Effect of caudal block using different volumes of local anaesthetic on optic nerve sheath diameter in children: a prospective, randomized trial

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1 British Journal of Anaesthesia, 118 (5): (2017) doi: /bja/aex078 Paediatrics PAEDIATRICS Effect of caudal block using different volumes of local anaesthetic on optic nerve sheath diameter in children: a prospective, randomized trial B. Lee 1,2, B.-N. Koo 1,2, Y. S. Choi 1,2, H. K. Kil 1,2, M.-S. Kim 1,2 and J. H. Lee 1,2, * 1 Department of Anesthesiology and Pain Medicine, Severance Hospital, 50-1 Yonsei-ro, Seodaemun-Gu, Seoul 03722, Republic of Korea and 2 Anesthesia and Pain Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-Gu, Seoul 03722, Republic of Korea *Corresponding author. NEOGENS@yuhs.ac Abstract Background: Caudal block is commonly administered for postoperative analgesia in children. Although caudal block with 1.5 ml kg 1 local anaesthetic has been reported to reduce cerebral oxygenation in infants, the effect of caudal block on intracranial pressure (ICP) in children has not been well investigated. Optic nerve sheath diameter (ONSD) correlates with degree of ICP. This study aimed to estimate the effects of caudal block on ICP according to volume of local anaesthetic using ultrasonographic measurement of ONSD in children. Methods: Eighty patients, 6- to 48-months-old, were randomly allocated to the high-volume (HV) or low-volume (LV) groups for caudal block with ropivacaine 0.15%, 1.5 ml kg 1 or 1.0 ml kg 1, respectively. Measurement of ONSD was performed before (T0), immediately after (T1), and 10 min (T2) and 30 min (T3) after caudal block. Results: The two groups exhibited significant differences in ONSD according to time (P Group x Time ¼0.003). The HV group exhibited significantly greater changes in ONSD from T0 to T2 and T3 than the LV group. However, in both groups, ONSDs at T1, T2 and T3 were significantly greater compared with those at T0, with the highest values at T2. Conclusions: Caudal block with a high volume of local anaesthetic can cause a greater increase in ICP than caudal block with a low volume of local anaesthetic. However, caudal block with 1.0 ml kg 1 of local anaesthetic can also result in a significant increase in ICP. Clinical trial registration. NCT Key words: anaesthesia, caudal; intracranial hypertension; optic nerve; paediatrics; ultrasonography Caudal block is commonly used for postoperative analgesia in paediatric patients because of its safety and efficacy in all types of surgery below the umbilicus. 1 2 Although a volume of ml kg 1 of local anaesthetic is generally used for caudal block for abdominal incision up to the thoracic dermatomes, 13 a higher volume (1.5 ml kg 1 ) of local anaesthetic has been reported to not only increase the level of cranial spread but also provide better quality and longer duration of analgesia in comparison with the conventional volume (1.0 ml kg 1 ). 4 However, caudal block with a high volume of local anaesthetic reduces cerebral blood flow and regional oxygenation probably by increasing intracranial pressure (ICP) in infants, which raises safety concerns regarding administration of high-volume (HV) caudal block. 5 Editorial decision: February 18, 2017; Accepted: February 23, 2017 VC The Author Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please journals.permissions@oup.com 781

2 782 Lee et al. Editor s key points Caudal block can lead to increases in intracranial pressure. The volume dependence of this effect was investigated in 80 children undergoing urological procedures. Both high (1.5 ml kg 1 ) and low (1.0 ml kg 1 ) volumes of local anaesthetic injected in the caudal space increased intracranial pressure measured as optic nerve sheath diameter. Direct ICP measurement in the ventricle or brain parenchyma (the gold standard method for ICP measurement) is an invasive procedure. 6 Among the non-invasive alternatives for ICP assessment, there is increasing evidence that optic nerve sheath diameter (ONSD) measured by ultrasonography correlates with degree of ICP and is able to detect intracranial hypertension. 7 9 Furthermore, the correlation between ONSD and ICP, and the diagnostic potential of ONSD for the detection of increased ICP (IICP), have been demonstrated in children However, the effects of caudal block on ONSD or ICP have rarely been investigated in paediatric patients. Therefore, this prospective, randomized, double-blinded study aimed to investigate the effect of caudal block on ICP with different volumes of local anaesthetics through ultrasonographic measurement of ONSD in children. Electrocardiography, pulse oximetry, non-invasive arterial blood pressure (NIBP), nasopharyngeal temperature, EtCO 2 measurement and gas analysis were employed as standard monitors. Caudal block Equal numbers of patients were randomly assigned to the HV or low-volume (LV) groups using a computer-generated randomization table ( Randomization and group assignment were performed by the principal investigator (J.H.L.). Three investigators (J.H.L., B.-N.K. and Y.S.C.) administered caudal blocks according to group allocation. The HV and LV groups were administered caudal block with ropivacaine 0.15%, 1.5 ml kg 1 and 1.0 ml kg 1, respectively. After induction of anaesthesia, the sacral cornua and hiatus were visualized by ultrasonography (E-CUBE i7, ALPINION Medical Systems, Seoul, Republic of Korea) in a left lateral decubitus position, and the needle-entry site was identified over the sacrococcygeal ligament between the cornua. The optimal angle for entering the sacral epidural space was measured, and a 5 cm bevelled 22- gauge block needle was inserted into the sacral epidural space. Aspiration test was performed to exclude intravascular placement. Local anaesthetic was then manually injected at a rate <0.5 ml s 1, during which turbulence in the sacral caudal space was analysed on transverse ultrasound images to confirm the spread of anaesthetic into the epidural space. Surgery was Methods Patients This study was approved by the Severance Hospital institutional review board (protocol number: ) and registered at ClinicalTrial.gov (NCT ). Written informed consent was obtained from the parents of all children. Among children undergoing urological surgery at Severance Hospital, 80 patients, 6- to 48-months-old, with body weight 16 kg and treatment plan for caudal block for analgesia, were enrolled. The limit on body weight was set because the maximum volume of local anaesthetic for caudal block in children is restricted to 25 ml. 1 Patients with the following conditions were excluded: symptoms or signs of spinal anomalies or infection at the sacral region; coagulopathy; increased ICP; ophthalmic diseases; history of increased ICP; and expected duration of surgery <30 min. Anaesthesia The procedure for anaesthesia was a modification of the routine anaesthetic protocol for paediatric urological procedures at our institution. Anaesthesia was induced with sodium thiopental (5 mg kg 1 ) (Pentothal sodium, 250 mg ampule 1, JW Pharm., Seoul, Korea) combined with sevoflurane 4% in 100% oxygen delivered through a face mask to ensure sufficient anaesthetic depth for securing the airway with a laryngeal mask. All patients were mechanically ventilated without muscle relaxation agents or opioids in order to maintain kpa of end-tidal carbon dioxide (EtCO 2 ). Anaesthesia was maintained with sevoflurane in a 40% O 2 /air mixture, and the inspired concentration of sevoflurane was adjusted to maintain mean arterial pressure (MAP) within % of the baseline value. Fig 1 Measurement of optic nerve sheath diameter (ONSD) by ultrasonography. Axial images of the orbit were acquired in the plane of the optic nerve. ONSDs were measured 3 mm posterior to the optic nerve head (A B).

3 Caudal block and optic nerve sheath diameter 783 started 15 min after caudal block. Patients who exhibited signs of inadequate analgesia during surgery [limb movement, increase in heart rate (HR) or MAP by >15%, or both] were administered fentanyl 1 2 mgkg 1. Measurement of ONSD ONSD was measured by transorbital sonography by two investigators (B.L. and M.-S.K.) with experience in over 30 cases of ultrasonographic ONSD measurement, who were blinded to group assignment. Transorbital sonography was performed using the E-CUBE i7 ultrasound system and a linear 6 13 Hz probe (ALPINION Medical Systems, Seoul, Republic of Korea) with the power output reduced (mechanical index, 0.2; thermal index, 0) to address safety concerns regarding the possibility of ultrasonic energy-induced eye injury. After applying a thick layer of sterile coupling gel on the closed upper eyelid, the probe was placed gently without exerting pressure. Axial images of the orbit were acquired in the plane of the optic nerve, and ONSD was measured 3 mm posterior to the optic nerve head as described previously (Fig. 1). 15 The required depth parameter was usually cm. Two measurements of each optic nerve sheath were acquired in each eye at the following time points: before (T0), immediately after (T1), and 10 min (T2) and 30 min (T3) after caudal block. The mean value of the four measurements was considered as the ONSD at each time point. In addition, HR, NIBP, EtCO 2 and end-tidal sevoflurane (EtSevo) concentrations, and peak inspiratory pressure (PIP) were assessed and recorded at each time point. Nasopharyngeal temperature was recorded only at T1, T2 and T3. Statistical analysis This study was designed to evaluate whether there would be any difference in ONSD after caudal block according to the volume of local anaesthetic. Based on the findings of a previous study, 15 we considered a difference in ONSD >0.3 mm (10% of mean ONSD in asymptomatic paediatric subjects [mean ONSD 3.08 (SD 0.36) mm]) to be clinically relevant. Considering a significance level of 5% and power of 80%, 31 subjects were required in each group. We decided to enrol 40 patients per group to compensate for dropouts and observational variation. Continuous variables are presented as mean (SD) or median (inter-quartile range), and categorical variables are presented as number (percentile). Patient characteristics and operative data were compared by unpaired t-test, Mann Whitney U-test, v 2 test Assessed for eligibility (n=81) Excluded (n=1) Not meeting inclusion criteria (n=1) Declined to participate (n=0) Randomized (n=80) Allocated to high-volume group (n=40) Received allocated intervention (n=40) Allocated to low-volume group (n=40) Received allocated intervention (n=40) Lost to follow-up (n=0) Discontinued intervention (n=0) Lost to follow-up (n=0) Discontinued intervention (n=0) Analysed (n=40) Analysed (n=40) Fig 2 Flow diagram of the study.

4 784 Lee et al. Table 1 Subject characteristics and operative data. Values are presented as median (inter-quartile range), mean (SD) or number of subjects High volume Low volume P-value Age (months) 14 (11 23) 13 (10 26) Height (cm) 81.3 (7.8) 84.5 (10.2) Weight (kg) 10.7 ( ) 10.9 ( ) Body mass index (kg m 2 ) 16.5 (1.8) 15.9 (1.9) ASA physical status (I/II) 38/2 38/2 >0.999 Anaesthesia time (min) 70 (60 74) 63 (50 75) Operation time (min) 40 (30 45) 35 (20 44) Recovery time (min) 40 (30 44) 35 (30 40) or Fisher s exact test, as appropriate. Except for ONSD, intergroup comparisons for repeated measures, including MAP, HR, EtSevo and EtCO 2 levels, and PIP were performed by unpaired t- test with Bonferroni correction. Repeated ONSD measurements were analysed by linear mixed models (LMM) for random and fixed effects between two groups. Intergroup comparison of changes in ONSD over time was performed by group-by-time interaction. An unstructured covariance matrix was used to correlate repeated measures. Post hoc analyses for ONSD with Bonferroni correction for multiple comparisons were performed when statistically significant differences were observed in the repeated-measures analysis. The LMMs and post hoc analyses for ONSD were also adjusted for parameters that might affect ONSD and/or ICP, including age, body mass index, EtSevo and EtCO2 levels, and PIP. All statistical tests were two-tailed, and P- values <0.05 were considered statistically significant. All statistical tests were performed using SPSS 22.0 (IBM, Armonk, NY, USA) and SAS 9.4 (SAS Inc., Cary, NC, USA). Results All 80 enrolled subjects completed the study (May August, 2016) without dropout (Fig. 2). There were no significant differences in subject characteristics or anaesthesia or surgery times between the two groups (Table 1). Urological surgeries that the subjects underwent included orchiopexy, inguinal hernioplasty, hydrocelectomy, penoplasty, fistula repair and diverticulectomy. Table 2 presents haemodynamic data and variables potentially affecting ICP. There were no significant differences in MBP, HR, EtCO 2 levels, PIP or body temperature between the HV and LV groups at any of the time points. Although the mean EtSevo concentrations in the LV group were higher compared with those in the HV group at T2 and T3, the difference was only 0.1%. The results of the LMM analysis revealed statistically significant differences between groups in terms of changes in ONSD (P GroupTime ¼0.003, Fig. 3). The results of the post hoc analysis (Table 3) revealed that ONSDs at T1, T2 and T3 were significantly increased from baseline values and that, in both groups, the values of ONSD after caudal block peaked at T2. Although there were no significant differences in ONSD between groups at any of the time points, the degrees of change in ONSD from T0 to T2 and T3 in the HV group were significantly greater compared with those in the LV group. Only two subjects in the LV group exhibited signs of inadequate analgesia, which was addressed by intravenous fentanyl administration. None of the subjects Table 2 Haemodynamic and other parameters associated with intracranial pressure at each time point. Values are presented as mean (SD) or median (inter-quartile range). Adjusted P- value indicates the Bonferroni-corrected P-value. EtCO 2,end-tidal carbon dioxide level; EtSevo, end-tidal sevoflurane concentration; T0, before caudal block; T1, immediately after caudal block; T2, 10 min after caudal block; T3, 30 min after caudal block. exhibited any symptoms or signs of neurological complications after surgery. Discussion High volume Low volume Adjusted P-value Heart rate (beats min 1 ) T0 150 (17) 146 (21) >0.999 T1 149 (15) 148 (17) >0.999 T2 142 (14) 143 (18) >0.999 T3 134 (13) 134 (16) >0.999 Mean arterial pressure (mm Hg) T0 68 (7) 68 (8) >0.999 T1 65 (8) 66 (9) >0.999 T2 62 (4) 65 (6) T3 60 (9) 64 (7) Peak inspiratory pressure (cm H 2 O) T0 12 (2) 12 (2) >0.999 T1 13 (2) 13 (2) >0.999 T2 13 (2) 13 (2) >0.999 T3 14 (2) 13 (2) >0.999 EtCO 2 (kpa) T0 5.0 (0.3) 5.1 (0.3) >0.999 T1 5.3 (0.3) 5.2 (0.3) T2 4.9 (0.2) 4.9 (0.2) >0.999 T3 4.9 (0.2) 4.9 (0.2) EtSevo (%) T0 3.4 (0.3) 3.4 (0.2) >0.999 T1 2.9 (0.3) 3.0 (0.2) >0.999 T2 2.5 (0.1) 2.6 (0.2) T3 2.4 (0.2) 2.5 (0.2) Body temperature ( C) T ( ) 36.7 ( ) T ( ) 36.8 ( ) T ( ) 36.9 ( ) >0.999 We estimated the effect of caudal block on ICP by measurement of ONSD in paediatric patients receiving caudal block. Caudal

5 Caudal block and optic nerve sheath diameter High volume Low volume Optic nerve sheath diameter (mm) * 3.5 T0 T1 T2 T3 Fig 3 Changes in optic nerve sheath diameter (ONSD). Values are expressed as mean (SD). *The two groups exhibited significant differences in changes in ONSD according to time in the linear mixed model (corrected for age, body mass index, end-tidal sevoflurane and carbon dioxide levels, and peak inspiratory pressure; PGroupTime¼0.003). T0, before caudal block; T1, immediately after caudal block; T2, 10 min after caudal block; T3, 30 min after caudal block. Table 3 Changes in optic nerve sheath diameter (ONSD) between time points. Values are presented as mean (SD). Adjusted P-value indicates the Bonferroni-corrected P-value. *P<0.005 vs T0; P<0.01 vs T1; and P<0.001 vs T2 in each group. This post hoc analysis is also adjusted for age, body mass index, end-tidal sevoflurane and carbon dioxide levels, and peak inspiratory pressure High volume Low volume Adjusted P-value ONSD (mm) T (0.50) 4.38 (0.57) >0.999 T (0.42)* 4.82 (0.58)* >0.999 T (0.48)*, 4.98 (0.50)*, T (0.53)*, 4.66 (0.54)*, Changes in ONSD (mm) T1 T (0.33) 0.44 (0.23) T2 T (0.37) 0.59 (0.30) T3 T (0.41) 0.28 (0.28) block with either volume (1.0 ml kg 1 or 1.5 ml kg 1 ) of local anaesthetic resulted in an increase in ONSD, which did not return to baseline level even 30 min after caudal block. The highest value of ONSD was observed at 10 min after caudal block. However, there were significant differences in changes in ONSD over time after caudal block between the two volumes of local anaesthetic. Specifically, subjects who were administered 1.5 ml kg 1 of local anaesthetic exhibited significantly greater increases in ONSD from baseline to 10 and 30 min after caudal block compared with those who were administered 1.0 ml kg 1 of local anaesthetic. The optic nerve is encircled by the distensible subarachnoid space. Therefore, an increase in ICP can displace cerebrospinal fluid (CSF) into the perineural subarachnoid space from the intracranial cavity, thus increasing ONSD. 16 According to a previous study on the relationship between ONSD and CSF pressure, 17 ONSD is linearly related to ICP within a limited ICP interval, which is above the normal range of ICP (the lower and upper limits of the limited interval correspond to the pressure levels at which ONSD starts to increase and plateau, respectively). Consistent with this information, several previous studies have shown that ultrasonographic measurement of ONSD is well correlated with ICP and is a useful method for detection of increased ICP. 7 9 Furthermore, a recent study by Padayachy and colleagues demonstrated that ONSD measured by ultrasonography correlated with ICP measured by invasive methods in children. 10 Therefore, our results indicating that the peak increment in ONSD after caudal block with 1.5 ml kg 1 of local anaesthetic was significantly higher compared with that with 1.0 ml kg 1 of local anaesthetic might imply that administration of 1.5 ml kg 1 of local anaesthetic for caudal block resulted in a greater increase in ICP than administration of 1.0 ml kg 1 of local anaesthetic. In addition, the difference in ONSD at 30 min after caudal block between the two volumes of local anaesthetic indicates that caudal block with 1.5 ml kg 1 had a significantly longer effect on ICP than that with 1.0 ml kg 1 volume. In previous studies, mean ONSD without general anaesthesia in children without increased ICP was <4 mm However, a recent study that evaluated ONSD under general volatile anaesthesia in children without evidence of increased ICP reported a mean value of 4.3 mm, 12 which is comparable with the

6 786 Lee et al. baseline ONSD value in the present study. The difference in normal ONSD between subjects with and without volatile anaesthesia is probably because of the effect of volatile anaesthetics on ICP or cerebral blood volume. Therefore, the present study required specific diagnostic criteria of ONSD for evaluation of increased ICP under volatile anaesthesia. Recently, Padayachy and colleagues suggested cut-off values of ONSD of 5.16 mm in infants ( one yr) and 5.75 mm in older children for diagnosis of increased ICP (20 mm Hg) under general anaesthesia. 10 According to these criteria, nine subjects (HV, four; LV, five) at T1, 19 (HV, 12; LV, seven) at T2 and 12 (HV, nine; LV, three) at T3 might have experienced increased ICP in the present study. The treatment threshold of ICP in children with traumatic brain injury has been reported to be 20 mm Hg. 19 Therefore, our findings might raise safety concerns regarding caudal block with not only 1.5 ml kg 1 but also 1.0 ml kg 1, especially in children with intracranial pathologies or risk factors associated with increased ICP. Because most previous studies have compared ONSD between patients with and without pre-existing increased ICP, little is known regarding how fast ONSD reflects acute changes in ICP. Monitoring of pressure in the epidural space has been reported to reflect real-time changes in ICP, and both intracranial and epidural pressures have been shown to peak just after epidural injection and decline thereafter The present findings regarding changes in ONSD after caudal block indicate that there is a delay of approximately 10 min between the increase in ONSD and acute increase in ICP. A recent investigation revealed that CSF moves bi-directionally between the cranial and spinal arachnoid spaces according to the pressure gradient. 24 Taken together, these findings suggest that, although caudal epidural block increases ICP and epidural pressure simultaneously, it might also cause a pressure difference between the cranial and spinal compartments, thus resulting in the movement of CSF from the spinal subarachnoid space into the intracranium, which increases ONSD. This phenomenon might explain the differences in cranial spread of local anaesthetic over time during caudal block. In a previous study, the levels of cranial spread immediately and 15 min after caudal block with 1.5 ml kg 1 of local anaesthetic were Th10 and Th8, respectively. 23 It is plausible that local anaesthetic might spread more cranially with the movement of CSF from the spinal into the intracranial subarachnoid space. This study has some limitations. First, body temperature was excluded from adjustment of variables that could possibly affect ICP in the LMM. Because the temperature probe was placed when the subjects were positioned supine after administration of caudal bock, temperature at T0 was not measured. However, given that body temperature was maintained within the normal range in all participants, we believe that it had no effect on ICP or ONSD data. Additional analysis of changes in various parameters, including body temperature, between T1 and T3 revealed no variable except patient age as significantly influencing ONSD (data not shown). Second, according to the protocol for caudal block at our institution, we administered ropivacaine 0.15%, which might have been associated with two events of inadequate analgesia during surgery. However, the two subjects were administered fentanyl, which is known to have no effect on ICP in patients under general anaesthesia. Therefore, these events might not have had any significant effects on our results. In conclusion, caudal block with 1.5 ml kg 1 of local anaesthetic causes a greater increase in ONSD than caudal block with 1.0 kg ml 1 of local anaesthetic. This suggests that HV caudal block might have a greater effect on ICP than LV caudal block. However, given the significant increase in ONSD with even the lower volume, ICP might increase notably even after caudal block with 1.0 ml kg 1 of local anaesthetic. While this effect is most likely irrelevant in children without intracranial pathologies, careful consideration should be given to patients that are at risk of increased ICP even with conventional volumes of local anaesthetic for caudal block. Authors contributions Patient recruitment, data collection and analysis, and preparation of first draft of the manuscript: B.L. Data collection and manuscript revision: B.-N.K., Y.S.C. Manuscript revision: H.K.K. Data collection: M.-S.K. Study design, randomisation, data collection and preparation of final version of the manuscript: J.H.L. Acknowledgements This research was supported by the Academic Assistance Program of ALPINION Medical Systems. We thank Jieun Moon and Hyejung Shin (Biostatistics Collaboration Unit, Medical Research Center, Yonsei University College of Medicine) for their contribution to the statistical analysis of this study. Declaration of interest None declared. Funding This research was supported by the Basic Science Research Program through the National Research Foundation of Korea, funded by the Ministry of Science, ICT and Future Planning (NRF-2014R1A1A ). References 1. Johr M, Berger TM. Caudal blocks. Paediatr Anaesth 2012; 22: Suresh S, Long J, Birmingham PK, De Oliveira GS Jr. Are caudal blocks for pain control safe in children? an analysis of 18,650 caudal blocks from the Pediatric Regional Anesthesia Network (PRAN) database. Anesth Analg 2015; 120: Ronald DM. 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