|Ahead of print publication
Intraoperative comparison and evaluation of intrathecal bupivacaine combined with clonidine versus fentanyl in children undergoing hernia repair or genital surgery: A prospective, randomized controlled trial
Kumar Parag, Madhuri Sharma, Hariom Khandelwal, Nidhi Anand, Nishith Govil
Department of Anesthesiology and Critical Care, Shri Guru Ram Rai Institute of Medical and Health Sciences, Dehradun, Uttarakhand, India
HN 93 C5, Ashima Vihar, Turner Road, Dehradun, Uttarakhand
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Nowadays, spinal anesthesia is commonly being used in infants and children for infraumblical surgeries. Intrathecal adjuvants such as clonidine and fentanyl are used with local anesthetics for additive effects. Aim: The present study aims to assess and compare the effects of adding clonidine versus fentanyl to bupivacaine intrathecally in terms of propofol consumption, hemodynamic profile, adverse events, and complications intraoperatively in pediatric patients. Settings and Design: A prospective randomized controlled trial was conducted between June 2016 and October 2018 in pediatric patients aged 3–8 years undergoing hernia repair or genital surgery under spinal anesthesia after approval of the Institutional Ethical Committee (Reference No: SGRR/IEC/04/16). Materials and Methods: Patients were randomly divided into two equal sized (n = 42) study groups, while analysis was done in (n = 40) each group. Group 1 (BC) received clonidine 1 μg/kg with 0.5% bupivacaine (heavy) and Group 2 (BF) received fentanyl 0.5 μg/kg with 0.5% bupivacaine (heavy). Statistical Analysis: Quantitative data were expressed in mean and standard deviation. Qualitative data were expressed in proportion and percentages. Independent t-test was applied to compare the means of quantitative data, and Chi-square test was used to compare categorical data. P < 0.05 was considered statistically significant. Results: Patient characteristics regarding age, weight, and surgical time were comparable in the two groups. The maintenance dose and bolus dose of propofol consumed during surgery were less in Group 1 than that in the Group 2 and were found to be statistically insignificant. The values of hemodynamic parameters such as heart rate, systolic blood pressure, and diastolic blood pressure were less in Group 1 and were statistically significant at different time intervals. Sedation scores were comparable in both groups. Intraoperative incidence of bradycardia, systolic hypotension, and diastolic hypotension were high in Group 1, whereas the incidence of desaturation was high in Group 2. Intraoperative complications such as apnea and respiratory obstruction were high in Group 2, but were statistically insignificant. Conclusion: We conclude that intrathecal adjuvant fentanyl maintains a better hemodynamic profile in terms of adverse events such as bradycardia, systolic hypotension, and diastolic hypotension. Intrathecal clonidine maintains a better sedation level requiring less propofol for sedation. Complications such as apnea and respiratory obstruction can be attributed more to the deep sedation caused by bolus of propofol rather than the inherent properties of intrathecal adjuvant clonidine or fentanyl.
Keywords: Bupivacaine, children, genital surgery, hernia repair surgery, intrathecal clonidine, intrathecal fentanyl, spinal anesthesia
|How to cite this URL:|
Parag K, Sharma M, Khandelwal H, Anand N, Govil N. Intraoperative comparison and evaluation of intrathecal bupivacaine combined with clonidine versus fentanyl in children undergoing hernia repair or genital surgery: A prospective, randomized controlled trial. Anesth Essays Res [Epub ahead of print] [cited 2019 May 26]. Available from: http://www.aeronline.org/preprintarticle.asp?id=255416
| Introduction|| |
Pediatric regional anesthesia is an age-old concept., However, in the past three decades, spinal anesthesia has gained immense popularity in newborns, infants, and children, especially for surgeries involving lower abdominal, perineal, urogenital, and lower extremities., It produces profound and uniformly distributed sensory block with rapid-onset and good muscle relaxation with minimal physiological alterations. Spinal anesthesia has been recommended for ex-premature infants at high risk for postoperative apnea after general anesthesia, and it has been specially recommended in conditions associated with intestinal obstruction, respiratory tract infection, and patients with a full stomach. Further, it has been shown that postdural puncture headache occurs less frequently in children as compared with adults.
Bupivacaine alone in spinal anesthesia provides a block which is of shorter duration in children. Therefore, to prolong the duration of spinal anesthesia, several adjuvants such as clonidine, morphine, and fentanyl are added to bupivacaine.
Clonidine is a centrally acting agent and stimulates alpha-2 adrenergic receptor which by various mechanisms causes sedative, sympatholytic, and anxiolytic effects. Intrathecal clonidine also acts on the dorsal horns of the spinal cord by acting on alpha-2 adrenergic receptors, leading to antinociceptive effect.
As fentanyl is a highly lipophilic drug, it has a rapid onset of action when used intrathecally. It provides more intense analgesia than the intravenous (IV) route and has the advantages of simplicity of administration and reliability and has been shown to improve the quality of intraoperative analgesia.
Propofol is required for sedation to prevent bodily movements and upper torso while doing lumbar puncture and during surgery, respectively. In a previous study, it has been shown that propofol requirement is less for sedation when fentanyl is used as an adjuvant in adults during spinal anesthesia. A study done on infants showed significantly less requirement of propofol maintenance infusion for sedation in bupivacaine-clonidine group as compared to bupivacaine-fentanyl group.
To our knowledge, no study has been done which compares and evaluates intrathecal adjuvants such as clonidine versus fentanyl in children (3–8 years) intraoperatively.
With this background, we conducted a prospective randomized controlled trial in children receiving fentanyl versus clonidine as adjuvants in spinal anesthesia to quantify propofol requirement, hemodynamic effects, sedation, adverse events, and complications intraoperatively.
| Materials and Methods|| |
We conducted this randomized controlled trial after approval from the Ethical Committee of our institute (Reference No: SGRR/IEC/04/16). The study was done from June 2016 to October 2018. The study was carried out in the American Society of Anesthesiologists (ASA) physical status Class 1 of either sex aged between 3 and 8 years posted for inguinal hernia repair or genital surgery (orchidopexy, chordee correction, and circumcision). Children aged 3–8 years were divided into two groups of 42 patients each using a randomization chart. However, forty patients in both the groups were analyzed. Exclusion criteria were spinal deformity, neurological disorder, history of bleeding disorder, heart disease, and any local infection at the site of injection.
Children were kept fasted as per the ASA guidelines. According to the ASA guidelines, minimum fasting periods for ingested materials are as follows: clear liquids 2 h, breastmilk 4 h, infant formula 6 h, nonhuman milk 6 h, light meal 6 h, and heavy meal (fried or fatty food) 8 h. All children were premedicated with oral midazolam 0.5 mg/kg half an hour before the surgery. EMLA cream was applied over the dorsum of the hand and on the back 1 h before the procedure. After shifting the child to the operation theater, monitoring (Patient monitor: MP50 IntelliVue, PHILIPS Healthcare, Amsterdam) of oxygen saturation, electrocardiogram, noninvasive blood pressure, respiratory rate, and end tidal carbon di oxide was done in all patients.
Once a baseline recording was recorded, the child was sedated with injection propofol 2.0 mg/kg bolus followed by an infusion of 50 μg/kg/min. Sedation level was assessed by using a 5-point sedation score: 1 – alert, 2 – drowsy, 3 – mildly sedated, 4 – moderately sedated, and 5 – unarousable. A score of 3 was considered adequate for lumbar puncture.
After a sedation score of 3 was achieved, the child was placed in lateral decubitus position, with lower extremities flexed and neck extended. For lumbar puncture, the overlying skin was cleaned thrice with povidone-iodine in cephalic to caudal direction in the midline and radially outward and was allowed to dry. The patient's back was draped with a sterile towel. The highest part of both iliac crests was palpated, and the line joining the two (Tufflier's line) corresponds to the fifth lumbar vertebra in children. The procedure was performed with a 50-mm 25G Sprotte paediatric spinal needle (PAJUNK, Germany) at L3/L4 or L4/L5 intervertebral space by midline approach. After obtaining free flow of cerebrospinal fluid (CSF) through the needle, the needle was advanced 1 mm more to avoid accidental injection into the subdural space. After confirmation of the free flow of CSF, the test drug was injected slowly to avoid excessive spread of the block. The dose of bupivacaine was based on a previous study which is <10 kg: 0.5 mg/kg and 10–20 kg: 0.4 mg/kg and >20 kg: 0.3 mg/kg.
The drug for spinal injection was prepared by one of the anesthesiologists who was not involved in the study, making it observer blind. Group 1 (BC) received clonidine 1 μg/kg with 0.5% bupivacaine (heavy), and Group 2 (BF) received fentanyl 0.5 μg/kg with 0.5% bupivacaine (heavy).
Immediately after the spinal block, children were turned to supine position. The level of sensory block was determined by attempting to elicit a grimace/acknowledgment of pain to bilateral pinprick at each dermatome. A block level of T10 was considered adequate for the hernia and genital surgery. After the level was achieved, surgery was started. Oxygen was supplemented through ventimask at a flow rate of 4 L/min.
Any movement of the child during the surgery was stopped by giving a bolus dose of 1 mg/kg propofol. The number of boluses administered during the surgery was noted. In case of deep sedation, propofol infusion was stopped and was titrated between 0 and 50 μg/kg/min to maintain a sedation level of 3. Maximal dose of propofol infusion used in our study was 50 μg/kg/min. Heart rate, systolic blood pressure, diastolic blood pressure, respiratory rate, saturation values, and sedation scores were noted at baseline, during sedation for lumbar puncture, during lumbar puncture, and thereafter every 5 min till 70 min after the start of surgery even if surgery ended before. All the surgeries in both groups ended by 70 min. At the end of the 70 min, propofol infusion was stopped and maintenance dose of propofol infusion used was recorded. After the child became conscious and crying to painful stimuli, it was shifted to the recovery room.
Heart rate <60 beats/min (bradycardia), systolic blood pressure <20% from the baseline (hypotension), and saturation values <94% (desaturation) were considered adverse events, and episodes of apnea (lasting longer than 15 s) and airway obstruction were considered the main intraoperative complications and were noted. Apnea was managed by stopping sedation and bag and mask ventilation, airway obstruction by maneuver-like jaw thrust, chin lift or inserting an oropharyngeal airway, bradycardia by IV atropine 0.02 mg/kg, hypotension by fluids, vasopressor IV mephentermine 0.1 mg/kg, and desaturation by mask ventilation with 100% saturation.
The sample size was computed considering a decrease of 5% in propofol maintenance dose in the clonidine group. For an alpha error of 5% and 7% margin of error, the sample size of forty patients was required for study in each group. Considering 5% dropout after randomization, 42 patients were recruited in each group. The data collected from eighty participants were entered in Microsoft Excel version 2016. Results of parametric variables were expressed as the mean and standard deviation (SD). Nonparametric data such as sedation scores were expressed as the median and interquartile range (IQR). Age, weight, and duration of surgery were sought by using Student's t-test. Heart rate, systolic blood pressure, diastolic blood pressure, and respiratory rate at different time intervals were compared between the groups by using Student's t-test. Qualitative data were expressed in proportion and percentages, Chi-square test was used to compare categorical data. P < 0.05 was considered statistically significant. Graphs were formed using Excel software.
| Results|| |
In this study, 84 patients were randomized; however, eighty patients were analyzed, with forty patients each in bupivacaine-clonidine group and bupivacaine-fentanyl group as illustrated in the consort flowchart [Figure 1].
Patient characteristics regarding age and weight were comparable in the two groups. There was no significant difference between the groups regarding the duration of surgery [Table 1].
|Table 1: Demographic data, duration of surgery, and mean propofol maintenance infusion dose in Group 1 and Group 2 with P values|
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Propofol requirement intraoperatively
The average requirement of dose of propofol infusion in Group 1 (BC) was 44.75 ± 8.4 μg/kg/min as compared to 47.38 ± 10.2 μg/kg/min in Group 2 (BF). The difference in both groups was not statistically significant [Table 1]. The number of boluses required in Group 1 was less than that in Group 2. In Group 2, 15 patients required one bolus, whereas in Group 1, ten patients had demand of one bolus. Seven patients in Group 2 required two bolus, whereas three patients in Group 1 received two bolus of propofol during surgery. P =0.17 was considered statistically insignificant [Table 2].
|Table 2: Number of propofol doses in response to movements in Group 1 and Group 2 with P values|
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Hemodynamics and respiration
Baseline heart rate, systolic blood pressure, diastolic blood pressure, and respiratory rate were comparable in both the groups.
The intraoperative (mean ± SD) heart rate was significantly less (P < 0.05) from 10 to 40 min after skin incision in Group 1 (BC) than in Group 2 (BF). Mean heart rate was also significantly less at 65 and 70 min after the start of surgery [Figure 2].
|Figure 2: Mean heart rate in Group 1 and Group 2. Bar represents standard deviation. *Significantly higher (P < 0.05) mean heart rate in Group 2 at different time intervals|
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Systolic blood pressure
Intergroup comparison of systolic blood pressure (mean ± SD) was done at various time intervals. Systolic blood pressure was comparable at all time intervals between the groups except at 5, 45, and 50 min after the start of surgery, which was significantly less in Group 1 (BC) (P = 0.04, 0.00, and 0.01, respectively) [Figure 3].
|Figure 3: Mean systolic blood pressure in Group 1 and Group 2. Bar represents standard deviation. *Significantly higher (P < 0.05) mean heart rate in Group 2 at different time intervals|
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Diastolic blood pressure
Intergroup comparison of diastolic blood pressure (mean ± SD) was done at various time intervals. Diastolic blood pressure was significantly less at 45 min after skin incision during surgery in Group 1 (P = 0.00). At other time intervals, it was comparable between the groups [Figure 4].
|Figure 4: Mean diastolic blood pressure in Group 1 and Group 2. Bar represents standard deviation. *Significantly higher (P < 0.05) mean heart rate in Group 2 at different time intervals|
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Significant difference in respiratory rate (mean ± SD) was observed between the groups at 15, 20, 50, and 60 min after the start of surgery. In Group 1, respiratory rate was significantly less at 15 and 20 min (P = 0.01 and 0.00, respectively), whereas it was significantly less in Group 2 at 50 and 60 min (P = 0.03 and 0.04, respectively).
Sedation scores (median [IQR]) were assessed by a 5-point sedation scale. Sedation scores were comparable in both the groups at different time intervals as propofol was titrated according to sedation to maintain it not <3 [Table 3].
|Table 3: Five-point sedation score (median [interquartile range]) with consolidated P values|
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The incidence of bradycardia, systolic hypotension, and diastolic hypotension was high in Group 1. Three patients had bradycardia (<60/min) in Group 1, while none had bradycardia in Group 2.
In Group 1, six patients had one episode and two patients had two episodes of systolic hypotension, whereas, in Group 2, four patients had one episode and one patient had two episodes of systolic hypotension according to the definition of systolic hypotension.
Diastolic hypotension was also more in Group 1. Intraoperative desaturation (<94%) was more common in Group 2. None of the parameters reached statistically significant values (P > 0.05) [Table 4].
The incidence of apnea and respiratory obstruction was more common in Group 2. Eight patients had apnea in Group 2, whereas three episodes were seen in Group 1. The incidence of respiratory obstruction was more common in Group 2 (four patients) compared to Group 1 (two patients). None of the values were statistically significant [Table 5] and [Table 6].
|Table 5: Incidence of intraoperative complications (apnea) with P values|
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|Table 6: Incidence of intraoperative complications (respiratory obstruction) with P values|
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| Discussion|| |
Spinal anesthesia is finding a place in pediatric day-care anesthesia as an alternative to general anesthesia. Spinal anesthesia is regarded as a technique of choice in ex-premature, high-risk infants undergoing inguinal herniotomies., It has the advantages of rapid onset, profound sensory and motor block, avoidance of volatile anesthetic agents, avoidance of tracheal intubation, and decrease in the incidence of side effects of systemic opioids.
During surgery under spinal anesthesia, children move the upper part of their torso or cry and need to be sedated to stay calm and quiet. Propofol is close to an ideal sedative agent in pediatric patients as it delivers acceptable sedation that can be easily titrated, provides fast recovery after discontinuation, and has no psychomimetic effect. Most commonly, propofol is used for sedation in pediatrics, and hence we used propofol in our study.
The dose of propofol used for induction of sedation in our study was 2.0 mg/kg. Many bolus doses have been used in previous studies for the induction of sedation. In pediatric critical care department, the dose of propofol used was 2.5 mg/kg bolus followed by 200 μg/kg/min, but hemodynamic adverse effect was seen. In cardiac-catheterization lab study, 1.5 mg/kg bolus of propofol was used. Singh et al. in their study on children used 2 mg/kg for induction and 1 mg/kg bolus in response to movements during surgery under spinal anesthesia. In our study, we also used the same bolus dose in response to the movements during surgery as used by Singh et al. In other studies, propofol maintenance dose of 25–50 μg/kg/min was used in infants and that of 20–50 μg/kg/min was used in children. In our study, we used propofol maintenance dose of 0–50 μg/kg/min titrated according to sedation and hemodynamics.
Our study revealed that intraoperatively, Group 1 (BC) required less boluses of propofol as bodily movements were less because the sedation was well maintained throughout the surgery in comparison to Group 2 (BF) though it was statistically insignificant. In Group 1, propofol infusion maintenance during surgery was less than that in Group 2; however, it was not statistically significant. In a study done by Batra et al. in infants undergoing lower abdominal surgeries, the authors revealed that propofol maintenance infusion dose was less in bupivacaine-clonidine group as opposed to bupivacaine-fentanyl group. Cao et al. in their study demonstrated that the combined intrathecal or IV clonidine with bupivacaine similarly provides better sedation and lesser propofol consumption in comparison to when bupivacaine was used alone intrathecally in children aged 6–8 years.
Lesser requirement of propofol in Group 1 can be attributed to the fact that clonidine has inherent sedative property. Clonidine is a selective α2 receptor agonist which causes stimulation of these receptors in locus coeruleus inside the brain. It has the property to act directly on the central nervous system with more cephalic migration through intrathecal route compared to fentanyl as fentanyl is more lipophilic and restricts itself at the spinal level, limiting cephalic migration. Although clonidine and fentanyl both have sedative effect, they do not yield the desired sedation that can keep the child calm intraoperatively, thus necessitating an additional sedative agent. We used clonidine at a dose of 1 μg/kg/min as it has been found to be safe in adolescents. Other studies also used the same dose in infants and children. Intrathecal fentanyl of 0.5 μg/kg/min was used in previous studies.
Sedation scores were comparable in both the groups as propofol bolus was administered on movement. Thus, sedation was maintained at 3 or more than 3 on the 5-point scale of sedation at all times intraoperatively.
Fentanyl and clonidine are the most common adjuvants used in spinal anesthesia both in adults and children. Numerous literatures are available in which clonidine or fentanyl has been used as an adjuvant in caudal or epidural blocks. Intrathecal fentanyl produces analgesia, increases the duration of analgesia, and enhances the quality of analgesia during sac traction in patients undergoing inguinal hernia repair. It increases the incidence of sedation and side effects such as nausea, retching, and pruritus in a dose-dependent manner.
Intrathecal clonidine produces profound analgesia and prolongs the time to regression of the sensory block and recovery of motor block, decreasing the need of rescue analgesia compared to intrathecal fentanyl. It also produces better sedation scores intraoperatively as well as postoperatively. However, hemodynamic instability is more of concern with clonidine as the incidence of bradycardia and hypotension is increased with increasing intrathecal doses.
Cardiovascular alterations, bradycardia, and hypotension are normal physiological responses during spinal anesthesia because of the sympathetic fiber block. Infants tolerate spinal anesthesia with minimal overall autonomic changes. In children, the cardiovascular stability has been good. As we know clonidine is a centrally acting agent and intrathecal clonidine migrates readily into the brain and stimulates central α2 receptor, which reduces the amount of norepinephrine release and decreases sympathetic outflow to the heart and vasculature, leading to decreased heart rate and decreased peripheral vascular resistance, thus decreasing blood pressure. Whereas fentanyl is highly a lipophilic drug, it has rapid onset of action when used intrathecally and gets fixed to the dermatome. Most of the effects of intrathecal fentanyl on cardiovascular system are by absorption of the drug into systemic circulation as opposed to clonidine which has a direct central effect. In our study, we found that the mean heart rate was less in Group 1 compared to Group 2, which was statistically significant from 10 min up to 40 min after skin incision. In three children in Group 1 and none of the children in Group 2, heart rate went up to 60 (bradycardia), thus rescue atropine was used in Group 1.
The mean intraoperative systolic blood pressure and diastolic blood pressure were lower in Group 1 than that in Group 2 and were significant at different time intervals. A few patients in both the groups had episodes of hypotension which were well managed by fluids, and none of the child required vasopressor. Barring a few episodes of bradycardia in Group 1 and a few systolic and diastolic hypotension in both the groups, the overall hemodynamic stability was well maintained. In a study done by Kokki et al., one patient had required atropine to treat bradycardia and another child required ephedrine to treat hypotension. No patients in our study required atropine or mephentermine. In another study done by Kokki and Hendolin, the authors had found a 2% incidence of bradycardia and 4% incidence of hypotension. They had used atropine to treat bradycardia and fluids for treating hypotension. In Sartorelli et al.'s study, one infant had apnea and two infants had bradycardia out of 142 patients.
It has been recommended that the saturation values remain above 94%. There were more episodes of desaturation in Group 2 when compared to Group 1. Most of the desaturation episodes were seen when the propofol bolus was administered in response to the movement intraoperatively. No patient, however, had a SpO2 below 90% at any time. The incidence of oxygen supplementation was more in Group 2 as compared to Group 1. In a study by Kokki et al., in 10% of the patients, SpO2 decreased below 90%.
Complications such as apnea and respiratory obstruction were more frequent in Group 2. These complications occurred just after boluses of propofol were administered in response to movement, leading to deep sedation. This emphasizes the necessity for intraoperative respiratory monitoring and administration of supplementary oxygen in all patients under regional anesthesia with sedation. We, in our study, had monitored ventilation by end-tidal carbon dioxide monitor using a nasal adaptor which measured the respiratory frequency and the EtCO2 partial pressure.
We restricted our maintenance dose of propofol up to a maximum of 50 μg/kg/min and administered bolus in response to the movement during surgery. These bolus doses might have led to the complication such as desaturation, apnea, and respiratory obstruction seen during the surgery.
| Conclusion|| |
We conclude that intrathecal adjuvant fentanyl maintains a better hemodynamic profile in terms of adverse events such as bradycardia, systolic hypotension, and diastolic hypotension. Intrathecal clonidine maintains a better sedation level requiring less propofol for sedation. Complications such as apnea and respiratory obstruction can be attributed more to the deep sedation caused by bolus of propofol rather than the inherent properties of intrathecal adjuvant clonidine or fentanyl.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]