 Results were rechecked by another independent anesthetist or surgeon who was not involved in the study. Consistent evaluation would be regarded as valid and reliable, with disagreements settled by a third care provider. In short, the types of PPCs included severe hypoxemia, atelectasis, pleural effusion, dyspnea, pneumonia, pneumothorax, and ARDS.
Table 1. -
A Detailed Description of PPCs Scoring System Modified From Previous Studies
||No signs or symptoms
|Microatelectasis: abnormal lung findings and temperature >37.5 °C without other documented cause; normal chest radiograph
|Dyspnea, not due to other documented cause
||Cough, productive, not due to other documented cause
|Bronchospasm: new wheezing or preexistent wheezing resulting in a change in therapy
2 ≤ 90%) in room air
|Atelectasis: radiological confirmation by 2 independent consultants plus either temperature >37.5 °C or abnormal lung findings
2 > 50 mm Hg) requiring treatment
||Pleural effusion undergoing thoracentesis
|Pneumonia: radiological evidence (by 2 independent consultants) plus 2 or more clinical symptoms (leucocytosis or leucopenia, abnormal temperature, purulent secretions) plus either bacteriologic findings (Gram stain or culture) or a required change in antibiotics
|Noninvasive ventilation, strictly applied to those with all of the following: (a) Spo
2 < 92% receiving supplemental oxygen; (b) supplemental oxygen >5 L/min; and respiratory rate ≥30 bpm
|Reintubation or requiring ventilator support (noninvasive or invasive ventilation) ≤ 48 h
||Respiratory failure: requiring ventilator support for more than 48 h
||Death before discharge
Abbreviations: PPC, postoperative pulmonary complications; Spo2, pulse oxygen saturation.
aClassified as grade 2 only when 2 or more items were met.
Intraoperative ventilation distribution was assessed using EIT (PulmoVista 500, Draeger Medical, Germany) and quantitatively analyzed with Draeger EIT Data Analysis Tool (Version 6.3, Draeger Medical) according to previous researches.10,11 A chest computed tomography (CT) scan (Philips, Netherlands) was performed 6 to 7 days after surgery. The total lung area and the area of atelectasis or pleural effusion were measured (Supplemental Digital Content 1, Methods, https://links.lww.com/AA/D553).
Respiratory and hemodynamic parameters, blood gas analysis, EIT, response entropy, and train-of-four stimulation were collected before intubation (baseline), after intubation, during PEEP titration (at each PEEP level), at 2 hours after the start of surgery, and at 1 hour after extubation. Oxygenation index, driving pressure, alveolar-arterial oxygen tension difference, intrapulmonary shunt (QS/QT), respiratory index, ratio of dead space to tidal volume (VD/VT), and respiratory power (collectively named derivative measurements) were calculated (Supplemental Digital Content 1, Methods, https://links.lww.com/AA/D553). Each time the status of PPCs was evaluated, pain severity, as well as the results of biochemical tests, were also obtained.
The primary outcome was the incidence of clinically significant PPCs (grade 2+, requiring therapeutic intervention) within the first 7 postoperative days. Secondary outcomes included the severity score of PPCs, and the area of atelectasis or pleural effusion. Exploratory outcomes consisted of the incidence of severe PPCs (grade 3+), ICU admission rate, length of hospital stay, 30-day mortality, physiological parameters, pain severity score, real-time EIT imaging, blood gas results during PEEP titration and the rest of the procedure, and the results of biochemical tests.
A modified intention-to-treat analysis was performed for all participants in whom outcome data were available according to the randomized group allocation. Continuous variables were expressed as mean ± standard deviation (SD) for data with a normal distribution (evaluated with Shapiro-Wilk test), otherwise as median and interquartile range (IQR). Categorical variables were summarized as number and percentage. The primary outcome was analyzed with a χ2 test. Secondary outcomes were evaluated with a t test for independent samples or a Mann-Whitney U test. Exploratory outcomes were compared using a χ2 test or a Fisher exact test (when expected counts are <5 for at least 25% of the cells) for categorical variables and a t test or Mann-Whitney U test for continuous variables. Comparisons between groups at several time points were analyzed using 2-way repeated measures analysis of variance, with Bonferroni correction used for multiple comparisons. Comparisons within a single group at several time points were analyzed using a 1-way repeated measures analysis of variance. A Kaplan-Meier curve with log-rank test was used to compare the probability of clinically significant PPCs between the 2 groups over time.20 A P value <.05 was considered statistically significant. Statistical analyses were performed using SPSS (version 21.0, IBM).
The sample size was calculated based on a reported incidence of PPCs (about 48%) in patients with intermediate-to-high risk.21,22 A relative reduction of 50% in the primary outcome (the incidence of clinically significant PPCs) with the use of individualized PEEP was expected. Using a type I error of 0.05 and power of 80%, we estimated that the required sample size was 124 (62 per group). The total sample size was increased to 148 to account for a 20% dropout rate.
Table 2. -
Patients’ Baseline Characteristics and Surgical Information
||Individualized PEEP group (n = 67)
||Fixed PEEP group (n = 67)
||60.6 ± 10.4
||60.6 ± 10.8
||166.8 ± 6.3
||165.0 ± 7.0
||63.7 ± 9.8
||62.3 ± 10.0
||22.8 ± 2.7
||22.8 ± 2.7
|ASA physical status (II/III)
|Smoking history (Y/N)
| Diabetes mellitus
| Preoperative hemoglobin <10 g/dL
| Preoperative pulse oxygen saturation <95%
| Liver resection
|Duration of anesthesia, min
||258.9 ± 54.6
||248.4 ± 53.0
|Duration of surgery, min
||225.8 ± 47.7
||222.1 ± 54.7
|Fluid volume, mL
|Estimated blood loss, mL
|Infusion of packed RBCs
|Blood transfusion, mL
|Urine output, mL
|Vasoactive drugs needed
Data are expressed as mean ± standard deviation, number (percentage), or median (interquartile range).
Abbreviations: ARISCAT, Assess Respiratory Risk in Surgical Patients in Catalonia; ASA, American Society of Anesthesiologists; BMI, body mass index; PEEP, positive end-expiratory pressure; RBCs, red blood cells.
A total of 230 patients were recruited, and 148 eligible participants were finally enrolled into the study between April 2017 and April 2019. Fourteen participants (7 in each group) dropped out because of changes in surgical procedure, severe complications, or the patient’s decision to withdraw. Therefore, altogether 134 patients (67 in each group) were included in the final analysis, and there were no other missing data (Figure 1). Participants’ characteristics are described in Table 2. The trial was conducted in accordance with registered protocol.
The incidence of clinically significant PPCs (grade 2+) was significantly lower in the individualized PEEP group than that in the fixed PEEP group in the first 7 days after surgery (26 of 67 [38.8%] vs 42 of 67 [62.7%], P = .006; relative risk [RR] = 0.619; 95% confidence intervals [CI], 0.435–0.881; Table 2; Figure 2 and Supplemental Digital Content 3, Figure S1, https://links.lww.com/AA/D555).
The severity score of PPCs was significantly reduced in the individualized PEEP group compared with that in the fixed PEEP group (median [IQR]: 1 [1–2] vs 2 [1–2]; P = .007; Table 3; Figure 2) within the 7 postoperative days.
Table 3. -
Summary of Outcomes in the Present Study
||Individualized PEEP group (n = 67)
||Fixed PEEP group (n = 67)
||Relative risk (95% CI)
| Clinically significant PPCs (within 7 d)
| Severity score of PPCs (within 7 d)
| Severe PPCs (within 7 d)
| ICU admission
| Planned ICU admission
| Unplanned ICU admission
| Hospital stay, d
| 30-d mortality
| Severe hypoxemia
| Pleural effusion
Data are expressed as mean ± standard deviation, number (percentage), median (interquartile range), or odds ratio (95% CI). PPCs were scored with a scale from 0 (no) to 5 (most severe) (see Methods and Table 1
). Clinically significant PPCs: with a score equal or greater than grade 2; severe PPCs: with a score equal or greater than grade 3. Severe hypoxemia: Spo2
< 90% in room air for more than 1 min. Pleural effusion: pleural effusion needing thoracentesis.
Abbreviations: ARDS, acute respiratory distress syndrome; CI, confidence interval; ICU, intensive care unit; PEEP, positive end-expiratory pressure; PPCs, postoperative pulmonary complications; Spo2, pulse oxygen saturation.
Statistical tests used: aχ2 test; bMann-Whitney U test; cFisher exact test.
dDefined according to the 2011 Berlin definition.
All patients underwent a postoperative chest CT scan on postoperative day 7, except 1 died in the fixed PEEP group. The percentage of atelectasis of total lung area was significantly decreased in the individualized PEEP group (median [IQR], 3.1% [0.9%–6.1%] vs 7.0% [2.1%–13.9%]; P = .0002). However, there was no significant difference in the percentage of pleural effusion between the 2 groups (median [IQR], 6.6% [3.7%–10.7%] vs 6.8% [3.3%–11.1%]; P = .801; Figure 3).
There were no significant differences in the incidence of severe PPCs (grade 3+) within the 7 postoperative days, planned and unplanned ICU admission rate, length of hospital stay, 30-day mortality, or the incidence of different types of PPCs between the 2 groups (Table 3). However, improved oxygenation was observed in the individualized PEEP group after surgery (Supplemental Digital Contents 4 and 5, Figures S2 and S3, https://links.lww.com/AA/D556, https://links.lww.com/AA/D557).
The median value of PEEP in the individualized group was 10 cm H2O (IQR, 8–10 cm H2O). The driving pressure was significantly lower (6.2 ± 1.3 vs 8.0 ± 1.8 cm H2O; P < .0001) and the respiratory compliance was significantly higher (60.4 ± 11.5 vs 49.2 ± 10.7 mL/cm H2O; P < .0001) during surgery in the individualized PEEP group compared with those in the fixed PEEP group (Supplemental Digital Content 2, Table S1, https://links.lww.com/AA/D554). The trend of driving pressure in the individualized PEEP group during the PEEP titration can be found in Supplemental Digital Content 6, Figure S4, https://links.lww.com/AA/D558. The reduction in driving pressure was associated with a marked reduction in atelectasis of dependent lung regions, as observed by EIT imaging during PEEP titration (Supplemental Digital Contents 7 and 8, Figures S5 and S6, https://links.lww.com/AA/D559, https://links.lww.com/AA/D560) and surgery (Supplemental Digital Contents 9 and 10, Figures S7 and S8, https://links.lww.com/AA/D561, https://links.lww.com/AA/D562).
Moreover, comparison of blood gas analysis and its derivative parameters can be found in Supplemental Digital Contents 11–14, Figures S9–S13, https://links.lww.com/AA/D563, https://links.lww.com/AA/D564, https://links.lww.com/AA/D565, https://links.lww.com/AA/D566, https://links.lww.com/AA/D567. We observed that the mechanical power in the individualized PEEP group was higher than that used in the fixed PEEP group during surgery (6.9 ± 1.5 vs 5.5 ± 1.2 J/min; P < .0001; Supplemental Digital Contents 2 and 16, Table S1 and Figure S14, https://links.lww.com/AA/D554, https://links.lww.com/AA/D568).
Our study showed that the incidence of clinically significant PPCs, the overall severity of PPCs, and the area of atelectasis were reduced in the experiment group. Aiming 2 major risk factors for PPCs,23,24 that is, the minimizing driving pressure to limit stress25 and optimizing PEEP to reduce atelectasis, the strategy we studied may explain the observed beneficial effects. The beneficial effect we showed in the individualized group was possibly due to the combined effects of both the optimal PEEP used and the process to “find” this optimal PEEP, as the incremental PEEP titration could be seen as a “prolonged” or “stepwise” recruitment maneuver, contributing to the improvement of respiratory system compliance. This can be seen in Supplemental Digital Content 6, Figure S4, https://links.lww.com/AA/D558, where compliance was further improved between the titrated 10 cm H2O and optimal PEEP (around 10 cm H2O).
Atelectasis, common in patients under general anesthesia,6,23,24 causing inhomogeneous expansion of the lung and high stress to the alveoli, renders the lung susceptible to injury from mechanical ventilation.26,27 Previous researches showed that atelectasis was significantly smaller with a moderate PEEP (7 or 9 cm H2O) than the absence of PEEP,23 and EIT-guided PEEP titration led to a lower percentage of collapsed lung.6 A similar result could be observed here in our study, demonstrated by real-time EIT imaging. No difference in pleural effusion indicates that the difference in atelectasis area was mainly due to intraoperative ventilation strategy, not external compression. Notably, although the average value of PEEP required in the study group was 10 cm H2O, the effect of individualized strategy was not equal to directly setting PEEP to 10 cm H2O, because of the effect of driving pressure and prolonged recruitment mentioned above. The dorsal-dependent part of lungs is the prone regions of atelectasis in animal experiment.28 We found that the dorsal-dependent area gradually expanded with the increase of PEEP, indicating the right spot for the reduction of atelectasis.
A decremental PEEP trial was used in previous study, for example, starting from 20 cm H2O in the Individualized Perioperative Open-lung Ventilation (iPROVE) study,22 different from what we used. Both a high level of PEEP and recruitment maneuvers can cause side effects, including increased strain, impaired hemodynamics, and decreased lung lymphatic drainage.29 The advantage of the incremental PEEP titration protocol is the avoidance of potential hemodynamic compromise and lung injury caused by overdistention. It could be reasonably assumed that overdistention and alveoli stress were prevented with this PEEP optimizing approach as the volume of dead space did not appear to increase. In addition, we did not observe any deterioration in physiological parameters or hemodynamics and did not need vasoactive drugs to maintain the blood pressure. These imply that the opened lung during titration can be maintained thereafter without notable adverse effects. However, it is not clear whether decremental and incremental protocols are equivalent in setting the optimal PEEP.
It is worth mentioning that each titration step lasted 8 minutes in the present study, a predetermined time period for observing and recording, which is not necessary when this technique is applied in clinical practice. In our experience, maintaining a PEEP level for 1 to 3 minute is enough for alteration in driving pressure in most patients, consistent with reported rapid change of end-expiratory lung volume and driving pressure during PEEP increase.30,31
In the present study, grade 2+ was defined as clinically significant PPCs to distinguish between those needing intervention and those do not. Grade 1 PPCs can be considered as mild ones, not necessarily requiring treatment. Therefore, the increase of grade 1 PPCs in the individualized group does not appear to be of clinical significance. In fact, we might infer that in the individualized PEEP group, the relative increase of participants with no PPCs or grade 1 PPCs can be explained by the relative decrease of participants with grade 2+ (clinically significant) PPCs.
Mechanical power is another novel target for preventing ventilator-induced lung injury.32 High mechanical power is generally associated with an increased risk for lung injury. In this study, we observed that the higher power along with the individualized PEEP did not seem to aggravate PPCs. A possible explanation is that the mechanical power in this PEEP setting did not reach the threshold for lung injury. Indeed, the average mechanical power in the individualized PEEP group was around 7 J/min, substantially lower than the reported threshold (12 J/min) for ventilation-related lung injury.
Although the results of reducing PPCs are quite promising, this study does not show any significant difference in the length of hospital stay or 30-day mortality between the 2 groups. Previous observations found that the threshold of driving pressure for increased mortality may be as high as 14 cm H2O,33 far beyond the driving pressure in this study (6.2 ± 1.3 cm H2O in the individualized PEEP group and 8.0 ± 1.8 cm H2O in fixed PEEP group).
Our results are significant in several aspects. First, the minimum driving pressure–guided PEEP titration is a relatively novel and straight-forward strategy for optimizing PEEP. Second, the mean driving pressure was reduced by 1.8 cm H2O in the individualized PEEP group. Of note, it had been demonstrated that even a small increase in the driving pressure might change clinical outcomes. For example, a 1 cm H2O increase in the driving pressure was associated with an increased risk for major morbidity (by 3.4%)34 and PPCs.35 Third, individualized PEEP effectively improved the ventilation of dorsal dependent regions, contributing to the reduction of atelectasis area and PPCs, as stated above.
There are several limitations in this study. Although the number of clinically significant PPCs was reduced by the implement of an individualized PEEP, the incidence of PPCs was still relatively high. The difference in definition, different types of surgery and perioperative management, as well as the accuracy of measurements, may all contribute to the different incidence of PPCs. Moreover, generalized estimating equations might be a better analytical approach for the composite end point we used to assess PPCs.36 Besides, we did not perform multiplicity adjustments for multiple secondary and exploratory outcomes, which may increase the probability of a type I error. In addition, the effect of recruitment induced by prolonged PEEP titration may also contribute to the beneficial effect we observed, and the result of shortening the titration process needs to be verified.
Based on this single-center trial, whether the beneficial results of PEEP guided by minimum driving pressure can be extrapolated to patients undergoing other types of surgery or from other regions remains unknown. Large multicenter trials are still required to support our findings.
In conclusion, individualized PEEP based on minimum driving pressure can reduce the severity of atelectasis, improve oxygenation, and ultimately reduce the incidence of clinically significant PPCs without causing obvious side effects in patients undergoing major upper abdominal surgery. Further studies are needed to validate the value of driving pressure–guided individualized PEEP in other surgical settings.
Name: Chengmi Zhang, MD, PhD.
Contribution: This author helped with the conceptualization of the idea, analyzed part of the data, and drafted the first edition of this manuscript.
Name: Fengying Xu, MD, PhD.
Contribution: This author helped with data analysis and visualization, and revised the content and language of this manuscript.
Name: Weiwei Li, MD, PhD.
Contribution: This author performed some of the statistical analysis, and provided critical review and commentary for this manuscript.
Name: Xingyu Tong, MD.
Contribution: This author took part in patient recruitment and data collection.
Name: Ran Xia, MD.
Contribution: This author took part in patient recruitment and data collection.
Name: Wei Wang, MD.
Contribution: This author took part in patient recruitment and data collection.
Name: Jianer Du, MD.
Contribution: This author helped with project administration and resource preparation.
Name: Xueyin Shi, MD.
Contribution: This author formed the research goals and aims, and took leadership responsibility for research activity.
This manuscript was handled by: Tong J. Gan, MD.
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