Protocols from the Children’s Oncology Group for the treatment of pediatric patients with blood cancers often require recurrent lumbar punctures that are performed repeatedly over months to years for intrathecal chemotherapy administration. Children are often sedated for lumbar punctures to decrease their stress and anxiety and to facilitate a successful procedure.1,2
Multiple studies have shown that exposure to all of the common intravenous (IV) and inhaled anesthetic agents is associated with altered brain development in immature animals, including nonhuman primates.3-6 In addition, the US Food and Drug Administration has issued a warning regarding the detrimental effects of repeated anesthesia on neurodevelopmental outcomes in children.7,8
Because medications that are frequently used for pediatric procedural sedation are general IV anesthetic agents, there is growing interest in the adjunctive use of topical anesthesia to minimize the sedation medication requirement in this population.9 Propofol is an amnestic sedative that is well-studied as a safe and effective agent in a procedural setting, although it has no analgesic qualities.10
The clinical advantages of using decreased amounts of sedation (ie, propofol) during painful procedures include lower rates of cardiorespiratory depression and decreased wake times.11 The American Academy of Pediatrics has advocated for a combination of sedative and analgesic medications for painful procedures in pediatric patients with cancer.12 Many institutions are likely to use the combination of a topical analgesic and a sedative agent because of the safety benefit; however, few studies have been published on this treatment.11,13,14
A topical eutectic mixture of local anesthetics reduces the pain associated with neonatal lumbar punctures, although the evidence showing clinical efficacy and safety is insufficient.13,14 In addition, when used in conjunction with propofol for the sedation of children with acute lymphoblastic leukemia (ALL), a eutectic mixture of local anesthetics has been shown to reduce the propofol requirement, as well as patient movement, during needle insertion.11
The addition of a eutectic mixture of a local anesthetics cream for procedural sedation during lumbar punctures in pediatric patients with cancer significantly improves pain management compared with 1% lidocaine injection.15 Caltagirone and colleagues evaluated the jet injection of 1% lidocaine for lumbar punctures in infants in the emergency department, demonstrating that its use was twice as likely to result in a successful lumbar puncture.16 However, the use of the jet injection system was not associated with improved pain control compared with the topical anesthetic cream.16
The use of lidocaine plus tetracaine topical patches has led to superior first-time success in venipuncture and IV placement in children compared with the use of a eutectic mixture of local anesthetics.17 The onset of action and time to anesthesia are significantly improved with the lidocaine plus tetracaine patch, at 20 to 30 minutes, compared with 1 hour for the eutectic mixture of local anesthetics, because of the heating element contained in that patch.17 In addition, the depth of anesthesia is 8 mm compared with the eutectic mixture of local anesthetics, which is time-dependent and peaks at 5 mm.18,19
Because a eutectic mixture of local anesthetics is beneficial in reducing the propofol requirement in lumbar punctures in pediatric patients with ALL,14 we sought to determine the potential benefit of lidocaine plus tetracaine patches in pediatric patients with leukemia or lymphoma. The objective of this study was to assess the efficacy of adding a lidocaine plus tetracaine patch for local pain control to propofol-based sedation in children receiving treatment for acute leukemia or lymphoma who underwent lumbar puncture for intrathecal chemotherapy.
The primary objective was to evaluate if the combination of propofol and a lidocaine plus tetracaine patch results in lower propofol doses during lumbar punctures compared with propofol plus placebo. The secondary objectives were the time from sedation to recovery, adverse events associated with the sedation, and postprocedure pain scores.
This was a randomized (1:1 ratio), placebo-controlled, double-blind crossover study at West Virginia University Medicine Children’s Hospital, a pediatric tertiary referral center for cancer, with approximately 15 new cases of leukemia or lymphoma diagnosed annually.
All patients aged 3 to 21 years at our hospital who were diagnosed with acute leukemia or lymphoma in the postinduction phase and who were undergoing lumbar puncture for intrathecal chemotherapy were identified during this 2-year study period between June 2016 and June 2018. Patients were included in the study if they had ≥2 future lumbar punctures planned as part of the Children’s Oncology Group chemotherapeutic protocol and procedural sedation20 that were planned to be provided by the pediatric intensive care unit (ICU) sedation team with a functioning central access catheter.
Patients were excluded if they had a platelet count of <50 × 103/µL at the time of the lumbar puncture; had a history of difficult lumbar puncture with planned lumbar puncture by interventional radiology; had concurrent procedures, such as bone marrow aspirate or venous access placement; had a hypersensitivity to propofol or its components; had a hypersensitivity to lidocaine, tetracaine, or to local anesthetics of the amide or ester type; or had a hypersensitivity to para-aminobenzoate, or an American Society of Anesthesiology (ASA) physical status classification of ASA ≥III.
The patients were randomized to the active patch group (N = 10) or the placebo patch group (N = 10). The Figure shows the randomization process in the 2 groups. All the patients received 2 lumbar punctures with intrathecal chemotherapy during the study.
The patients were evaluated during the 2 study periods; the first period was from the day the patients had undergone a lumbar puncture, including procedure time plus recovery time, during which they received the active drug patch (group 1) or the placebo patch (group 2). The second study period began the day the patient received the second lumbar puncture, which was followed by the placebo patch (group 1) or the active drug patch (group 2), and included procedure time plus recovery time, as the first study period.
A washout period of a minimum of 1 week (Figure) was set between the 2 procedural sedations, and the second procedural sedation was scheduled to coincide with the next intrathecal chemotherapy dose. If, at that time after the first procedure, the patient met an exclusion criterion, the second study period for that patient was postponed until the next scheduled intrathecal chemotherapy session, when the patient could be reassessed for inclusion. Procedural sedations for the study patients outside of the 2 study periods proceeded according to the sedation attending physician’s preference.
The time to recovery was defined as the time from the end of the lumbar puncture procedure until the achievement of a University of Michigan Sedation Scale (UMSS)21 score of 0 (Table 1). Adverse events related to the sedation included oxygen saturation of <90% for more than 30 seconds; airway obstruction requiring intervention; hypotension (systolic blood pressure less than the fifth percentile mean for age, for 2 consecutive time periods in patients aged <18 years), and blood pressure of ≤90 mm Hg/60 mm Hg in patients aged ≥18 years; as well as a decrease in heart rate of >20% from the presedation baseline.
The postprocedure pain score was measured by the Face, Legs, Activity, Cry, Consolability (FLACC) scale score for patients aged ≤7 years,22 and by a numeric rating scale (NRS) for patients aged >7 years.23 The numeric score was defined as 0 for no pain, 5 for moderate pain, and 10 for severe pain.
During the study period, the active or the placebo patch was applied 30 minutes before the scheduled procedural sedation time at the outpatient oncology clinic by the infusion center nurse, after the patient’s back was marked by the pediatric oncologist. Patients were then transported to the sedation suite. At the end of the 30-minute application time, and before the sedating pediatric ICU attending and pediatric oncologist entered the suite, the patch was removed by the pediatric ICU sedation nurse.
To minimize the number of lumbar puncture attempts, only experienced pediatric oncologists performed the procedures during the study. The pediatric oncologist who performed the first lumbar puncture also performed the second lumbar puncture. Procedural sedation was provided by one of the pediatric ICU attending physicians who staff the sedation service. As with the pediatric oncologist performing the lumbar puncture, the sedation physician who provided the first sedation also provided the second sedation.
Propofol was the sole IV agent used for procedural sedation of all patients during this study. The sedation intensivist followed a standardized administration protocol. Propofol boluses of 0.5 mg/kg were delivered via the MedFusion 4000 syringe pump and were repeated to achieve and then maintain a UMSS score of 3 (Table 1) during the procedure.
Heart rate, respiratory rate, blood pressure, and UMSS score were measured before the lumbar puncture procedure, every 3 minutes during the procedure, and every 5 minutes during the recovery period (ie, when the needle was removed until the UMSS score was 0). Oxygen saturation was continuously monitored, and the pain score was evaluated when the UMSS score was 0.
The group assignment (to the placebo or the active drug patch) was determined by a computer-based randomization generator.
The active patch and the placebo patches, which are identical in appearance, were donated to one of the authors for this study by Galen US, the manufacturer of the intervention patch.24 The placebo patch contains a heating component to simulate the effect of the active drug patch, but it has no active local anesthetic ingredient.
Descriptive statistics (mean, range, standard deviation [SD]) were conducted on each variable to identify outliers in the database, and areas in which we would need to consider corrective approaches if the data were not normative. These values were also used to characterize the sample in terms of demographics (eg, weight, age) and key variables (ie, recovery time, procedure time, mean propofol use). We conducted a multivariate analysis of variance to examine the potential differences in outcomes between the 2 groups (active vs placebo patch). Group assignment was the independent variable in this study.
The study was reviewed and approved by the West Virginia University Institutional Review Board. The patients, physicians, and pharmacists were blinded during this study. Consent was obtained from 1 parent of each patient, and assent was obtained from patients aged ≥7 years. The dependent variables in the study included the average procedure time across the various assessment points and pain scores.
All statistical analyses were conducted using IBM SPSS Statistics 26 (IBM Corporation; Armonk, NY). Significance was defined as P <.05. Based on our institution’s quality improvement audit conducted 3 months before the study initiation, the average total dose of propofol use in the study was 5.17 mg/kg (SD, 1.9). We determined that a study sample size of 20 patients would have at least 80% power to detect 25% reduction in infusion rates for propofol, using a 2-sided paired t-test at .05 significance level.
A total of 25 patients or their caregivers gave their consent to participate in the study, of which 5 patients were excluded because of death (N = 1), a history of high propofol requirement (defined as a ≥10 mg/kg total for the procedure; N = 1), nonadherence with the study patch (N = 1), and declining the treatment after consent (N = 2). A total of 20 patients completed the study.
Table 2 describes the patients’ and treatments’ characteristics. The median patient age was 8.4 years (range, 3-20 years), and 11 (55%) of the patients were female. Of the 20 patients, 18 received treatment for precursor B-cell ALL or T-cell ALL, and 2 patients received treatment for Burkitt lymphoma.
Of the 18 patients with ALL, 10 were considered high risk (defined as having an initial white blood cell count of >50,000 µL; age >10 years; or having a central nervous system [CNS] disease, as defined by the Children’s Oncology Group criteria20). The other 8 patients were determined to have standard-risk ALL (Table 2).
Of the 18 patients with ALL, 2 patients had CNS-2 status, which included blasts present and a white blood cell count of <5 µL in the cerebral spinal fluid. The 16 remaining patients had CNS-1 status, meaning no blasts in the cerebral spinal fluid.
A significant difference was found between the 2 study periods, based on the mean procedure time and the recovery time, with the lidocaine plus tetracaine patch requiring increased time versus the placebo patch (Table 3). The average procedure time (ie, time from the propofol start to the removal of the needle) was 11.7 minutes in the placebo group versus 15.3 minutes in the lidocaine plus tetracaine patch group (P <.02). The recovery time was 16.10 minutes in the lidocaine plus tetracaine patch group versus 9.8 minutes in the placebo patch group (P <.05; Table 3). Both groups had the patch in place for at least 20 minutes.
The use of a lidocaine plus tetracaine patch did not produce a significant reduction in propofol use (F = .016). Patients who received the lidocaine plus tetracaine patch required 4.6 mg/kg (range, 2-8.9 mg/kg) of propofol. The patients who received the placebo patch required 4.8 mg/kg (range, 2-6.9 mg/kg). Of the 20 patients, 9 (45%) received a decreased dose of propofol after receiving the lidocaine plus tetracaine patch compared with the patients who received the placebo patch.
In addition, no statistical difference was observed between the 2 groups in the mean heart rate change at 6 assessment points, but the means within the active treatment group were lower than those in the placebo group in several heart rate measures, including: heart rate 1, 98.90 beats per minute (bpm) with placebo versus 98.40 bpm with the lidocaine plus tetracaine patch (P = .94); heart rate 2, 89.22 bpm versus 96.04 bpm, respectively (P = .24); heart rate 3, 84.79 bpm versus 90.45 bpm, respectively (P = .352); heart rate 4, 99.89 bpm versus 94.00 bpm, respectively (P = .439); heart rate 5, 95.27 bpm versus 90.40 bpm, respectively (P = .302); and heart rate 6, 89.67 bpm versus 86.47 bpm, respectively (P = .408).
The mean pain score postprocedure in the placebo group was 0.8 (SD, 2.2) versus 0.2 (SD, 0.4) in the active treatment group. This did not reach statistical significance (F = .615), but the means showed a lower trend in the treatment group versus the placebo group. No incidents of hypoxia or bradycardia occurred in either group. A similar number of events of mild hypotension occurred in the 2 groups; none of the patients required an intervention.
The addition of the lidocaine plus tetracaine patch to IV propofol sedation for young patients with acute leukemia or lymphoma who were undergoing lumbar puncture for intrathecal chemotherapy did not decrease the total dose of propofol compared with patients who received the placebo patch. The patients who received the active patch required 4.6 mg/kg of propofol versus patients receiving the placebo patch who required 4.8 mg/kg of propofol.
One possible reason for this lack of difference in propofol dose between the 2 groups is that although topical lidocaine plus tetracaine provide excellent local anesthesia to the skin, the penetration is likely insufficient to cover the entire course of the needle track to reach the spinal canal. In our study, the lidocaine plus tetracaine patch remained in place for an average of 28 minutes, which corresponds with the manufacturer’s recommended time of 30 minutes24; this yields a theoretical depth of analgesia of up to 8 mm.
It is unclear if a longer time of the patch application would result in deeper medication penetration. However, Whitlow and colleagues showed the benefits of using a eutectic mixture of local anesthetics cream versus a placebo cream in pediatric lumbar punctures, based on the knowledge that the depth of penetration of only 5 mm after 120 minutes of receiving the eutectic mixture of local anesthetics, as shown by Bjerring and colleagues.14,18
Furthermore, no difference was found between the 2 groups in the total amount of sedative administered, likely because of the relatively short duration of the painful phase during a lumbar puncture. Typically, patients report that most of the pain associated with a lumbar puncture occurs during the insertion of the needle through the skin and the intervertebral space into the spinal canal.25 Because our oncology faculty members have experience with performing lumbar punctures, the period from needle insertion to cerebral spinal fluid flow is very short, typically seconds. This may not alter the requirement for, or allow the time to administer, additional doses of propofol.
In addition, we were unable to detect any decrease in pain associated with the use of the lidocaine plus tetracaine patch. Procedural pain is difficult to assess in pediatric patients undergoing lumbar puncture.26 Patients often report higher pain scores than the scores actually are, because of patients’ fear and anxiety.26,27 In both study groups, the patients reported low postprocedural pain scores, making a significant change in pain score difficult to detect with the lidocaine plus tetracaine patch.
Although not significantly different, the pain score was higher among the placebo group than in the active patch group. A more sensitive pain scale than the FLACC or the NRS might have been able to detect a change in pain score. It is also possible that the pain assessments performed after anesthesia may not be reliable in general.
The lidocaine plus tetracaine patch group had a significantly longer recovery time in our study than the placebo group (P <.05). This difference may be because the patients in the active patch group were less uncomfortable than those in the placebo patch group after the lumbar puncture, because of the local anesthesia. Although the pain scores were generally low, it is possible that the patients in the active patch group had a lower stimulus to rouse at the end of the sedation, because of their reduced local pain than the placebo group, which resulted in the longer recovery times.
Our results indicate that the use of the lidocaine plus tetracaine patch does not decrease propofol dosing during lumbar punctures in sedated pediatric patients with cancer. This contrasts with other studies showing that topical analgesics with propofol decrease the pain associated with medical procedures more than propofol-based analgesics alone.14,18
This study has several limitations. The small study size is a considerable limitation. The lidocaine plus tetracaine patch should allow for decreased pain at the lumbar puncture site, less movement during the lumbar puncture needle insertion, and, therefore, less lumbar puncture attempts, as shown by Whitlow and colleagues.14 With fewer lumbar puncture attempts, the patient would likely receive a decreased amount of propofol, leading to a shorter sedation time. A larger sample size might have shown a significant difference between the 2 groups.
Furthermore, we did not report the number of lumbar puncture attempts with the lidocaine plus tetracaine patch versus the placebo patch. It may be expected that there would be more lumbar puncture attempts with the placebo patch because of an increase in patient movement during the puncture, and because with lower pain control, the typical reaction to pain is a withdrawal reﬂex, even in deeply sedated patients.28
In addition, we excluded patients undergoing bone marrow aspirate, which is often performed with lumbar punctures; therefore, we cannot extrapolate our findings to that patient population.
The patients’ total number of lumbar punctures, and time in the treatment regimen, were also not evaluated; some patients might have a tolerance to propofol over time, requiring increased dosing to achieve the same therapeutic effect.29
We also did not record patient movement during lumbar puncture; an increase or decrease in movement to painful stimuli might have been a helpful marker in assessing the patients’ comfort.
Finally, although statistically insignificant, our results show that pain scores and the heart rate trend were better with the use of the lidocaine plus tetracaine patch than the placebo patch. Nevertheless, we cannot confirm that the use of the active patch is associated with lower propofol dosing than a placebo patch.
The use of the lidocaine plus tetracaine patch before lumbar punctures performed under deep sedation did not decrease the propofol sedation requirement, which contrasts with the results of previous studies. Although topical analgesia might have been achieved with the lidocaine and tetracaine patch application, patients were under deep sedation during the procedure and therefore were unable to report intraprocedural pain scores. After emergence from sedation, the patients in the placebo and intervention groups reported low pain scores that were not statistically significant.
Topical sedation may be beneficial in improving pain control in nonsedated or lightly sedated patients, but the deeply sedated patients in this study had a low level of postprocedural pain, which did not give an opportunity for meaningful improvement after the use of topical anesthesia.
The authors are grateful to Galen US for the donation of the placebo and the active patches for this study.
Author Disclosure Statement
Dr Garavaglia, Dr Casey, Dr Cottrell, Dr Wright, Dr Faraon-Pogaceanu, and Dr Paul have no conflicts of interest to report.
- Ljungman G, Gordh T, Sörensen S, Kreuger A. Pain in paediatric oncology: interviews with children, adolescents and their parents. Acta Paediatr. 1999;88:623-630.
- Hertzog JH, Dalton HJ, Anderson BD, et al. Prospective evaluation of propofol anesthesia in the pediatric intensive care unit for elective oncology procedures in ambulatory and hospitalized children. Pediatrics. 2000;106:742-747.
- Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23:876-882.
- Vutskits L, Davidson A. Update on developmental anesthesia neurotoxicity. Curr Opin Anaesthesiol. 2017;30:337-342.
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- Liu X, Ji J, Zhao GQ. General anesthesia affecting on developing brain: evidence from animal to clinical research. J Anesth. 2020;34:765-772.
- US Food and Drug Administration. FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women. Safety announcement; December 14, 2016. www.fda.gov/media/101937/download. Accessed December 6, 2021.
- Andropoulos DB, Greene MF. Anesthesia and developing brains—implications of the FDA warning. N Engl J Med. 2017;376:905-907.
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- Zeltzer LK, Altman A, Cohen D, et al. American Academy of Pediatrics report of the Subcommittee on the Management of Pain Associated with Procedures in Children with Cancer. Pediatrics. 1990;86(pt 2):826-831.
- Kaur G, Gupta P, Kumar A. A randomized trial of eutectic mixture of local anesthetics during lumbar puncture in newborns. Arch Pediatr Adolesc Med. 2003;157:1065-1070.
- Foster JP, Taylor C, Spence K. Topical anaesthesia for needle‐related pain in newborn infants. Cochrane Database Syst Rev. 2017:CD010331. doi: 10.1002/14651858.CD010331.pub2.
- Cruickshank A, Qeadan F, Kuttesch JF, Agarwal HS. Eutectic mixture of lidocaine and prilocaine versus 1% lidocaine injection for lumbar punctures in pediatric oncology patients. Pediatr Blood Cancer. 2019;66:e27957. doi: 10.1002/pbc.27957.
- Caltagirone R, Raghavan VR, Adelgais K, Roosevelt GE. A randomized double blind trial of needle-free injected lidocaine versus topical anesthesia for infant lumbar puncture. Acad Emerg Med. 2018;25:310-316.
- Cozzi G, Borrometi F, Benini F, et al. First-time success with needle procedures was higher with a warm lidocaine and tetracaine patch than an eutectic mixture of lidocaine and prilocaine cream. Acta Paediatr. 2017;106:773-778.
- Bjerring P, Arendt-Nielsen L. Depth and duration of skin analgesia to needle insertion after topical application of EMLA cream. Br J Anaesth. 1990;64:173-177.
- Wallace MS, Kopecky EA, Ma T, et al. Evaluation of the depth and duration of anesthesia from heated lidocaine/tetracaine (Synera) patches compared with placebo patches applied to healthy adult volunteers. Reg Anesth Pain Med. 2010;35:507-513.
- Maloney KW, Devidas M, Wang C, et al. Outcome in children with standard-risk B-cell acute lymphoblastic leukemia: results of Children’s Oncology Group trial AALL0331. J Clin Oncol. 2020;38:602-612. Epub 2019 Dec 11.
- Malviya S, Voepel-Lewis T, Tait AR, et al. Depth of sedation in children undergoing computed tomography: validity and reliability of the University of Michigan Sedation Scale (UMSS). Br J Anaesth. 2002;88:241-245.
- Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S. The FLACC: a behavioral scale for scoring postoperative pain in young children. Pediatr Nurs. 1997;23:293-297.
- Bijur PE, Latimer CT, Gallagher EJ. Validation of a verbally administered numerical rating scale of acute pain for use in the emergency department. Acad Emerg Med. 2003;10:390-392.
- Synera (lidocaine and tetracaine) topical patch [prescribing information]. Galen US; Dececmber 2020.
- Evans RW. Complications of lumbar puncture. Neurol Clin. 1998;16:83-105.
- Fein D, Avner JR, Khine H. Pattern of pain management during lumbar puncture in children. Pediatr Emerg Care. 2010;26:357-360.
- Holdsworth MT, Raisch DW, Winter SS, et al. Pain and distress from bone marrow aspirations and lumbar punctures. Ann Pharmacother. 2003;37:17-22.
- American Society of Anesthesiologists. Continuum of depth of sedation: definition of general anesthesia and levels of sedation/analgesia. Updated 2019. www.asahq.org/standards-and-guidelines/continuum-of-depth-of-sedation-definition-of-general-anesthesia-and-levels-of-sedationanalgesia. Accessed January 18, 2022.
- Ypsilantis P, Mikroulis D, Politou M, et al. Tolerance to propofol’s sedative effect in mechanically ventilated rabbits. Anesth Analg. 2006;103:359-365.