Basic Treatment Combined With Atomized Inhalation of Amikacin for Ventilator-associated Pneumonia: A Meta-analysis of Randomized Controlled Trials

Background: Compared with single intravenous therapy, nebulized amikacin combined with intravenous therapy can signicantly benet ventilator-associated pneumonia (VAP). However, the existing literature provides controversial conclusions. Methods: We systematically searched PubMed, Embase, Cochrane, CNKI, VIP, and Wanfang databases (without language restriction) for randomized controlled trials (RCTs) involving atomization inhalation of amikacin in the treatment of VAP published before October 2020. Literature screening, data extraction, and quality evaluation were performed according to the preferred reporting items for systematic reviews and meta-analyses guidelines. Results : A total of 9 RCTs were found eligible and included in our analysis (1162 patients with VAP). The results of this meta-analysis showed a signicant benet of combination treatment for improving the clinical cure (odds ratio, 2.40; 95% CI, 1.50–3.84; p = 0.006), Pathogen clearance rate (odds ratio, 3.46; 95% CI, 2.41–4.97; p <0.001), bronchospasm rate (odds ratio, 2.82; 95% CI, 1.38–5.78; p = 0.005) and Clinical pulmonary Infection Score (CPIS) (MD,-0.90; 95% CI, -1.23 to -0.57; p<0.001), No signicant difference was found in 28-day mortality (odds ratio, 1.15; 95%CI, 0.81–1.63; p = 0.45) and renal impairment (odds ratio, 0.88; 95% CI, 0.60–1.30; p = 0.53). Conclusion : The addition of atomization inhalation of amikacin to intravenous antibiotics treatment in VAP patients signicantly improves the clinical cure rate and pathogen clearance rate, t can also help reduce the 28-day mortality, bronchospasm rate and CPIS outcome. In addition, the combination has no signicant difference in the rate of renal impairment over the conventional intravenous treatment. alone in the disease’s outcomes. The results showed that the combined medication group improved the clinical cure rate and pathogen clearance rate, and reduced the bronchospasm rate and CPIS outcome. Simultaneous, the combination therapy had no effect on the outcome of 28-day mortality rate and renal damage rate. Our main outcome endpoint is the clinical cure rate. In the sensitivity analysis, Michael’s study is the main reason. In Michael’s study, aerosolized antibiotics cannot relieve pneumonia symptoms faster. Consider the following reasons for this heterogeneity: First of all, this study is only aimed at mechanically ventilated patients with gram-negative pneumonia, while the bacteria detected in patients with ventilator pneumonia are the existence of widespread ora, and aminoglycoside antibiotics also have a certain sterilization effect on the positive ora. effect. Second, the observation in the gure shows that the large sample data of Michael's study is the cause of this heterogeneity, but the result of the large sample study with negative results is still positive after the inclusion of the negative result, and the sensitivity analysis is also stable. After comprehensive consideration, atomization The clinical cure rate of amikacin is a denite improvement. Same as CPIS, although the results in the gure show that the ve included studies have high heterogeneity, the lung infection scores after combined treatment with nebulized amikacin in all studies showed a downward trend after treatment, while the yue study declined more signicant. The current rst-line treatment for ventilator-associated pneumonia (VAP) is intravenous administration of antibiotics, which are associated with systemic adverse effects. Aerosol inhalation of aminoglycoside antibiotics has been proposed as a treatment strategy for ventilator pneumonia in mechanically ventilated patients intensive care units. administered and cross


Background
Ventilator-associated pneumonia (VAP), de ned as parenchymal infection in patients exposed to invasive mechanical ventilation for at least 48 hours, is an important cause of nosocomial pneumonia in the intensive care unit (ICU) [1,2]. The incidence of VAP in mechanically ventilated patients is reported to be 5-40%, and the crude mortality rate can reach 20-70% [3][4][5]. The onset of VAP complicates the patient's original condition and consequently makes the treatment more di cult. This can signi cantly increase the duration of mechanical ventilation, length of hospital stay, and mortality of patients [6].
The current rst-line treatment for VAP is intravenous and intramuscular administration of antibiotics. However, multidrug-resistant bacteria and gramnegative bacilli, such as Acinetobacter baumannii, Pseudomonas aeruginous, and Klebsiella pneumoniae, which are the main causative pathogens of VAP, are often insensitive to commonly used antibiotics, and the e cacy of the basic intravenous antibiotic therapy is often poor. While these pathogens may be sensitive to polymyxins and aminoglycosides, these antibiotics are associated with adverse effects [7]. Moreover, it is di cult to achieve an effective drug concentration in the lung tissue with conventional intravenous antibiotics, because an increase in the drug dose could increase the incidence of adverse reactions [8].
Compared to basic treatment, that is, intravenous antibiotics treatments alone, aerosol antibiotic therapy is a popular therapy widely used in respiratory diseases at present. In this method, the drug is added into an atomization device so that it forms fog drops and delivers the drug directly to the lungs, thereby achieving a 20-200-fold higher drug concentration in the target organ [9,10]. At the same time, due to the presence of an alveolar-capillary barrier, the amount of drug reaching the systemic circulation is low with atomization inhalation, and consequently, the risk of systemic adverse effects is also signi cantly reduced. While the bene ts of nebulized antibiotics in the treatment and prognosis of patients with VAP in the ICU ward are clear, The European Society for Clinical Microbiology and Infectious Diseases also states that [11] there is currently insu cient evidence on the effectiveness of using inhalational therapy. Therefore, this systematic review and meta-analysis study was conducted to updated the e cacy and safety of amikacin aerosol therapy(AAT).

Database and search strategy
This systematic review and meta-analysis were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [12] ). There were no restrictions on search language, date, region, or publication status. The reference lists of relevant reviews were also searched to ensure a thorough search of the included articles.

Selection criteria and study selection
Our meta-analysis included studies involving adult patients (over 18 years of age and of either sex) diagnosed with VAP who underwent mechanical ventilation in the ICU and randomized controlled studies of the e cacy of nebulized amikacin in comparison with basic treatment strategies with at least 1 week of intervention, details of intervention measures such as treatment duration and application methods, and dose. The studies were included only if data on de nite outcome variables were available. Studies comparing different routes of administration; animal experiments; studies less than 7 days; observational and retrospective studies; and articles with insu cient data were excluded. The initial screening was based on the titles and abstracts of all search results to exclude ineligible studies. The full text was browsed to assess whether the study met the inclusion criteria. Then, study selection was performed independently by two authors (Q.H.Huang and X.J.Feng)according to the search strategy, and any differences were resolved by discussion or consensus with a third author(H.H.Guo).

Data extraction
We extracted the following data from each selected study: total number of participants, age, sex, treatment duration, underlying treatment, literature source, randomization method, concealment of allocation, investigator blinding, patient blinding, completeness, follow-up, and outcome measures. Clinical outcomes included clinical cure rate, pathogen clearance rate, Clinical Pulmonary Infection Score(CPIS)(mean [SD]), and adverse reactions included mortality, bronchospasm rate, and renal damage rate.

Assessment for risk of bias
Two reviewers(Q.H.Huang and X.J.Feng)assessed the risk of bias for each study using the Cochrane risk of bias tool. Factors such as random sequence generation, allocation concealment, blinding of participants and investigators, blinding of analysts, incomplete result data, selective reporting, and con ict of interest were considered in the assessment. Disagreements about risk assessment were resolved by discussion between two other reviewers.

Data synthesis
Data analysis was performed using RevMan software (version 5.3) provided on the Cochrane website. Continuous variables are presented as differences in the mean with a 95% con dence interval (95% CI). The odds ratio (OR) was used as the in uencing index for dichotomous variables. Heterogeneity was assessed by the Cochrane Q statistic and the I 2 statistic. A P value ≤ 0.10 together with an I 2 value ≥ 50% indicates signi cant heterogeneity. I 2 values ≤ 50% represented acceptable between-study heterogeneity, and the xed-effects model was selected. Otherwise, the random-effects model was selected [13,14]. Heterogeneous causes can be analyzed, such as age, sex, course of treatment, dose or other factors, etc. The Stata software was used for We used the STATA program (Stata Corporation, College Station, Texas) for sensitivity analysis, which was used to eliminate possible heterogeneity factors.

Retrieval of basic information and evaluation of quality
According to the search strategy, we retrieved a total of 90 relevant articles and nally included 9 [15][16][17][18][19][20][21][22][23] RCTs involving atomization inhalation of amikacin in VAP patients. The basic treatment in those 9 studies was conventional ventilator support and treatment with systemic antibiotics. The experimental group received atomized inhalation of amikacin on the basis of intravenous antibiotics, and we called it the AAT group. The quality scores of the 9 included studies were above 4, which means high-quality RCTs. The literature screening owchart and basic information of a total of 1162 patients included are shown in Fig. 1

Clinical cure rate
Nine RCTs including 1162 patients reported data on the in-hospital clinical cure ,The results showed that the cure rate was 75%(431/582) in the AAT group and 61%(357/578) in the basic treatment group. There was a signi cant difference between the two groups using the randomed effect model (OR = 2.40;95% CI,1.50-3.84; p = 0.0002), with high heterogeneity (χ2 = 21.49, I2 = 63%). Sensitivity analysis concluded that the study by Niederman M was the main reason affecting this heterogeneity. After excluding this study, the heterogeneity was found to be low (I 2 = 0%, P = 0.99). (Fig. 3-4).

Pathogen clearance rate
Seven RCTs including 586 patients reported data on the pathogen clearance rate, The results showed that the rate was 65.2%(191/293) in the AAT group and 38.1%(111/291) in the basic treatment group. Meta-analysis using the randomed-effects model showed that the AAT group signi cantly reduced the pathogen clearance rate(OR = 3.46; 95% CI, 2.41-4.97,p < 0.001; p for heterogeneity 0.89, I 2 = 0%). A signi cant difference was observed upon comparing the results of the two groups, indicating that addition of atomization inhalation of amikacin to the basic treatment can improve the pathogen clearance rate in VAP patients (Fig. 5).

28-day mortality
Four RCTs including 758 patients reported data on the in-hospital mortality with overall incidence of 21.2%(85/380 in AAT group,76/378 in basic treatments group). There was statistically signi cant between the two groups with the random effects model (OR = 1.15;95% CI, 0.81-1.63;p = 0.45; p for heterogeneity = 0.60,I2 = 0%). The difference suggesting that combining atomized amikacin with basic treatment could not reduce the 28-day mortality of VAP patients (Fig. 6).

CPIS
In 5 RCTs including 346 subjects,Clinical pulmonary infection score (CPIS) was reported. The did not show any difference in the two groups with the random effects model either (MD=-1.71; 95% CI, -3.30 to -0.12; p = 0.04) with high heterogeneity (χ2 = 120.91, I 2 = 97%). In order to reduce heterogeneity in the study design or intervention maneuver, We rst adopted the method of one-item elimination, and after excluding the study by Yue, the heterogeneity was found to be low (χ2 = 2.89, I 2 = 0%,). Analysis of CPIS in 5 groups showed that the CPIS of patients in the AAT group was lower than that of patients in the basic treatments group (Fig. 7).

Rate of bronchospasm
Four RCTs including 794 patients reported data on the bronchospasm rate, The results showed that the rate was 7.5%(30/398) in the AAT group and 2.8% (11/396) in the basic treatment group. The difference was statistically signi cant between the two groups with random effects model(OR = 2.89; 95% CI, 1.42-5.87; p = 0.003; p for heterogeneity = 0.84,I 2 = 0%) (Fig. 8).

Rate of renal impairment
Amikacin is a semisynthetic aminoglycoside antibiotic, and intravenous administration of amikacin in the ICU is limited by its main adverse effect of renal damage. Four RCTs including 794 patients reported data on the renal impairment rate, The results showed that the rate was 14.6%(58/398) in the AAT group and 16.2%(64/396) in the basic treatment group. There was no signi cant difference between the two groups with random effects model(OR = 0.88;95% CI, 0.60-1.30;p = 0.53;p for heterogeneity = 0.85,I 2 = 0%) (Fig. 9).

Publication bias
Outcome measures of the clinical cure rate after combined atomization inhalation of amikacin compared with basic treatment were analyzed to detect publication bias. The funnel plot was slightly asymmetric between the study groups, suggesting a high possibility of publication bias. Other relevant treatment outcome measures, due to the small number of included studies, were not tested for publication bias.

Discussion
We included 10 trials that presented at least one of the primary outcomes in the updated meta-analysis. In VAP patients, The ndings revealed an improvement with the addition of atomizatied amikacin compared with intravenous treatments alone in the disease's outcomes. The results showed that the combined medication group improved the clinical cure rate and pathogen clearance rate, and reduced the bronchospasm rate and CPIS outcome.
Simultaneous, the combination therapy had no effect on the outcome of 28-day mortality rate and renal damage rate. Our main outcome endpoint is the clinical cure rate. In the sensitivity analysis, Michael's study is the main reason. In Michael's study, aerosolized antibiotics cannot relieve pneumonia symptoms faster. Consider the following reasons for this heterogeneity: First of all, this study is only aimed at mechanically ventilated patients with gramnegative pneumonia, while the bacteria detected in patients with ventilator pneumonia are the existence of widespread ora, and aminoglycoside antibiotics also have a certain sterilization effect on the positive ora. effect. Second, the observation in the gure shows that the large sample data of Michael's study is the cause of this heterogeneity, but the result of the large sample study with negative results is still positive after the inclusion of the negative result, and the sensitivity analysis is also stable. After comprehensive consideration, atomization The clinical cure rate of amikacin is a de nite improvement. Same as CPIS, although the results in the gure show that the ve included studies have high heterogeneity, the lung infection scores after combined treatment with nebulized amikacin in all studies showed a downward trend after treatment, while the yue study declined more signi cant.
The current rst-line treatment for ventilator-associated pneumonia (VAP) is intravenous administration of antibiotics, which are associated with systemic adverse effects. Aerosol inhalation of aminoglycoside antibiotics has been proposed as a treatment strategy for ventilator pneumonia in mechanically ventilated patients in intensive care units. Intravenously administered aminoglycoside antibiotics and vancomycin do not effectively cross the alveolarcapillary barrier and have a low concentration at the site of pulmonary lesions, reducing their antibacterial effectiveness. In recent years, the application of aerosol inhaled antibiotics has become a research hotspot. Aerosol antibiotics can reach a higher concentration in the lesion area to avoid adverse system reactions [24]. Animal experiments and related clinical studies have shown that aerosol inhalation of amikacin can reach the far end of the most severe infection, and is effective in clinical cure rate and signs of pneumonia [25,26]. The 2016 VAP guidelines of the American Thoracic Society/American Society of Infectious Diseases recommended that patients with VAP caused by aminoglycosides or polymyxin-sensitive Gram-negative bacilli should use inhaled and systemic avidin instead of systemic antibiotics alone[6]. Nebulized antibiotics can increase the concentration of local antibiotics and signi cantly enhance the antibacterial effect. At the same time, nebulization makes the antibiotics con ned in the lungs, which can reduce the occurrence of systemic toxicity [27]. According to current clinical practical applications, the choice of nebulizer, the setting of the pipeline, and the setting of the ventilator parameters will affect the concentration of the drug in the lung tissue, the loss of drug delivery, and systemic side effects. The safety, effectiveness and clinical effects of nebulized inhalation will also be affected by factors such as patient age, different underlying diseases, and humanmachine cooperation [28]. Therefore, we further research is required before advocating the application of atomization inhalation of amikacin in the treatment of VAP.
This study has certain limitations: This study included a total of 9 RCTs and a total of 1162 patients, indicating that the number of included studies and patients was relatively small. 7 of the 9 included RCTs did not adequately describe the blinding method; therefore, this may lead to some selection bias.
Because of the delay in the diagnosis of VAP due to the timeliness and the interference of various parameters such as the complex condition, it is di cult to accurately locate the treatment effect. Meta-analysis is essentially an observational study, and every step may produce some deviations. However, the 9 RCTs included in this study were of high quality, with scores above 4 and low statistical heterogeneity, which increased the reliability of the results to a certain extent.
In summary, the combination of aeroseurol inhalation of amikacin and basic treatment can improve the clinical cure and removal of pathogens. It also helps to reduce the bronchospasm rate and CPIS outcomes in patients with VAP, but there is no signi cant difference in the rate of 28-day mortality and renal damage. Analysis of many prospective, large-sample, multicenter RCTs is needed to establish the e cacy and safety of combining atomization inhalation of amikacin with the basic treatment in VAP patients.   Sensitivity analysis of cure rate heterogeneity Figure 5 Forest plot of pathogen clearance between the two groups Figure 6 Forest plot of 28-day mortality between the two groups  Forest plot of bronchospasm rate between the two groups Forest plot of renal impairment rate between the two groups