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 Table of Contents  
STUDY PROTOCOL
Year : 2016  |  Volume : 1  |  Issue : 3  |  Page : 124-130

Effects of lung protective ventilation on pulmonary function, inflammation, and oxidative stress in patients undergoing craniotomy: study protocol for a multi-center, randomized, parallel, controlled trial


1 Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province; Department of Anesthesiology, Anhui Provincial Hospital (Southern District), Hefei, Anhui Province, China
2 Department of Anesthesiology, Anhui Provincial Hospital (Southern District), Hefei, Anhui Province, China
3 Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China

Date of Web Publication29-Jul-2016

Correspondence Address:
Zhong-yuan Xia
Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2468-5577.187078

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  Abstract 

Background: Conventional mechanical ventilation often leads to lung inflammatory responses and oxidative stress, influencing a patient's prognosis. Lung protective ventilation has been widely used during one-lung ventilation and abdominal surgeries as it can reduce lung tissue injury and improve systemic oxygenation. However, there are few reports on its use during craniotomy.
Methods/Design: This multi-center, randomized, parallel, controlled trial will be performed at Anhui Provincial Hospital (Southern District), and the Renmin Hospital of Wuhan University, China. Sixty patients scheduled to undergo craniotomy and meeting our eligibility criteria will be randomly allocated to undergo either lung protective ventilation (6 mL/kg tidal volume, 10 cmH 2 O positive end-expiratory pressure, respiratory frequency 15 breaths/min; n = 30) or conventional mechanical ventilation (10 mL/kg tidal volume, respiratory frequency 12 breaths/min; n = 30). All patients will be evaluated from just prior to surgery (at changing of the ventilation mode) to immediately after extubation. The primary outcome measure will be dynamic lung compliance. The secondary outcome measures will be respiratory index, mean airway pressure, plateau pressure, alveolar and plasma markers of inflammation, and oxidative stress.
Discussion: The outcomes will reveal the effects of a protective ventilation strategy using low tidal volumes and the use of positive end-expiratory pressure on respiratory status, postoperative pulmonary and systemic inflammation, and oxidative stress in patients undergoing craniotomy. This will provide objective evidence for the safety of protective ventilation during craniotomy.
Trial registration: This trial was registered at Chinese Clinical Trial Registry (registration number: ChiCTR-IPR-16008029) on 1 March 2016.
Ethics: The study protocol was approved by the Ethics Committee of Anhui Provincial Hospital, China (approval number: 2014-59) on 27 November 2014 and will be performed in accordance with the guidelines of the Declaration of Helsinki, formulated by the World Medical Association.
Informed consent: Written informed consent will be obtained from participants or their guardians.

Keywords: clinical trial; protective ventilation strategy; craniotomy; pulmonary function; inflammation; oxidative stress; multi-center randomized, parallel-controlled trial


How to cite this article:
Tang Cl, Li J, Zhao B, Hou Jb, Xia Zy. Effects of lung protective ventilation on pulmonary function, inflammation, and oxidative stress in patients undergoing craniotomy: study protocol for a multi-center, randomized, parallel, controlled trial. Asia Pac J Clin Trials Nerv Syst Dis 2016;1:124-30

How to cite this URL:
Tang Cl, Li J, Zhao B, Hou Jb, Xia Zy. Effects of lung protective ventilation on pulmonary function, inflammation, and oxidative stress in patients undergoing craniotomy: study protocol for a multi-center, randomized, parallel, controlled trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2016 [cited 2019 Sep 19];1:124-30. Available from: http://www.actnjournal.com/text.asp?2016/1/3/124/187078


  Background Top


Mechanical ventilation is the most effective means of providing respiratory support in critically ill patients. Annually approximately 2.5 million patients rely on mechanical ventilation during surgery (Weiser et al., 2008). General anesthesia can cause changes in lung tissue structure and diaphragm position, and inappropriate ventilator settings are likely to cause air pressure injury and atelectasis, leading to postoperative inflammation (Duggan and Kavanagh, 2005; Brueckmann et al., 2013). General anesthesia complicated by surgical trauma can also lead to postoperative local, and even systemic, inflammatory responses and pulmonary complications (The Acute Respiratory Distress Syndrome Network, 1999, 2000; Bouadma et al., 2004, 2007; Gajic et al., 2004; Hess, 2011). A lung protective ventilation strategy has recently been developed to reduce ventilator-associated lung tissue injury and simultaneously improve systemic oxygenation (Schilling et al., 2005). Lung protective ventilation regulates positive end-expiratory pressure (PEEP), maintains more pulmonary alveoli in an open state (i.e., to maintain end-expiratory lung volumes), avoids elevated end-expiratory lung volume, maintains targeted tidal volumes, and alleviates the injury caused by elevated lung volume and abnormal tidal volumes (Schilling et al., 2005). PEEP can prevent the collapse of open pulmonary alveoli (Lachmann, 1992), maintain lung volume and the function of pulmonary surfactants, and reduce the shear stress caused by repeated/loss of alveolar or bronchiolar recruitment(s). High tidal volume ventilation maintains the partial pressure of oxygen in arterial blood (PaO 2 ) at normal levels, but it can cause excessive expansion of the lung with normal oxygenation. In 1993, mechanical ventilation with low tidal volumes was recommended (Slutsky, 1993). Lung protective ventilation has been widely used in the clinic, particularly in one-lung ventilation and abdominal surgeries. We searched PubMed for relevant articles published in the past 3 years and three original research articles regarding the use of lung protective ventilation in abdominal and pulmonary surgeries were retrieved ([Table 1]). No articles about the use of lung protective ventilation in craniocerebral surgeries were retrieved. Only three similar trials have been registered in ClinicalTrials.gov, but no conclusions have been obtained ([Table 2]).
Table 1: Previous studies of lung protective ventilation in clinical surgeries

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Table 2: Studies, registered in ClinicalTrials.gov, regarding the lung protective ventilation in brain injuries

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There is evidence that mechanical ventilation of the healthy lung can induce up-regulation of cytokines, leading to pre-inflammatory cytokine gene transcription, predisposing the organism to infection and oxidative stress (Brégeon et al., 2002). This study protocol has been designed to investigate the safety of a lung protective ventilation strategy with low tidal volume and PEEP on respiratory status, postoperative pulmonary and systematic inflammation, and oxidative stress in patients undergoing craniotomy.


  Methods/Design Top


Study design

A multi-center, randomized, parallel, controlled trial.

Study setting

Anhui Provincial Hospital (Southern District) and Renmin Hospital of Wuhan University, China.

Study procedure

Sixty eligible patients scheduled to undergo craniotomy will be randomly allocated to undergo either lung protective ventilation (6 mL/kg tidal volume, 10 cmH 2 O PEEP, respiratory frequency 15 breaths/min; n = 30) or conventional mechanical ventilation (10 mL/kg tidal volume, respiratory frequency 12 breaths/min; n = 30). All patients will be evaluated from just prior to changing the ventilation mode before surgery until immediately after extubation. The primary outcome measure will be dynamic lung compliance, an index used to evaluate the degree of pulmonary function impairment. The secondary outcome measures will be respiratory index, mean airway pressure (P mean ), plateau pressure (P plat ), alveolar and plasma markers of inflammation and oxidative stress. The planned flow of participants through the trial is shown in [Figure 1].
Figure 1: Flow chart of the trial protocol.
Note: T1: Time point just before changing the ventilation mode (i.e., following stabilization of the patient's hemodynamics after intubation); T2: after 1 hour of ventilation; T3: after 3 hours of ventilation; T4: at the end of surgery; T5: immediately after extubation. Dynamic lung compliance, respiratory index, mean airway pressure, plateau pressure, heart rate, and mean arterial pressure will be evaluated at all time points. Alveolar and plasma markers of inflammation and oxidative stress will be also evaluated at T1 and T4. PEEP: Positive end-expiratory pressure.


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Study participants

Patients scheduled to undergo craniotomy at Anhui Provincial Hospital (Southern District) or Renmin Hospital of Wuhan University, China.

Inclusion criteria

Patients meeting all the following criteria will be considered for admission to the trial:

  • Scheduled to undergo craniotomy following CT/MRI examination
  • American Society of Anesthesiologists (ASA) Physical Status Scale class I- II (Fitz-Henry, 2011)
  • Body mass index 18.5-30 kg/m 2
  • Normal pre-operative pulmonary function
  • Age 18-70 years


Exclusion criteria

Patients with any of the following will be excluded from the trial:

  • Bronchial infection
  • Severe hypertension or cardiovascular disease
  • Liver and kidney dysfunction


Withdrawal criteria

Patients will be withdrawn from the trial under any of the following circumstances:

  • Disease aggravation during anesthesia
  • Complications or comorbidities likely to influence the curative effect evaluation or any safety concerns


Sample size

According to previous studies (Jiao and Cai, 2007; Chen et al., 2013; Wang et al., 2015), the effective sample was determined to be n = 30 per group. Outcomes will be analyzed in accordance with the intention-to-treat principle.

Recruitment

Potential patients from the wards and clinics in Anhui Provincial Hospital (Southern District) and Renmin Hospital of Wuhan University, China will be recruited into this study. After receiving written informed consent from patients or their relatives, each patient will be screened according to the inclusion and exclusion criteria above.

Grouping


A cohort of 60 patients will be assigned to either the protective ventilation group or conventional mechanical ventilation group. Group allocation will be blinded to patients and outcome assessors.

Interventions


All patients will have preoperative preparation 60 minutes before surgery. Prior to anesthesia, blood oxygen saturation (SpO 2 ), non-invasive blood pressure and electrocardiogram measurements, followed by intravenous administration of 10-15 mL/kg Ringer lactate solution, will be performed. Each patient's heart rate and mean arterial pressure will be monitored through the use of multi-parameter monitors (Philips HP50, the Netherlands) and radial arterial puncture for arterial blood gas analysis will be performed. Intravenous sufentanil (0.4 μg/kg), vecuronium bromide (0.12 mg/kg) and etomidate (0.2 mg/kg) will be administered to facilitate tracheal intubation for mechanical ventilation. Intravenous sufentanil (Cp 3-4 ng/mL), vecuronium bromide (4 mg/h), sevoflurane (1.0%) and propofol (Cp 3-4 μg/mL) will be used to maintain anesthesia and muscle relaxation.

The brain surgery required will be performed on each patient, while maintaining the following ventilation conditions:

Protective ventilation: 6 mL/kg tidal volume, 10 cmH 2 O PEEP, and respiratory frequency 15 breaths/min.

Conventional mechanical ventilation: 10 mL/kg tidal volume and respiratory frequency 12 breaths/min.

Outcome measures

Primary outcomes


Dynamic lung compliance will be evaluated from just prior to changing the ventilation mode to immediately after extubation. Dynamic lung compliance is defined as a change in lung volume at defined units of transpulmonary pressure. It is an important parameter used to evaluate alveolar ventilation efficacy and pulmonary function impairment as it reflects the degree of difficulty in pulmonary expansion under unit pressure and generally reflects lung tissue elasticity (Dixon et al., 1979). Dynamic lung compliance = tidal volume/P plat .

Secondary outcomes

The following outcomes will be assessed throughout the procedure, from just prior to changing the ventilation mode before surgery, until immediately after extubation:

(1) Respiratory index: This reflects pulmonary ventilation and oxygen exchange function (Sganga et al., 1985; Hodgkins et al., 1990). Respiratory index = alveolar-arterial oxygen tension difference (PA-aDO 2 )/arterial PaO 2 . PA-aDO 2 = 713 × FiO 2 − 1.25 × PaCO 2 - PaO 2 . FiO 2 is inhaled oxygen concentration.

(2) P mean : This reveals the mean airway pressure during the entire respiratory cycle that indirectly indicates the mean alveolar pressure (Luecke et al., 2003). The effects of ventilation methods on hemodynamics and gas exchange are closely related to the occurrence of air pressure injury.

(3) P plat : This reveals the airway pressure measured after a 0.5-second pause at the end of inspiration (inspiratory and expiratory valves closed, gas flow rate of 0 (L/min) and it is closely related to alveolar peak pressure (Kallet, 2005). The following will be assessed just prior to changing the ventilation mode, and then again immediately following extubation:

(4) Alveolar and plasma markers of inflammation including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, -8, and -10 (Bhatia and Moochhala, 2004; Wilson et al., 2005; Shen et al., 2011; Lederer et al., 2013; Hiroshima et al., 2014; Wang et al., 2014). A fiber optic bronchoscope will be placed as far as possible into the trachea. After a continuous drip infusion of 20 mL of physiological saline, bronchoalveolar lavage fluid will be collected, and then centrifuged at 200 × g for 10 minutes. The supernatant and 3 mL of peripheral venous blood will be preserved at -80°C for later detection of TNF-α, IL-6, -8, and -10 levels by ELISA method.

(5) Alveolar and plasma markers of oxidative stress: Malondialdehyde and superoxide dismutase will be detected by colorimetric assays (Lu et al., 2015; Tsikas et al., 2016).

Other outcomes

Heart rate, mean arterial pressure, duration of surgery, duration of ventilation, and adverse events will be monitored from the time of change of ventilation mode to after extubation.

Patient's baseline data and the timing for outcome assessments are shown in [Table 3] and [Table 4], respectively.
Table 3: Baseline information of included patients

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Table 4: Timing of outcome assessment

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Data collection, management, analysis, and open accesss

Data collection


Case report forms with accurate, complete and timely filled data will be reported by the clinical researchers. The original paper forms will be preserved. To ensure the validity of the data, the date of, and the time taken for, form completion will be provided. The data manager will be responsible for the data input and management. The data will be recorded in an electronic database using a double-data entry strategy by two data managers and collated. The case report forms will be completed by the researchers and the data managers will modify the data according to the researchers' responses. A modified question form will be generated by the data managers if necessary.

Data management

Following blinded peer review, the electronic database will be locked by the researchers in charge and statisticians, and will not be altered. Paper and electronic data regarding screening, informed consent, and clinical outcomes will be preserved at each study center. After completion of the study, the original data will be preserved in the lead center and copies of the data stored at each center. All paper-based data will be permanently preserved.

Data analysis

The electronic database will be made available to a professional statistician for statistical analysis. An outcome analysis report will be made by the statistician and submitted to the lead researchers.

Data open access

Anonymized trial data will be published at http://www.figshare.com.

Statistical analysis

All data will be analyzed using SPSS 11.0 software (SPSS, Chicago, IL, USA). Baseline information will be evaluated using Fisher's exact test. Normally distributed data will be expressed as the mean ± SD. Paired t-tests will be used for comparisons between groups, and repeated measures analysis of variance for comparisons between different time points in the same group. Non-normally distributed data will be expressed as medians (interquartile range) [M(IQR)]. The Mann Whitney U test will be used for comparisons between two groups and the Wilcoxon signed-rank test for comparisons between different time points in the same group. The chi-square test will be used to compare numeration data between the groups. A level of P < 0.05 will be considered statistically significant.

Auditing


Trial progression will be reported to the ethics committee of Anhui Provincial Hospital (Southern District), China every 6 months and the trial's status will be updated at Chinese Clinical Trial Registry.

Confidentiality

Any data provided by the sponsors, including protocol design, performance, outcomes, case report forms, and informed consent will be preserved in secure, locked facilities and not disclosed to any non-authorized people.


  Discussion Top


In this study, we will elucidate the safety of lung protective ventilation strategy used in craniocerebral surgeries by investigating dynamic lung compliance, respiratory index, P mean , P plat , alveolar and plasma markers of inflammation, and oxidative stress. Because of the small sample size, a large age range, both sexes, short observation times, limited precision of measuring instrument, differences in craniocerebral surgery type and duration of surgery, and other indices, such as intrapulmonary shunt rate, will be not monitored in this study. Some uncertainties, such as the precise ventilation parameters and individualized lung ventilation protocols, will be investigated in future studies aiming to determine the optimal lung protective ventilation strategy.

Trial status

Recruitment of participants is ongoing at the time of submission. [33]

 
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Conflicts of interest
None declared.
Author contributions
CLT, JL and ZYX conceive and design the protocol. CLT, BZ and JBH are responsible for data collection. All authors approve the final version of this manuscript for publication.
Plagiarism check
This paper was screened twice using CrossCheck to verify originality before publication.
Peer review
This paper was double-blinded and stringently reviewed by international expert reviewers.


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