TITLE: Premedication with midazolam prior to cesarean delivery in preeclamptic parturients: A randomized controlled trial

  ABSTRACT.BACKGROUND:
Anxiety is a concern in obstetrics, especially in preeclamptic mothers. Sedation is not commonly used in parturients for fear of adverse neonatal effect. We investigated maternal and neonatal outcome of midazolam as an adjuvant to spinal anesthesia for elective cesarean delivery.

ABSTRACT.METHODS:
A prospective randomized controlled trial, in which eighty preeclamptic parturients received either an intravenous dose of 0.035 mg/kg of midazolam or an equal volume of normal saline, 30 min before spinal anesthesia. Maternal anxiety was assessed using Amsterdam Preoperative Anxiety and Information Scale (APAIS); postoperative maternal satisfaction was assessed using Maternal Satisfaction Scale for Cesarean Section (MSSCS). Newborns were assessed using Apgar score, Neonatal Neurologic and Adaptive Capacity Score (NACS), and umbilical artery blood gases.

ABSTRACT.RESULTS:
Mothers premedicated with midazolam showed a lower level of preoperative anxiety and a higher degree of postoperative satisfaction than the control group. There were no between-group differences regarding the neonatal outcome.

ABSTRACT.CONCLUSION:
Preeclamptic parturients premedicated with midazolam (0.035 mg/kg) before spinal anesthesia have lower anxiety and higher postoperative satisfaction levels, with no adverse effects on the newborns.

BODY.INTRODUCTION:
Neuraxial anesthesia is progressively used for elective cesarean delivery as it is associated with the best maternal and neonatal outcomes. In preeclampsia, spinal anesthesia provides hemodynamic stability and best risk-benefit outcome; it avoids the detrimental effects of general anesthesia on maternal blood pressure and the risk of difficult intubation.[1] By the mid-1990s, clinical trials demonstrated the safety of neuraxial anesthesia as an accepted alternative to general anesthesia for preeclamptic patients.[234] Recently, a focused review confirmed this fact.[5]  One study has reported that 60–80% of patients suffers from preoperative anxiety.[6] Some studies showed a clear correlation between anxiety and preeclampsia.[78] Anxiety is a particular concern in obstetrics, as it may lead to autonomic vasoconstriction in the uterine arteries, which may induce fetal distress.[910] Parturients may endure a great level of anxiety and discomfort during the placement of the spinal needle; a condition could be worsened by preeclampsia.  Sedation for neuraxial blockade in pregnant patients remained controversial, based on its potential adverse effects on the fetus, such as decreased motor tone and respiratory compromise. In the 1960s, several case reports showed decreased motor tone in newborns related to maternal diazepam.[1112] In contrast, midazolam is three to four times more potent than diazepam and is used mainly for maternal sedation. Although it crosses the placental barrier, in small doses, it does not cause any adverse effects in the neonate.[13] However, when used in high doses of 0.3 mg/kg for the induction of general anesthesia, the umbilical vein to maternal vein ratio was high (0.96), and the elimination half-life in the neonate was 6.3 h.[14]  In the 1980s, a few reports discussed the intravenous (iv) administration of midazolam during pregnancy without providing much information about its use close to delivery.[1516] More recent studies investigated the sedative effect of midazolam with or without narcotics on normal parturients.[171819] However, the impact of midazolam as a sedative on preeclamptics has not been sufficiently studied prospectively. In this concern, we decided to study the maternal and neonatal outcomes of a sedative dose of midazolam in these cases.

BODY.INTRODUCTION.AIMS:
This work aimed to determine the effect of premedication with midazolam on preoperative anxiety, perioperative hemodynamics, and postoperative satisfaction of preeclamptic parturients scheduled for elective cesarean delivery under spinal anesthesia. It was also designed to observe the adverse effects of midazolam on the neonatal outcome.

BODY.METHODS:
After approval of our Institutional Ethical Committee and obtaining informed written consents from all parturients included in this study, this prospective randomized controlled study was conducted on eighty full-term, of American Society of Anesthesiologists (ASA) Class I or II, 18–40-year-old parturients presenting with mild preeclampsia as defined by the American College of Obstetricians and Gynecologists.[20] They were scheduled for elective cesarean delivery under spinal anesthesia after excluding the contraindications of technique. This study was performed in our university hospital from October 1, 2014, to September 30, 2015.  Emergency cases, patients with evidence of intrauterine growth restriction or fetal compromise, patients with severe preeclampsia, thrombocytopenia, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet levels), parturients receiving magnesium therapy, or with a body mass index >30 were excluded from the study. History of cardiac, pulmonary, hepatic, renal, neuropsychiatric or other diseases or substance abuse also were excluded from the study. All patients had fetal heart monitoring preoperatively to exclude fetal heart rate (HR) abnormalities.  Preoperatively, a complete blood count, prothrombin time, liver and kidney function tests were done and recorded for each participant. All patients were assessed clinically and investigated for the exclusion of any of the above-mentioned contraindications.  All patients were randomly allocated into two groups, midazolam group (Group M) and normal saline control group (Group S), using a computer-generated randomization list and a sealed envelope technique (n = 40/group). The study solution (midazolam or normal saline) was prepared in a 2 mL volume, by an anesthesiologist not involved in the care of the woman or collecting the data for the study. Another anesthesiologist who was blinded to the study provided perioperative care and collected perioperative data.  All patients were booked on a morning list, instructed for the same preoperative fasting protocol and were educated as to how to complete the questionnaires required for the study.  On arrival of the patients to the preoperative waiting room, routine monitoring (Electrocardiography, pulse oximeter probe, and a noninvasive blood pressure cuff) were applied, and wide-bore venous access was established for the infusion of lactated Ringer's solution. Thirty minutes before the induction of spinal anesthesia, group (M) was given iv premedication with midazolam (0.035 mg/kg) in 2 mL solution, whereas group (S) was given an equal quantity of normal saline.  The Amsterdam Preoperative Anxiety and Information Scale (APAIS) was used in this study for the objective analysis of anxiety in all patients [Figure 1]. It consists of six questions receiving a score between one (none) and five (most), with a total score of 30, investigating patients' concerns and anxieties. It is short, reliable, and easy to administer.  Figure 1Amsterdam Preoperative Anxiety and Information Scale  APAIS was applied twice by the same anesthesia assistant in a preoperative visit to all patients in their rooms 1⁄2 h before their transfer to the operating theater (A1), and 5 min after the administration of the study drug (A2).  Twenty minutes before the induction of spinal anesthesia, all patients received a rapid iv infusion of 500 mL of lactated Ringer's solution as a preload, followed by a replacement rate of 15 mL/kg/h. For spinal anesthesia, 2.5 mL of intrathecal hyperbaric bupivacaine (0.5%) was injected using a 25-gauge spinal needle with patients in the lateral decubitus position at the L 3/4 interspace, under strict aseptic precautions. Parturients were then immediately placed in the tilted supine position. The level of sensory block was determined with cold and pinprick tests. Oxygen by nasal cannula (2 L/min) was applied to all patients. Urinary catheterization was performed, and surgery started when a sufficient level of sensory block (T4) was achieved.  The maternal HR, systolic blood pressure (SBP), and diastolic blood pressure (DBP) noninvasive arterial pressure were recorded on arrival to the preoperative waiting room (T0), 5 min after injecting the tested drug (T1), during the insertion of spinal needle (TS), 2 min (T2), and 5 min (T5) after the induction of spinal anesthesia.  Hypotension was defined as a drop of SBP <100 mmHg or a drop >20% from (T1), which was considered as the baseline value. SBP <90 mmHg was treated with ivboluses of ephedrine in increments of 10 mg. Tachycardia was defined as HR >100 and bradycardia when HR <60. When HR was lower than 50 beats/min, atropine 0.5 mg ivwas administered.  Once the baby was delivered, the umbilical cord was double-clamped, and a blood sample from an umbilical artery (UA) was collected for blood gas analysis. Basic neonatal examination was performed, and Apgar scores were recorded at min 1 and 5, and the Neonatal Neurological and Adaptive Capacity Scoring (NACS) was measured and recorded at 15 min.[21]  Postoperatively, patients were kept in the recovery room for 1 h and then sent to the ward.  The Maternal Satisfaction Scale for cesarean section (MSSCS)[22] is a 22-item questionnaire specifically designed to evaluate maternal satisfaction with neuraxial anesthesia for elective cesarean delivery. Each item has a 7-point scale with minimum total score of 22 and maximum of 154, a higher score representing higher satisfaction. It was applied to all patients on the 1st postoperative day between 8:00 am and 1:00 pm.  The development of seizures in cases of mild preeclampsia is extremely rare; however, if it took place, our protocol was to treat it with magnesium sulfate (loading dose of 4–6 g followed by continuous infusion of 1-2 g/h),[120] and the case was dropped out from the study.  For sample size calculation, preoperative anxiety was taken as a primary parameter of interest. The power analysis is based on independent sample t-test and a 25% decrease of the APAIS score; the α value was 0.05 and the power (1-β) of the study was 0.80. Depending on the previous studies,[1823] it was calculated that a minimum of 36 patients would be required per group. However, we enrolled eighty patients (40/group) to allow for drop-outs.  Data were analyzed using the SPSS statistics program (Version 16, SPSS Inc., Chicago, IL, USA). According to the type of data, they were represented as mean and standard deviation or frequencies and percentages. Comparisons of the two studied groups were performed using independent sample t-test or Mann–Whitney U-test as appropriate while repeated measures within the same group were compared using paired t-test. In all tests, results were considered statistically significant if P < 0.05.

BODY.RESULTS:
Eighty cases were initially investigated, but five cases were excluded during the study; two cases in group (M) and one case in group (S) due to an inadequate spinal block, and one case in each group because of failure to collect umbilical arterial blood.  In both groups, there were no significant differences regarding age, body weight, height, and spinal injection to delivery time as shown in Table 1.   Table 1 Patients characteristics in both groups   After administration of the tested drug (midazolam or normal saline), there was a significant reduction in APAIS readings (A2) in group (M); with a significant difference in (A2) between the two groups while there was no between-group difference before administration (A1) as shown in Table 2. Maternal Satisfaction Scale for cesarean section showed a significant level of maternal satisfaction in group (M) compared to group (S). There was no difference between the groups regarding the newborn Apgar or NACS scores as shown in Table 2. No significant differences were found between the two groups regarding the pH, PaCO2, PaO2, and base deficit in the umbilical arterial samples as listed in Table 3.  Table 2 Amsterdam Preoperative Anxiety and Information Scale, Maternal Satisfaction Scale for cesarean section, Apgar score and neonatal neurologic and adaptive capacity score in both groups   Table 3 Blood gas analysis of umbilical artery blood samples in both groups   Regarding maternal hemodynamics, baseline HR, SBP, and DBP were comparable between the two groups before the administration of the tested drug. However, 5 min after injecting the tested drug, there was a significant decrease in all parameters in group (M) compared to group (S). During insertion of the spinal needle, there was a rise in HR and SBP in group (S) compared to group (M) while DBP was at a lower level in group (M). After the induction of spinal anesthesia and placing the patient into the tilted supine position, there was an increase in HR with some decrease in blood pressure parameters in both groups as shown in Tables 4–6.  Table 4 Maternal heart rate in both groups   Table 5 Systolic blood pressure in both groups   Table 6 Diastolic blood pressure in both groups   Hypotension occurred in three patients in the group (M) and one patient in the group (S), requiring a single bolus of ephedrine for each. No bradycardia was observed in any patient. Hemodynamic parameters then remained stable and comparable in both groups.

BODY.DISCUSSION:
This study has shown a significant improvement of preoperative anxiety and postoperative satisfaction in parturients premedicated with midazolam compared to those in the control group, with no significant neonatal adverse effects. The study also documented improved maternal hemodynamics in the treated group before the administration of spinal anesthesia. However, there was no significant difference between groups regarding maternal hemodynamics throughout the rest of the procedure.  The progressive increase in the number of cesarean sections[24] draws the attention to the psychological aspects of parturients, including their level of anxiety and perception of obstetric care they received.[25] Some studies tried to solve the problem of preoperative anxiety via nonpharmacological measures, such as the use of a preoperative information video in obstetric[26] and nonobstetric[27] patients, but their results were disappointing. However, other studies applied a preoperative information system and proved its effectiveness on the level of anxiety and postoperative satisfaction in nonobstetric patients.[282930]  Midazolam is a commonly used sedative as it is fast-acting and of short duration, making it superior to other benzodiazepines. It is a lipophilic drug that can cross the placenta by passive diffusion. In large induction doses, midazolam and its metabolites cross the placenta in both animal[31] and human[14] studies. However, early in 1984, Kanto et al.[32] proved its excellent sedative effect following cesarean delivery performed under epidural anesthesia. They gave a relatively large iv dose (0.075 mg/kg) following baby removal, resulted in a rapid and marked sedative effect lasted for 2–3 h while patients were completely cooperative in the recovery room.  Frölich et al.[19] gave a single iv dose of 0.02 mg/kg midazolam plus 1 μg/kg fentanyl to parturients undergoing cesarean delivery shortly before spinal needle insertion. Similar to our study, Apgar scores showed no difference between the treated group and the control group. They evaluated maternal anxiety with two methods; maternal plasma catecholamine levels at the time of delivery and three postoperative questions. They found a higher level of patient satisfaction in the treated group; otherwise, there were no between-group differences.  In contrast, Senel and Mergan[18] gave a single iv dose of 0.025 mg/kg midazolam to parturients 30 min before cesarean delivery. They evaluated maternal anxiety using APAIS score and newborns with Apgar and NACS scores. They reported significantly lower anxiety scores in the treated groups, without any adverse neonatal outcome. However, they recommended further clinical trials with higher sample size to assess the larger doses of midazolam. Similar findings were found by Fung et al. in 1992, where 90% of mothers fell asleep with midazolam premedication before the start of surgery, with no adverse neonatal outcome; comparing the Apgar scores and umbilical venous pH values to the control group.[17]  We chose the midazolam dose (0.035 mg/kg) based on these previous studies,[1819] and according to our own experience with Egyptian parturients, aiming for the best degree of maternal satisfaction without causing maternal hypoventilation or neonatal depression. We chose a single bolus based on body weight; however, in clinical practice, some may prefer to titrate iv drugs to effect. Thus, our results cannot be compared to other studies with repeated doses or iv infusion.  The timing of premedication is also crucial. We chose it 30 min before the induction of spinal anesthesia, to allow enough time for suppression of anxiety; an important consideration in preeclampsia, whose cardiovascular responses are exaggerated. This is in contrast to Frölich et al., who gave their premedication immediately before the spinal anesthesia procedure.  We employed several parameters of neonatal outcome. The Apgar scoring system is routinely used, due to its clear physiological correlation with neonatal well-being.[33] It is easily applied and gives a quick idea about newborn's clinical condition and efficiency of resuscitation efforts. We also used the NACS scoring system, a neurobehavioral scale that allows for the evaluation of potential effects of neonatal drug exposure. It is designed to distinguish drug-induced neonatal depression from that secondary to asphyxia. It stresses on motor tone as a main indicator of drug-induced depression.[21] However, Brockhurst et al. indicate its poor reliability regarding obstetric anesthesia research.[21] We also recorded UA blood gas values and noted no significant difference between groups. Again, the reliability of this test to detect neonatal depression has been questioned.[3435] That is why we employed a combination of several parameters to assess neonatal outcome.  As part of this study, we evaluated the postoperative maternal satisfaction of anesthesia and birth. It is an important outcome that is commonly reported;[253637] since in healthy parturients, a pleasant experience is expected. Furthermore, anxiety may decrease the level of overall satisfaction with perioperative care.[38] In 1998, Robinson et al. highlighted some important factors that may affect satisfaction in the obstetric patient.[36]  The development of a reliable and valid satisfaction scale for cesarean delivery has allowed to assess the effectiveness of sedatives on maternal satisfaction.[22] MSCCS has proven more sensitive than the standard VAS as it samples from the various physiological and psychological factors that make up satisfaction.[39] The reliability of a scale is directly related to the number of its items so that VAS would be expected to be of low reliability.[22]  Our data revealed a remarkable level of maternal satisfaction in the group premedicated with midazolam compared to the control group. To the best of our knowledge, none of the studies concerned with sedatives during cesarean delivery under spinal anesthesia focused on this scale. Instead, Frölich et al. applied a simple questionnaire of three questions while Senel and Mergan and Fung et al. did not focus on this important outcome.  The main limitation of this study was the inability to measure the placental transfer of midazolam and its plasma level in the fetal circulation, due to financial difficulties. However, this had been widely investigated by several authors.[143140] Another limitation is this study only enrolled mild preeclamptic patients. Thus, the extension of these findings to those with more severe features of preeclampsia (and potentially more adverse uteroplacental blood flow) remains to be investigated.

BODY.CONCLUSION:
A dose of 0.035 mg/kg of iv midazolam, administered 30 min before spinal anesthesia, is associated with improved preoperative anxiety, postoperative satisfaction, and maternal hemodynamics in preeclamptic parturients scheduled for elective cesarean delivery, with no adverse effects on the newborn.

BODY.CONCLUSION.FINANCIAL SUPPORT AND SPONSORSHIP:
Nil.

BODY.CONCLUSION.CONFLICTS OF INTEREST:
There are no conflicts of interest.

Question: Compared to equal volume of normal saline, 30 min before spinal anesthesia what was the result of intravenous dose of 0.035 mg/kg of midazolam on preoperative anxiety?
Evidence: Mothers premedicated with midazolam showed a lower level of preoperative anxiety and a higher degree of postoperative satisfaction than the control group.
Answer: significantly decreased