Fetal and Maternal Responses to Dexmedetomidine Intrathecal Application During Cesarean Section: A Meta-Analysis.

BACKGROUND Intrathecal dexmedetomidine (DEX) can improve the blockade of spinal anesthesia, but there is no clear conclusion on whether it has an effect on the fetus during cesarean section. Our meta-analysis evaluated the safety and efficacy of intrathecal DEX in cesarean delivery. MATERIAL AND METHODS We searched Cochrane, Embase, PubMed, and CBM for eligible studies, and used the Revised Cochrane Risk of Bias Tool (RoB 2.0) to assess the risk of bias of each study. RevMan was used for statistical analyses. We have registered this meta-analysis on PROSPERO (CRD42019120995). RESULTS The meta-analysis included 10 RCTs, but only 5 were prospectively registered. The results of preregistration studies, including the 1- or 5-min Apgar score (mean difference [MD], -0.03; 95% confidence intervals [CI], -0.16 to 0.10; P=0.64 or MD, 0.00; 95% CI, -0.09 to 0.09; P=1), the umbilical arterial oxygen or carbon dioxide partial pressure (MD, 0.90; 95% CI, -4.92 to 6.72; P=0.76 or MD, 1.20; 95% CI, -2.06 to 4.46; P=0.47), and the cord blood pH (MD, -0.01; 95% CI, -0.05 to 0.03; P=0.72), showed that intrathecal DEX had no significant difference in neonatal outcomes compared with placebo. In maternal outcomes, intrathecal DEX significantly prolonged postoperative pain-free period and reduced the incidence of postoperative shivering, which did not increase spinal anesthesia-associated adverse effects. CONCLUSIONS Intrathecal DEX is safe for the fetus during cesarean section and can improve the blockade effects of spinal anesthesia on puerperae.

Background

Cesarean section is an effective means of solving dystocia and certain obstetric complications to save maternal and perinatal life [1]. Spinal anesthesia has always been the preferred anesthesia for cesarean section because it can avoid the risk of general anesthesia such as tracheal intubation failure, aspiration, high medical expenses, and lung infection, and can provide excellent postoperative analgesia [2-4]. In addition, spinal anesthesia can ensure that the mother is awake during cesarean section and fully experience the birth process of the fetus, thus promoting early breastfeeding and contact between mother and infant. More importantly, spinal anesthesia can better prevent direct effects of general anesthetics (e.g., opioids) on the fetus through placental transfer compared with general anesthesia [5]. General anesthesia has been shown to reduce neonatal Apgar scores as early as the 1970s [6]. With the advancement of anesthesia techniques and the development of anesthetics, recent studies have shown that general anesthesia has little effect on cord blood gas parameters and neonatal Apgar scores [7]. However, more high-quality clinical studies are needed to confirm whether general anesthesia can replace spinal anesthesia as the preferred anesthesia for cesarean section in the future.

In clinical practice, spinal anesthesia with small doses of local anesthetics is not sufficient to inhibit visceral pain and often causes maternal pain and discomfort intraoperatively and insufficient postoperative analgesia, while high-dose local anesthetics are prone to cause maternal hypotension and neonatal acidosis [8,9]. Prolonging postoperative analgesia without affecting early activity is the common goal of most puerperae. To overcome these limitations and further improve spinal anesthesia, the application of local anesthetics combined with adjuvants has gradually become a focus of anesthesiologists [10]. Recent research shows that many drugs can be used intrathecally in combination with local anesthetics to improve spinal anesthesia, of which dexmedetomidine (DEX) is a good choice [11,12].

DEX has sedative, analgesic, and anti-sympathetic effects, and has no significant effect on respiration [13]. Use of DEX in cesarean section anesthesia has received more and more attention. Studies have shown that DEX can be used as an auxiliary for general anesthesia and intrathecal anesthesia in cesarean section; it can enhance the anesthetic effects, prevent and reduce adverse reactions of anesthetics, and reduce the amount of anesthetic drugs used [14-16]. However, when DEX is used in cesarean section to improve anesthesia, there are concerns about whether DEX will adversely affect the fetus. Our present meta-analysis was based on the intrathecal application of DEX, and the use of large sample sizes to confirm the safety of intrathecal DEX to the fetus. In addition, few high-quality studies have evaluated the effect of intrathecal DEX on spinal anesthesia during cesarean section, and some of the results are still controversial. The secondary aim of our meta-analysis was to evaluate whether intrathecal DEX has an improved effect for spinal anesthesia and adverse effects on puerpera during cesarean section. Due to the lack of studies on the long-term physiological effects of intrathecal DEX on neonates, this meta-analysis only focused on short-term neonatal outcomes, such as neonatal Apgar score, umbilical blood carbon dioxide partial pressure, umbilical blood oxygen partial pressure, and umbilical blood pH.

Material and Methods

This meta-analysis was registered with PROSPERO (), and the registration code is CRD42019120995. The preparation of our manuscript is based on the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) [17].

Searching strategy

The electronic databases Cochrane Library, Embase, PubMed, and CBM were searched by 2 researchers to find available randomized controlled trials (RCTs). The search strategy used of Medical Subject Headings (MeSH) terms and corresponding free words. The phrases for MeSH search included: “DEX”, “Anesthesia, Spinal”, “Injections, Spinal”, “Bupivacaine”, “Ropivacaine”, “Cesarean Section”, and “Randomized controlled trial”. The last search was performed on December 18, 2018. In addition, the searchers read the references to find other eligible articles.

Study inclusion criteria

Our meta-analysis included RCTs in which adult full-term pregnant women who underwent selective cesarean section under spinal anesthesia were randomly divided into groups, including an intrathecal DEX group and a blank control group without any adjuvant. We excluded studies in which there were premature delivery (<37 weeks of pregnancy), multiple pregnancies, cardiovascular disease (e.g., pre-eclampsia and hypertension), drug addiction, allergy to DEX or local anesthetics, and patients who cannot undergo spinal anesthesia.

Data extraction

A pre-designed data table was used to collect data from the included studies, including: the first author’s name, published time, countries, registration number, the included studies application, sample size, local anesthetics, and total volume (Table 1). The 2 reviewers completed data extraction independently, and disagreements between reviewers were resolved through discussions with third parties.

Table 1

Characteristics of included studies in the meta-analysis.

Author	Years	Country	Registration number	Application (ug)	Sample size	Local anesthetics (mg)	Total volume (ml)
Bi et al. [10]	2017	China	ChiCTR-IIR-16008497	NS/D3/D5	20/20/20	Bup 10	2
Fawzy et al. [21]*	2016	Egypt	–	NS/D5	30/30	Bup 12.5	2.5
He et al. [22]	2017	China	ChiCTR-IIR-15007548	NS/D2.5/D5	30/30/30	Bup 12.5	3
Kamali et al. [23]*	2018	Iran	–	T25/D25/NS	36/36/36	Lid 100	2
Li et al. [24]*	2015	China	–	NS/F15/C75/D10	21/21/21/21	Bup 10	-
Nasseri et al. [25]	2017	Iran	IRCT201511301766N7	D5/NS	25/25	Bup 12.5	3
Qi et al. [26]	2016	China	ChiCTR-TRC-14005227	D5/M100/NS	40/40/40	Bup 10	2
Sun et al. [27]*	2015	China	–	NS/F25/D10	30/30/30	Bup 10	3
Teymourian et al. [28]*	2018	Iran	–	D10/NS	76/76	Bup 15	3
Xia et al. [29]	2018	China	ChiCTR-IPR-16009699	D5/NS	45/45	Bup 8.4/12.1	3

Studies are unregistered studies.

NS – saline; D – dexmedetomidine; T – tramadol; F – fentanyl; C – clonidine; M – morphine; Bup – bupivacaine; Lid – lidocaine.

Assessment of risk of bias

The methodological quality of each of the studies we included was independently assessed by 2 reviewers using the Revised Cochrane Risk of Bias Tool (RoB 2.0) [18]. The tool considers 5 different areas, each of which was classified as low risk of bias, some concerns, or high risk of bias. If all 5 of the areas are low risk, the overall risk of bias is low; if the assessment results in any of the areas are high risk, or the assessment results in multiple areas are some concerns, the overall risk of bias is high; otherwise, the overall risk of bias is some concerns. Any disagreement on method quality assessment can be resolved through group consensus and discussion.

Statistical analysis

The statistical analyses were performed using RevMan version 5.3 (The Cochrane Collaboration, Oxford, UK), and Stata 12.0 (StataCorp, College Station, TX, USA) was used for Begg’s test. For dichotomous data, the Mantel-Haenszel method was used to calculate the risk ratio (RR) with 95% confidence interval (95% CI). For continuous data, if the measurement methods or units of the indicators among included studies were the same, the inverse variance method was used to calculate the mean difference (MD) with 95% CI; otherwise, the standardized mean difference (SMD) with 95% CI was calculated. The Z test was used to assess the overall effect of the indicator, and the difference was considered statistically significant when 95% CI did not include 1 for RR and 0 for MD or SMD. Testing for heterogeneity of the pooled results was performed using the I-square (I) test. A random-effects model was used when a large heterogeneity was presented (I>50%); otherwise, a fixed-effect model was used in meta-analysis. In addition, when heterogeneity was significant, we performed subgroup analysis or sensitivity analysis to find sources of heterogeneity and minimize heterogeneity. The publication bias of primary outcomes (neonatal outcomes with more than 3 studies) was quantitatively assessed using Begg’s test. Some indicators of included studies, such as Apgar score and VAS score, expressed clinical efficacy by median and its range. To analyze variables, mean and standard deviation (SD) of the indicators were obtained by using the online calculator () based on the sample size, median, and range, and the indicators mean was estimated using the method of Luo et al. [19] while the SD was estimated using the method of Wan et al. [20].

Results

Characteristics of eligible studies and risk of bias

The meta-analysis ultimately included 10 RCTs (Figure 1) with a total of 706 patients, of which 9 studies [10,21,22,24-29] used bupivacaine and 1 study [23] used lidocaine for spinal anesthesia. In these studies, 6 compared DEX with saline, and the remaining 4 studies compared DEX with tramadol and saline, clonidine with DEX and saline and fentanyl, DEX with morphine and saline, and DEX with saline and fentanyl, respectively. The main objective of this meta-analysis was to assess the effect of intrathecal DEX on neonates during cesarean section, so only DEX versus placebo (saline) was compared, and we ignored the data on clonidine, tramadol, fentanyl, and morphine. However, 5 [21,23-24,27,28] of these studies were not registered prospectively.

Figure 1

Flow chart for articles selection.

The 2 reviewers were completely consistent in the assessment results on the potential risk bias of included studies, which showed that 3 of the included studies were low risk and the remaining 7 were some concerns, as shown in Figure 2.

Figure 2

Risk-of-bias graph of the included studies. low risk; some concerns; high risk.

Neonatal outcomes

Seven RCTs [10,21,22,24,26-28] reported Apgar scores of newborns at 1 and 5 min, 3 RCTs [10,24,27] reported umbilical carbon dioxide partial pressure and oxygen partial pressure, and 4 RCTs [10,24,27,29] reported pH values of cord blood. These indicators – the 1-min Apgar score (MD, 0.14; 95% CI, −0.19 to 0.47; P=0.4; I=93%), the 5-min Apgar score (MD, 0.00; 95% CI, −0.06 to 0.06; P=1; I=0), the umbilical arterial oxygen partial pressure (MD, 0.09; 95% CI, −2.46 to 2.64; P=0.95; I=0) and umbilical carbon dioxide partial pressure (MD, 0.85; 95% CI, −1.56 to 3.26; P=0.49; I=0), and the cord blood pH values (MD, −0.00; 95% CI, −0.04 to 0.04; P=0.96; I=63%) – showed there was no significant difference in neonatal outcome between the 2 groups (Figure 3).

Figure 3

Forest plot for neonatal outcomes. (A) Apgar score at 1 min; (B) Apgar score at 5 min; (C) Cord blood oxygen partial pressure data; (D) Cord blood carbon dioxide partial pressure data; (E) Data on pH.

There was a significant heterogeneity in the indicator of neonatal 1-min Apgar score (I=93%; P<0.001). We observed that 1 [21] of the 7 studies had significantly lower Apgar scores than the others. After removal of the study, the heterogeneity of this indicator was significantly reduced among other studies (I=0; P=0.56) using a fixed-effects model for pooling, and the results showed that the difference was still not statistically significant (MD, 0.02; 95% CI, −0.09 to 0.12; P=0.77; I=0, Figure 4A). Removal of the study also showed that there was no statistically significant difference in neonatal Apgar score at 1 min between intrathecal DEX and placebo groups.

Figure 4

Forest plot for sensitivity analysis and subgroup analysis of neonatal outcomes. (A) The sensitivity analysis of Apgar score at 1 min; (B) The subgroup analysis of Apgar score at 1 min; (C) The subgroup analysis of Apgar score at 5 min; (D) The subgroup analysis of umbilical oxygen partial pressure; (E) The subgroup analysis of umbilical dioxide partial pressure; (F) The subgroup analysis of umbilical blood PH.

Subgroup analysis: 5 [10,22,25,26,29] of the included 10 RCTs were prospectively registered. We performed a subgroup analysis of the neonatal outcomes based on whether the included studies were registered prospectively. The results of studies with prospective registration, including 1- or 5-min Apgar score (MD, −0.03; 95% CI, −0.16 to 0.10; P=0.64 or MD, 0.00; 95% CI, −0.09 to 0.09; P=1), umbilical arterial oxygen or carbon dioxide partial pressure (MD, 0.90; 95% CI, −4.92 to 6.72; P=0.76 or MD, 1.20; 95% CI, −2.06 to 4.46; P=0.47), and cord blood PH values (MD, −0.01; 95% CI, −0.05 to 0.03; P=0.72), were consistent with unregistered studies, which showed intrathecal DEX had no significant effect on the short-term neonatal outcomes compared with placebo (Figure 4B–4F). The 1-min Apgar score of one study [21] was significantly lower than others, and it was excluded from the subgroup analysis of Apgar score at 1 min because it caused greater heterogeneity in the pooled results (Figure 4B).

Pregnant woman outcomes

The block onset and duration

Four studies [24,26,27,29] compared the effect of DEX as the intrathecal local anesthetics adjuvant on the onset of blockade, and 6 studies [10,19,21,24,26,27] reported the duration of blockade. As part of spinal anesthesia, intrathecal DEX accelerates the onset of motor block (MD, −0.47; 95% CI, −0.95 to 0.01; P=0.05; I=46%), while it has no obvious improvement effect on the onset of sensory block (MD, −0.34; 95% CI, −1.49 to 0.80; P=0.55; I=81%, Figure 5A), and DEX can significantly prolong the blockade time, as shown in Figure 5B, whether it is sensory block (MD, 57.25; 95% CI, 48.44 to 66.07; P<0.001, I=36%) or motor block (SMD, 1.16; 95% CI, 0.27 to 2.05; P=0.01; I=91%).

Figure 5

(A) Forest plot comparing the onset of sensory and motor block between DEX and placebo groups; (B) Forest plot comparing the duration of sensory and motor block between DEX and placebo groups.

DEX improved the analgesic effect

Under spinal anesthesia, DEX as a local anesthetics adjuvant significantly reduced the analgesia score 4 hours after cesarean section (MD, −1.63; 95% CI, −3.01 to −0.26; P=0.02, I=98%) and significantly prolonged postoperative analgesia (SMD, 2.90; 95% CI, 1.86 to 3.93; P<0.001, I=93%), as shown in Figure 6A. However, the effect of intrathecal DEX on improving maternal analgesia was limited. We found no significant difference between the 2 groups in VAS scores at 12 h after cesarean section (MD, −0.06; 95% CI, −1.14 to 1.02; P=0.91; I=94%, Figure 6B). The heterogeneity among the pooled studies was very significant, which may be related to differences in ethnicity, indicator units, local anesthetic types, and the definition of pain-free period in different studies. Although we performed subgroup analysis and sensitivity analysis based on local anesthetic types, indicator units, prospective registration, and ethnicity, it did not significantly reduce the heterogeneity among studies, and the results of subgroup analysis and sensitivity analysis were consistent with previous results.

Figure 6

(A) Forest plot for the VAS score of postoperation 4 h and the pain-free period; (B) Forest plot for the VAS score of postoperation 12 h.

Effect of DEX on maternal postoperative shivering

There were 8 studies [10,21-23,25-27,29] reporting the incidence of postoperative shivering. Our meta-analysis showed that the incidence of maternal postoperative shivering was significantly reduced by intrathecal DEX relative to placebo (RR, 0.45; 95% CI, 0.32 to 0.63; P<0.001; I=37%, Figure 7A).

Figure 7

(A) Forest plot for postoperative shivering; (B) Forest plot for hypotension and bradycardia; (C) Forest plot for other adverse effects.

The adverse effects

Data from 7 studies [21,22,24-27,29] found that intrathecal DEX did not increase the risk of maternal hypotension (RR, 0.88; 95% CI, 0.71 to 1.08; P=0.22; I=22%) and bradycardia (RR, 1.00; 95% CI, 0.51 to 1.96; P=1.00; I=0) compared with placebo (Figure 7B). In addition to hypotension and bradycardia, we also observed other spinal anesthesia-related complications, such as itching, nausea, and vomiting. The results also showed that intrathecal application of DEX did not increase other maternal adverse events associated with spinal anesthesia (RR, 0.88; 95% CI, 0.66 to 1.16; P=0.35; I=23%), as shown in Figure 7C.

Publication bias

We used Stata software to assess the publication bias of the main results. The P values of Begg’s test on the 1-min Apgar score, 5-min Apgar score, and umbilical blood PH were 0.176, 1, and 1, respectively. Therefore, we believe that the risk of publication bias is low in this meta-analysis.

Discussion

In clinical practice, spinal anesthesia is a good anesthesia program for cesarean section, which can avoid the adverse reactions in the fetus, such as potential respiratory depression caused by general anesthesia drugs through the placenta, while reducing the amount of local anesthetics to reduce the potential risk of local anesthetics poisoning and significantly shortening the onset time of anesthesia compared with epidural anesthesia. However, single spinal anesthesia often has limited time for postoperative analgesia. Increasing the amount of local anesthetic drugs to prolong the analgesic time can cause serious inhibition of circulation and adverse effects such as central nervous system problems and cardiotoxicity [30]. Therefore, the addition of appropriate adjuvants to local anesthetics during spinal anesthesia with the synergistic analgesic effect of adjuvants to prolong postoperative analgesia while avoiding the use of large doses of local anesthetics has gradually become a new choice for anesthesiologists [12].

Several studies have confirmed that DEX is a more promising local anesthetics adjuvant than other drugs (e.g., fentanyl, morphine, and clonidine) for intrathecal application, and can better improve the blockade quality of spinal anesthesia, prolong the pain-free period of patients, and no cause significant adverse effects [12,26,31-33]. However, as DEX is applied intrathecally during cesarean section, we are most worried about whether DEX affects the fetus, such as neonatal respiratory depression, lower Apgar score, and acidosis, because if the neonatal 5-min Apgar score is <7 or pH is <7.20, the newborn needs to stay in the neonatal intensive care unit (NICU) for treatment, or even requires establishing an artificial airway, which will undoubtedly lead to an increase in neonatal mortality [5,34,35]. DEX was first approved as a sedative for use in the ICU. Therefore, a comprehensive and effective evaluation of whether intrathecal DEX has an effect on the fetus is important during cesarean section, although it had been previously reported that, due to the fat-soluble characteristics of DEX, it is not easily transferred through the placenta [36,37].

Our meta-analysis based on 10 RCTs indicates that intrathecal use of DEX as the local anesthetics adjuvant did not increase neonatal adverse reactions during cesarean section. Compared with the placebo, there were no significant differences in neonatal 1- and 5-min Apgar scores or cord blood gas parameters. In addition, 1 [10] of the studies also reported no statistically significant differences in umbilical glucose and lactate of newborns between the 2 groups. Since only 1 study reported the parameter, this meta-analysis did not incorporate this indicator. Our results demonstrate the safety of intrathecal use of DEX in cesarean section. In addition, we found that intrathecal application of DEX can significantly increase maternal sensory and motor block time, and the incidence of postoperative shivering was significantly reduced, which was mainly due to DEX inhibiting central thermoregulation and attenuating the stress response in the perioperative period [38], and it did not increase the incidence of adverse reactions such as maternal bradycardia and hypotension. More importantly, the use of intrathecal DEX for spinal anesthesia can significantly prolong the analgesic time and improve the analgesic effect after cesarean section. This is mainly related to inhibition of C-fiber transmitter and substance P release, as well as α2 receptor agonist-related post-synaptic horn neuron hyperpolarization and upregulation of adrenergic receptor subtypes in the dorsal root ganglia [39,40]. However, unlike a previous meta-analysis [5], there was no obvious improvement effect on the onset of sensory block of spinal anesthesia.

Our meta-analysis has some limitations. First, although we tried to find all the studies that met the inclusion criteria, it is still possible that some relevant studies were omitted. Second, some indicators related to puerpera have significant heterogeneity affecting the stability of the results, and this may be related to the small sample size of the included studies, the difference in local anesthetics (bupivacaine, lidocaine), different drug doses, and different ethnicity. Third, our results were based on intrathecal application of low-dose DEX (≤25 ug), and it is unknown whether a larger dose of DEX will affect the fetus. Fourth, the included studies in this meta-analysis were mainly from China and Iran, and 1 was from Egypt, which resulted in geographical limitations of this study. In addition, 5 of the included studies [21,23,24,27,28] lacked prospective registration. Finally, we only focused on the short-term effects, so whether intrathecal DEX during cesarean section has a long-term effect on the fetus is not clear. These shortcomings need to be addressed in future research.

Conclusions

Intrathecal DEX appears to be safe for the fetus during cesarean section, and can significantly prolong postoperative analgesia and reduce the incidence of postoperative shivering of puerperae. However, the adjuvants are not necessary during spinal anesthesia and the adjuvant itself may cause unnecessary adverse reactions (e.g., intrathecal application of opioids often causes itching, and DEX can induce bradycardia). In addition, the most worrying adverse reaction from intrathecal DEX during spinal anesthesia is its neurotoxicity, although some animal studies have confirmed that a very large dose of DEX is required to cause demyelination of the white matter [41], and there have been no reports of DEX neurotoxicity in clinical practice. However, the possibility of long-term neurotoxicity still needs to be assessed.