TITLE: 
Comparison of Efficacy of Oral versus Regional Clonidine for Postoperative Analgesia following Ilioinguinal/iliohypogastric Block in Children: A Prospective, Randomized, Double-blinded, Placebo-controlled Study



ABSTRACT.BACKGROUND:
Clonidine improves quality and prolongs the duration of analgesia in ilioinguinal/iliohypogastric nerve block when given along with local anesthetic and as well as premedication. The objective of this study was to compare the efficacy of oral and regional clonidine for postoperative analgesia in pediatric population after ilioinguinal/iliohypogastric block.

ABSTRACT.MATERIALS AND METHODS:
Sixty children aged between 1 and 8 years scheduled for elective hernia surgery were randomly allocated to three groups. Group I received oral midazolam and regional bupivacaine, Group II received oral midazolam with oral clonidine and regional bupivacaine, and Group III received oral midazolam and regional clonidine with bupivacaine. Preoperative sedation and separation score and postoperative duration and quality of analgesia, analgesic need, sedation score, and side effects of clonidine were assessed up to 6 h, postoperatively.

ABSTRACT.RESULTS:
Duration of analgesia was prolonged in Group II (2.83 ± 2.01 h) and Group III (4.43 ± 2.29 h) compared to Group I (3.98 ± 2.58 h), but the difference was not statistically significant (P = 0.161). Analgesic requirement was comparable between all the groups intraoperatively (P = 0.708) and postoperatively (P = 0.644). Group II had better parental separation (P < 0.001) and sedation score (P < 0.001) compared to Group I and III. Postoperatively, patients of Group II and III were more sedated compared to Group I up to 120 min. Adverse effects of clonidine were equally distributed in all the groups.

ABSTRACT.CONCLUSION:
Both oral and regional clonidine was equally efficacious in prolongation of duration and quality of analgesia. Oral clonidine produces better preoperative sedation and parenteral separation which is an added advantage in pediatric population.

BODY.I:NTRODUCTION
Ilioinguinal/iliohypogastric nerve block is widely used in pediatric patients to provide intra- and post-operative pain relief for inguinal hernia repair and orchidopexy surgery.[1] Inguinal field block with wound infiltration has been shown to be superior to general anesthesia for inguinal hernia repair and as effective as or even superior to caudal block.[2] Bupivacaine (0.25%–0.5%) has been used commonly for ilioinguinal/iliohypogastric block which provides postoperative analgesia for 3–6 h.[3] Various adjuvants such as clonidine, epinephrine, ketamine, and fentanyl have been used with local anesthetics to prolong and potentiate analgesia.[4] Clonidine, an imidazoline derivative, is a selective alpha-2 receptor agonist. It has multiple effects such as sedative, analgesic, anxiolytic, anesthetic, and opioid-sparing properties and is effective in hemodynamic maintenance and prevention of emergence agitation.[5] These properties are observed when clonidine is used for oral premedication or as an adjuvant to local anesthetics. When used for oral premedication, clonidine apart from prolongation of postoperative analgesia produces significant sedation, better parental separation, mask acceptance as well as lesser postoperative nausea vomiting (PONV), and shivering when compared to conventional benzodiazepines.[6]
Both oral clonidine as premedicant and regional clonidine with local anesthetic for ilioinguinal block in same doses can produce prolonged postoperative analgesia and sedation. However, there is a dearth of literature comparing the analgesic property and adverse effect profile of these two routes of drug administration of clonidine. The primary objective of the current study was to compare the efficacy of oral versus regional clonidine for postoperative analgesia following ilioinguinal/iliohypogastric block in children. The secondary objective was to find out any adverse events related to oral/regional clonidine administration in children.

BODY.M:ATERIALS AND METHODS
The study was a hospital-based, randomized, double-blinded, prospective trial conducted in the Department of Anesthesiology, Pain Medicine and Intensive Care, All India Institute of Medical Sciences, New Delhi, from May 2012 to April 2014. The study was approved by the Institutional Ethics Committee. Since the study was conducted in pediatric population, consent for participation was obtained from the parents/guardians. They were explained that the participation was voluntary and refusal would not affect adequate anesthesia care. On their approval, written informed consent was obtained from the parents/guardians of the participants. A total of sixty consecutive children belonging to age group of 1–8 years and American Society of Anesthesiologist Grade of I and II (ASA) undergoing inguinal hernia repair in our institute were selected for the study. Children with upper respiratory tract infection, heart diseases, neurological diseases, receiving antiepileptic drugs, cough syrups, antihistamines, analgesics, and contraindication to regional anesthesia were excluded from the study. Since this was the first study of its kind, an arbitrary sample size of sixty was selected taking into consideration, the frequency of pediatric hernia repair surgery in our institute from previous years. Sixty children were divided into three groups, namely, Group I (control), Group II (oral clonidine), and Group III (regional clonidine) of twenty patients each, based on random numbers generated from computer. Group I received oral midazolam (0.5 mg/kg) and regional bupivacaine (0.5%, 0.25 ml/kg), Group II received oral midazolam (0.5 mg/kg) with oral clonidine (4 μg/kg) and regional bupivacaine (0.5%, 0.25 ml/kg), and Group III received oral midazolam (0.5 mg/kg) and regional clonidine (4 μg/kg) with bupivacaine (0.5%, 0.25 ml/kg) [Table 1]. Since oral clonidine is bitter in taste and not easily acceptable by the children, sweet in taste midazolam syrup is added to clonidine in premedication solution to make it easily palatable for children. For the purpose of blinding, saline equivalent to calculated volume of clonidine was added to both premedication and block solution of those children who were not receiving clonidine according to the group allocation [Table 1]. All the drugs were colorless, odorless, and remained transparent even after final preparation. The premedication drugs and study drugs for ilioinguinal block/iliohypogastric block were prepared in separate capped 5 ml plastic syringes and kept into specific boxes according to the groups by one nurse who was not part of the study. Both the surgeon and anaesthetist were blinded to the drug allocation. All the patients were monitored and followed up in the pre-, intra-, and post-operative period up to 6 h. Analysis of the records was done by a biostatistician from our institute who was blinded to the study.
Table 1Group distribution
Premedications were given in the preanesthesia room approximately 30–45 min before the anticipated time of induction by a blinded nurse, who was posted at that time in the preanesthesia room in the presence of parents and guardians. All the children were monitored for oxygen saturation (SpO2), heart rate (HR), blood pressure (BP), and respiratory rate (RR) until they were shifted to the operation theater (OT). Parents were allowed to stay with the children. Before shifting the patient to the OT, sedation and parental separation were assessed using 6-point Ramsay Sedation Scale[7] and Parental Separation Scoring system. Parental separation was assessed by a 4-point scale: 1 = excellent, patient unafraid, cooperative, or asleep, 2 = good, slight fear, and/or crying, but quite with reassurance, 3 = fair, moderate fear and/or crying, not quite with reassurance, and 4 = poor, crying with need for restraint. After shifting the patient to the OT, standard monitoring devices were attached, and baseline vitals were noted (HR, BP, SpO2, and RR). Patients were induced either with propofol (1–2 mg/kg) or thiopentone (3–5 mg/kg) if intravenous access was present or with 7%–8% sevoflurane in 100% O2 and an intravenous access was secured. Vecuronium (100 mcg/kg) was used for neuromuscular blocking thereafter. Airway was managed with laryngeal mask airway (LMA) of appropriate size. Anesthesia was maintained with 50% O2 in nitrous oxide, isoflurane (minimum alveolar concentration 1–1.5), and the ventilation was controlled to maintain EtCO2 within normal limit.
An ilioinguinal/iliohypogastric block was given postinduction. The site of drug injection was selected at the junction of lateral one-fourth and medial three-fourths of the line joining the anterior superior iliac spine to the umbilicus. A 23-gauge, one-inch, short-beveled needle was inserted in the drug injection site at an angle of 45–60°, pointing toward the midpoint of the inguinal ligament until the superficial layer of the external oblique muscle was pierced with a clearly identifiable “loss of resistance”. The study solution was distributed in a fan-shape manner after negative aspiration to blood or peritoneal fluid. The surgery was allowed 10 min after the block.
Intraoperatively, vitals were noted every 5 min. HR and BP were kept within 20% of the baseline by administering fentanyl (0.5 μg/kg) boluses. Injection fentanyl was repeated every 15 min if the HR or BP remained elevated >20% of the baseline. Maximum five boluses of fentanyl were allowed to maintain hemodynamics. Concerned anesthesiologist was allowed to use any other analgesics for pain control and maintaining hemodynamics according to his discretion for those children requiring >5 fentanyl boluses. All intraoperative analgesic supplementations were recorded and analyzed. Any side effects such as hypotension (<20% of baseline) and bradycardia (<20% of baseline) were recorded and treated. At the end of the surgery, LMA was removed after reversing the patient with neostigmine (50 mcg/kg) and glycopyrrolate (10 mcg/kg). Postoperatively, patient was monitored for pain, analgesic requirement, vitals, sedation, and side effects of clonidine such as bradycardia, hypotension, desaturation, shivering, and PONV. The data were recorded at every 30 min for the first 2 h, then in the 4th h and 6th h.
Quality of analgesia was assessed by 10-point visual analog scale (VAS) for children older than 6 years or 10-point Objective Pain Score (OPS)[8] for children <6 years of age. If OPS/VAS score was >4 at or in between the time of recording, fentanyl (0.5 μg/kg) was given and repeated every 15 min till a score of 4 or less was recorded. If pain still was not controlled, other pain management protocols were followed and documented. The duration of analgesia was noted as the time duration between the nerve block and the time for the first requirement of postoperative analgesics. Postoperative sedation was assessed by Ramsey Sedation Score. Children were monitored for common adverse effects (bradycardia, hypotension, shivering, nausea, and vomiting) of clonidine in postoperative period. If HR was <50 beats/min and if bradycardia was associated with hypotension, atropine 10 μg/kg was administered. PONV was treated with injection ondansetron 0.1 mg/kg and recorded.
Descriptive analysis (mean, standard deviation, frequency, and significance) was calculated for all parameters of our study population. Chi-square test was used to determine categorical outcome. Intergroup comparison for continuous variables was assessed using analysis of variance. Post hoc analysis was performed using Bonferroni test. All data were analyzed by Statistical Package for the Social Sciences (SPSS) version 21 (Armonk, NY: IBM Corp). P < 0.05 was considered statistically significant.

BODY.R:ESULTS
A randomized, double-blinded, and prospective study was conducted on sixty ASA I or ASA II children aged between 1 and 8 years, who underwent elective day-care surgery for inguinal hernia. No patients were excluded from the study. All the children accepted the premedication in the presence of their parents and guardians. Intraoperatively, no child required additional analgesic supplementation other than fentanyl. All the children were monitored up to 6 h in the postoperative follow-up period.
All the patients of the three groups who underwent elective inguinal hernia repair surgery were comparable with respect to age, sex, weight, and duration of anesthesia [Table 2]. Time for the first analgesic request was shorter in Group I (2.83 h) compared to Group II (4.43 h) and Group III (3.98 h), but there was no significant difference between the groups (P = 0.161) [Table 3]. Intergroup comparison [Table 4] using post hoc Bonferroni analysis showed a mean difference between Group II versus Group I was 1.60 with 95% confidence interval (CI) ([−0.505] − [3.705]), between Group III versus Group I was 1.146 (95% CI: [−0.958] − [3.252]), and between Group II versus Group III was 0.453 (95% CI: [−1.652] − [2.558]). The quality of analgesia was compared using VAS/OPS scoring. Group I had significantly higher VAS/OPS scores when compared to other two groups at all time points. VAS/OPS score of Group II and Group III were comparable among themselves throughout 6 h of follow-up period [Figure 1]. Group II had best parental separation and sedation score when compared to other groups (P < 0.05). Most of the patients of Group II had a preoperative sedation score of 4 and 5 and separation score of 1 and 2, whereas children of Group I and III had a sedation score of 1 and 2 and separation score of 3 and 4. Group I and III had comparable parental separation and sedation score (P = 1.000 and P = 0.674, respectively) [Table 4]. Analgesic requirement was comparable between all the groups intraoperatively (P = 0.708) and postoperatively (P = 0.644). There was a significant difference of postoperative sedation score between the groups at 0, 30, 60, 90, 120 min postextubation. Children of Group II and III had better postoperative sedation score compared to Group I at the mentioned time points. However, there was no difference in sedation score in between Group II and III. Sedation scores beyond 120 min were comparable between groups [Figure 2]. Hence, those children who received clonidine through either oral or regional route had prolonged sedation in the postoperative period when compared to the control group. Incidence of adverse effects was similar in all three groups [Table 5]. Cumulatively, bradycardia was the most common side effect in all the groups. One patient in Group III and two patients in Group II required atropine administration for postoperative bradycardia leading to hypotension. Few patients in each group developed postoperative shivering, for which warm blankets were applied. PONV was equally distributed in all the groups. Those children who had vomiting received ondansetron just after the episode. There was no further episode of vomiting in any of these children.
Table 2Demographic parameter
Table 3Duration of analgesia, preinduction sedation, and separation score among groups
Table 4Inter group comparison of duration of analgesia, preinduction sedation, and separation scores
Figure 1Trend of visual analog scale scores among groups
Figure 2Postoperative sedation among groups
Table 5Postoperative side effects

BODY.D:ISCUSSION
Primary objective of the study was to compare the efficacy of oral and regional clonidine in postoperative analgesia after ilioinguinal/iliohypogastric block in children. It was also attempted to find out if there were any adverse events due to oral/regional clonidine in children and the efficacy of oral clonidine in providing preoperative sedation and parental separation.
In our present study, clonidine was found to prolong the duration and quality of analgesia in both oral and regional route, but statistically, it could not highlight the preferred route of administration for clonidine. Quality of analgesia and postoperative sedation was also better in groups receiving clonidine, but there was no significant difference between oral and regional route. Oral clonidine increased the duration of preoperative sedation and produced better parental separation; this may be an added advantage in pediatric population. There was no additional side effect due to clonidine use irrespective of its route.
The efficacy of clonidine has been studied in three different doses (2 μg/kg, 4 μg/kg, and 6 μg/kg) in similar studies and 4 μg/kg was found to be more effective with lesser adverse events.[5] Hence, in our study, 4 μg/kg dose was chosen both for oral premedication and ilioinguinal/iliohypogastric nerve block.
There are conflicting reports about the duration of analgesia after ilioinguinal nerve block with clonidine from different studies. The mean duration of analgesia with regional block was less in the study by Kaabachi et al. (93.6 min) when compared to that in the present study (238.8 min).[9] This can be explained by the fact that they have not given any premedication, the effect of which cannot be denied on postoperative pain relief. They used small doses of clonidine (1 μg/kg compared to 4 μg/kg in the present study) and included orchidopexy surgery in the inclusion criteria where ilioinguinal/iliohypogastric nerve block is less effective during cord traction or peritoneum manipulation.[9] Marc Beaussier et al. studied the impact of adding clonidine with ropivacaine in adult inguinal herniorrhaphy under monitored anesthesia care.[10] Time to first request of supplemental analgesics was 10 h (7.1–14.5 h) and 9 h (6.4–>24 h), respectively, in the clonidine and control groups (P = 0.83).[10] Prolonged duration of analgesia in this study may be because of adult population compared to child population; in our study, use of ropivacaine which theoretically has a longer duration of action than bupivacaine and use of intraoperative sufentanil and propofol target controlled infusion. In the study by Ivani et al., the effect of caudal clonidine was compared with regional clonidine in ilioinguinal nerve block.[2] Clonidine produced a longer duration of analgesia in regional nerve block (265 min) when compared to caudal route (160 min). This study showed a better trend for postoperative analgesia following peripheral administration of clonidine when compared to caudal application. The duration of analgesia (265 min) in regional route (ilioinguinal) was comparable to the finding of the present study where the mean duration was 238.8 min.
Quality of analgesia in our study was assessed with10-point VAS or OPS scale depending on the age of the children. VAS is a 10-point subjective pain scale. All children above 6 years were explained about the 0–10 cm VAS for postoperative assessment of pain; 0 was taken as no pain and 10 as the maximum imaginable pain. OPS is a 10-point objective physician rated pain scale, which is suitable for smaller children (even nonverbal children), whereas VAS being a subjective scale, can only be applied for older children.[8] Previous studies have inferred that both VAS and OPS give comparable results while assessing the intensity of pain in the pediatric population. Hence, they can be used interchangeably.[11] For both the scales, analgesic supplementation was done when a score of 4 or more was reported. Both the groups with oral and regional clonidine had significantly lower pain scores as compared to the control group at all times during the 6 h postoperative follow-up period. However, there was no statistically significant difference in pain scores between oral and regional clonidine groups. This finding could not be corroborated due to lack of similar studies comparing regional and systemic routes of clonidine administration
One of the observations from this study was that oral clonidine produced better parental separation and sedation in the preoperative period. It has already been established by multiple investigators that clonidine as oral premedicant causes longer sedation, better parental separation, anxiolysis, and better mask acceptance than benzodiazepines such as diazepam and midazolam.[51213] Clonidine is also known to have the additional advantage of less perioperative sympathetic stimulation and significant postoperative analgesia and sedation.[13] Our study too demonstrated longer postoperative sedation in both the groups where clonidine was used irrespective of its route of administration. Postoperative sedation is particularly beneficial in pediatric population unlike in adult population where clonidine-induced sedation can delay attainment of postoperative discharge criteria.
Anticholinergics are used as a common premedication in the pediatric population. In the present study, anticholinergics were not added in premedication, since they can mask bradycardia, which is the most common adverse effect of clonidine. Secondary objective of our study was to find out any adverse effects associated with clonidine administration. Bradycardia was the most common side effects among the children. However, it was asymptomatic in most of the cases, not found to be associated with hypotension, and did not require any treatment. Similar findings have also been reported from other studies using clonidine.[510] In one such study, it was associated with orthostatic hypotension in the 2nd postoperative h. In the ambulatory setting, this side effect can lead to a prolongation of hospitalization. In the present study, as the study population was children, orthostatic hypotension could not be assessed.[10] Few investigators premedicated the study children with atropine to reduce the incidence of bradycardia.[512] In some previous studies, clonidine was found to reduce postoperative shivering by inhibition of vasoconstriction and a decrease of shivering threshold.[514] In our study, there was no difference in the incidence of postoperative shivering among different groups.
The present study had a few limitations. First, we only followed up the children for 6 h postoperatively. Inguinal hernia repair was a day-care surgery, and all the children were discharged 6 h postoperatively according to hospital protocol. Hence, we could not follow up our children for a longer duration. Observation for larger duration might have revealed differences in postoperative analgesic requirement among the groups. Second, sample size was small and it was a single-centered study. Larger sample size and multicenter involvement may produce outcome with better validation. Finally, ultrasound guidance increases the accuracy of ilioinguinal block and produces a better result than blind drug administration in landmark technique. Ultrasound was not available during the study period in our hospital; hence, we could not take advantage of this novel instrument. However, none of the blocks performed in the study population were considered failure and no child was excluded from the study for this reason.

BODY.C:ONCLUSION
Clonidine enhanced the duration and quality of analgesia in ilioinguinal/iliohypogastric nerve block when used in both oral and regional route. However, oral clonidine was found to have slightly better analgesic efficacy than regional clonidine in terms of duration of analgesia. Addition of clonidine did not increase the risk of side effects in any of the groups. Both the clonidine groups were observed to produce significant sedation in initial 2 h of postoperative period which may be an advantage in pediatric patients though oral clonidine produces better parental separation compared to others. Further large-scale multicentric studies are needed to establish superiority between oral and regional clonidine.
BODY.FINANCIAL SUPPORT AND SPONSORSHIP:
Nil.

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

Question: Compared to oral midazolam and regional bupivacaine or oral midazolam and regional clonidine with bupivacaine what was the result of oral midazolam with oral clonidine and regional bupivacaine  on parental separation and sedation score?
Evidence: Time for the first analgesic request was shorter in Group I (2.83 h) compared to Group II (4.43 h) and Group III (3.98 h), but there was no significant difference between the groups (P = 0.161) [Table 3].
Answer: significantly increased