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Scientific Reports
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10.1038/s41598-024-71556-3
Article
Ventilatory pressure parameters impact the association between acute gastrointestinal injury and all-cause mortality in mechanically ventilated patients
Ziqiang Shao 1
Jiale Li 1
Renhua Sun 1
Aiping Wu 1
Yin Ni 1
Jingquan Liu 1
Feng Guo 2
Lijun Ying 3
Guoping Ge 4
Aijun Ding 5
Yunchao Shi 6
Changwen Liu 7
Lei Xu 8
Ronglin Jiang 9
Jun Lu 10
Ronghai Lin 11
Yannan Zhu 12
Weidong Wu 13
Bo Xie 14
Bangchuan Hu hubangchuanicu@163.com

1
1 grid.417401.7 0000 0004 1798 6507 Emergency and Critical Care Center, ICU, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Shangtang Road 158, Hangzhou, 310014 Zhejiang China
2 https://ror.org/00ka6rp58 grid.415999.9 0000 0004 1798 9361 ICU, Sir Run Run Shaw Hospital Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang China
3 https://ror.org/05v58y004 grid.415644.6 0000 0004 1798 6662 ICU, Shaoxing People’s Hospital, Zhongxing North Road, Shaoxing, 321000 China
4 ICU, Jinhua People’s Hospital, 228 Xinhua Street, Jinhua, 321000 China
5 https://ror.org/0491qs096 grid.495377.b ICU, The Third Affiliated Hospital of Zhejiang Chinese Medical University, 219 Moganshan Road, Hangzhou, 310014 China
6 https://ror.org/03q5hbn76 grid.459505.8 0000 0004 4669 7165 ICU, The First Hospital of Jiaxing, 529 Hexin South Road, Jiaxing, 314000 China
7 https://ror.org/05pwsw714 grid.413642.6 ICU, Hangzhou First People’s Hospital, 261, Huansha Road, Hangzhou, 310006 China
8 ICU, Ningbo Medical Treatment Center Lihuili Hospital, 57 Xingning Road, Ningbo, 315000 China
9 https://ror.org/04epb4p87 grid.268505.c 0000 0000 8744 8924 ICU, The First Affiliated Hospital of Zhejiang Chinese Medical University, 54 Youdian Road, Hangzhou, 310006 China
10 grid.268505.c 0000 0000 8744 8924 ICU, The Second Affiliated Hospital of Zhejiang Chinese Medical University, 318 Chaowang Road, Hangzhou, 310005 China
11 grid.469636.8 ICU, Taizhou Hospital of Zhejiang Province, 150 Ziyang Old Street, Linhai, 317000 China
12 ICU, Zhuji People’s Hospital of Zhejiang Province, 9 Jianming Road, Shaoxin, China
13 ICU, The Central Hospital of Lishui City, 15 Dazhong Street, Lishui, 323000 China
14 https://ror.org/01czx1v82 grid.413679.e 0000 0004 0517 0981 ICU, Huzhou Central Hospital, 198 Hongqi Road, Huzhou, 313003 China
5 9 2024
5 9 2024
2024
14 2076324 2 2024
29 8 2024
© The Author(s) 2024
2024
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Acute gastrointestinal injury (AGI) is common in mechanically ventilated (MV) patients, but the potential association between ventilatory pressure parameters and AGI grade and their impact on mortality remains unclear. This study aimed to explore the association between ventilatory pressure parameters and AGI grade, and their interaction on all-cause mortality in MV patients. This study was a secondary analysis of a multicenter, prospective, observational study that enrolled adult patients with an expected duration of mechanical ventilation ≥ 48 h from 14 general intensive care units in Zhejiang Province between March and August 2014. The AGI grade was assessed daily on the basis of gastrointestinal symptoms, intra-abdominal pressures, and feeding intolerance in the first week of admission to the ICU. This study included 331 patients (69.2% men; mean age, 64.6 ± 18.9 years). Multivariate regression analysis showed that plateau pressure (Pplat) (OR 1.044, 95% CI 1.009–1.081, P = 0.013), serum creatinine (OR 1.003, 95% CI 1.001–1.006, P = 0.042) and APACHE II score (OR 1.035, 95% CI 1.021–1.072, P = 0.045) were independently associated with global AGI grade III/IV within 7 days of ICU admission. Moreover, global AGI grade (HR 2.228, 95% CI 1.561–3.182, P < 0.001), serum creatinine (HR 1.002, 95% CI 1.001–1.003, P = 0.012) and APACHE II score (HR 1.039, 95% CI 1.015–1.063, P = 0.001) were independently associated with 60-day mortality. In addition, there were significant (Pint ≤ 0.028) interactions of Pplat and DP with AGI grade in relation to 60-days mortality, whereas no interaction (Pint = 0.061) between PEEP and AGI grade on 60-days mortality was observed. In the presence of Pplat ≥ 19 cmH2O, the patients with AGI grade III/IV had 60-day mortality rate of 72.2%, significantly higher than those with AGI grade I/II (48.7%, P = 0.018), whereas there were no significant differences (27.9% vs. 33.7%, P = 0.39) in 60-days mortality between AGI grade I/II and III/IV among the patients with Pplat < 19 cmH2O. In comparison with Pplat, DP had a similar interaction (Pint = 0.028) with AGI grade on 60-day mortality. Ventilatory pressure parameters (Pplat and DP) are independent risk factors of AGI grade III/IV. Pplat and DP interact with AGI grade on 60-days mortality, highlighting the importance of optimizing ventilatory pressure parameters to improve gastrointestinal function and survival outcomes of MV patients.

Trial registration: ChiCTR-OCS-13003824.

Keywords

Mechanical ventilation
Acute gastrointestinal injury
All-cause mortality
Plateau pressure
Driving pressure
Positive end-expiratory pressure
Interaction
Subject terms

Gastroenterology
Medical research
Risk factors
Key Research and Development Project of the Science Technology Department of Zhejiang Province2020C03031 http://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China 82272188 81971857 Jingquan Liu issue-copyright-statement© Springer Nature Limited 2024
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pmcIntroduction

Gastrointestinal injury in critically ill patients is very common and is considered as an initiating factor for multi-organ dysfunction1,2. With the weakening of the intestinal barrier function, intestinal bacteria can translocate into blood and cause sepsis3. In 2012, the European Association of Intensive Care Medicine (ESICM) Working Group on Abdominal Problems defined acute gastrointestinal injury (AGI) as gastrointestinal dysfunction in critically ill patients due to their acute illness, they proposed a four-grade severity system based on available medical evidence and current understanding of pathophysiology4. Previously, the AGI grade system was used to predict the severity and adverse clinical outcomes in critically ill patients. AGI grade III/IV is an independent risk factor for poor outcomes in ICU patients5,6. However, few studies have been done on AGI risk factors, making it difficult for physicians to apply necessary strategies to prevent AGI and its progression.

Mechanical ventilation (MV) is a common respiratory support technology for critically ill patients, but it also brings many related complications that can significantly affect the prognosis of ICU patients7. Gastrointestinal signs are common and can be observed in up to 60% MV patients8,9. Stress-related mucosal damage (SRMD) is the most common cause of gastrointestinal bleeding in MV patients10. Gastrointestinal hypomotility manifesting as decreased bowel sounds or abdominal distention is common and reported in up to half of patients with MV11. Although MV is well known to cause gastrointestinal dysfunction, few studies investigate the impact of ventilatory pressure parameters on gastrointestinal function in ICU patients.

Inspiratory airway pressure [plateau pressure (Pplat) = positive end-expiratory pressure (PEEP) + driving pressure (DP)] is used as a surrogate for lung stress evaluation during MV12. Inspiratory airway pressure emerged as a potential target for optimizing MV to improve patient outcomes12. High pressure applied to the lungs can be harmful in patients with or without acute respiratory distress syndrome (ARDS). Recent studies have shown that high Pplat and DP were independent risk factors for in-hospital mortality13,14. In patients with COVID-19, AGI was associated with a longer duration of MV and an increased risk of death15. Despite a body of evidence suggesting that PP, DP and AGI grade were associated with mortality, there is a lack of research on the interaction between ventilatory pressure parameters and AGI grade on the prognosis of critically ill patients.

Therefore, this multicenter study aimed to investigate the associations of the ventilatory pressure parameters (Pplat, DP and PEEP) with AGI grade III/IV and further explore ventilatory pressure parameters impact the association between AGI grade and all-cause mortality in MV patients.

Methods

Study design and patients

This study was a secondary analysis of pooled data from the AGI grade study, which was a multicenter, prospective, observational study conducted at 14 general intensive care units (ICUs) of the Zhejiang Province (China) from 1 March to 31 August 2014. The study design and nutrition protocol have been previously described5. Briefly, the enteral nutrition (EN) for the ICU patients included in this study was initiated as a principle of permissive underfeeding in the first week of ICU admission according to current clinical practice guidelines for nutrition support in critically ill patients16–18. The nutritional target was set for all patients at 20 kcal/kg body weight per day within the first week of ICU admission. In addition, the Harris-Benedict equation was also used to determine the energy target for EN. After ICU admission, if the patients had stable hemodynamics or had no EN contraindications, patients were recommended to receive EN starting 24–48 h, and subsequently strive to reach a caloric target of 80%-100% of the energy requirement (25–30 kcal/kg body weight per day after the first week of ICU admission), and only as tolerated the energy target of 20 kcal/kg body weight per day within the first week of ICU admission. The EN infusion rate was determined based on the patient’s FI (no severe abdominal distention, diarrhea, vomiting, or gastric residual volume) and the total daily infusion amount. If the EN did not reach 60% of the nutritional goal (20 kcal/kg body weight/day during the first week of ICU admission), patients with protein-caloric malnutrition at ICU admission received supplemental parenteral nutrition (SPN) from the fourth day of ICU admission19. The study protocol was approved by the local ethics committees of each hospital and conducted in accordance with the latest version of the Declaration of Helsinki. All patients or their legal representatives provided written informed consent according to the local ethical regulations. The study was registered in the Chinese Clinical Trial Registry (registration no. ChiCTR-OCS-13003824).

The patients were screened for eligibility within 24 h of ICU admission. The inclusion criteria were (1) > 18 years old, (2) Acute Physiology and Chronic Health Evaluation II (APACHE II) score > 8, and (3) required MV for at least 48 h in the ICU. The exclusion criteria were (1) AGI could not be evaluated for any reason, (2) advanced cancer, (3) any terminal stage disease, (4) delayed initiation of enteral nutrition (EN, > 48 h), in the absence of contraindication to EN, evidence for intolerance of EN or hemodynamic instability, (5) missing PP or PEEP data.

Data collection and definition

A specific case report was used for data collection. Briefly, data regarding baseline demographic and clinical characteristics, AGI grade, and ventilatory variables were collected within the first week of ICU admission5. GI symptoms and feeding intolerance (FI) were predefined according to the recommendations of the ESICM. The GI symptoms (vomiting/regurgitation, high gastric residual volume, abnormal bowel sounds, diarrhea, bowel distention, and GI bleeding), abdominal perfusion pressure (APP), intro-abdominal pressure (IAP) and feeding details were documented each day. FI was considered if at least 20 kcal/kg body weight per day (or for ideal body weight in patients with body mass index > 30 kg/m2) via the enteral route could not be reached within 72 h of feeding attempt or if EN had to be stopped for any clinical reason. The AGI grade was assessed daily according to the recommendation of the ESICM grading system during the first week of the subject’s ICU stay. This system is based mainly on GI symptoms and IAP on days 1–3 of ICU admission, and it is concomitantly combined with FI and organ dysfunction on the remaining 4 days. The global AGI grade was determined on the basis of worst AGI grade within the first week of ICU admission.

ARDS diagnosis on ICU admission was based on the Berlin definition criteria20. The ARDS patients received lung protective ventilation strategy, which was defined as the combination of tidal volume 8 ml/kg predicted body weight or lower and PEEP 5 cmH2O or higher, with or without a recruitment maneuver. Ventilatory variables included respiratory rate, tidal volume (VT), PEEP, Ppeak and Pplat were obtained. Respiratory mechanics were monitored every 6 h for a total of four measurements per day, and mean daily ventilatory pressure parameters were calculated as the average of the four measurements within one day. All ventilatory variables were extracted under controlled mechanical ventilation. Pplat was measured by a minimum 0.5 s inspiratory hold maneuver at zero flow in patients on volume-controlled ventilation, or Ppeak was considered equal to Pplat in patients on pressure-controlled modes. While measuring Pplat in patients with synchronized intermittent mandatory ventilation (SIMV), SIMV needed to be switched to the volume-controlled ventilation, and the patients required deep sedation to avoid making respiratory efforts. PEEP was recorded directly from the ventilator. DP was calculated as Pplat minus PEEP. Patients who survived were followed-up by telephone, and the information on vital status was obtained from patients, relatives, and general practitioners. An unfavorable outcome was defined as 28- and 60-day all-cause mortality after ICU admission.

Statistical analysis

SAS 9.13 software (SAS Institute, Cary, NC, USA) was used for database management and statistical analyses. Values were presented as the mean (standard deviation) or median [interquartile range (IQR)] for continuous variables as appropriate and as the total number (percentage) for categorical variables. Comparisons of means and proportions relied on the standard normal z-test and Fisher’s exact test, respectively. Continuous variables with a skewed distribution were normalized by logarithmic transformation and presented as geometric mean and 95% CI. Because of the relatively small sample size, AGI grade was handled as a binary variable as I/II vs. III/IV for regression analysis. Multivariate logistic regression models including mean ventilatory pressure parameters on the first day of ICU admission were used to identify independent risk factors for global AGI III/IV. Considering that Pplat is the sum of PEEP and DP, the Pplat, PEEP and DP were separately incorporated into two multivariate regression models. The prognostic value of the variables was assessed using a univariate Cox proportional hazards regression model. The variables with P values < 0.10 were entered in a multivariate Cox proportional hazards regression to determine the independent predictors of mortality. To further evaluate the interaction effect between AGI grade and ventilatory pressure parameters on mortality, multivariate Cox proportional hazards regression was extended by the interaction term (AGI grade × pressure parameters) with adjustment for covariates in each Cox regression model. Kaplan–Meier survival analysis was performed to estimate the cumulative probability of survival. The survival rates of different subgroups of patients stratified by global AGI grade (I/II vs. III/IV) and ventilation pressure parameters (median) were compared using the log-rank test. Two-sided P values < 0.05 were considered statistically significant.

Results

Characteristics of the patients

Figure 1 presents the patient flowchart. Between March 1, 2014, and April 30, 2014, 702 patients from general 14 ICUs were screened. Among them, 28 patients did not meet the inclusion criteria; 124 patients met the criteria but could not be dynamically evaluated for AGI in the first week of ICU admission. In addition, 244 patients had to be excluded because of not receiving MV (n = 87), receiving MV for less than 48 h (n = 33), missing data on ventilatory pressure parameters (n = 99) or lost to follow-up (n = 25). Therefore, 331 patients were available for the analyses (Fig. 1). Among the studied patients who received MV, 229 (69.2%) were males; mean age and APACHE II score were 64.6 ± 18.9 years and 20.3 ± 7.98, respectively. The leading causes of acute respiratory failure requiring MV were pneumonia (20.8%), postoperative (16.9%), cerebrovascular disease (15.1%), ARDS (10.9%), chronic obstructive pulmonary disease (9.36%), congestive heart failure (8.76%), and sepsis (8.46%). Coronary artery disease, diabetes mellitus, and acute kidney injury accounted for 14.2%, 16.6%, and 22.4%, respectively. The median Pplat, DP, and PEEP in the first day of ICU admission was 19cmH2O, 15cmH2O, and 5cmH2O, respectively.Fig. 1 Enrollment flowchart. AGI, acute gastrointestinal injury; EN, enteral nutrition; IAP, intro-abdominal pressure; ICU, intensive care unit; SPN, supplemental parenteral nutrition.

The distribution of the global AGI grades was 15.4% for grade I (n = 51), 51.1% for grade II (n = 169), 27.2% for grade III (n = 90), and 6.3% for grade IV (n = 21). There were no differences among the patients with different grades of AGI for age (P = 0.76), sex (P = 0.62), and related disorders (P ≥ 0.10). There were significant differences in serum levels of creatinine and lactate (P ≤ 0.007), systolic and diastolic blood pressures (P ≤ 0.013), central venous pressure (P = 0.011), IAP (P = 0.001), the use of vasoactive drugs and renal replacement therapy (P ≤ 0.011), APACHE II score (P = 0.002), and SOFA score (P = 0.01) among different grades of AGI grade. In addition, the patients with AGI grade III/IV had significantly higher 28-day (53.1% vs. 29.5%, P < 0.001) and 60-day (55.8% vs. 31.3%, P < 0.001) mortality rates than those with AGI grade I/II (Table 1).Table 1 Characteristics of the patients according to acute gastrointestinal injury grade.

Variables	Total (n = 331)	AGI grades I/II (n = 220)	AGI grades III/IV (n = 111)	P	
Age, years	64.6 ± 18.9	64.9 ± 19.5	64.3 ± 18.7	0.76	
Male sex, n (%)	229 (69.2)	150 (68.2)	79 (71.2)	0.62	
Body mass index, kg/vs	22.1 ± 1.66	22.1 ± 1.13	22.2 ± 2.38	0.52	
Use of vasoactive drug, n (%)	120 (36.2)	69 (31.3)	51 (45.9)	0.011	
Systolic blood pressurea, mmHg	103.2 ± 21.8	108.9 ± 22.7	97.7 ± 22.5	0.013	
Diastolic blood pressurea, mmHg	55.4 ± 13.6	56.7 ± 13.4	52.6 ± 12.6	0.008	
Central venous pressurea, cmH2O	12.1 ± 4.46	11.6 ± 4.29	13.1 ± 4.57	0.011	
Intra-abdominal pressurea, mmHg	9.99 ± 3.68	9.22 ± 2.97	11.3 ± 4.36	 < 0.001	
Abdominal perfusion pressurea, mmHg	59.7 ± 14.8	61.3 ± 14.3	56.9 ± 15.3	0.02	
Main reason for mechanical ventilation	
 Pneumonia, n (%)	69 (20.8)	48 (21.8)	21 (18.9)	0.57	
 Postoperative, n (%)	56 (16.9)	33 (15.0)	23 (20.7)	0.19	
 Cerebrovascular disease, n (%)	50 (15.1)	35 (15.9)	15 (13.5)	0.62	
 ARDS, n (%)	36 (10.9)	17 (7.73)	19 (17.1)	0.014	
 COPD, n (%)	31 (9.36)	19 (11.8)	12 (4.50)	0.52	
 Congestive heart disease, n (%)	29 (8.76)	21 (9.55)	8 (7.21)	0.47	
Ventilatory mode	0.36	
 Volume-controlled ventilation, n (%)	49 (14.8)	29 (13.2)	20 (18.0)		
 Pressure-controlled ventilation, n (%)	108 (32.6)	70 (31.8)	38 (34.2)		
 Synchronized intermittent mandatory ventilation, n (%)	174 (52.6)	121 (55.0)	53 (47.7)		
 Respiration ratea, breaths/min	22.2 ± 7.15	22.2 ± 6.52	23.5 ± 8.23	0.13	
 PaO2/FiO2, mmHg	241.7 ± 128.6	244.8 ± 130.0	235.6 ± 126.1	0.54	
 Plateau pressurea, cmH2O	20.0 ± 6.73	18.9 ± 6.24	21.2 ± 7.20	0.002	
 Positive end expiratory pressurea, cmH2O	5.04 ± 2.04	4.82 ± 1.97	5.29 ± 2.10	0.06	
 Driving pressurea, cmH2O	15.0 ± 6.55	14.1 ± 5.98	16.0 ± 7.06	0.007	
Related disorders	
 Sepsis, n (%)	96 (29.0)	57 (25.9)	39 (35.1)	0.10	
 Diabetes, n (%)	55 (16.6)	37 (16.8)	18 (16.2)	0.89	
 Coronary artery disease, n (%)	47 (14.2)	32 (14.5)	15 (13.5)	0.47	
 Hypertension, n (%)	156 (47.1)	105 (47.7)	51 (45.9)	0.82	
 Acute kidney injury, n (%)	74 (22.4)	35 (15.9)	39 (35.1)	 < 0.001	
 Renal replacement therapy, n (%)	42 (12.7)	17 (7.73)	25 (22.5)	 < 0.001	
 Serum lactatea, median (IQR) mmol/L	1.9 (1.2, 3.5)	1.7 (1.20, 3.2)	2.2 (1.4, 4.3)	0.007	
 Plateleta, median (IQR) 109/L	152 (102, 208)	155 (110, 214)	146 (76, 195)	0.04	
 Serum creatininea, µmol/L	117.1 ± 96.1	101.6 ± 90.2	135.9 ± 99.8	 < 0.001	
 Glucosea, mmol/L	9.35 ± 4.49	9.11 ± 4.24	9.80 ± 4.95	0.22	
 Gastric residual volumes, ml	82.4 ± 63.5	49.3 ± 36.2	126.8 ± 101.6	 < 0.001	
 Calorie intake of EN on the third day in ICU	849 ± 158	1046 ± 182	572 ± 163	 < 0.001	
 Calorie intake of EN on the Seventh day in ICU	1076 ± 182	1305 ± 206	684 ± 173	 < 0.001	
 APACHE II score	20.3 ± 7.98	19.2 ± 7.81	21.8 ± 7.96	0.002	
 SOFA score	9.28 ± 4.54	8.70 ± 4.27	9.99 ± 4.78	0.01	
 Duration of mechanical ventilation, median (IQR) days	10 (6, 18)	10 (6, 19)	9 (5, 17)	0.06	
 28-days mortality, n (%)	124 (37.5)	65 (29.5)	59 (53.1)	 < 0.001	
 60-days mortality, n (%)	131 (39.5)	69 (31.3)	62 (55.8)	 < 0.001	
AGI, acute gastrointestinal injury; ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmonary disease; APACHE II, acute physiology and chronic health evaluation II; EN, enteral nutrition; ICU, intensive care unit; IQR, interquartile range; SOFA sequential organ failure assessment.

Values are presented as mean ± SD, median (IQR) or as number of subjects (percentage of the column total). P values for differences AGI grades were calculated for comparisons on the basis of analysis of variance or Fisher’s exact test (proportions).

aAssessed within 24 h of ICU admission.

Association between ventilatory pressure parameters and AGI grade

The patients with AGI grade III/IV had significantly higher Pplat (21.2 ± 7.20 vs. 18.9 ± 6.24 cmH2O, P = 0.002) and DP (16.0 ± 7.06 vs. 14.1 ± 5.98 cmH2O, P = 0.007) than those with AGI grade I/II. The univariate logistic regression analysis showed that acute kidney injury, Pplat, DP, APACHE II score, platelet, serum creatinine and lactate were significantly (P ≤ 0.043) associated with the global AGI grade. In the multivariate analysis of two separated models including these variables, Pplat (OR 1.044, 95% CI 1.009–1.081, P = 0.013) and DP (OR 1.040, 95% CI 1.004–1.077, P = 0.031) remained an independent predictor for AGI grade III/IV, respectively (Table 2). In addition, the patients with Pplat ≥ 19 cmH2O had significantly lower APP (62.0 ± 13.5 vs. 57.6 ± 15.6 mmHg, P = 0.013), higher CVP (12.6 ± 4.81 vs. 11.4 ± 4.16 cmH2O, P = 0.045) and IAP (10.2 ± 4.05 vs. 9.28 ± 3.77 mmHg, P = 0.048) than those with Pplat < 19 cmH2O. (Fig. 2).Table 2 Univariate and multivariate logistic regression analysis for AGI grade III/IV within 7 days of ICU admission.

Variables	Univariate	Multivariate	Multivariatea	
OR (95% CI)	P	OR (95% CI)	P	OR (95% CI)	P	
Use of vasoactive drugs	1.619 (1.218–2.423)	0.043					
Serum creatinine (μmol/L)	1.005 (1.002–1.008)	0.003	1.003 (1.001–1.006)	0.042	1.003 (1.001–1.006)	0.037	
Plateau pressure (cmH2O)	1.053 (1.019–1.089)	0.002	1.044 (1.009–1.081)	0.013			
Driving Pressure (cmH2O)	1.047 (1.012–1.083)	0.008			1.040 (1.004–1.077)	0.031	
Positive end expiratory pressure, cmH2O	1.182 (0.963–1.416)	0.072					
Serum lactate (μmol/L)	1.097 (1.005–1.199)	0.039					
Platelet, 109/L	0.997 (0.994–0.999)	0.012					
APACHE II score	1.043 (1.014–1.074)	0.003	1.035 (1.021–1.072)	0.045	1.031 (1.00–1.062)	0.048	
AGI, acute gastrointestinal injury; APACHE II, acute physiology and chronic health evaluation II; OR, odds ratio.

aPlateau pressure was divided into positive end expiratory pressure and driving pressure entered as two variables in multivariate regression model.

Fig. 2 The differences for APP, IAP and CVP between the patients with Pplat ≥ 19 cmH2O and those with Pplat < 19 cmH2O. APP, abdominal perfusion pressure; IAP, intro-abdominal pressure; CVP, central venous pressure.

Univariate and multivariate analyses for 60-day mortality

The univariate Cox regression analysis showed that age, systolic blood pressure, use of vasoactive drugs, serum lactate and creatinine, platelet, acute kidney injury, Pplat, PEEP, DP, global AGI grade, and APACHE II score were significantly (P ≤ 0.045) associated with the 60-day mortality. In the multivariable Cox regression analysis including these variables, serum creatinine (HR 1.002, 95% CI 1.001–1.003, P = 0.012), global AGI grade (HR 2.228, 95% CI 1.561–3.182, P < 0.001), and APACHE II score (HR 1.039, 95% CI 1.015–1.063, P = 0.001) were independent risk factors for 60-day all-cause mortality (Table 3).Table 3 Univariate and multivariate Cox regression analysis for 60-days mortality.

Variables	Univariate	Multivariate	Multivariatea	P value	
HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	
Age (years)	1.011 (1.002–1.021)	0.014					
Systolic blood pressure (mmHg)	0.991 (0.983–0.999)	0.019					
Use of vasoactive drugs	1.623 (1.163–2.264)	0.004					
Serum creatinine (μmol/L)	1.003 (1.001–1.004)	 < 0.001	1.002 (1.001–1.003)	0.012	1.002 (1.001–1.003)	0.007	
Plateau pressure (cmH2O)	1.037 (1.013–1.061)	0.003	1.021 (0.998–1.047)	0.074			
Driving Pressure (cmH2O)	1.031 (1.007–1.056)	0.015			1.018 (0.996–1.043)	0.092	
Positive end expiratory pressure, cmH2O	1.084 (1.007–1.168)	0.042					
Global AGI grade (I/II vs. III/IV)	2.456 (1.746–3.455)	 < 0.001	2.228 (1.561–3.182)	 < 0.001	2.224 (1.558–3.174)	 < 0.001	
Serum lactate (μmol/L)	1.071 (1.030–1.132)	0.045					
Platelet, 109/L	0.997 (0.994–0.999)	0.012					
APACHE II score	1.056 (1.035–1.077)	 < 0.001	1.039 (1.015–1.063)	0.001	1.041 (1.016–1.065)	 < 0.001	
AGI, acute gastrointestinal injury; APACHE II, acute physiology and chronic health evaluation II; HR, hazard ratio.

aPlateau pressure was divided into positive end expiratory pressure and driving pressure entered as two variables in multivariate regression model.

Ventilation pressure parameters and AGI grade interaction on 60-day mortality

With adjustment for age, systolic blood pressure, use of vasoactive drugs, serum lactate and creatinine, and APACHE II score, there were significant (Pint ≤ 0.028) interactions of Pplat and DP on the first day of ICU admission with global AGI grade in relation to 60-day mortality. Pplat was significantly (HR = 1.019, 95% CI 1.003–1.035, P = 0.018) associated with 60-day mortality in patients with AGI grade III/IV, whereas no significant association between Pplat and 60-days mortality was observed in patients with AGI grade I/II (P = 0.39). Similarly, DP was significantly (HR 1.020, 95% CI 1.002–1.038, P = 0.029) associated with 60-day mortality in patients with AGI grade III/IV compared to those with AGI grade I/II. However, no significant interaction (Pint = 0.061) between PEEP and AGI grade on 60-day mortality was observed (Fig. 3).Fig. 3 Hazard ratio of 60-days mortality associated with global AGI grade in patients above or below the median of Pplat, DP, and PEEP. Vertical lines denote 95% confidence intervals. For each hazard ratio, the P value is given. AGI, acute gastrointestinal injury; Pplat, plateau pressure; DP, driving pressure; PEEP, positive end-expiratory pressure.

The Kaplan–Meier survival analysis

Figure 4 showed the Kaplan–Meier curves stratified on AGI grade (I/II vs. III/IV) and Ventilatory pressure parameters (median) for 28- and 60-days mortality. In the presence of Pplat ≥ 19 cmH2O (above median), the patients with AGI grade III/IV had 60-day mortality rate of 72.2%, significantly higher than those with AGI grade I/II (48.7%, P = 0.018), whereas there were no significant differences (27.9% vs 33.7%, P = 0.39) in 60-day mortality between AGI grade I/II and III/IV among the patients with Pplat < 19 cmH2O (below median) (Fig. 4a). Similarly, in the presence of DP ≥ 15 cmH2O, the patients with AGI grade III/IV had significantly higher risk of 60-day mortality than those with AGI grade I/II (72.9% vs 48.8%, P = 0.029), whereas there were no significant differences (P = 0.66) in 60-days mortality between AGI grade I/II and III/IV in the presence of DP < 15 cmH2O (Fig. 4b).Fig. 4 The Kaplan–Meier curves stratified on the basis of global AGI grade (I/II vs. III/IV) and median of ventilatory pressure parameters for 28 day and 60-days mortality. the cut off values of median Pplat and DP were 19 cmH2O (a) and 15 cmH2O (b), respectively. P values were for differences among the four categories by Log-rank test. Pplat, plateau pressure; DP, driving pressure.

Discussion

The main findings of our study can be summarized as follows. First, ventilatory pressure parameters (Pplat and DP) were independent risk factors of AGI grade III/IV. Second, global AGI grade but not ventilatory pressure parameters was an independent risk factor of 60-day mortality. Third, our study was first to indicate that Pplat and DP interacted with AGI grade on 60-day mortality, highlighting the importance of optimizing pressure parameters to improve gastrointestinal function and survival outcomes of MV patients.

In previous studies, MV was demonstrated to increase the risk of gastrointestinal complications in critically ill patients7,9,15,21, but no studies examined the impact of ventilatory pressure parameters on AGI. Still, previous studies lacked clear and systematic definitions regarding gastrointestinal dysfunction and injury. Since the introduction of the AGI definition and grading system by ESICM in 20124, it has been effective in accurately reflecting the severity of gastrointestinal function damage. This study identified ventilatory pressure parameters as independent risk factors for AGI grade III/IV, providing supportive evidence for the impact of MV on gastrointestinal function damage.

Although the association between MV and AGI is well-established, the relationships between MV parameters and AGI are less well-understood. In the present study, the ventilatory pressure parameters (i.e., the Pplat and its component DP) were independent risk factors for AGI grade III/IV within the first week of ICU admission. The present study results are supported by previous studies in which the investigators examined the association between MV pressure parameters and gastrointestinal complications assessed by FI or intra-abdominal hypertension (IAH)2,22,23. Indeed, in a prospective study of 50 patients with MV and 50 patients without MV, de Dios Soler Morejon et al.22 reported that MV was an independent risk factor for IAH. In addition, a multiple linear regression analysis showed that PEEP was independently related to IAH in MV patients. In a study of 264 adults with MV for ≥ 24 h, Reintam et al.2 observed that PEEP and Pplat were higher in patients with IAH than in those without IAH. PEEP and Pplat were also higher in patients with FI. In addition, Pplat > 30 cmH2O was significantly correlated to IAH (OR 5.9, 95% CI 1.91–18.6, P = 0.002) in a prospective cohort study of 175 patients23. These findings reinforce the theory of a cross-talking between MV and the gastrointestinal system, and an increasement of ventilatory pressure parameters can lead to worsening intestinal function.

The mechanisms underlying MV-induced gastrointestinal dysfunction include aspects such as pressure transmission, venous return, and cardiac output7,9,15,21. Indeed, positive pressure ventilation increases intrathoracic pressure, decreases venous return, and then reduces cardiac preload and cardiac output. Animal experiments confirmed that the splanchnic blood flow in these settings decreases in parallel with the MV-induced reductions in cardiac output, even when mean arterial pressure is maintained24. Gastric mucosal ischemia caused by hypoperfusion is the most common cause of gastrointestinal bleeding in patients receiving MV. A retrospective study of 283 ICU patients with MV for > 48 h showed that a peak inspiratory pressure of ≥ 30 cmH2O was an independent risk factor for gastrointestinal bleeding in MV patients25. In addition, positive pressure ventilation leads to block venous return, resulting in gastrointestinal tract congestion, edema, and FI. Recently, in a retrospective study of 97 adult patients, Abe et al.26 showed that high CVP during the week after left ventricular assist device implantation was an independent risk factor related to decreased EN calorie intake. Furthermore, due to the thoracic-abdominal pressure transmission, intrathoracic pressure caused by MV leads to elevated IAP. Hence, higher ventilatory pressure parameters have been suggested to worsen gastrointestinal function by affecting IAP27,28. Accordingly, in the present study, greater Pplat correlated with a decreased APP and increased IAP and CVP, in accordance with the mechanisms of gastrointestinal function deterioration caused by MV. However, the exact reason why Pplat and DP, but not PEEP, associated with global AGI III/IV needs to be clarified. First, both DP and PEEP could lead to elevated IAP through intra-thoracic pressure transmission, which is associated with the increased risk of gastrointestinal dysfunction. However, in 563 MV patients, PEEP > 10 cmH2O was reported as an independent risk factors for intra-abdominal hypertension29. Therefore, the PEEP values were set at relatively low levels (mean PEEP of 5 cmH2O) in our study, which might conceal the effect of PEEP on gastrointestinal dysfunction. In addition, elevated DP could also worsen pulmonary vascular resistance by inducing the effect of lung distension on pulmonary capillaries, consequently leading to increased right ventricular afterload and gastrointestinal dysfunction, whereas a mean PEEP of 8 cmH2O in patients with moderate-to-severe ARDS was reported to be potentially responsible for lung derecruitment, less affecting the change of pulmonary vascular resistance30. Hence, although the impact of ventilatory pressure parameters on gastrointestinal function is evident, the mechanisms are complex and require further research to optimize protective ventilation strategies.

Beyond AGI, our present study is the first to demonstrate that Pplat and DP (but not PEEP) interacted with AGI grade to affect the 60-days mortality of MV patients. Accumulating evidence has suggested that ventilatory pressure parameters and AGI grades are important determinants in the clinical outcome of ICU patients. Pplat and DP reflect stress on the lungs, which is associated with higher odds of mortality31–34. In a prospective cohort study of 1132 patients receiving MV from 59 ICUs across the United States, Sahetya et al.13 observed that a greater DP was associated with increased mortality in patients without and with ARDS. Likewise, our previous study5 was the first to demonstrate that the severity of AGI grade was a strong predictor of mortality, which has been validated by subsequent studies8,21,35. Chen et al.35 showed that MV was associated with a 63-fold increased risk of death in ICU patients, independently from AGI (which increased the death risk by four times), but they did not examine the interaction between MV and AGI on mortality. In a prospective study of 377 adult patients from 40 ICUs with an expected duration of MV of at least 6 h, Reintam et al.8 reported that gastrointestinal failure (defined as three or more gastrointestinal symptoms on day 1 of ICU admission) was independently associated with a threefold increased risk of mortality. The exact mechanism underlying the interaction between ventilatory pressure parameters (Pplat and DP) and AGI grade in relation to 60-day mortality remains to be elucidated. The mechanical stress on the lungs due to MV involves increased inflammation36,37. Hence, increased inflammation in the lungs due to high Pplat and DP could interact with AGI grade III/IV to increase the 60-days mortality through a mix of inflammatory factors, circulatory disorders and gut dysbiosis, as suggested by previous studies revealing increased mortality in patients with gut dysbiosis and lung injury38,39. This finding may provide some implications for clinical practice. Ventilatory strategies such as lowering Pplat and appropriate PEEP not only contribute to lung protection40, but also reduce the risk of severe AGI in MV patients. In addition, patients with AGI grade III/IV may benefit more from relatively lower Pplat or DP levels, especially DP.

Our study should be interpreted within the context of its strengths and limitations. We conducted a multicenter, prospective, observational study with a relatively large sample size. Furthermore, the AGI grade was assessed daily during the first week of ICU stay and could dynamically reflect the change of gastrointestinal dysfunction. Nevertheless, the present study has still some limitations. First, the global AGI grade was determined based on the worst AGI grade within the first week of ICU admission, which could potentially lead to an overestimation of the risk of AGI. Second, only ventilatory pressure parameters monitored in the first day of ICU admission were included into multivariate regression model to identify independent risk factors for global AGI III/IV, which could bias the results, and thus it should be cautiously interpreted. Third, the Pplat and DP could be collinearity with disease severity in critically ill patients, potentially affecting their results as independent risk factors for AGI grade III/IV. Furthermore, the DP value was obtained by calculating formula from the secondary analysis, also potentially affecting its accuracy. Fourth, the inclusion of a relatively large number of patients with SIMV and a small percentage of ARDS patients limits the generalizability of these results. In addition, it was an observational study, and causality could not be established.

In conclusion, this study showed that ventilatory pressure parameters (Pplat and DP) were independently associated with AGI grades III/IV. Pplat and DP interacts with AGI grade to affect the mortality of ICU patients. The results suggest that avoiding excessive DP and Pplat in patients with severe AGI could improve MV patients’ outcomes. Larger randomized controlled studies are needed to further validate these results.

Abbreviations

AGI Acute gastrointestinal injury

APACHE Acute physiologic assessment and chronic health evaluation

APP Abdominal perfusion pressure

ARDS Acute respiratory distress syndrome

CVP Central venous pressure

DP Driving pressure

EN Enteral nutrition

ESICM European society of intensive care medicine

FI Feeding intolerance

MV Mechanical ventilation

IAP Intra-abdominal pressure

ICU Intensive care unit

Pplat Plateau pressure

PEEP Positive end expiratory pressure

SIMV Synchronized intermittent mandatory ventilation

SOFA Sequential organ failure assessment score

Acknowledgements

We gratefully acknowledge all of the physicians, nurses, dietitians, patients and the local investigators of each hospital involved at the 14 participating centers for their dedication to the study. We also thank Dr. Li Jun and Liu zhihong for their kind help to perform the statistical analysis and revise the manuscript.

Author contributions

Z.S., R.S. and B.H. conceived of the study design, analyzed and interpreted the data, and drafted the manuscript. A.W. and Y.N. contributed substantially to interpreting the data and critically revised the manuscript for important intellectual content. J.L. contributed to collecting the data and performing the statistical analysis. F.G., L.Y., G.G., and A.D. participated in the design of the study, acquired the data, and helped to revise the manuscript. Y.S., C.L., L.X., R.J., J.L., R.L., Y.Z., W.W., and B.X. contributed to the conception and coordination of the study, acquisition of the data, and interpretation of the results. All authors read and approved the final manuscript.

Funding

The study was financially supported by grants from Key Research and Development Project of the Science Technology Department of Zhejiang Province (2020C03031), and National Natural Science Foundation of China (82272188 and 81971857).

Data availability

The datasets generated and/or analyzed during the current study are not publicly available due to privacy concerns, but are available from the corresponding author and all co-authors on reasonable request.

Competing interests

The authors declare no competing interests.

Ethical approval and consent to participate

The study protocol was approved by the local ethics committee for each hospital, and registered in the Chinese Clinical Trial Registry (Registration No. ChiCTR-OCS-13003824). All patients or their legal representative provided an informed written consent according to the local ethical rules.

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Shao Ziqiang and Li Jiale.
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