Caudal Analgesia for Hypospadias in Pediatrics: Comparative Evaluation of Adjuvants Dexamethasone and Dexmedetomidine Combination versus Dexamethasone or Dexmedetomidine to Bupivacaine: A Prospective, Double-Blinded, Randomized Comparative Study.

BACKGROUND: Caudal block is the most commonly used regional anesthetic technique in pediatric surgeries; different additives have been used for better and safer outcome. AIM: The aim of this study is to compare the combination of dexamethasone and dexmedetomidine as adjuvants to bupivacaine versus using each agent solely with bupivacaine in pediatric caudal block as regards their efficiency in pain relief (the duration of postoperative analgesia, first time to request analgesia, and modified objective pain score [MOPS]). STUDY
DESIGN: This was a prospective, double-blinded, randomized study. PATIENTS AND METHODS: Patients and
Methods: Sixty-three children scheduled for hypospadias surgery wererandomized into three groupsaccording to the adjuvant drug added to caudal bupivacaine : Group I (n = 21): dexamethasone 0.1 mg/kg + 0.5 mg/kg bupivacaine 0.25%, Group II (n = 21): dexmedetomidine0.01 μg/kg + 0.5 mg/kg bupivacaine 0.25% and Group III (n = 21): dexamethasone 0.1 mg/kg + dexmedetomidine 0.01 μg/kg + 0.5 mg/kgbupivacaine 0.25%. Intraoperative and postoperative hemodynamics were recorded. In postoperative anesthesia care unit and then the ward, MOPS and sedation score were recorded at 30 min and 1, 2, 3, 6 and 12 h. Further, the time of first analgesic request and side effects were recorded. STATISTICAL ANALYSIS: Categorical data were presented as frequencies (%) and analyzed using Chi-square test. Continuous data were presented as mean (standard deviation) and median (quartiles). Continuous data were analyzed using one-way analysis of variance for single measures and two-way mixed model for repeated measures. Kaplan-Meier analysis was performed for the duration of analgesia.
RESULTS: In Group III, MOPS was lower than Groups I and II at the study times. Further, Group III had prolonged time for first request of analgesic. Sedation scores were prolonged in Group III and Group II than in Group I. There was a reduction in heart rates in Group III more than Group I and Group II but with no significant difference. However, there was a significant reduction in mean arterial blood pressure 30 min intraoperatively and postoperatively in Group III as compared to Groups I and II.
CONCLUSION: The addition of combined dexmedetomidine at a dose of 1 μg/kg and dexamethasone 0.1 mg/kg to caudal bupivacaine seemed to be an attractive alternative to each drug if used alone with more prolonged analgesia and almost no adverse effects.

INTRODUCTION

Pain is defined as an unpleasant sensation. It is a subjective feeling which cannot be easily measured, thus making it extremely difficult to be expressed in children who depend on their parents or care providers.[1]

Various methods have been used for postoperative pain relief in children undergoing surgical procedures, for example, opioids; however, the chance of serious side effects limits their use in this age group. A caudal block is a commonly used regional route for pediatric infraumbilical surgeries; it is widely used for intraoperative as well as postoperative analgesia. It is safe, is simple, and has a high success rate. However, the main disadvantage is its limited duration of action. For this reason, various adjuncts have been added to the caudal block to extend its postoperative analgesic time, for example, fentanyl, neostigmine, clonidine, and most recently dexamethasone and dexmedetomidine.[23]

Dexamethasone has various perioperative uses, mainly to reduce inflammation and to prevent nausea and vomiting.[45] Another useful use for dexamethasone is the synergistic analgesic effect when added to local anesthetics epidurally that reduce postoperative analgesic needs. Different theories attempt to explain its analgesic effects. One theory stated that dexamethasone might have a direct local anesthetic effect on the nerve.[67]

While dexmedetomidine is an alpha 2 agonist which has sedative, analgesic, and opioid-sparing effect.[8] It prolongs the duration of analgesia by its local vasoconstrictive effect and by increasing the potassium conductance in A-delta and C-fibers.[910] It also exerts its analgesic action centrally via systemic absorption or by diffusion into the cerebrospinal fluid and reaches alpha 2 receptors in the superficial laminae of the spinal cord and brainstem[11] or indirectly activating spinal cholinergic neurons.[12] The sedative effects of dexmedetomidine are mostly due to stimulation of the alpha 2 adrenoceptor in the locus coeruleus.[13]

To the best of our knowledge, this is the first study to investigate the combination of both dexmedetomidine and dexamethasone as adjuncts to local anesthetics in the pediatric caudal block. We compared each adjuvant solely with bupivacaine and their combination with bupivacaine to detect which one had the best result regarding pain relief and adverse effects.

The aim of this study is to compare the combination of dexamethasone and dexmedetomidine as adjuvants to bupivacaine versus using each agent solely with bupivacaine in the pediatric caudal block as regards their efficiency in pain relief (the duration of postoperative analgesia, first time to request analgesia, and modified objective pain score [MOPS]), and also the effect of each drug used alone or in combination with hemodynamics, sedation, and safety in the first 12 h postoperatively.

PATIENTS AND METHODS

A prospective, randomized double-blinded clinical study was conducted at Abu El-Reesh Pediatric Hospital, Cairo University, from December 2015 to February 2017. After approval of the ethical committee, written informed consent is obtained from the parents of the patients or their guardians; 63 patients with American Society of Anesthesiologists Physical Status Classes I and II aged from 1 to 6 years scheduled for hypospadias surgery. Patients with contraindications to caudal anesthesia (coagulopathy, deformities of the spine), cardiovascular diseases, drug allergies, or type I diabetes, mentally retarded children, or those patients whose families did not approve participating in the study were excluded from the study. Patients were randomly divided in the morning of surgery into three groups: Group I (dexamethasone, 21 patients), Group II (dexmedetomidine, 21 patients), and Group III (dexmedetomidine and dexamethasone, 21 patients). The patients were allocated to study groups using computer-generated random list, and group assignment was sealed in sequentially numbered opaque envelopes that were opened after induction of anesthesia by a blinded to the study nurse. The anesthesiologist interviewed the guardians, examined the patients, and checked all routine investigations including complete blood count, coagulation profile, liver function tests, renal function tests, blood grouping, chest X-ray, and recent if available proper assessment of the airway. Food was not allowed 6 h before surgery, but clear fluid was allowed up to 2 h before surgery.

In the operating room, the standard monitors including pulse oximetry, electrocardiogram, pericardial stethoscope, and noninvasive blood pressure were applied. The 22-gauge cannula was inserted. Fluids (dextrose saline) were warmed and given at 10 ml/kg. Body temperature was measured by oropharyngeal temperature probe and maintained between 36°C and 37°C using warm mattress and warm fluids. All patients received general anesthesia by the face mask sevoflurane 6% and 100% oxygen followed by orotracheal intubation of appropriate size and maintained by spontaneous ventilation with 100% O2 at 2% sevoflurane. The patient was tilted on his lateral side, and caudal anesthesia was done under complete aseptic condition using 5-cm short-beveled 22-gauge needle, and by the loss of resistance technique, the injection was done after aspiration to exclude intravascular injection. The patients were divided into three groups (21 patients for each) and the anesthesiologist was blinded for the contents of the syringe presented to him for the caudal block.

Group I (dexamethasone group): In this group the patientsreceived 0.5 mg/kg of bupivacaine 0.25% + 0.1 mg/kg dexamethasone caudally. (Medical Union Pharmaceuticals, Egypt)

Group II (dexmedetomidine group): In thisgroup, the patients received the same mixture ofGroup I0.5 mg/kg of bupivacaine 0.25% + 0.1 mg/kg dexamethasone+ dexmedetomidine (Precedex; AbbotLaboratories, North Chicago, IL, USA) (1 μg/kg)caudally

Group III (combination group): In this group, the patients received the same mixture and doses of Group I + dexamethasone (0.1 mg/kg) and dexmedetomidine (1 μg/kg) caudally.

After 15 min from the caudal block, the surgical procedure was started. Bradycardia (if heart rate [HR] was <20% of baseline) was treated by atropine 0.02 mg/kg. Hypotension (decrease in basal mean arterial blood pressure [MAP] by 20%) was treated with intravenous (iv) fluid and an incremental dose of ephedrine 5 mg/kg. After the completion of the surgery, the volatile anesthesia was stopped and the patients were extubated when adequate spontaneous ventilation was established. Patients were transferred to the recovery room and then to the surgical ward after fulfilling modified Aldrete's criteria for discharge from the postoperative anesthesia care unit (PACU).

Measurements (timing of measurements compared with results timing)

The demographic data (age, weight, and duration of surgery) were recorded.

The parameters assessed were intraoperative and postoperative HR and MAP at baseline, after induction, after giving caudal block, and every 30 min for 3 h from the start of surgery.

In the PACU, the MOPS[14] was assessed by an anesthesia nurse who was blinded to the study at 30 min, 1, 2, 3, 6, and 12 h in the surgical ward.

The MOPS consists of five parameters: (1) crying (0 = none, 1 = consolable, 2 = non consolable); (2) movements (0 = none, 1 = restless, 2 = thrashing); (3) agitation (0 = asleep or calm, 1 = mild, 2 = hysterical); (4) posture (0 = normal, 1 = flexed, 2 = holds injury site); (5) verbal (0 = asleep or not complaint, 1 = complaint but cannot localized, 2 = complaint but can localize).

If the MOPS >4, the patient was given supplementary paracetamol iv injection (15 mg/kg) as a rescue analgesia.

The first time to require analgesia was recorded (the time from caudal block to the first time to paracetamol injection).

Ramsay sedation score[15] was also assessed at the time of the pain (1 = anxiety and completely awake, 2 = completely awake, 3 = awake but drowsy, 4 = asleep but responsive to verbal commands, 5 = asleep but responsive to tactile stimulus, and 6 = asleep and not responsive to any stimulus).

The adverse effects to be assessed were hypotension, bradycardia, respiratory depression (the SpO2 < 95%), need O2 supplementation, and nausea and vomiting.

Primary outcome was time of the first request of analgesia and pain scores. Secondary outcomes were hemodynamic variables, sedation scores, and short-term side effects detection.

Statistical analysis

The sample size was calculated to detect a mean difference 20% in duration of analgesia (2.4 h) between the study groups. A total number of 62 patients at least were needed to have a study power of 80% and an alpha error of 0.025.

SPSS software (IBM Corp, Armonk, NY) was used for statistical analysis. Categorical data were presented as frequencies (%) and analyzed using Chi-square test. Continuous data were presented as mean (standard deviation) and median (quartiles). Continuous data were analyzed using one-way analysis of variance for single measures and two-way mixed model for repeated measures. Kaplan–Meier analysis was performed for duration of analgesia. A P = 0.05 considered statistically significant.

RESULTS

Sixty-three patients were included in our study and were divided into three groups, each group having 21 patients [Figure 1]. There was no significant difference between three groups with regard to age, weight, and duration of surgery [Table 1], P > 0.05.

Figure 1

Consort chart

Table 1

Patients characteristics, duration of surgery and first time of analgesia

As regards MOPS, there was a significant reduction in pain score in Group III compared to Group I and II at times and 30 min and 1, 2, and 6 h postoperatively with P < 0.01. MOPS increased in Group III more than Groups II and I at 12 h postoperatively with the start of first request of analgesics but with no statistical difference (P = 0.2) [Figure 2].

Figure 2

*P < 0.05 significant difference between Dexmedetomidine group and decadron group, #P < 0.05 significant difference between Combined (dex + decadron) group and decadron group, πP < 0.05 significant difference between Dexmedetomidine group and combined group. T1 ½ h, T2 1hr, T3 2hr, T4 3hr, T5 6hr, T6 12hr postoperatively

There was reduction in HR in Group III more than Groups I and II but with no significant difference (P > 0.05) [Table 2].

Table 2

intraoperative and postoperative hemodynamic measures data presented as mean±SD

As regards MAP, there was a significant reduction in MAP 30 min intraoperatively (T3) and postoperatively (T4) in Group III as compared to Group I and II with P = 0.017 and P < 0.001, respectively [Table 2].

In all groups, HR was higher at baseline (T1), then started to decrease at induction (T2), continued to decrease with lowest reading at T3, and then started to increase slightly postoperatively; however, always, the reading was lower than T1 and T2 with P = 0.01 [Figure 3].

Figure 3

Heart rate changes at different times in each group. Data expressed as mean ± standard deviation. T1 Baseline, T2 at induction, T3 30 min intraoperative, T4 postoperative

As regards MAP, the highest reading was at T1, then started to decrease at T2, continue to decrease at T3 to reach the lowest, and then increased slightly at T4, but still lower than T1and T2, P < 0.05 [Figure 4].

Figure 4

Blood pressure changes at different times in each group. Data expressed as mean ± standard deviation. T1 Baseline, T2 at induction, T3 30 min intraoperative, T4 postoperative

In all groups, the changes in HR and MAP showed a significant difference in relation to time with P < 0.01 [Table 3].

Table 3

Hemodynamic changes at different times in three study groups

As regards sedation, sedation score (Ramsay score) was higher in Groups II and III than Group I at 30 min, and 1, 2, 3, 6, and 12 h postoperatively which was statistically different, P < 0.01 [Figure 5].

Figure 5

Sedation score between three groups at different study times. Data expressed as median (interquartile range). T1 ½h, T2 1 h, T3 2 h, T4 3 h, T5 6 h, T6 12 h postoperatively

Group III was the last group to request analgesia, longer than Groups I and II, which was statistically significant. P < 0.01 as presented in Kaplan–Meier graph [Figure 6].

Figure 6

Kaplan–Meier graph presenting first time to analgesia difference between the three groups

As regards postoperative complications, one patient in Group III had bradycardia – which is defined as 20% decrease in HR from the baseline reading – while two patients had bradycardia in the other two groups but with no significant difference, P = 0.79 [Table 4].

Table 4

Postoperative complications data expressed as count and percentage

Two patients in Group II had hypotension which is defined as 20% decrease in MAP from the baseline reading, while only one patient in Group III and no one in Group I with no significant difference, P = 0.034 [Table 4].

Only in Group I, two patients had nausea and vomiting with no statistical significance, P = 0.12. None of our patients experienced respiratory depression [Table 4].

DISCUSSION

In our study, the degree of pain was evaluated by MOPS, which was significantly better in Group III at times, 30 min, and 1, 2, and 6 h postoperatively with P < 0.01. However, the MOPS started to increase at 12 h in all groups, especially Group III, compared to the previous scores in the same group but with no statistical difference (P = 0.2) as presented in Kaplan–Meier graph. However, it showed highly significant reduction in pain score in Group III in all study times as compared to Group I and II.

First request of analgesia and analysis of pain score showed the lowest pain scores in Group III with prolonged duration of analgesia followed by Group II and Group I (11.3 ± 3.5 h versus 7.4 ± 1.5 h and 4.5 ± 2.8 h, respectively) with P < 0.01. We observed that the combination of both adjuvants had a synergistic effect to the caudal block, leading to prolonged and satisfactory sensory block.

In agreement with our findings, El-Feky et al.[16] concluded that both dexmedetomidine and dexamethasone added separately to bupivacaine in caudal block prolonged the duration of analgesia and had less pain scores than the fentanyl and control groups in pediatric lower abdominal surgeries.

In addition, a study done by Kim et al.[17] concluded that the addition of dexamethasone to ropivacaine in caudal block in children undergoing orchidopexy prolonged the duration of analgesia and decreased the pain scores.

Another study done by Xiang et al.[18] proved that the addition of dexmedetomidine to caudal bupivacaine could reduce the response to hernial sac traction and could prolong the duration of postoperative analgesia in children undergoing inguinal hernia repair.

The same conclusion reached by Nasr and Abdelhamid[19] and Dutt et al.,[20] where they found that dexmedetomidine added to caudal block in pediatric lower abdominal surgeries prolonged the duration of analgesia and decreased the pain scores when compared to caudal fentanyl added to bupivacaine.

Dexmedetomidine is also known for its strong sedative effect which is mostly due to stimulation of the alpha 2 adrenoceptor in the locus coeruleus[13] unlike dexamethasone which is not known to cause sedation, especially after a single dose. Sedation score analysis of this study has shown that it was higher in Group II more than Group I and III up to 6 h postoperatively with statistical significance.

Two studies support our results, El-Feky et al. and Saadawy et al., respectively, reported prolonged sedation in dexmedetomidine group when added to caudal bupivacaine in pediatric lower abdominal surgeries as compared to caudal dexamethasone bupivacaine or caudal bupivacaine alone.[1621] Anand et al.,[1] who studied the effects of dexmedetomidine added to caudal ropivacaine in pediatric lower abdominal surgeries, proved that dexmedetomidine group achieved significantly lower postoperative pain score with prolonged duration of arousal sedation.

In our study, although the least sedation was reported in the dexamethasone group, yet the analgesic effect was not as satisfactory as the combined dexmedetomidine–dexamethasone group. On the other hand, the sedation score in the combined group was accepted apparently from the effect of dexmedetomidine in the mixture which was also very convenient to the parents as well.

Hemodynamic changes with caudal block and additives combined were closely monitored, and statistically, we foundthat, in Group III, MAP was significantly lower at 30 minintraoperatively with P = 0.017 as well a significant reductionpostoperatively with P < 0.01, in contrast to HR was lowerat 30 mins and postoperatively but with no statistical significance. In all groups, the changes in HR and MAP showed significant difference in relation to time with lowest reading at 30 min intraoperatively with P < 0.01.

There was reduction of HR and MAP in Group III more than Group II, and finally Group I, in agreement with Nasr and Abdelhamid,[19] who found reduction in HR and MAP in caudal dexmedetomidine group when compared to caudal fentanyl group in pediatric cardiac surgery. This similarity may be explained by the high volume of caudal block used (1.6 ml/kg) while in our study was more due to analgesic effects of both dexmedetomidine and dexamethasone.

In contrast to our results, El-Feky et al.[16] compared the hemodynamic parameters between caudal dexmedetomidine, caudal fentanyl, and caudal dexamethasone in pediatric lower abdominal surgeries and found no statistical difference in this regard; this discrepancy in results may be due to the fact that El-Feky et al. have used a combination of bupivacaine and lidocaine as the local anesthetic in their caudal block.

Three more studies by Mahendru et al.,[22] Dutt et al.,[20] and Mohammed et al.[23] have found contrasting results to our study.

Mahendru et al. compared the intrathecal administration of fentanyl, clonidine, and dexmedetomidine in the lower limb surgeries and found that the mean values of MAP and HR were comparable between the studied groups throughout the intraoperative and postoperative periods but with no statistical difference. The contrast to our study may be related to the different routes used, while we used the extra-dural route for our block. Mahendru et al. have used fixed doses of fentanyl, clonidine, and dexmedetomidine and they used the intrathecal route. Moreover, their study was done in adult patients, while our study was done on pediatric patients.

Dutt et al.[20] compared caudal dexmedetomidine and caudal fentanyl added to ropivacaine in pediatric lower abdominal and lower limb surgery and found no statistical difference. Mohammed et al.[23] studied the effect of caudal dexamethasone or caudal ropivacaine alone in normal labor on HR and MAP and found no statistical difference. The afore-mentioned results fortify that the use of dexamethasone has the least effect on hemodynamics.

Postoperative hemodynamic complications, bradycardia, and hypotension are most common with alpha 2 agonist, but it is less prominent in children than adults, and easily can be managed by volume expansion, sympathomimetic drugs, or both.[2124]

In our study, one patient in Group III experienced bradycardia versus two patients but with no significant difference, P = 0.79.

Two patients in Group II experienced hypotension, while only one patient in Group III, and no one in Group I with no significant difference managed and solved only by volume expansion.

As regards nausea and vomiting, only in Group I, two patients had nausea and vomiting with no statistical significance which was unpredicted as dexamethasone is a potent antiemetic drug; however, it can be explained by inefficient pain relief or oversensitivity to inhalational anesthesia-induced nausea and vomiting. None of our patients suffered respiratory depression, mostly as it is a rare complication in children as well as shivering. They did not experience any other unexpected complications in the first12 h postoperative observation as well.

In agreement with our results, El-Feky et al.[16] showed that the incidence of nausea and vomiting was high with fentanyl group than dexmedetomidine group. Furthermore, Anand et al.[1] found that the addition of dexmedetomidine (2 μg/kg) to caudal ropivacaine had no significant postoperative bradycardia, hypotension, postoperative nausea and vomiting, or respiratory depression in pediatric lower abdominal surgeries.

This study has certain limitations as it was done in a single center for young and healthy children undergoing one type of lower abdominal surgery. The follow-up period was short (12 h postoperative). Hence, the effect of this combined adjuvants in older children with comorbidities undergoing longer and more complicated surgeries needs to be investigated more as well the interval of postoperative side effect observation needs to be prolonged.

We recommend in other studies to record MOPS more frequently (e.g., every 30 min for the first 3 h postoperatively) and use different doses of the combined drugs to obtain the best analgesic effect with least possible side effects.

CONCLUSION

The addition of both dexmedetomidine at dose 1 μg/kg and dexamethasone 0.1 mg/kg to caudal bupivacaine seemed to be an attractive alternative as opposed to each drug alone with more prolonged analgesia and almost no adverse effects.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.