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A Fixed Nitrous Oxide and Oxygen Mixture for Analgesia in Children With Leukemia With Lumbar Puncture–induced Pain: A Randomized, Double-blind Controlled Trial

Open ArchivePublished:March 07, 2019DOI:https://doi.org/10.1016/j.jpainsymman.2019.02.029

      Abstract

      Context

      Leukemia is the most common cancer in the childhood population. Lumbar puncture (LP) plays central role in the diagnosis and treatment process, but options for analgesia are limited.

      Objectives

      The present study aims to evaluate the efficacy of a fixed N2O/O2 mixture to reduce pain in children with leukemia during LP as compared with placebo.

      Methods

      A double-blind, placebo-controlled, and randomized clinical trial involving children who needed LP for diagnosis or treatment was conducted in the pediatrics department of the General Hospital of Ningxia Medical University. Eligible patients were randomly assigned to inhale either a fixed N2O/O2 mixture or O2. The primary endpoint was the maximal pain level felt by the patient during the procedure measured using a numerical rating scale (0–10).

      Results

      One-hundred fourteen consecutive patients were enrolled in this study and randomized. Pain scores during the procedure showed a significant decrease in N2O/O2 mixture–treated patients to 1.05 ± 1.40 versus 8.00 ± 2.13 in controls (P < 0.01). No serious adverse effects were attributed to N2O/O2 mixture inhalation. Analysis of the satisfaction of patients receiving N2O/O2 mixture indicated that medical staff were satisfied with this treatment.

      Conclusions

      This study demonstrated that self-administered fixed N2O/O2 is efficient to reduce pain related to LP in children with leukemia.

      Key Words

      Background

      Leukemia is the most common cancer in the childhood population,
      • Jadad A.R.
      • Browman G.P.
      The WHO analgesic ladder for cancer pain management. Stepping up the quality of its evaluation.
      accounting for more than one-third of the total number of cancer cases in many developed countries.
      • Stiller C.
      Epidemiology and genetics of childhood cancer.
      Over 70% of leukemia cases in children involve acute leukemia.
      • Darling S.J.
      • Luca C De
      • Anderson V.
      • et al.
      White Matter Microstructure and Information Processing at the completion of chemotherapy-only treatment for pediatric acute lymphoblastic leukemia.
      • Mulatsih S.
      • Dwiprahasto I.
      Implementation of medication safety practice in childhood acute lymphoblastic leukemia treatment.
      Over the past decade, development of new therapy techniques has allowed the cure of pediatric acute leukemia.
      • O'Donnell M.R.
      • Tallman M.S.
      • Abboud C.N.
      • et al.
      Acute myeloid leukemia, version 3.2017, NCCN Clinical Practice Guidelines in Oncology.
      The five-year survival rate of childhood acute leukemia has improved to over 80% in the U.S. and 70% in China.
      • Ward E.
      • Desantis C.
      • Robbins A.
      • Kohler B.
      • Jemal A.
      Childhood and adolescent cancer statistics , 2014.
      • Zheng R.
      • Peng X.
      • Zeng H.
      • et al.
      Incidence, mortality and survival of childhood cancer in China during 2000-2010 period: a population-based study.
      However, increasing evidence shows that children and their parents exhibit high levels of stress and uncertainty after diagnosis and subsequent treatment.
      • Wang Y.
      • Liu Q.
      • Yu J.
      • et al.
      Perceptions of parents and paediatricians on pain induced by bone marrow aspiration and lumbar puncture among children with acute leukaemia : a qualitative study in China.
      In China, treatment of pediatric acute leukemia has been estimated to require approximately 12 cycles of bone marrow aspiration and over 15 lumbar punctures (LPs) for intrathecal chemotherapy.
      • Wang Y.
      • Liu Q.
      • Yu J.
      • et al.
      Perceptions of parents and paediatricians on pain induced by bone marrow aspiration and lumbar puncture among children with acute leukaemia : a qualitative study in China.
      These repeated painful invasive procedures cause a common and distressing symptom among the pediatric population.
      Unrelieved pediatric pain, as one of the most unbearable symptoms reported, significantly impairs patients' overall quality of life accompanied by negative physiological and psychological consequences.
      • Lee G.Y.
      • Yamada J.
      • Kyololo O.
      • Shorkey A.
      • Stevens B.
      Pediatric clinical practice guidelines for acute procedural pain: a systematic review.
      Studies demonstrate that many children with acute leukemia undergoing LPs and bone marrow aspirations without optimal interventions report high levels of anxiety and pain.
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      • Duijnstee M.S.H.
      • Pool A.
      • van Delden J.J.M.
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      Being there: parenting the child with acute lymphoblastic leukaemia.
      As a consequence, the risk of failures increases in undertreated patients because of patient movement and noncooperation.
      The World Health Organization three-step analgesia and clinical practice guidelines are widely used to control all kinds of pain.
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      WHO guidelines for the use of analgesics in cancer pain.
      Numerous studies focus on pharmacologic and nonpharmacologic measurements to control children procedural pain.
      • Hjortholm N.
      • Jaddini E.
      Strategies of pain reduction during the bone marrow biopsy.
      • Zahid M.F.
      Methods of reducing pain during bone marrow biopsy : a narrative review.
      However, the lack of a specific reference standard for pediatric procedural pain management has led to poor management of LP pain in Northwest China.
      • Wang Y.
      • Liu Q.
      • Yu J.
      • et al.
      Perceptions of parents and paediatricians on pain induced by bone marrow aspiration and lumbar puncture among children with acute leukaemia : a qualitative study in China.
      The use of a fixed self-administered inhaled N2O/O2 mixture has been well studied in control burn dressing debridement pain, breakthrough cancer pain, trauma pain, and other medical conditions.
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      A fixed nitrous oxide/oxygen mixture as an analgesic for trauma patients in emergency department: study protocol for a randomized, controlled trial.
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      Nitrous oxide-oxygen mixture during burn wound dressing: A double-blind randomized controlled study.
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      Nitrous oxide/oxygen mixture for analgesia in adult cancer patients with breakthrough pain: a randomized, double-blind controlled trial.
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      • et al.
      A fixed inhaled nitrous oxide/oxygen mixture as an analgesic for adult cancer patients with breakthrough pain: study protocol for a randomized controlled trial.
      • Meskine N.
      • Vullierme M.-P.
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      • d'Assignies G.
      • Sibert A.
      • Vilgrain V.
      Evaluation of analgesic effect of equimolar mixture of oxygen and nitrous oxide inhalation during percutaneous biopsy of focal liver lesions: a double-blind randomized study.
      It has potent analgesic properties without causing loss of consciousness. The safety of self-administered N2O/O2 mixture for pain management has also been demonstrated in previous studies.
      • Aboumarzouk O.M.
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      Nitrous oxide for colonoscopy.
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      Update on nitrous oxide and its use in anesthesia practice.
      In the present study, we aim to test the hypothesis that a fixed N2O/O2 mixture can provide the same analgesic effect in controlling pain in patients with acute leukemia during their LP procedure.

      Methods

      Design

      The present study was a randomized, double-blind, and placebo-controlled trial. Patients who met the described criteria were randomly assigned to receive standard pain management plus N2O/O2 mixture or standard pain management plus O2. This study was evaluated and approved by the General Hospital of Ningxia Medical University Ethics Service Committee (2015-130), and the trial was registered in the China Registry of Clinical Trials (ChiCTR-INR-16007989). Patients' consent was obtained in accordance with national regulations. This article was drafted in accordance with the Consolidated Standards of Reporting Trials (CONSORT) statement recommendations (Additional File 1).

      Study Participants

      Patients aged five to 14 years and suffering from leukemia, needing LP, capable of reporting pain, and able to provide consent were recruited between February 2015 and July 2016 at the General Hospital of Ningxia Medical University. The specific inclusion and exclusion criteria are shown in Table 1.
      Table 1Patients' Inclusion and Exclusion Criteria
      Inclusion Criteria
       Patient aged five to 14 years
       Patient suffering from acute leukemia
       Patients need lumbar puncture
       Written informed consent for participation obtained before any study procedures
      Exclusion Criteria
       Patient with mental disorder and altered mental status
       Patient has difficulty to report pain
       Other N2O/O2 contraindications, such as abdominal distension or suspected bowel obstruction, air embolism, and pneumothorax

      Treatments

      Eligible patients received local injection of lidocaine for standard pain management. They also received a pre-prepared N2O/O2 mixture in the treatment group or O2 in the control group 5 minutes before the procedure started and lasted until the treatment finished. The N2O/O2 mixture was self-administered by each patient through a self-demand mask with a one-way valve. In this way, overdose is nearly impossible because the patient's consciousness controlled their ability to inhale the gas.
      • Liu Q.
      • Wang Y.
      • Luo X.-J.
      • et al.
      A fixed inhaled nitrous oxide/oxygen mixture as an analgesic for adult cancer patients with breakthrough pain: study protocol for a randomized controlled trial.

      Randomization, Allocation Concealment, and Binding

      A total of 114 patients were assigned to the treatment or control groups by using a computer-generated randomization list. Thirty-eight patients received standard pain management plus O2, and 76 patients were allocated to standard pain treatment plus N2O/O2 mixture. The randomization list was sealed and kept by an independent program director, who took charge of the gas distribution for each enrolled patient. Besides the program director, no other medical worker or data collector knew of the intervention allocation. The project participants were blinded to the list.

      Sample Size Determination

      The sample size was based on a previous randomized study showing analgesic superiority of nitrous oxide/oxygen mixture over placebo (O2) in adult patients undergoing LP. The patient material consisted of 33 patients in each group. To enhance power and provide substitution for possible dropouts, we decided to recruit 114 patients in treatment and control groups in a ratio of 2:1, 38 patients to control group and 76 patients to treatment group.

      Measurement

      The patient's demographic data, including age, sex, and nationality, were recorded by the researchers. Our primary outcome was the numerical rating scale score measured 5 minutes before the procedure (T0), during the procedure (T1), and 5 minutes after the procedure (T2). The patients were instructed to rate their pain with a self-rating tool (ranging from 0 to 10, 0 = no pain, 10 = worst pain).
      • Tsze D.S.
      • von Baeyer C.L.
      • Pahalyants V.
      • Dayan P.S.
      Validity and reliability of the verbal numerical rating scale for children aged 4 to 17 years with acute pain.
      The secondary outcome was measured by focusing on the patients' blood pressure, heart rate, O2 saturation, and satisfaction of the medical staff. Satisfaction was assessed by a five-point scale (5, very satisfied; 4, satisfied; 3, uncertain; 2, dissatisfied; and 1, very dissatisfied). Patients' anxiety during the procedure was assessed using a numerical rating scale (0–10, with 0 equal to the absence of anxiety and 10 equal to high anxiety). The measurement of anxiety occurred at the same time as pain assessment.

      Statistical Analysis

      Statistical analysis was performed using SPSS 24.0 (SPSS Inc., IBM Company, Chicago, IL, USA) following the intention to treat principle that includes all interventions of the patients. We used the Kolmogorov-Smirnov test to determine whether the study data were normally distributed or not. Student's t-test was applied to determine differences in terms of age. We used the chi-squared test to determine gender differences between the two groups. Heart rate, blood pressure, O2 saturation, and pain score were assessed using repeated-measures analysis of variance. The last observation carried forward method was applied in case of missing data.
      Statistical significance was considered at P < 0.05.

      Results

      From 1 February 2015 to 23 July 2016, among the 134 patients who were eligible and provided consent for participation, a subset of 114 patients were randomly assigned to the two groups in this study and 109 patients were analyzed (Figure 1). Overall, 84 male and 30 female patients aged five to 14 years (9.55 ± 3.41 years) were included. Seventy-six patients were allocated to the N2O/O2 group, and 38 patients were enrolled in the control group. No difference was observed between the two groups in terms of age and gender. Table 2 shows the patients' demographic and baseline characteristics. No differences with respect to pain score at T0 (no pain) was noted.
      Table 2Clinical Characteristics of Patients at T0 by Group
      VariableGroupP
      N2O/O2 (n = 76)O2 (n = 38)
      Age (yrs)
      Based on t-test.
      9.94 ± 3.309.11 ± 3.590.218
      Males
      Based on chi-square test.
      60 (80%)24 (63.2%)0.072
      Heart rate (minute−1)
      Based on t-test.
      88.21 ± 13.0390.03 ± 15.230.516
      Systolic blood pressure (mm Hg)
      Based on t-test.
      108.67 ± 13.65109.03 ± 13.120.866
      Diastolic blood pressure (mm Hg)
      Based on t-test.
      73.54 ± 11.8474.28 ± 7.500.580
      SpO2 (%)
      Based on t-test.
      98.37 ± 0.87798.50 ± 0.7750.393
      Number of prior LPs experienced by each patient before the study procedure
       025 (32.9%)14 (36.8%)0.804
       119 (25.0%)9 (23.7%)
       214 (18.4%)8 (21.1%)
       312 (15.8%)3 (7.9%)
       ≥46 (7.9%)4 (10.5%)
      Results are expressed as n (%) or means ± standard deviation.
      a Based on t-test.
      b Based on chi-square test.
      Patients pretreated with the N2O/O2 mixture reported low pain intensity compared with the control group (1.05 ± 1.40 vs. 8.00 ± 2.13, P < 0.01) (Figure 2). In the N2O/O2 mixture group, heart rates decreased from 88.21 ± 13.03 (T0) to 86.04 ± 12.00 (T1) and 85.99 ± 13.54 (T2). In the O2 group, heart rates increased from 90.03 ± 15.23 (T0) to 125.42 ± 16.66 (T1) and 94.84 ± 13.50 (T2). The systolic and diastolic blood pressures of the O2 group were higher than those of the N2O/O2 mixture group at T1. The mean O2 saturation levels at T0, T1, and T2 in the N2O/O2 mixture group were 98.37 ± 0.88, 98.51 ± 0.84, and 98.66 ± 0.70, respectively; by comparison, those of the control were 98.50 ± 0.78, 99.00 ± 0.79, and 98.97 ± 0.56, respectively (Table 3). Analysis of the satisfaction of patients receiving N2O/O2 mixture indicated that medical staff were satisfied with this treatment (Z = −11.96, P < 0.01). The anxiety level of patients receiving N2O/O2 significantly decreased during the procedure (2.32 ± 2.14 vs. 8.24 ± 0.88, P < 0.001).
      Figure thumbnail gr2
      Fig. 2Pain score based on NRS for the case and control groups at T0, T1, and T2. NRS = numerical rating scale. *P < 0.01 (based on t-test).
      Table 3Heart Rate, Systolic Blood Pressure, Diastolic Blood Pressure, and O2 Saturation (SpO2) at T0, T1, and T2 in All Patients
      VariableGroupT0T1T2Main Effect of Group
      Determined using repeated-measures analysis of variance (ANOVA). Significance set at P < 0.05.
      Group × Time Interaction
      Determined using repeated-measures analysis of variance (ANOVA). Significance set at P < 0.05.
      Main Effect of time
      Determined using repeated-measures analysis of variance (ANOVA). Significance set at P < 0.05.
      Heart rateN2O/O2 (n = 76)88.21 ± 13.0386.04 ± 12.0085.99 ± 13.54P < 0.001 (F = 78.173)P < 0.001 (F = 65.303)P < 0.001 (F = 55.921)
      O2 (n = 38)90.03 ± 15.23125.42 ± 16.6694.84 ± 13.50
      Systolic blood pressureN2O/O2 (n = 76)108.67 ± 13.65110.90 ± 13.61104.65 ± 13.09P < 0.001 (F = 77.702)P < 0.001 (F = 64.974)P < 0.001 (F = 55.637)
      O2 (n = 38)109.03 ± 13.12130.38 ± 18.70121.09 ± 17.53
      Diastolic blood pressureN2O/O2 (n = 76)73.54 ± 11.8473.26 ± 11.7968.88 ± 9.95P = 0.043 (F = 4.208)P = 0.001 (F = 7.113)P < 0.001 (F = 18.376)
      O2 (n = 38)74.28 ± 7.5082.03 ± 7.2969.56 ± 12.02
      O2 saturationN2O/O2 (n = 76)98.37 ± 0.87798.51 ± 0.84198.66 ± 0.703P = 0.002 (F = 9.829)P = 0.252 (F = 1.385)P = 0.001 (F = 7.384)
      O2 (n = 38)98.50 ± 0.77599.00 ± 0.79398.97 ± 0.560
      Results are presented as mean ± standard deviation and median (interquartile range).
      a Determined using repeated-measures analysis of variance (ANOVA). Significance set at P < 0.05.
      No serious adverse events related to N2O/O2 mixture treatment were observed (Table 4). Among patients with mild side effects (such as nausea and vomiting), no treatment was usually required. All adverse effect symptoms disappeared 4 hours after completion of the procedure.
      Table 4Adverse Events Over the Entire Course of Intervention by Group
      GroupN2O/O2 (n = 76)O2 (n = 38)
      Nausea7 (9.2%)0 (0%)
      Somnolence2 (2.6%)0 (0%)
      Dizziness3 (3.95%)1 (2.6%)
      Total
      Based on chi-squared test. P < 0.001.
      12 (15.79%)1 (2.6%)
      Results are expressed as n (%).
      a Based on chi-squared test. P < 0.001.

      Discussion

      Multiple procedures, especially LP, are performed in children in pediatric department for the treatment of acute leukemia. Relieving pediatric pain and anxiety related to invasive procedures, such as LP aspirates for acute leukemia, is a shared goal. Several studies have shown that poor management of pain may place children at high risk for depression and anxiety.
      • Kircher J.
      • Drendel A.L.
      • Newton A.S.
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      • Ali S.
      Pediatric musculoskeletal pain in the emergency department: a medical record review of practice variation.
      • Tsze D.S.
      • von Baeyer C.L.
      • Pahalyants V.
      • Dayan P.S.
      Validity and reliability of the verbal numerical rating scale for children aged 4 to 17 years with acute pain.
      • Wang Y.
      • Liu Q.
      • Yu J.
      • et al.
      Perceptions of parents and paediatricians on pain induced by bone marrow aspiration and lumbar puncture among children with acute leukaemia : a qualitative study in China.
      Recent studies also show that many families report dissatisfaction with the light-sedation regimen when their children undergo painful procedures.
      • Alexander J.
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      Underuse of analgesia in very young pediatric patients with isolated painful injuries.
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      • Ali S.
      Pediatric musculoskeletal pain in the emergency department: a medical record review of practice variation.
      • O'Donnell J.
      • Ferguson L.P.
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      Use of analgesia in a paediatric accident and emergency department following limb trauma.
      Therefore, controlling procedural pain in children is critical. A recent review offered numerous strategies to alleviate pain related to invasive procedures, and the literature indicates that both pharmacologic and nonpharmacologic interventions are effective.
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      Strategies of pain reduction during the bone marrow biopsy.
      In the present study, we found that the pre-prepared N2O/O2 mixture is an effective analgesic for management of LP pain in children when used in conjunction with local injection of lidocaine. LP is an extremely painful procedure for pediatric patients. This procedure is usually performed after local injection of anesthetic infiltration.
      • Baek I.C.
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      Studies demonstrate that using eutectic mixture of local anesthetics patch for at least 1 hour is efficient and avoids the first puncture of anesthetic injection.
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      Intravenous sedation, such as with lorazepam, midazolam, or diazepam, has been recommended for pain reduction during LP for this group of patients.
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      In this case, the child should be in the operating room and anesthetized by anesthesiologists to prevent complications. A prospective observational study of propofol/fentanyl in 202 patients aged six months to 14 years for short-term painful procedures in the pediatric oncology ward demonstrated that children benefit from general anesthesia by propofol and fentanyl, although 11.9% of them displayed complications, such as vomiting, agitation, and headache.
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      Moreover, this medication is much expensive, and some families cannot afford it.
      Physiological variables, such as heart rate and blood pressure measurements, have been well studied for signs of acute pain in children.
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      Statistical analysis by repeated-measures one-way analysis of variance showed significant differences between the two groups in terms of heart rate and blood pressure. In the present study, the heart rate and blood pressure in the N2O/O2 mixture group significantly decreased during the procedure compared with those in the control group (P < 0.01). This result indirectly indicates decreased pain in the N2O/O2 treatment group.
      N2O, first used in anesthesia in 1772,
      • Knuf K.
      • Maani C.V.
      Nitrous oxide.
      has been extensively studied in various procedures and areas, such as dental care, pulmonary endoscopy, venous cannulation, clip removal, fractures, and minor procedures (burn dressing and abscess drainage) because of its pain relief properties.
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      • Sheehan C.
      • Hosseinian L.
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      N2O/O2 mixture is suitable for use as an analgesic in various procedures because of its analgesic properties, safety profile, rapid reversal, and self-administration by patients.
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      • Wodo N.
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      Nitrous oxide provides safe and effective analgesia for minor paediatric procedures–a systematic review.
      A randomized, double-blinded trial compared 50% N2O/O2 inhalation with medical air inhalation to treat moderate-to-severe acute pain. The median pain scores at 15 minutes were 2 (interquartile range 1–4) in the study group versus 5 (interquartile range 3–6) in the control group (P < 0.05).
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      • et al.
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      Another randomized double-blinded study that compared a 50:50 ratio of N2O:O2 with 50:50 N2:O2 (placebo) for cutaneous, muscle, and bone/joint procedure-related pain in 100 patients aged one to 18 years found that pain scores were lower in the 50:50 N2O:O2 group than in the placebo group and with rare minor side effects.
      • Reinoso-Barbero F.
      • Pascual-Pascual S.I.
      • de Lucas R.
      • et al.
      Equimolar nitrous oxide/oxygen versus placebo for procedural pain in children: a randomized trial.
      The effect size in our study is notably higher than that in the adult population possibly because children are sensitive to N2O than adults. In the present study, the patients also showed rare and minor adverse effects. Overall, N2O, as one of the earliest analgesics, is a safe and effective analgesic for procedural pain control in children.

      Limitations

      The limitations of the present study include the recruitment of young patients in a single department. The study findings should be confirmed in different ages of patients, such as older patients, to determine true analgesia effects, adverse drug events, and the satisfaction of both health workers and patients. Another potential limitation is that we did not perform blinding evaluation. Large-sample studies should be implemented to test the analgesic effect of N2O/O2 mixture in multicenter randomized controlled trials.

      Conclusion

      This study aims to demonstrate the efficacy, feasibility, and medical staff satisfaction of N2O/O2 mixture plus local anesthesia of lidocaine to treat LP-related pain. We can conclude that N2O/O2 provides significant pain relief to children with a low incidence of side effects during procedural pain. Health care providers in low-resource settings should consider inhalation of N2O/O2 mixture as an effective approach to alleviate procedural pain in children.

      Disclosures and Acknowledgments

      The invaluable contributions of the patients and staff of Ningxia Medical University, General Hospital of Ningxia Medical University, are gratefully acknowledged.
      The study was supported by the Science and Technology Department of Ningxia (Project No.: 2018CMG03005).
      The authors have no conflicts of interests to declare.

      Supplementary Data

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