INTRODUCTION
Dexmedetomidine is a highly selective α-2 adrenergic receptor agonist with several diverse actions like sedation, anxiolysis, sympatholysis, analgesia, and decreased intraoperative anesthetic requirements (narcotic, inhalational), cardiovascular stability, smooth recovery when used as an adjunct to general anesthesia, and above all, preserves respiratory function. It was approved by United States Food and Drug Administration (US FDA) in 1999 for use in humans for short term sedation and analgesia in Intensive Care Unit (ICU) for less than 24 hours.[12]
There are several off label uses of dexmedetomidine like sedation for FOB (fiberoptic bronchoscopy) and intubation, sedation for Magnetic Resonance Imaging (MRI), endoscopies and ophthalmic surgeries, as an anti-shivering agent post operatively, for alcohol and opioid withdrawal.[123] Though not approved for use in pediatric patients, especially infants, there is a lot of literature available in the form of case reports and review articles that describes successful use of dexmedetomidine in this group of patients as well.[4] It is been rigorously explored as an adjunct to local anesthetic in spinal and epidural anesthesia.[56] But there is some reluctance in using dexmedetomidine by anesthesiologists in parturients; the reason being possible uteroplacental transfer and untoward effects on the baby.[7] There are several case reports describing successful use of dexmedetomidine in labor analgesia if regional was contraindicated, if patient not willing for labor epidural or as an adjunct to labor epidural if pain relief was not satisfactory, without any adverse fetal outcomes in the recommended doses (1 ug/kg loading dose over 10-15 minutes followed by an infusion at 0.2-0.7 ug/kg/hour). Remifentanil is now considered safe for use in labor analgesia as it gets metabolized by esterases and thus has negligible uteroplacental transfer.[89] Similarly, literature describes that as dexmedetomidine has a high placental retention, it doesn't cross the placenta to reach the fetus.[10] Epidural analgesia remains the gold standard for labor. But in parturients with cardiac ailments who cannot tolerate hemodynamic disturbance during labor, parturients in whom epidural is contraindicated (coagulopathy, spinal cord diseases, etc) or epidural is not effective, dexmedetomidine can be used by experienced clinicians.
SEARCH STRATEGY
We conducted a search of case reports, articles in PUBMED, MEDKNOW, and GOOGLE to find out how much literature is available describing use of dexmedetomidine in labor analgesia or as an adjunct to general anesthesia. The search strategy was done using following words: Dexmedetomidine, pregnancy, and anesthesia. We also cross-checked relevant articles from the reference list. In our review of literature, we included articles/publications that described the use of dexmedetomidine in parturient humans and animals for labor analgesia, Cesarean section or for non-obstetric surgery.
REVIEW OF LITERATURE
We have described the review of literature in animals and humans separately.
Studies in animals
Karamon et al., published their study of direct effects of dexmedetomidine on isolated gravid rat myometrium and demonstrated that dexmedetomidine increased spontaneous contractions in rat myometrium (Advanced Therapy, 2006).[10]
Tariq et al., published in Basic Clinical Pharmacology Toxicology, 2008, a study of effects of sub-chronic versus acute exposure of dexmedetomidine on fetal development in rats. They concluded that acute exposure of dexmedetomidine at anticipated delivery time had no adverse effects on birth weight, crown-rump length and post-natal behavior and that chronic exposure lead to decreased birth weight and crown rump length.[11] Uemura et al studied effect of dexmedetomidine infusion on pregnant sheep who were subjected to preterm surgical deliveries. They recorded maternal and fetal cardiovascular status, fetal blood gas and cerebral oxygen levels before, during and 3 hours after dexmedetomidine infusion. They found that the infusion produced sedation without respiratory depression. It was observed that although there was decrease in maternal BP and heart rate, there was no significant effect on fetal heart rate and mean arterial pressure and had no effect on fetal cerebral oxygenation as well (International Journal of Obstetric Anesthesia, 2012).[12]
STUDIES/CASE REPORTS IN HUMANS
Sia et al., studied the effects of clonidine and dexmedetomidine on strips of pregnant human myometrium obtained from 6 individuals during elective Lower Segment Cesarian Section (LSCS) and explained that dexmedetomidine increases uterine contractility at plasma concentrations 1 × 10-9 g/ml. Hence, they suggested that detailed clinical investigation needs to be done to use it in obstetric anesthesia (International Journal of Obstetric Anesthesia, 2005).[13] De Souza et al., published a case report in Rev Bras Anesthesiol, 2005 (Article in Portuguese) in which they described the successful surgical management of cerebral aneurysm in a 19-year-old pregnant patient who was in 27 weeks of gestation. They used dexmedetomidine with fentanyl and propofol for general anesthesia and justified the use of dexmedetomidine to control hemodynamic responses during surgery (induction, handling of aneurysm, and extubation). They mentioned that fetal viability was maintained throughout the peri-operative period. Ten weeks later, the patient underwent LSCS and delivered a healthy baby with normal Apgar scores.[14] Toyama et al., reported successful use of dexmedetomidine in a 30-year-old pregnant women who had Primary Pulmonary Hypertension diagnosed in 23rd week of gestation, who was posted for LSCS at 32 weeks of gestation under general anesthesia with a combination of Nitric oxide, prostacyclin infusion, Nitroglycerine, and dobutamine infusion. Dexmedetomidine was specifically used to prevent hemodynamic response during induction and emergence so as to prevent cardiac failure (International Journal of Obstetric Anesthesia, 2009).[15]
Abu-Halawah et al., described the successful use of intravenous (IV) dexmedetomidine infusion in a pregnant women with diabetes mellitus and pregnancy-induced hypertension (PIH) who refused labor epidural. LSCS was done under general anesthesia with dexmedetomidine infusion uneventfully with no untoward maternal and child adverse events (European Journal of Anesthesiology, 2009).[16] Palanisamy et al., published a case report in International Journal of Obstetric Anesthesia, 2012 regarding use of dexmedetomidine in a 31-year-old parturient with spina-bifida occulta with a tethered spinal cord reaching L5-S1 who was on Fentanyl Intravenous Patient Controlled Analgesia (IVPCA) for labor analgesia which was not helping her. She was administered general anesthesia for prolonged first stage of labor and suspected chorioamnionitis with dexmedetomidine infusion on flow. A healthy baby was delivered with normal Apgar scores and no deficits.[17] Juliana Maria Mendoza Villa published two case reports in Rev Colomb Anesthesiol, 2012 where dexmedetomidine was used as an adjunct for labor analgesia along with remifentanil. Both patients underwent vaginal delivery, although the first patient had instrumentation. Babies were delivered with normal Apgar scores at 1 and 5 minutes.[18]
El-Tahan et al., studied the efficacy of dexmedetomidine in suppressing cardiovascular and hormonal response to general anesthesia for cesarean section. They randomly recruited 68 parturients for study and, as per randomization, parturients received 0.2, 0.4, or 0.6 ug/kg/hour of dexmedetomidine 20 minutes before induction or placebo. With Sellick's manouvre, general anesthesia was administered with propofol and suxamethonium and maintained on 0.5-0.75 MAC of sevoflurane. They recorded maternal heart rate, mean arterial pressure, MAC of sevoflurane, uterine tone, serum cortisol level, Apgar scores, Neurologic Adaptive Capacity scores, and acid base status. They concluded that pre-operative administration of dexmedetomidine in a dose of 0.4 and 0.6 attenuates maternal hemodynamics and hormonal response to cesarean section without adverse neonatal effects.[19] (International journal of Obstetric Anesthesia, 2012). Neumann et al., published a case report of successful use of dexmedetomidine for awake fiber optic intubation in a parturient with spinal muscular dystrophy type III for cesarean section.
A 35-years G4P4A3, 41 kg parturient underwent endotracheal intubation with dexmedetomidine sedation and infusion was continued throughout the surgery. Baby was delivered at 68 minutes after which the infusion was stopped. Maternal hemodynamics and Apgar scores at 1 and 5 minutes were acceptable.[20] (International Journal of Obstetric Anesthesia, 2009). Alex T. Sia and Ban L. Sng in their editorial in International Journal of Obstetric Anesthesia, mentioned that dexmedetomidine if used in a properly, selected parturient can provide sedation and hemodynamic stability with minimal risk of respiratory depression. However, they stressed that more research is required as there is a possibility of synergy with narcotics and nitrous oxide.[21] (International Journal of Obstetric Anesthesia, 2009). Katsumi et al., published in Masui, 2009 about use of dexmedetomidine in two patients with myasthenia gravis in which the first patient was a 39 year old parturient for an emergency cesarean section. Patient received vecuronium as muscle relaxant and was ventilated post-operatively with dexmedetomidine infusion on flow. Extubation was done after patient recovered completely from the effect of muscle relaxant. They concluded that although dexmedetomidine is considered useful in peri-operative management of patients with myasthenia gravis, further research is required for safe use in future. The second patient in the case report was not a parturient.[22]
DISCUSSION
Using sedatives and narcotics in a parturient have always been controversial as these drugs tend to cross the uteroplacental barrier and can have deleterious effects on the baby. But newerdrugs like remifentanil and dexmedetomidine due to their different and unique pharmacokinetics do not cross placenta significantly. Dexmedetomidine has a high placental retention (0.77 maternal/fetal index). Also, it is highly lipophilic as a result of which it is retained in placental tissue.[1011] Because of these properties, it doesn't cross the uteroplacental barrier, and even if it does cross, it is negligible. Also, it increases the frequency and amplitude of uterine contraction directly. But one must be able to justify the use of dexmedetomidine in a parturient, as it is still an off-label use, if used for labor analgesia or as an adjunct to general anesthesia for cesarean section. However, in maternal conditions like Pulmonary Hypertension (primary/acquired), PIH Rheumatic Heart Disease (especially mitral Stenosis), Thyrotoxicosis, and Coronary artery disease were hemodynamic fluctuations during labor or cesarean section can be disastrous, dexmedetomidine can be used in recommended doses due to its desirable properties of analgesia, sedation, sympatholysis, and ability to reduce anesthetic requirement. But dexmedetomidine must be used by an experienced Anesthesiologist in a well-equipped set up with meticulous hemodynamic monitoring. Most of the case reports that described the use of dexmedetomidine in parturients have mentioned that babies delivered were with normal Apgar scores which proves that even if there is any uteroplacental transfer, it doesn't affect the fetal well-being. However caution has to be taken while using dexmedetomidine in presence of bradyarrhythmias, severe left ventricular or biventricular dysfunction and in volume depleted patients. Also, use of dexmedetomidine requires dose adjustment in presence of hepatic or renal dysfunction.
CONCLUSION
With vigilant monitoring of hemodynamics and proper selection of patient, dexmedetomidine may be used in a parturient having medical conditions in which tachycardia and hypertension is not desirable. Literature suggests that dexmedetomidine doesn't cross uteroplacental barrier due to its high placental extraction but as its use in labor analgesia/as an adjunct to general anesthesia still remains off label, the concerned Anesthesiologist must select the patient carefully and should be able to justify its use. One should try to avoid the use of dexmedetomidine in presence of bradyarrhythmias, severe left ventricular/biventricular dysfunction and hypovolemic states. Dose adjustment is required as recommended in presence of hepatic and renal dysfunction.
REFERENCES
1. Kaur M, Singh PM. Current role of dexmedetomidine in clinical anesthesia and intensive care Anesth Essays Res. 2011;5:128–33
2. Grewal A. Dexmedetomidine: New avenues J Anaesthesiol Clin Pharmacol. 2011;27:297–302
3. Gertler R, Brown HC, Mitchell DH, Silvius EN. Dexmedetomidine: A novel sedative-analgesic agent BUMC Proceedings. 2001;14:13–21
4. Phan H, Nahata S. Clinical uses of dexmedetomidine in pediatric patients Paediatr Drugs. 2008;10:49–69
5. Al-Mustafa MM, Abu-Halawah SA, Aloweidi AS, Murshidi MM, Ammari BA, Awwad ZM, et al Effect of dexmedetomidine added to spinal bupivacaine for urological procedures Saudi Med J. 2009;30:365–70
6. Bajwa SA, Arora V, Kaur J, Singh A, Parmar SS. Comparative evaluation of dexmedetomidine and fentanyl for epidural analgesia in lower limb orthopedic surgeries Saudi J Anaesth. 2011;5:365–70
7. Mattingly JE, D'Alessio J, Ramanathan J. Effects of obstetric analgesics and anesthetics on the neonate: A review Paediatr Drugs. 2003;5:615–27
8. Blair JM, Hill DA, Fee JP. Patient-controlled analgesia for labor using remifentanil: A feasibility study Br J Anaesth. 2001;87:415–20
9. Volikas I, Butwick A, Wilkinson C, Pleming A, Nicholson G. Maternal and neonatal side-effects of remifentanil patient-controlled analgesia in labor Br J Anaesth. 2005;95:504–9
10. Karaman S, Evren V, Firat V, Cankayali I. The effects of dexmedetomidine on spontaneous contractions of isolated gravid rat myometrium Adv Ther. 2006;23:238–43
11. Tariq M, Cerny V, Elfaki I, Khan HA. Effects of subchronic versus acute
in utero exposure to dexmedetomidine on fetal development in rats Basic Clin Pharmacol Toxicol. 2008;103:180–5
12. Uemera K, Shimazutsu K, McClaine RJ, McClaine DJ, Manson RJ, White WD, et al Maternal and preterm fetal sheep responses to dexmedetomidine Int J Obstet Anesth. 2012;21:339–47
13. Sia AT, Kwek K, Yeo GS. The
in vitro effects of clonidine and dexmedetomidine on human myometrium Int J Obstet Anesth. 2005;14:104–7
14. de Souza KM, Anzoategui LC, Pedroso WC, Gemperti WA. Dexmedetomidine in general anesthesia for surgical treatment of cerebral aneurysm in pregnant patient with specific hypertensive disease of pregnancy: Case report Rev Bras Anestesiol. 2005;55:212–6
15. Toyoma H, Wagatsuma T, Ejima Y, Matsubara M, Kurosawa S. Cesarean section and primary pulmonary hypertension: The role of intravenous dexmedetomidine Int J Obstet Anesth. 2009;18:262–7
16. Abu-Halaweh SA, Al Oweidi AK, Abu-Malooh H, Zabalawi M, Alkazaleh F, Abu-Ali H, et al Intravenous dexmedetomidine infusion for labor analgesia in patient with preeclampsia Eur J Anaesthesiol. 2009;26:86–7
17. Palanisamy A, Klickovich RJ, Ramsay M, Ouvang DW, Tsen LC. Intravenous dexmedetomidine as an adjunct for labor analgesia and cesarean delivery anesthesia in a parturient with tethered spinal cord Int J Obstet Anesth. 2009;18:258–61
18. Mendoza Villa JM. Dexmedetomidine as adjuvant for analgesia in labor: A report of two case Rev Colomb Anestesiol. 2012;40:79–81
19. El-Tahan MR, Mowafi HA, Al Sheikh IH, Khidr AM, Al-Juhaiman RA. Efficacy of dexmedetomidine in suppressing cardiovascular and hormonal responses to general anesthesia for caesarean section: A dose-response study Int J Obstet Anesth. 2012;21:222–9
20. Neumann MM, Davio MB, Macknet MR, Applegate RL 2 nd. Dexmedetomidine for awake fiber optic intubation in a parturient with spinal muscular dystrophy type III for cesarean delivery Int J Obstet Anesth. 2009;18:403–7
21. Sia AT, Sng BL. Intravenous dexmedetomidine for obstetric anaesthesia and analgesia: Converting a challenge into an opportunity? Int J Obstet Anesth. 2009;18:204–6
22. Katsumi N, Kunisawa T, Suzuki A, Kurosawa A, Takahata O, Iwasaki H. Perioperative management of a patient with myasthenia gravis using dexmedetomidine Masui. 2009;58:1450–2
