Effect of dexmedetomidine on lung function and prognosis a systematic review and meta-analysis


 Background: This systematic review and meta-analysis aimed to evaluate the effect of dexmedetomidine on lung function and prognosis.Methods: We searched PubMed, Embase and the Cochrane Library from inception to January 30, 2020 following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement guidelines. Randomized controlled trials of dexmedetomidine associated with lung function were assessed. The primary outcomes are pH, PaO2, PaCO2, respiratory index (RI) and time to extubation. The secondary outcomes are PaO2/FiO2, length of hospital stay and events of pulmonary complications.Results: 17 trials of 924 patients were included. Compared with placebo group, dexmedetomidine group had higher PaO2 (MD: 10.96; 95% CI: from 0.77 to 21.15; p=0.04) and PaO2/FiO2 (MD: 30.77; 95% CI: from 19.11 to 42.43; p<0.00001). The dexmedetomidine group had lower PaCO2 (MD: -0.88; 95% CI: from -1.66 to -0.11; p=0.002) and shorter length of hospital stay (MD: -1.19; 95% CI: from -2.21 to -0.16; p=0.02). The dexmedetomidine group had lower occurrence of pulmonary complications (RR: 0.28; 95% CI: from 0.09 to 0.82; p=0.02). However, there is no significant difference in pH, respiratory index and extubation time.Conclusion: Dexmedetomidine has better influence on lung function and prognosis.


Background
Lung function is consisted of oxygenation and pulmonary ventilation which refers to airway ow and capacity (1). The dysfunction of the respiratory system is associated with many other diseases especially the cardiovascular diseases (1). There are many ways to evaluate lung function such as spirometry and blood gas analysis. To evaluate the oxygenation, the blood gas analysis is more often to use. Arterial blood sample gives us the precise assessment of oxygenation by PaO 2 and ventilatory status by PaCO 2 (2).
Perioperative lung injury is considered as a series of disease including the in ammation of the lung, abnormal thoracic radiograph, dysfunction of gas exchange and respiratory failure (3). It mainly consists of these following pathologies: atelectasis, ventilator induced lung injury and acute respiratory distress syndrome (3). Atelectasis leads to many side effects such as intrapulmonary shunting, increased pulmonary vascular resistance, decreased pulmonary compliance and potentially in ammatory lung injury (4). Ventilator induced lung injury mainly refers to high tidal volumes and high inspiratory pressures which leads to regional alveolar overdistention (5). According to Berlin de nition, patients with acute respiratory distress syndrome are divided into mild, moderate and severe categories in terms of the scale of hypoxemia (6). Postoperative pulmonary complications occurred in approximately 11% and 59% of the patients which causes signi cantly higher morbidity, mortality and increasing the burden of hospital resources (3). There are many ways for perioperative lung protection. Several preoperative methods were proven to be useful for lung protection such as smoking cessation, rehabilitation and optimization of respiratory status (7). Useful intraoperative interventions include lung protective mechanical ventilation, appropriate uid management and enough analgesia (7). Protective ventilation is usually used. The wellknown lung protective intervention may be the usage of low tidal volumes (3). Positive end expiratory pressure has been con rmed to be useful in preventing atelectasis during operation. Some small sample size RCTs reported that patients receiving 5 cmH 2 O positive end expiratory pressure experiencing better oxygenation and pulmonary compliance and less postoperative atelectasis than patients that receiving zero positive end expiratory pressure in laparoscopic surgery (8). Non-invasive positive pressure ventilation has been proven to prevent and treat respiratory failure. The possible mechanism is through reducing atelectasis (3,9). Fluid overload may damage pulmonary endothelial which results in the damage of capillary and causes pulmonary edema (7,10). But restrictive uid management may decrease organ perfusion. The current trend of uid management is individualization (7,10). It has been reported that when the patients receiving thoracotomy were free to cough and felt mild pain of the thorax, the less pulmonary dysfunction and complications would occur (7). Postoperative lung protection that aims to expand the lung have shown to signi cantly reduce perioperative pulmonary complications.
These interventions are mainly contented of respiratory physiotherapy and non-invasive ventilation.
Respiratory physiotherapy includes a series of movements such as deep breathing, postural drainage, cough and vibration (7). But, some of these interventions still have con icting evidences, several studies have reported that after major surgeries there is no difference in outcomes in patients undergoing preoperative exercise program (11). High quality data suggests that high tidal volumes may be more protective than low tidal volumes (12,13). High concentration of oxygen is common used in anesthesia, however, high value of FiO 2 can also result in resorption atelectasis and make in ammatory lung injury worse (14,15).
Dexmedetomidine which has been widely used perioperatively is an alpha-2-adrenergic receptor agonist of the imidazole subclass (16). It can activate alpha-2-adrenoceptors in the vascular intact endothelial cell which activates the production of nitric oxide which results in decreasing of intrapulmonary shunting and improving of arterial oxygenation (17). Dexmedetomidine has been proven to decrease antiin ammatory properties against pulmonary impairment caused by sepsis. It provides sedation and analgesia without respiratory depression (18). Several randomized controlled trials have compared dexmedetomidine and placebo on the in uence of lung function, but the results are not same and the studying cohorts were small (19,20).
Thus, we conducted this systematic review and meta-analysis to evaluate whether dexmedetomidine has better in uence such as improving the PaO 2 and PaO 2 /FiO 2 and decreasing pulmonary complications than the placebo on lung function and prognosis.

Method
This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) and the Cochrane Handbook for Systematic Reviews of Interventions (21).
Our study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (registration no. CRD42020173726).

Search strategy
We searched for clinical trials on the administration of dexmedetomidine with lung function on PubMed, Embase, and the Cochrane Library from inception to January 30, 2020, without restriction on patient sex, patient age, dates, or languages. The following search strings were used in [Title/Abstract]: "pulm*", "lung", and "dexmedetomidine". When the same population were studied in multiple articles, the most recent or the complete article was used.

Inclusion and exclusion criteria
Clinical trials that compare the arterial blood gas with or without using dexmedetomidine were considered eligible. Trials with data which were not extractable were excluded. Trials with high risk were excluded from this review. Case reports, letters, review articles and animal experimental studies were excluded.
Outcomes Primary outcomes 1. pH based on the arterial blood gas after using the dexmedetomidine were reported.
2. PaO 2 based on the arterial blood gas after using the dexmedetomidine were analyzed. The higher PaO 2 indicates the better oxygenation.
3. PaCO 2 based on the arterial blood gas after using the dexmedetomidine were assessed. 4. Respiratory index (RI) were analyzed. The lower RI suggests the better lung function. 5. The time to extubation were assessed. The shorter time means the faster recovery from anesthesia. Secondary outcome 1. PaO 2 /FiO 2 after using the dexmedetomidine based on the arterial blood gas were compared. The higher PaO 2 /FiO 2 , the better oxygenation.
2. The length of hospital stay was analyzed. The shorter length of hospital stay indicates the better recovery.
3. Events of pulmonary complications were assessed such as atelectasis and acute lung injury.

Data collection
The data were extracted separately and cross-checked by two authors (C.B, Y.W). Data collected included patient ages, types of surgery, the administration method of dexmedetomidine, pH, PaO 2 , PaCO 2 and PaO 2 /FiO 2 based on the arterial blood gas, respiratory index, time to extubation, length of hospital stay and pulmonary complications.

Statistics analyses
Review Manager software (RevMan, version 5.2; The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark) was used for all analyses and forest plots. We used the Cochrane collaboration's tool to assess the risk of bias. We compared continuous data, such as pH, PaO 2 , PaCO 2 , PaO 2 /FiO 2 , respiratory index, time to extubation and length of hospital stay using mean and standard deviation. We compared dichotomous data such as events of pulmonary complications using risk ratio and 95% CI. Statistical heterogeneity was assessed by the I 2 statistic: when the value is smaller than 40%, it indicates mild heterogeneity. When we believe that the treatment effects are different across the studies, the random-effcets model was used; otherwise the xed-effects model was used. Subgroup analyses were conducted to compare different administration method of dexmedetomidine.

Basic characteristics of included studies
The characteristics of the included studies are shown in Figure 2. There are 12 studies written in English (16, 19, 20, 24-27, 29, 31-34), 5 studies written in Chinese (22,23,28,30,35). Trial sizes from 19 to 124 patients. A total of 461 and 463 patients were included in the dexmedetomidine group and control group, respectively. The type of surgeries was mainly thoracic surgery, others included gastrectomy (28,31) and lower limb surgery (30,32).

Risk of bias assessment
The risk of bias of the seventeen trials was assessed and summarized in Figure 3. Two trials didn't give enough information about their randomization (19,20). Six trials had the right method of their allocation concealment (16,20,27,29,31,33). Blinding was used in thirteen trials (16, 19, 20, 22, 24-27, 29-31, 33, 34). Only one trial had attrition bias (24). All the seventeen trials reported all the end points in their method sections.

Results of meta-analysis
Meta-analysis of pH The time to extubation was reported by two trials including 140 patients (25,33). The pooled data showed no signi cant difference between the dexmedetomidine group and the placebo group (MD: 0.28; 95% CI: from -3.65 to 4.20; p=0.89). (Figure 9)

Meta-analysis of length of hospital stay
The length of hospital stay was reported by three trials including 206 patients (16,22,33). The pooled data showed signi cant difference between the dexmedetomidine group and the placebo group (MD: -1.19; 95% CI: from -2.21 to -0.16; p=0.02). (Figure 10)

Meta-analysis of events of pulmonary complications
Three trials including 140 patients reported the events of pulmonary complications (16,22,33). The pooled data showed signi cant difference between the dexmedetomidine group and the placebo group (RR: 0.28; 95% CI: from 0.09 to 0.82; p=0.02). (Figure 11)

Subgroup analysis
Dexmedetomidine group compared with control group administrated by I.V.
As shown in Figure 4 Dexmedetomidine group compared with control group administrated by Non-I.V.
Subgroup analysis was not performed for PaO 2 /FiO 2 because of lacking of data. (Figure 4 According to our meta-analysis, we observed that dexmedetomidine compared with placebo can signi cantly increase PaO 2 . Rui et al (20) revealed that the decreasing of intrapulmonary shunt and improving of arterial oxygenation was resulted from the inhibition of oxidative stress which is induced by intravenous administration of dexmedetomidine and inhalation of iso urane. Elhakim et al (26) found that epidural administration of dexmedetomidine decreases the anesthetic requirements and improves intraoperative oxygenation. The heterogeneity is relatively high between the studies. We did subgroup analysis based on the administration method of the dexmedetomidine and used random-effects model to evaluate the overall result. In both groups, the heterogeneity is still high, the results showed no signi cant difference, but the overall result showed signi cant difference which indicated that the administration method may not be the source of the heterogeneity.
We noticed that dexmedetomidine compared with placebo can signi cant decrease PaCO 2 which indicates that dexmedetomidine can improve pulmonary ventilation. Ahmed et al (31) found that patients using dexmedetomidine showed higher compliance, lower plateau pressure and lower dead space compared with the placebo which leads to better pulmonary ventilation. Zhang et al (22) had the similar conclusion that dexmedetomidine improves pulmonary ventilation through decreasing dead space and improving compliance. The overall heterogeneity is relatively high between the studies. We did subgroup analysis based on the administration method of the dexmedetomidine. In the two subgroups, the heterogeneity is small which suggests the source of the heterogeneity is from the administration method. Moreover, in the dexmedetomidine group used through veins, the PaCO 2 is signi cant lower than the placebo group.
As for PaO 2 /FiO 2 , our meta-analysis showed that dexmedetomidine can improve the PaO 2 /FiO 2 signi cantly compared with placebo which means that dexmedetomidine can improve pulmonary oxygenation. Guo et al (35) revealed that dexmedetomidine help to decrease the pulmonary in ammatory response and improve the lung function. Scott et al (29) believed that the effect of improving oxygenation in the patients using dexmedetomidine may be resulted from the decreasing requirements for inhalational anesthetic agents of their hypoxic pulmonary vasoconstriction effects.
In our study, the respiratory index showed no signi cant difference. The RI is a parameter that reveals ventilatory and oxygenation, the higher RI, the worse lung function. However, the heterogeneity is relatively high and the included sample were relatively small, we believe that the result may not represent the real condition about the effect of dexmedetomidine on lung function. Similarly, the result of time to extubation reveals the same limitation which is small sample.
The pooled data of length of hospital stay showed that dexmedetomidine was associated with shorter length of hospital stay which suggested that dexmedetomidine had better in uence on prognosis. Many factors can in uence the length of hospital stay such as postoperative pulmonary function (33). Other studies also found that poor recovery leads to poor quality of life postoperatively which may prolong the length of hospital stay (36).
In our study, the dexmedetomidine group had signi cantly lower events of pulmonary complications such as atelectasis, pneumonia and acute lung injury. The low occurrence of pulmonary complications also had better in uence on the length of hospital stay. It gave us the sign that dexmedetomidine had better effect on the prognosis and help to reduce the burden of the patients.
There are also several limitations to this study. First, the included studies and the sample size were still relatively small. Second, the source of heterogeneity for the evaluation of the PaO 2 remains unclear. The inhaled oxygen concentration was not reported in all studies. It is hard to say that the difference between PaO 2 was caused by dexmedetomidine or the inhaled oxygen concentration. Third, the different administration method of the dexmedetomidine may lead to the high heterogeneity of current study. Fourth, several studies didn't point out whether their outcome assessment was blind which may lead to detection bias.

Conclusion
In conclusion, our study showed that dexmedetomidine could decrease PaCO 2 and events of pulmonary complications and shorten the length of hospital stay and increase PaO 2 and PaO 2 /FiO 2 than the placebo perioperatively.
Abbreviations RI: respiratory index.

Declarations
Ethics approval and consent to participate Not applicable.

Consent for publication
Not applicable.
Availability of data and materials The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
The study was supported in part by grants from Outstanding Young Teacher Training Program of Sun Yat-sen University, China (Grant no. 19ykpy23 for Weifeng Yao).
Author contributions ZH and WY conceived and designed the study. BC, JY, GS and WY performed the meta-analysis. BC wrote the paper. All authors read and approved the manuscript.