Pre-eclampsia has an adverse effect on maternal and perinatal health, especially in the developing countries.1 Although neuraxial anaesthesia is generally the technique of choice in patients with pre-eclampsia, it is not always appropriate, or may be refused by the mother. In this situation, general anaesthesia remains the only option. However, in response to endotracheal intubation, there is stimulation of the sympathetic nervous system with catecholamine release and subsequent increases in blood pressure (BP), heart rate (HR) and left ventricular afterload. These changes may result in both maternal and neonatal complications. Therefore, the attenuation of the haemodynamic responses to tracheal intubation in these patients is a requirement for both the health of the mother and the foetus.2,3
Many different sedative and opioid drugs have been used to blunt the stress response associated with endotracheal intubation but, as such drugs cross the uteroplacental barrier, their use has always been controversial because of possible effects on the foetus.4–6 The continued search for a drug that inhibits the stress response to surgical stimuli in these clinical settings has led to increasing use of α2 adrenergic agonists.2 Dexmedetomidine is a highly selective α2 adrenergic receptor agonist which, when used as an adjunct to general anaesthesia, has several useful actions, including sedation, anxiolysis, sympatholysis, analgesia, decreased intra-operative anaesthetic requirements, cardiovascular stability and smooth recovery.7 Dexmedetomidine is highly lipophilic and, because of this property, it tends to be retained in placental tissues, thus reducing the amount crossing the uteroplacental barrier to the foetal circulation. However, despite the above advantages, the off-label use of dexmedetomidine for labour analgesia or as an adjunct to general anaesthesia for caesarean section must be justified.8
The current study used two different doses of dexmedetomidine (0.4 and 0.6 μg kg−1)9 as a part of general anaesthesia for patients with pre-eclampsia undergoing caesarean delivery, and we assessed the effects on the intubation-related stress response, intra-operative haemodynamics, postoperative analgesia, foetal outcome and the correlation between the maternal and the foetal plasma levels of dexmedetomidine.
Ethical approval was obtained from the Local Ethics and Research Committee of the Anaesthesia Department, Faculty of Medicine, Menoufiya University Hospitals, Menoufiya, Egypt (Chairperson Prof A. Abdelraouf) on 3 July 2016. The study was also registered at the Pan African Clinical Trial Registry (PACTR201706002303170), (www.pactr.org).
The current prospective double-blind, randomised controlled trial involved 60 patients with pre-eclampsia undergoing caesarean section from August 2016 to May 2017. Inclusion criteria were 18 to 40 years old, a gestational age at least 34 weeks, hypertension (but SBP < 160 mmHg and a DBP < 110 mmHg) proteinuria (urinary protein dipstick + or ++) and without other signs of systemic effects. Exclusion criteria were patient refusal, allergy to dexmedetomidine, BMI more than 40 kg m−2, systemic diseases (e.g. cardiac, pulmonary, hepatic, renal, neurological, neuromuscular, diabetes mellitus, anaemia, coagulation disorders, bleeding disorders, seizures), HELLP syndrome, patients receiving anticoagulant or antipsychotic drugs, ante partum haemorrhage, foetal distress and multiple pregnancy.
Before surgery, all the patients had their hypertension treated with methyldopa and, pre-operatively, underwent a thorough clinical examination with laboratory investigations. The visual analogue pain score (VAS) was explained to the patients (score 0 to 10 cm with 0 = no pain and 10 = worst pain imaginable).
When the patient arrived in the pre-operative holding area, a wide bore cannula was inserted, and an infusion of Ringer's lactate solution was commenced. The following monitors were applied: noninvasive BP, pulse oximetry and ECG. Patients were divided randomly into three groups of 20 with codes contained in sealed, opaque envelopes: two dexmedetomidine groups (D1, D2) and a control group (C). Before the planned surgery, the pharmacy department supplied three ready-made infusions to the anaesthesia department, and the appropriate volume was administered using a controlled infusion device. Neither the anaesthesia provider nor the assessors knew the contents of the infusion.
The sealed, opaque envelopes were opened by the pharmacist to allocate the patients to a group. Patients in groups D1 and D2 received a dexmedetomidine 1 μg kg−1 loading dose over 10 min, then either an infusion of dexmedetomidine at a rate of 0.4 μg kg−1 h−1 (D1) or at a rate of 0.6 μg kg−1 h−1 (D2). The infusions continued throughout surgery until skin closure. Patients in group C (control group) received similar volumes of 0.9% saline. The doses of dexmedetomidine chosen were based on similar doses used as part of a general anaesthesia technique in healthy parturients during caesarian section.9
Induction of general anaesthesia was started at the end of the loading dose infusion of dexmedetomidine. Rapid sequence induction was performed with propofol (2.5 mg kg−1) followed by rocuronium (0.6 mg kg−1): a dexmedetomidine infusion of 1 μg kg−1 for 10 min reduces the required intubating dose of rocuronium to 0.6 mg kg−1.10 Anaesthesia was maintained with sevoflurane in oxygen, at a minimal alveolar concentration of one minimum alveolar concentration (inspired) with 0.1 mg kg−1 increments of rocuronium as required. After delivery of the baby, 1 μg kg−1 of fentanyl was administered and 20 U of oxytocin was added to 200 ml 0.9% saline and infused through a separate line. If hypotension (defined as a decrease in the maternal mean arterial BP by 20%) developed, 5-mg incremental doses of ephedrine were given. If bradycardia occurred (defined as a decrease in the HR to <50 bpm), 0.5-mg doses of atropine were given. If hypertension occurred [defined as an increase in mean arterial pressure (MAP) by ≥20%], a nitroglycerine infusion was commenced and the patient was excluded from the study. After the completion of surgery, the patient's trachea was extubated after administering 50 μg kg−1 prostigmine and 20 μg kg−1 atropine to reverse the muscle relaxant. Postoperatively, incremental doses of 2-mg morphine (intravenous) were given when the VAS was at least 4.
Intra-operative maternal measurements
- The primary outcomes were mean arterial BP and HR measured before giving the loading dose of dexmedetomidine, after the loading dose of dexmedetomidine (just before induction of general anaesthesia), 1 and 5 min after intubation, and then every 5 min until 10 min after extubation.
- Blood samples for glucose and serum cortisol were obtained before and after the dexmedetomidine loading dose, and at 1 and 5 min after intubation.
- A blood sample was obtained for maternal dexmedetomidine concentration at the time of the uterine incision.
Postoperative maternal measurements
- Time to first request for analgesia (measured from time of extubation).
- Postoperative VAS after end of surgery, every hour for 6 h, then every 6 h up to 48 h.
- The total consumption of morphine in the first 48 h.
- Ramsay sedation score (RSS) on arrival in the recovery room, and then every 15 min until the score reached 2.
- Foetal HR before the dexmedetomidine/0.9% saline infusions commenced.
- Neonatal Apgar score at 1 and 5 min.
- Dexmedetomidine concentration from the umbilical vein.
Sample size calculation
When designing the study, we assumed the differences in MAP between the dose groups and the SDs would be 25%. Setting alpha to 0.05 and beta to 20%, we calculated that an appropriate group size would require 16 patients. We planned to include 20 patients per group (n=60) to allow for potential dropouts or protocol violations
Statistical analysis was done using Statistical Package for Social Science program (SPSS, version 13; SPSS Inc, Chicago, Illinois, USA). Data are presented as numerical or categorical, as appropriate, and were tested for normality using Kolmogorov–Smirnov test and are expressed as mean ± SD unless stated otherwise. Analysis of variance and Kruskal–Wallis tests were used as appropriate to measure association between quantitative variables, with Student's Newman–Keuls post hoc test. The mother's and infant's dexmedetomidine levels were further compared by Student's t tests or Mann–Whitney U tests, as appropriate. The χ-squared test was used to measure association between qualitative variables. P (probability) of 0.05 or less was considered to be of statistical significance.
From the 65 women randomised, five assigned to the control group required nitroglycerine for hypertension and were excluded from further analysis. The remaining 60 women completed the study (Fig. 1). The maternal, foetal and surgical characteristics were comparable in all groups (Table 1).
The HR was significantly lower in both groups D1 and D2 than in the control group before induction of general anaesthesia, 1 min after induction and 1 min after extubation. In general, HR in D2 was significantly lower than both D1 and C groups (Fig. 2). MAP was significantly lower in both D1 and D2 groups than group C at all times. MAP was significantly lower in D2 than D1 group at 1 and 5 min after induction, whereas the rest of measures showed no significant difference (Fig. 3). No patients required ephedrine but nine required atropine (three in group D1, five in group D2, one in group C): these differences were not statistically significant.
Compared with the control group, the glucose concentration was significantly lower in D1 and D2 at 1 and 5 min after induction, but there were no significant differences between groups D1 and D2 at any time (Table 2). There were no significant differences in cortisol levels across the three groups before induction and 1 min after induction, but at 5 min after induction, the level was significantly higher in the control group than in either groups D1 or D2. There were no significant differences in cortisol levels between groups D1 and D2 (Table 2).
On arrival in the recovery room, the sedation scores were significantly higher in the dexmedetomidine groups than in the control, and group D2 patients were more sedated than those in group D1 (Table 3). At 15 and 30 min, there was no statistically significant difference in the RSS between D1 and D2, although both of these groups were still significantly more sedated than group C. By 45 min, RSS was comparable in all three groups (Table 3).
The time to first request for analgesia after surgery was significantly longer in the dexmedetomidine groups than in group C, and this time was also significantly longer in group D2 than group D1 (Table 1). The VAS was significantly lower in the two dexmedetomidine groups than in the control group at 1, 2, 3 and 5 h, whereas the VAS was comparable in both D1 and D2 groups (Table 4). Six hours after the end of surgery, the VAS was comparable in the three groups. Compared with the control group, total morphine consumption was significantly lower in both the dexmedetomidine groups, and patients in group D2 required significantly less morphine those in group D1 (Table 1).
The 1 and 5 min Apgar scores were comparable among the three groups (Table 1). There was a significant difference in the maternal dexmedetomidine concentrations between the D1 and D2 groups. There was also a significant difference in the placental vein dexmedetomidine concentrations between the D1 and D2 groups. However, the placental vein : maternal dexmedetomidine ratio was similar between the two groups (Table 5). The foetal HR was comparable among the studied groups before the start of the dexmedetomidine or 0.9% saline infusions, and the neonatal HR was comparable when assessed as part of the Apgar score.
The current randomised double-blind controlled trial assessing the effects of dexmedetomidine on maternal and foetal outcome in patients with pre-eclampsia undergoing caesarean section with general anaesthesia showed that dexmedetomidine blunted the stress response associated with endotracheal intubation (i.e. reduced MAP, HR and serum cortisol compared with the control group) and also improved postoperative analgesia (i.e. decreased morphine requirement) without any effect on the newborn Apgar scores.
Compared with the control group, the decrease in MAP and HR in the dexmedetomidine groups was never more than 20% of baseline, indicating that dexmedetomidine maintains haemodynamic stability while reducing the stress response to the stimulation of both intubation and surgery. This result is consistent with the observed effects of dexmedetomidine during general anaesthesia in other studies of pregnant and nonpregnant patients.10–15 In addition, Abu-Halaweh et al.16 used a dexmedetomidine infusion for labour analgesia in pre-eclamptic patients without any significant maternal and neonatal side effects. The observed decreases in maternal HR and BP may be related to dexmedetomidine-activating central postsynaptic α-2 adrenoceptors, leading to decreased sympathetic activity with consequent decreases in BP and HR.17 Baroreceptor reflexes are well preserved in the presence of dexmedetomidine, and bradycardia, should it occur, is easily treated.18
The blood glucose and cortisol levels were significantly higher in the control group than in either group D1 or D2 groups, similar to the findings in patients undergoing general anaesthesia for caesarean section.9
Postoperatively, dexmedetomidine enhanced analgesia, as evidenced not only by the longer times to first request for analgesia but also by the lower pain scores and reduced morphine consumption. Similar analgesic enhancement by dexmedetomidine has been observed in other studies. Abu-Halaweh et al.16 noted a decrease in the total dose of opioids required during labour when an epidural technique was contraindicated, and Park et al.19 in their study of patients undergoing laparoscopic cholecystectomy, noted a statistically significant reduction in postoperative analgesic requirements.
On arrival in recovery, patients in group D2 were significantly more sedated than those in group D1, and the latter were significantly more sedated than those in the control group, but by 45 min, there were no differences across the three groups. In an editorial, Sia and Sng20 felt that a low-dose dexmedetomidine infusion in properly selected parturients could provide useful sedation and haemodynamic stability with minimal risk of respiratory depression in labouring women. Dexmedetomidine is chemically related to clonidine, but is approximately eight times more specific for α-2 adrenoceptors, with α-2 : α-1 selectivity ratio of 1620 : 1, especially for the 2a subtype. These characteristics make dexmedetomidine more effective than clonidine for sedation and analgesia.21 Dexmedetomidine also incorporates an imidazoline structure, thus having an agonist effect on imidazoline receptors, adding a sedation element to the α-2 agonist action.22,23
The 1 and 5 min Apgar scores were comparable among the studied groups with no correlation between the infant dexmedetomidine level and the Apgar scores. These results concur with case reports on the use of dexmedetomidine in labouring women or for caesarean section in which the infants had normal Apgar scores,14 adding further evidence to suggest that even though there is uteroplacental transfer, this does not affect the neonatal Apgar scores. Also, Mendoza24 published two case reports in which dexmedetomidine was used as an adjunct for labour analgesia along with remifentanil: both babies were delivered with normal Apgar scores at 1 and 5 min. Likewise, Palanisamy et al.15 published a case report in which dexmedetomidine was used in a 31-year-old parturient with spina-bifida occulta and a tethered spinal cord reaching L5-S1: a healthy baby was delivered with normal Apgar scores. Li et al.25 compared the effect of remifentanil and dexmedetomidine during general anaesthesia for caesarian delivery and noted that all neonates had Apgar scores more than 7 at 5 min.
Like other anaesthetic drugs, dexmedetomidine can pass through the placental barrier: foetal : maternal ratios were similar in the two dexmedetomidine groups (70.9% in D1 vs. 75.7% in D2). However, the placental transfer of dexmedetomidine is much lower than that of clonidine (foetal : maternal ratio, 85%)26 or remifentanil (foetal : maternal ratio, 88%),27 which may be caused by dexmedetomidine being more lipid soluble and thus is retained within placental tissues.26 Concomitant with our results, Yu et al.11 reported that dexmedetomidine foetal : maternal ratio was 76% without adverse effect on the newborn: mean Apgar scores were 8 and 9 at 1 and 5 min, respectively, in the dexmedetomidine group.
Our current study included a relatively small number of patients and larger studies will be needed to verify the safety of dexmedetomidine in both mothers with pre-eclampsia and their infants.
The main finding in the current study was that administration of dexmedetomidine in doses of 0.4 to 0.6 μg kg−1 h−1 was associated with significant haemodynamic and hormonal stability. In addition, dexmedetomidine reduced postoperative analgesic requirements without causing significant adverse neonatal outcome. According to our results, we would recommend the use of 0.6 μg kg−1 h−1 dexmedetomidine, as this produced the best haemodynamic, hormonal and analgesic effects.
Acknowledgements relating to this article
Assistance with the study: none.
Financial support and sponsorship: this study was supported by the Menoufiya University Hospitals, Menoufiya, Egypt and funded by the authors.
Conflicts of interest: none.
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