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Effect of dexmedetomidine and propofol sedation on the prognosis of children with severe respiratory failure: a systematic review and meta-analysis

Background During treatment of acute respiratory failure (ARF) in children, sedation can reduce pain, improve tolerance, and reduce the incidence of adverse events, so selecting an appropriate sedation strategy is very important for improving prognosis and quality of life. Both dexmedetomidine and propofol have good sedative effects, so we investigated the application of these drugs in critically ill children with ARF by literature search and meta-analysis. Methods We searched Embase, The Cochrane Library, PubMed, Ovid, Clinicaltrials.org, and Google Scholar for randomized controlled trials (RCTs) preferentially but not exclusively, and used RevMan 5.4 to analyze the screened literature. Results Seven studies were included in the quantitative meta-analysis, with a total of 1,188 patients. There was no significant difference in the effect of dexmedetomidine and propofol on the duration of tracheal intubation in children with ARF [mean difference (MD) =−0.05; 95% confidence interval (CI): (−0.42, 0.32); Z=0.26; P=0.79], but dexmedetomidine sedation could reduce the intensive care unit (ICU) stay in children with ARF [MD =−0.62; 95% CI: (−1.08, −0.16); Z=2.65; P=0.008], and shorten the total hospital stay [MD =−1.94; 95% CI: (−2.63, −1.25); Z=5.48; P<0.00001]. There was no significant effect on mortality between the two groups [odds ratio (OR) =0.48; 95% CI: (0.19, 1.25); Z=1.50; P=0.13]. The incidence rate of bradycardia with dexmedetomidine sedation was higher than with propofol [OR =12.30; 95% CI: (2.28, 66.47); Z=2.92; P=0.004], and the incidence of hypotension was also higher [OR =6.99, 95% CI: (1.22, 39.86); Z=2.19; P=0.03]. Discussion Compared with propofol, dexmedetomidine can significantly reduce the ICU stay and hospital stay. However, bradycardia and hypotension may occur during the use of dexmedetomidine, which requires close attention and timely intervention.


Introduction
Respiratory failure in children is defined as dyspnea due to various causes of respiratory physiological dysfunction, and acute respiratory failure (ARF) is common (1,2). Pediatric respiratory failure is a clinically critical illness that can cause death in children in the pediatric intensive care unit (PICU). In addition to effective control of the primary disease (pulmonary infection, cerebral edema), oxygen therapy should be given to patients with respiratory insufficiency, and tracheal intubation and mechanical ventilation (MV) should be given when necessary (3). During treatment, sedative therapy can reduce the pain and subjective discomfort caused by MV, improve the tolerance of the pediatric patient, reduce the incidence of accidental removal of ventilation catheters, ultimately reduce cardiovascular and respiratory instability, shorten the PICU admission time and total hospital stay, and reduce mortality (4,5). However, prolonged sedation may also lead to adverse effects such as memory and cognitive impairment, respiratory depression, and changes in cardiovascular dynamics; therefore, the selection of an appropriate sedation strategy is important for improving the prognosis and quality of life (6). Dexmedetomidine, a highly potent and selective pharmacological α2-adrenergic receptor agonist, is widely used for clinical surgical anesthesia and intensive care unit (ICU) sedation because of its good analgesic, sedative, and anti-sympathetic effects (7). However, there is still a lack of evidence on whether its use is superior to other commonly used sedative drugs (e.g., midazolam and propofol) in the treatment of MV children with respiratory failure. Kim et al. (8) compared the outcomes between dexmedetomidine as a tranquilizer and propofol in the course of pediatric MRI, but there is no clinical comparison in children with respiratory failure yet. A recent meta-analysis by Dong (9) compared dexmedetomidine with other sedative drugs in MV, but the included patients were all adults, not children. In this study we summarized the relevant studies to on the application of dexmedetomidine for sedative effect in the treatment of ARF in children. We present the following article in accordance with the PRISMA reporting checklist (available at https://tp.amegroups.com/article/ view/10.21037/tp-22-20/rc).

Database and search strategy
We searched Embase, The Cochrane Library, PubMed, Ovid, and additionally searched the clinical experimental research in Clinicaltrials.org. We also used the search function of Google Scholar to search for other possibly relevant literature. We set the search time from database construction to November 2021 and used the keyword combination of (dexmedetomidine OR DEX) AND (propofol) OR (sedation) OR (respiratory failure OR acute respiratory failure OR ARF) OR (Mechanical ventilation OR MV).

Literature inclusion criteria
(I) Study type: English language only, and randomized controlled trials (RCTs) preferred. (II) Study subjects: all patients were admitted to a PICU, aged <18 years, with respiratory failure caused by primary disease (pneumonia infection, cerebral edema, pulmonary edema), with hypoxemia or hypercapnia as the main symptom. (III) Intervention measures: all children were given MV and either dexmedetomidine or propofol to expected depth of sedation (i.e., two cohorts or groups). (IV) At least one expected outcome indicator: length of hospital stay, mortality, PICU stay, duration of MV, adverse reaction rate, and complete data are available.

Literature exclusion criteria
(I) Subjects were mainly adults; (II) investigations, case analysis and review of non-RCT; (III) incomplete or no data.

Literature screening
After literature retrieval, all studies were imported into Endnote X9 software for exclusion of duplicate literature. Next, two researchers read the title and abstract for further screening. If the original text was not available, the correspondence author was contacted by email and telephone to obtain the full text.

Literature quality evaluation and risk of bias assessment
The analysis tool RevMan 5.4 provided by the Cochrane Collaboration was used to assess the risk of bias of the included articles. We used Jadad scale to evaluate the quality of the study, and a score of more than 3 was regarded as a high-quality study.

Outcome indicators
We only counted and analyzed the six most common outcome indicators: (I) duration of endotracheal intubation; (II) ICU length of stay; (III) length of hospital stay; (IV) mortality; (V) incidence of adverse reactions (bradycardia); (VI) incidence of adverse reactions (hypotension).

Data extraction
Two researchers independently extracted the relevant data: author, publication year and month, grouping method, number of cases in each group, age of children, sex ratio, weight, primary disease diagnosis, complications, intervention methods and sedative dose. After data extraction, the results of each researcher were cross-checked and any differences generated were discussed and finally determined.

Statistical methods
(I) Meta-analysis software was RevMan 5.4. (II) Continuous variables were statistically analyzed by inverse variance, effect size is reported using mean difference (MD) and 95% confidence interval (CI), and effect size is reported as odds ratio (OR) and 95% CI for binary variables; P<0.05 indicated the results were statistically significant. (III) Forest plot descriptive statistics were used for comparisons. (IV) Literature heterogeneity was analyzed by I 2 analysis and Q test; heterogeneity of results was indicated by I 2 >50% or P<0.1; the OR value was obtained using a random-effects or fixed-effects model as applicable. (V) If the heterogeneity analysis suggested heterogeneity between studies, a heterogeneity source survey was performed using a case-by-case exclusion method, and general description analysis was adopted when the heterogeneity source could not be judged. (VI) Sensitivity analysis was performed by comparing the random-effect and fixed-effect results. (VII) Funnel plot was used to indicate publication bias.

Literature screening
The flow chart of literature selection is shown in Figure 1: 7 studies with a total of 1,188 patients were finally included in the quantitative meta-analysis (10)(11)(12)(13)(14)(15)(16). Basic characteristics, intervention measures and outcome indicators of all studies are shown in Table 1.

Literature quality and bias evaluation
All studies (10)(11)(12)(13)(14)(15)(16) were RCTs in the type of random grouping and all described the generation method of random sequence. However, the allocation concealment method was not described in all the literature (12,14), the others used sealed opaque envelopes to conceal the numbers. The studies (10-13) clearly indicated that the blind method was not implemented, which might introduce bias to the final results. All studies recorded the dropout cases in detail, without significant selective reporting bias and other biases, as shown in Figures 2,3.

Length of hospital stay (days)
A total of 3 studies (10-12) reported the total hospital stay after the intervention of the two sedatives. There was no statistical heterogeneity (I 2 =0%; P=0.81). The fixed-effects model was used. Meta-analysis showed that using dexmedetomidine for sedation reduced the total hospital stay of children with ARF compared with propofol   ARF, acute respiratory failure; CI, confidence interval; SD, standard deviation.    There was no statistical heterogeneity among the literature for hypotension (I 2 =0%; P=0.81). The fixedeffects model was used. Meta-analysis results showed that the incidence rate of hypotension with dexmedetomidine sedation was higher than that with propofol [OR =6.99; 95% CI: (1.22, 39.86); Z=2.19; P=0.03], as shown in Figure 9.

Source of heterogeneity and sensitivity analysis
In the analysis of indicators of ICU length of stay, there was statistical heterogeneity among the studies (I 2 =61%; P=0.03). The generation of heterogeneity can be related to the age and primary disease of the children. However, most of the included studies did not specify the mean age and primary disease type of the children, so we could not perform a subgroup analysis. However, there was little difference in the results between the random-effects model and the fixed-effects model, showing that the results had good stability (good sensitivity).

Analysis of publication bias
In the analysis of ICU admission time indicators, the funnel plot ( Figure 10) was essentially evenly distributed, suggesting that the publication bias was small.

Discussion
Using dexmedetomidine as the sedative could reduce the length of stay in the PICU and reduce the total length of hospital stay for children with ARF compared with propofol, but there was no statistically significant difference in the effects on MV time or mortality. Studies have shown that dexmedetomidine can significantly reduce the occurrence of delirium in elderly patients compared with propofol (17,18), but because no study reported this index in our study, it is impossible to determine the effect of dexmedetomidine on the occurrence of postoperative delirium in children.
Dexmedetomidine, as a highly selective α2-adrenergic receptor agonist, has a much greater affinity for α2 receptors than α1, and in addition to its sedative effect, also exerts analgesic effects by binding to α2 receptors in the spinal cord, thereby reducing the dose of opioids (19). Propofol is a short-acting anesthetic and commonly used in induction and maintenance of anesthesia in adults. When used as a sedative drug for patients undergoing artificial ventilation under intensive monitoring, the infusion rate should be adjusted according to the required depth of sedation. Generally, within 0.3-0.4 mg/kg/h should obtain a satisfactory sedative effect (20). Zhang et al. found that dexmedetomidine was superior to propofol in reducing ICU length of stay and reducing the risk of delirium for sedation in ICU patients, but adverse effects occurred when dexmedetomidine was administered at a loading dose or at a high infusion rate (21).
Adverse effects of dexmedetomidine are primarily cardiovascular, and it can cause bradycardia and hypotension by acting on the α2 receptors of the heart (22). In this study, dexmedetomidine was used as a sedative in children with ARF, and the incidence rates of bradycardia and hypotension were higher than with propofol. Therefore, special attention should be paid to the safety of dexmedetomidine in critically ill pediatric patients, and if bradycardia or hypotension occurs, the infusion of dexmedetomidine should be reduced or discontinued immediately, fluid replacement should be increased, or vasoactive drugs should be administered (23).
Dexmedetomidine is widely used in clinical pediatric medicine, such as cardiac catheterization (24), magnetic resonance imaging (25), airway foreign body removal (26), and the application of dexmedetomidine sedation can reduce pain in children and improve their compliance. Piastra et al. stated in a case series that early use of dexmedetomidine in infants/children receiving a ventilator for ARF can be considered safe, with the ability to improve recruitment and support ventilator synchrony in patients (27).
The use of dexmedetomidine for sedation in pediatric patients requires special attention to dosage; Erkonen et al. reported a 2-year-old child with traumatic brain injury who developed hypertension several hours after dexmedetomidine infusion at 4 mg/kg/h (28). In the study by Sayed et al. (29), the investigators divided MV infants/children into highdose and low-dose groups according to the dosage of dexmedetomidine. The low-dose group was given a dosage of 0.25 µg/kg for 10 min, followed by a maintenance dose rate of 0.25 µg/kg/h for 50 min, while the high-dose group was given a dosage of 0.5 µg/kg for 10 min, followed by a maintenance dose rate of 0.5 µg/kg/h for 50 min. Their results showed that the high-dose group had better depth of sedation, and shorter ICU and hospital stays, which suggested that a dose rate of 0.5 µg/kg/h was safe.
It has been suggested that dexmedetomidine is a better option from an economic point of view than standard sedatives when providing mild to moderate ICU sedation for more than 24 h (30), and the potential reason for its savings is mainly a reduction in extubation time.
In this study, the heterogeneity among the literature came from multiple aspects such as the age and disease characteristics of the children. The funnel plot suggested that the publication bias was small. Some of the studies included in this meta-analysis did not perform a blind method (10)(11)(12)(13), the number of included studies was small, and the sample sizes were on average small.

Conclusions
A total of 1,188 patients in 7 studies were included in this meta-analysis. The results showed that the application of dexmedetomidine as the main sedative in the treatment of children with ARF could significantly reduce the PICU and hospital stays compared with propofol, but bradycardia and hypotension may occur during treatment, which requires close attention and timely intervention. However, due to the small number of included studies, this topic still needs to be deeply explored in a RCT.