Clonidine premedication reduces maternal requirement for intravenous morphine after cesarean delivery without affecting newborn's outcome

Clonidine Premedication Reduces Maternal Requirement for Intravenous Morphine After Cesarean Delivery Without Affecting Newborn’s Outcome Fumi Yanagidate, M.D., Yoshihiro Hamaya, M.D., Ph.D., and Shuji Dohi, M.D., Ph.D. Background and Objectives: The ␣2-agonist clonidine has several benefits for patients undergoing surgery. During and after elective cesarean delivery (C-section), we assessed the condition of parturient and neonate when one half of the parturients were pretreated with oral clonidine. Methods: Forty-six consenting parturients were studied in a randomized, double-blinded manner. Preanesthetic medication was atropine and famotidine with or without clonidine 4 ␮g/kg. After baseline measurements in parturients and fetuses, combined spinal and epidural anesthesia was established (1.6 mL of 0.5% tetracaine diluted with 10% dextrose in water). C-section was performed while breathing oxygen spontaneously (3 L/min) through a facemask. After delivery, neonates were assessed at 1 and 5 minutes, and the condition of mother and neonate was observed for 48 hours. Results: Parturients receiving clonidine showed no hemodynamic instability during and after C-section, and while their visual analog scale (VAS) scores, verbal descriptive scale (VDS) scores, and sedation scores did not differ from those without clonidine, they needed significantly less patient-controlled analgesia (PCA) morphine for postoperative pain for the first 2 days (P ⬍ .01). Fetal heart rate, umbilical artery and vein pH and gas tensions, and the Apgar-scores of the newborns showed no intergroup differences. No neonatal depression or bradycardia was observed for 48 hours after delivery. Conclusion: The present results indicate that oral clonidine reduces the PCA morphine requirement after C-section without compromising the condition of the fetus or newborn. Further study including larger number of patients would be needed before we conclude that oral clonidine for parturients is safe for their newborns. Reg Anesth Pain Med 2001;26:461-467. Key Words:

Clonidine, ␣2-Agonist, Cesarean delivery, PCA morphine, Neonatal condition.

lonidine, an ␣2-adrenergic agonist, has been widely used as a premedicant to attenuate perioperative cardiovascular instability, to reduce the requirement for anesthetics during surgical operations,1-6 and to reduce the need for postoperative analgesics.5-7 Clonidine was originally developed

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From the Department of Anesthesia, Gifu Social Insurance Hospital (F.Y., Y.H.), Kani City, Gifu, Japan; and the Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine (S.D.), Gifu City, Gifu, Japan. Accepted for publication April 24, 2001. Presented in part at the Annual Meeting of the American Society of Anesthesiologists, October 9-13, 1999, Dallas, TX. Reprint requests: Shuji Dohi, M.D., Ph.D., Department of Anesthesiology and CCM, Gifu University School of Medicine, 40 Tsukasamachi, Gifu City, Gifu 500-8705, Japan. E-mail: [email protected] © 2001 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/01/2605-0014$35.00/0 doi:10.1053/rapm.2001.25934

and used as an antihypertensive drug,8 so indication for parturients with hypertension seemed reasonable. Indeed, clonidine has been reported to be a safe and efficient agent for hypertensive parturients without any apparent effect on fetal outcome.9-11 There are also several reports indicating that clonidine effectively reduces narcotic requirements while enhancing analgesia in parturients when administered intrathecally or by the epidural route.12-16 Despite the widespread postoperative use of epidural and spinal clonidine,2 little is known about the beneficial and/or detrimental effects of oral clonidine on either the normotensive parturient or the fetus. The anesthetic care given before and during cesarean delivery (C-section) must safely provide for the parturient. Therefore, in addition to examining the effects of clonidine on parturients, we assessed the overall effects of maternal clonidine on the fetus

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and newborn after elective C-section by monitoring heart rate (HR), the pH and gas tensions of umbilical venous and arterial blood, and the Apgar score of the newborn.

Methods After institutional approval, 46 consenting parturients of American Society of Anesthesiologists (ASA) physical status I or II were studied in a randomized, double-blinded manner. One hour before arrival in the operating room (OR), each parturient was administered oral clonidine approximately 4 ␮g/kg, atropine 0.5 mg and famotidine 20 mg (n ⫽ 23), or atropine 0.5 mg and famotidine 20 mg (n ⫽ 23). Preanesthetic drugs were prescribed by a physician not involved in the intra-anesthetic and postanesthetic care of the parturients. Continuous monitoring of fetal HR was started before maternal premedication and continued until the start of the C-section. At least 1 L of lactated Ringer’s solution was administered before parturient’s arrival at the OR. Combined spinal and epidural anesthesia was administered (via a 27-gauge Whitacre needle passed through a 17-gauge Tuohy needle at the lumbar level) using spinal tetracaine 8 mg diluted in 1.6 mL of 10% glucose in water, and subsequently a catheter placed into the epidural space. The analgesic level obtained was confirmed to be above the T7 dermatome by use of the pinprick method, and if the analgesia was found to be inadequate, a 5-mL increment of 2% lidocaine solution was planned to be administered via the epidural catheter. The parturients breathed oxygen (3 L/min) spontaneously through a facemask during the C-section. The maternal systemic arterial blood pressure (AP; by sphygmomanometry), HR (by electrocardiography), and oxyhemoglobin saturation level (SpO2; by pulse oximetry) were monitored continuously. Intravenous ephedrine, 5 mg, was administered if systolic AP decreased to below 80 mm Hg or by 20% of the parturient’s resting systolic AP after spinal anesthesia. When the parturients complained of pain during the surgery, intravenous fentanyl 100 ␮g was given incrementally as required. After delivery, all parturients received droperidol 5 mg and metoclopramide 10 mg intravenously. After C-section, a patient-controlled analgesia (PCA) apparatus (Baxter Healthcare Corp, Round Lake, IL) provided intravenous morphine (1-mg bolus; 10minute lockout interval; no continuous infusion). Both the number of PCA requests and the actual injections administered were recorded hourly for 48 hours by the PCA apparatus. To examine the efficacy of the treatment regimens used, we recorded the following values every

2 hours after the C-section for 8 hours, then once a day on the first and second postoperative days: (1) pain score on a 10-cm visual analog scale (VAS) (0 mm ⫽ no pain, 100 mm ⫽ worst unbearable pain), (2) a score on a verbal descriptive scale (VDS) of the fulfillment of the parturient’s need for analgesia (a number from 0 to 10; 0 ⫽ most satisfactory, 10 ⫽ worst status), (3) a 5-grade sedation score (a number from 0 to 4; 0 ⫽ awake and no sedation, 4 ⫽ asleep and difficulty in responding), (4) the uppermost dermatome level of hypesthesia, (5) and a score on a modified Bromage motor block scale (BMBS) (1 ⫽ complete, 2 ⫽ almost complete, 3 ⫽ partial, 4 ⫽ no motor block). Maternal respiratory rate (RR) was also recorded over the same time period. After delivery, the Apgar scores of the newborn at 1 and 5 minutes, together with blood gas tensions and pH for umbilical cord blood (both arterial and venous), were recorded. The HR, RR, and body temperature of the newborn were recorded every 3 or 6 hours for 48 hours after delivery. All data are expressed either as the mean ⫾ SD (parametric values) or as the median ⫾ the 95th percentile (nonparametric values) unless specifically stated otherwise, and were analyzed with using either Student’s t-test for parametrics or the Mann-Whitney U-test for nonparametrics. Qualitative parameters were compared using the chisquared test. P value less than .05 was considered significant.

Results Demographic Data for Parturients With or Without Clonidine The parturient groups were comparable in terms of age, height, and body weight (Table 1). The mean dose of clonidine in the clonidine group was 4.14 ⫾ 0.65 ␮g/kg. No significant differences existed between the 2 groups with amounts of ephedrine and fentanyl administered to the parturients intraoperatively (Table 1). SpO2 exceeded 95% in all parturients, and their RR neither differed between the 2 groups nor decreased below 12 breaths/min throughout the surgery. No parturients were excluded from this study. Parturients’ Postoperative Evaluation The number of requests for and the amount of intravenous PCA morphine injected were significantly smaller in the parturients administered clonidine (Fig 1). There was no significant difference in either VAS pain score or VDS satisfaction score between the 2 groups (Fig 2). The uppermost

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Table 1. Parturients’ Profile and Drug Requirements During and After C-Section

Age (yr) Height (cm) Weight (kg) Hb (g/dL) Ht (%) Na (mEq/L) K (mEq/L) Arterial pressure (mm Hg) in OR Heart rate (beats/min) in OR No. requiring fentanyl Amount of fentanyl used (␮g) Amount of ephedrine used (mg)

With Clonidine (n ⫽ 23)

Without Clonidine (n ⫽ 23)

29 ⫾ 5 157 ⫾ 4 66 ⫾ 9 11.3 ⫾ 1 33.9 ⫾ 2.9 138 ⫾ 1.8 4⫾0 107 ⫾ 14 86 ⫾ 8 7 (32%) 36 ⫾ 58 10 ⫾ 5

28 ⫾ 4 157 ⫾ 4 65 ⫾ 11 11.2 ⫾ 1 33.9 ⫾ 2.7 137 ⫾ 1.7 4⫾0 114 ⫾ 13 84 ⫾ 18 10 (43%) 95 ⫾ 128 8⫾5

NOTE. Values indicate mean ⫾ SD or number of parturients (% in parentheses).

dermatomal level of hypersthesia at 2 hours after delivery was significantly higher in the parturients who received clonidine. There was no significant difference in either BMBS score or sedation score between the 2 groups (Table 2). No parturients in either group reported postdural puncture headache. The frequency of nausea, vomiting, or other side effects likely related to clonidine and/or spinal epidural anesthesia or PCA morphine did not differ between parturients with or without clonidine (Table 3).

Fig 2. Changes in VAS score and VDS score in parturients who received clonidine (n ⫽ 23) or without clonidine (n ⫽ 23) at 0, 2, 4, 6, and 8 hours postoperatively and the second postoperative day. There were no differences between parturients with or without clonidine. The box represents the 25th to 75th percentiles; the line in the box is the median; the extended bars represent the 5th to 95th percentiles.

Fetal HR, Umbilical Blood PO2, PCO2, and pH, and Apgar Scores of Newborns There were no significant differences in fetal HR before and after premedication between parturients with or without clonidine. The umbilical arterial and venous blood values of pH, PCO2, PO2, HCO3⫺, and base excess were comparable at both 1 minute and 5 minutes after delivery, and the Apgar scores were similar between the 2 groups (Table 4). Newborns’ HR, RR, and Body Temperature Fig 1. Cumulative doses of intravenous morphine via PCA in parturients who received clonidine (n ⫽ 23) or clonidine (n ⫽ 23) during 48 hours after C-section. The required dose of PCA intravenous morphine was significantly smaller in the clonidine group. Values are mean ⫾ SD. There were differences in parturients with or without clonidine at each hour for 48 hours, except at 1 and 2 hours (*P ⬍ .05).

For 48 hours after delivery, there were no episodes indicating fetal distress. Only at 12 and 24 hours was RR in the newborns with maternal clonidine significantly greater than in those without clonidine. There was neither significant difference in body temperature between newborns with or without maternal clonidine (Fig 3), nor evidence of

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Regional Anesthesia and Pain Medicine Vol. 26 No. 5 September–October 2001 Table 2. Postoperative Assessments

Sedation score 0h 2h 4h 6h 8h Bromage’s Motor Block Scale 0h 2h 4h 6h 8h Highest sensory block 0h 2h 4h 6h

With Clonidine (n ⫽ 23)

Without Clonidine (n ⫽ 23)

2 (2) 1 (1.4) 1 (1.4) 1 (1.4) 1 (1.4)

1 (2) 1 (1.5) 1 (1.5) 1 (2) 1 (1.5)

1 (1) 1 (2) 3 (4) 4 (4) 4 (4)

1 (2.4) 2 (4) 3 (4) 4 (4) 4 (4)

T4 ⫾ 1 T12 ⫾ 2* L3 ⫾ 2 L5 ⫾ 1

T4 ⫾ 2 L2 ⫾ 3 L4 ⫾ 2 L5 ⫾ 2

NOTE. Values are median (95th percentile). *P ⬍ .05 v parturients without clonidine.

other adverse effects on the infants. Newborns’ HR at 3 hours after delivery was significantly higher in the maternal clonidine group, but none had an HR decrease below 100 beats/min in the 48 hours after delivery.

Discussion The results of the present study show that parturients who received clonidine as an oral premedicant had a reduced requirement for intravenous PCA morphine after C-section, and that the clonidine did not compromise those variables measured in the fetuses or newborns. Maternal clonidine caused neither maternal hemodynamic instability during or after C-section, nor neonatal depression such as bradycardia, hypoxia, or acidosis either immediately after delivery or for 48 hours thereafter. Because the Apgar scores of the newborns, and their umbilical blood pH and gas tensions did not differ between groups, it would seem that oral clonidine, 4 ␮g/kg, for parturients does not or minimally impacts their fetus or newborn when administered 1 hour before elective C-section. Although only a few studies indicated that oral Table 3. Incidence of Side Effects

Nausea Vomiting Pruritus Dizziness Urination difficulty Postspinal headache

With Clonidine

Without Clonidine

1 (4.4%) 0 0 0 1 (4.4%) 0

2 (8.8%) 0 2 (8.8%) 3 (13.2%) 1 (4.4%) 0

NOTE. Values are number of parturients (% in parentheses).

Table 4. Fetal HR, Apgar Score at 1 and 5 Minutes, and Blood Gas Analyses in Umbilical Artery and Vein With Clonidine (n ⫽ 23) Fetal HR Before premedication (beats/min) 139 ⫾ 11 After premedication (beats/min) 136 ⫾ 13 Apgar score 1 min after birth 9 (9) 5 min after birth 10 (10) Umbilical blood Artery pHa PCO2 (mm Hg) PO2 (mm Hg) HCO3⫺ (mEq/L) Base excess (mEq/L) Vein pHv PCO2 (mm Hg) PO2 (mm Hg) HCO3⫺ (mEq/L) Base excess (mEq/L)

Without Clonidine (n ⫽ 23) 145 ⫾ 13 143 ⫾ 15 9 (10) 10 (10)

7.29 ⫾ 0.04 56.7 ⫾ 7 15 ⫾ 4 27 ⫾ 2 0.8 ⫾ 1.8

7.31 ⫾ 0 52.8 ⫾ 7 15 ⫾ 5 26 ⫾ 2 0.1 ⫾ 2

7.35 ⫾ 0 45 ⫾ 4 30 ⫾ 6 25 ⫾ 2 1 ⫾ 2.1

7.36 ⫾ 0 42 ⫾ 6 30 ⫾ 6 23 ⫾ 3 ⫺1.8 ⫾ 3

NOTE. Values are mean ⫾ SD and median (95th percentile).

administration of clonidine as a premedicant can (1) enhance morphine analgesia for postoperative pain5-7 and (2) reduce the sympathetic activation associated with postoperative pain,17,18 the existing evidence was strong enough for us to anticipate that the above effect of clonidine on morphine requirements would occur in parturients undergoing elective C-section. In addition, maternal dependence on the sympathetic nervous system for the maintenance of hemodynamic stability increases progressively during pregnancy and reaches a peak at term, and in hypertensive parturients AP can be effectively treated with clonidine.9,10 Thus, it was not a surprise to find a clonidine-induced 40% reduction in PCA morphine without hemodynamic instability for patients undergone C-section. However, because oral clonidine is rapidly and almost completely absorbed, with the time to reach maximum plasma concentration being between 1.5 and 2 hours, and since clonidine rapidly crosses the placenta19 and the blood brain barrier as well,20 the peak plasma concentration of clonidine in the fetus is reached at 1 hour after its maternal administration, with the ratio of its concentrations in fetal and maternal blood (F/M ratio) reaching about 0.8519,21 at 90 minutes after its administration. Thus, the fetal plasma concentration of clonidine could have been maximal approximately 90 minutes after its maternal administration at about 4 ␮g/kg, and theoretically its most significant influence would occur in the neonate at approximately the time of delivery. Therefore, our major concern in the present study was whether it might compromise the condi-

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Fig 3. Newborns’ HR, RR, and body temperature in parturients who received clonidine (n ⫽ 23) or without clonidine (n ⫽ 23). Respiratory rate at 12 hours and 1 postoperative day were higher in parturients who received clonidine. Values are mean ⫾ SD. *P ⬍ .05 compared between the groups.

tion of the fetus or newborn by causing fetal distress or neonatal depression. Nevertheless, none of the newborns manifested with a decrease in HR and/or depression attributable directly to clonidine or to its interaction with the other drugs administered during delivery. There was no evidence that neonatal Apgar scores, umbilical blood gas tensions and pH, HR, RR, or temperature for 48 hours after C-section were altered. Our findings are in accord with those by Hartikainen-Sorri et al.,22 who also showed no differences on neurologic examination or in serum electrolytes and blood glucose concentrations between neonates with and without predelivery maternal clonidine. Although the present study has limitations due to the small number of patients studied and the limited observation of newborn neurobehavioral examinations, we believe mater-

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nal clonidine, at a dose of 4 ␮g/kg, is unlikely to affect a full-term neonate’s condition assessed by Apgar score that is relevant to prediction of neonatal outcome or evaluation of the newborn as recently reported by Casey et al.23 It is unclear as to the reason(s) for the significantly higher RR observed at 12 and 24 hours after delivery in the newborns in maternal clonidine group (Fig 3). The respiratory response to hypoxia in the newborn appears to be an initial increase in RR followed by sustained decrease in rate.24 Because clonidine concentration in maternal milk is approximately twice that in the maternal serum,25 it may be that early breast feeding to the infants (which was started 12 to 18 hours after the delivery) who had already been exposed to clonidine via the maternal and fetal circulation might further increase their plasma concentration of clonidine. Theoretically, this might manifest an increased RR as a sign of metabolic acidosis or hypoxia. Although no decrease in HR occurred and the RR normalized in the second 24 hours after delivery, one may argue against such a possibility, and we cannot exclude the possibility without measuring neonate’s plasma concentration of clonidine. The autonomic nervous system is relatively immature even in term fetuses, and the parasympathetic innervation develops earlier, so that it is present to a more complete extent than the adrenergic innervation at birth.24 Thus, in the fetus or newborn the typical response to hypotension and bradycardia might be seriously impaired by maternal clonidine. The finding that fetal depression due to arterial hypoxemia, acidosis, or central nervous system depression is associated with minimal to absent variability in HR24 suggests that an increase in neonatal HR is unlikely to occur under maternal clonidine. The normal full-term fetus exhibits beatto-beat variability of HR which indicates the integrity of the neural pathway from the fetal cerebral cortex through the medulla, vagal nerve, and cardiac conduction system, all of which clonidine would affect.8 The neonatal cardiac output appears to depend heavily on changes in HR,26 and fetal and neonatal bradycardia is associated with a marked decrease in cardiac output.24,26 The newborns in this study exposed to clonidine did not show any significant decrease in HR compared with those without maternal clonidine; indeed, their HR was always above 100 beats/min. Thus, maternal clonidine at the dose administered seems unlikely to cause a high-frequency fetal or neonatal bradycardia, even though the sympathetic system is not fully matured at birth. Although the pregnant state is associated with a decreased response to pressor agents such as ephed-

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rine and phenylephrine,27 adult patients administered oral clonidine have augmented responses to those pressors28,29 but blunted HR response to atropine.30 Our full-term fetuses and newborns showed no bradycardia in the 48 hours after delivery, but since cardiac output in fetuses and newborns is heavily dependent on HR,24,26 it is important to know whether those exposed to maternal clonidine have a depressed HR response to atropine. It is reported that atropine rapidly crosses the placenta, with an F/M ratio of approximately 0.93 being attained at 5 min,31 which eliminates short-term fetal HR variability.31 The hypotension and bradycardia seen with clonidine are known to be principally due to the central effects of this drug (mediated by decreased sympathetic outflow),8 and future studies will need to determine whether the responses to ephedrine and atropine are maintained in the fetus and newborn exposed to maternal clonidine. In conclusion, preanesthetic administration of oral clonidine to parturients reduced the requirement for intravenous PCA morphine after elective C-section without compromising variables measured in the fetuses or newborns. However, because we administered only clonidine, 4 ␮/kg, to parturients having full-term infants by C-section, we should still be cautious of administering oral clonidine to a parturient delivering an immature fetus or one undergoing normal vaginal delivery during which the fetus would experience maternal uterine contractions.

Acknowledgment The authors thank the gynecologists and nurses of Gifu Social Insurance Hospital, Kani City, Gifu, Japan, for their support.

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