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The Efficacy of Premixed Nitrous Oxide and Oxygen for Fiberoptic Bronchoscopy in Pediatric Patients^*

A Randomized, Double-Blind, Controlled Study

^* From the Service de Pneumologie Pédiatrique et INSERM 213 (Drs. Fauroux and Clément), Hôpital d’Enfants Armand Trousseau, Paris; Air Liquide Santé International (Dr. Onody), Paris; and Unité de Traitement de la Douleur (Drs. Gall and Tourniaire), Hôpital d’Enfants Armand Trousseau, Paris; and Département de Statistique Médicale (Dr. Koscielny), Institute Gustave Roussy, Villejuif, France.

Correspondence to: Brigitte Fauroux, MD, PhD, Service de Pneumologie Pédiatrique and INSERM 213, Hôpital d’Enfants Armand Trousseau, 28 avenue du Docteur Arnold Netter, 75012 Paris, France; e-mail: brigitte.fauroux{at}trs.ap-hop-paris.fr

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Study objectives: The aim of the study was to evaluate the efficacy and safety of premixed 50% nitrous oxide and oxygen on the quality of sedation and pain control during fiberoptic bronchoscopy (FB) in children.

Design: A prospective, randomized, double-blind study.

Setting: Pediatric pulmonary department in a pediatric tertiary university hospital.

Patients: One hundred five children aged 1 month to 18 years.

Interventions: Patients inhaled after sedation and local anesthesia either premixed 50% nitrous oxide and oxygen (nitrous oxide group) or premixed 50% nitrogen and oxygen (control group) during FB.

Measurement and results: The rate of failure was significantly greater in the control group (62%) than in the nitrous oxide group (21%, p = 0.00003). The efficacy of premixed 50% nitrous oxide and oxygen was also demonstrated with higher satisfaction scores (p = 0.000001), lower Children’s Hospital of Eastern Ontario Pain Scores (p = 0.002), better visual analog scale ratings (p = 0.03), and improved behavior scores. Side effects were minor and similar in both groups.

Conclusions: This study demonstrates the improved efficacy of sedation, pain control, and safety of premixed 50% nitrous oxide and oxygen for FB in children.

Key Words: children • Children’s Hospital of Eastern Ontario Pain Score • fiberoptic bronchoscopy • pain control • premixed 50% nitrous oxide and oxygen • safety • sedation • videotape recording

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Fiberoptic bronchoscopy (FB) is commonly used in children for a variety of diagnostic and therapeutic procedures.^{1 2} It is a procedure that is relatively quick and safe, but is still performed in some pediatric units under general anesthesia in the operating room.^{2 3} Although the main reason for using general anesthesia is to provide greater comfort for the patient and thus facilitate the procedure for the operator, the drawbacks are that a more complicated and costly organizational set-up is required combined with the unavoidable risks to all children associated with general anesthesia. Furthermore, some dynamic airway abnormalities, such as tracheomalacia or bronchomalacia, cannot be evaluated during general anesthesia. For these reasons, some centers, including our own, have developed FB using only sedation and local anesthesia, a technique that is becoming a reference for numerous pediatric centers.^{4 5 6}

Although invasive procedures such as bronchoscopy may be technically feasible without general anesthesia, there is increasing awareness that high-quality medical care must include adequate control of discomfort or pain related to a procedure, especially in the pediatric field. A study performed in adult patients undergoing flexible bronchoscopy showed that patient reported pain control was judged fair or poor by 10% of the patients despite sedation, analgesics, and topical anesthetics.⁷

Nitrous oxide is commonly administered at a concentration of 50% in oxygen to induce analgesia. In children, this mixture has proved to be efficacious and safe in various minor procedures such as venous cannulation, lumbar punctures, bone marrow aspirations, laceration repairs, and dental care.^{8 9 10} An open, uncontrolled pilot study¹¹ showed premixed 50% nitrous oxide and oxygen in children undergoing GI endoscopy to be effective and well tolerated. The present study was undertaken to evaluate the efficacy on quality of sedation and pain control and the safety of premixed 50% nitrous oxide and oxygen combined with sedation and local anesthesia, in pediatric patients undergoing FB without general anesthesia.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Study Participants
The protocol was approved by the institutional board for human subjects of Saint Antoine University (Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale). Written informed consent was obtained from all the parents, and assent was obtained from children > 6 years old after careful explanation of the procedure to the patient and his/her parents by the endoscopist. One hundred five children from the pediatric pulmonary department of Armand Trousseau University Hospital were enrolled in this prospective study, performed from July 1999 to February 2000. Patients were eligible if they were undergoing diagnostic or therapeutic FB. They were ineligible if they had severe respiratory distress defined by a PaCO₂ > 50 mm Hg, hemodynamic instability, impaired consciousness, vitamin B₁₂ deficiency, intracranial hypertension, pneumothorax, or fractures of the facial bones. The patients were randomly assigned to receive either premixed 50% nitrous oxide and oxygen (Kalinox; Air Liquide; Paris, France) [nitrous oxide group] or premixed 50% nitrogen and oxygen (control group). The endoscopy team was unaware of the mixture inhaled by the patient, and the patients were also blinded to the mixture inhaled.

Procedure
All FBs were performed in the pediatric endoscopy unit of the department by skilled pediatric pulmonologists. The duration of the fasting period in infants < 6 months of age was milk and solid food until 4 h and clear liquids until 2 h before the procedure; in infants between the age of 6 months and 36 months, milk and solid food until 6 h and clear liquids until 2 to 3 h before the procedure; and in children > 36 months old, milk and solid food until 8 h and clear liquids until 2 to 3 h before the procedure.¹² Patients were prepared for FB with intrarectal atropine (0.02 mg/kg) and midazolam (0.3 mg/kg) for children 30 kg, and flunitrazepam (0.03 mg/kg po) for those > 30 kg. The patients were then transferred to the operating table, wrapped in a sheet, and restrained with three straps on the thorax, hips, and knees. An endoscopy-trained nurse and an auxiliary nurse assisted the endoscopist with each procedure. The patients were continuously monitored with a pulse oximeter (Datex Ohmeda 3800; Datex Ohmeda Corporation; Louisville, CO). The type of bronchoscope (BF type 3C10, 3C20, 3C30, and P20D; Olympus Corporation; Rungis, France), with diameters of either 2.6 mm or 3.6 mm, was chosen depending on the size of the patient’s airway. A compact camera (model MH-972/MH-973, Olympus Corporation) attached to the bronchoscope and connected to a videotape recorder (model TV-S5; Olympus Corporation) recorded each procedure at standard-play speed. A videotape recording (Sony 72X Handycam; Sony; Paris, France) of the patient was taken during the whole procedure, from the application of topical anesthesia up to 5 min after the end of the endoscopy.

The procedure started with spraying of topical anesthesia into the right nostril, provided by two sprays of lidocaine hydrochloride (Xylocaine; Astra-Zeneca; Rueil-Malmaison, France) applied to the pharynx and the vocal cords. Lidocaine concentrations of 1%, 2%, and 5% were used in children 18 months of age, between the age of 18 months and 10 years, and > 10 years, respectively. The patient then inhaled the premixed 50% nitrous oxide in oxygen or premixed 50% nitrogen in oxygen mixture through a close-fitting scented face mask for 3 min, with two holes, one in front of the right nostril for the passage of the bronchoscope and another in front of the mouth for aspiration of secretions. During this time period, 2 mL of the same concentration of lidocaine (1 mL for infants < 18 months) was administered via syringe through a side port in the mask into the right nostril. After 3 min of inhalation, the bronchoscope was inserted through the facemask gently through the nose into the lower airways. When a nasal passage was not possible, the bronchoscope was passed through the mouth after two sprays with lidocaine. During the endoscopy, the patient inhaled the gas mixture continuously and a supplemental injection of 1 or 2% lidocaine was applied through the bronchoscope channel as the bronchoscope reached the carina (except for infants < 18 months old).

A standard method of BAL was used if indicated by the clinical condition.^{5 6} Briefly, the bronchoscope was wedged into a subsegmental bronchus of the lower right lobe. A volume of sterile normal saline solution was instilled equivalent to 3 mL/kg body weight. This sterile solution at 37°C was injected in six aliquots and withdrawn by gentle aspiration. The first aliquot was considered as a bronchial sample and analyzed separately. All subsequent aliquots were pooled to represent an alveolar sample. Recovery rate was approximately 60%. Bronchial biopsy for analysis of the ciliary beat frequency and morphology was performed in 11 patients.

The inhalation of the gas mixture was stopped when the endoscopist withdrew the bronchoscope. After withdrawal of the bronchoscope, the patient remained for observation in the operating room for at least 10 min and in the hospital under continuous cardiovascular and pulse oximetry monitoring for at least 6 h.

Primary Outcome: Rate of Failure of the First Inhalation Mixture
The primary outcome was the number of treatment failures with the blinded inhalation mixture. The principle of the protocol was carefully explained to patients > 6 years old, who could decide to switch to an open inhalation of premixed 50% nitrous oxide and oxygen if they felt pain or discomfort at any moment during the procedure. For patients < 6 years of age, the endoscopy team decided consensually whether the procedure was continued with the first inhalation mixture or not. This decision was based on the pain expressed by the patient during the procedure, assessed on the vocalizations and the behavior of the patient. In case of failure following the administration of the first blinded mixture, premixed 50% nitrous oxide and oxygen was inhaled from a different bottle in an open way for 3 min before and during the whole FB procedure.

Secondary Outcomes
The secondary outcomes were the quality of sedation and pain control. This was evaluated by the endoscopy team (Children’s Hospital of Eastern Ontario Pain Score [CHEOPS]), by the patient in a self-reported assessment, and by a quantitative analysis of behavior reactions displayed during the procedure. After the completion of the procedure, the endoscopy team rated global pain control on a 4-point scale (poor, fair, good, very good). Patients > 6 years old were asked to report pain control using a visual analog scale (VAS). The patients rated the intensity of pain on an interval scale, which was a 10-cm horizontal line with the words "no pain" and "very painful" on the left-hand and the right-hand ends, respectively. The patients were instructed to place a vertical mark on the line such that its position relative to the two extremes indicated the magnitude of their pain. The pain score was expressed in mm (from 0 to 100) and was the distance of the mark from the left-hand end of the VAS.

Pain assessed with the CHEOPS was rated by the endoscopy team before and immediately after the procedure.^{13 14} The CHEOPS is a composite measure that addresses six behavioral items (crying, facial expression, verbal expression, torso posture, touch, and leg position), which has been most frequently used in studies investigating pain management during various procedures in children.

An additional aim was to characterize children’s pain experience, and thus the behavioral responses elicited by painful stimuli during the whole procedure were analyzed from a videotape. Independent observers who were pediatric anesthesiologists and were unaware of group assignment, scored the videotapes using a digital images indexation software (Observer Video pro; Noldus Information Technology; Wageningen, the Netherlands). Three behavioral items were considered: vocalization, phasic body movement, and tonic body movement involving legs and torso that tensioned the restraining straps. Since children’s faces were hidden by the facemask, no attempt could be made to quantify facial actions. Vocalization was defined as a behavioral state. It was considered as present when the child was emitting audible sounds, cry, or scream, and defined as absent when the child was silent or had a positive verbal expression. Phasic body movements were defined by short-lived squirming and kicking movements that did not tension the restraining straps. These were considered absent when the legs were relaxed or involved in tonic movements. Tonic body movements were defined as movements involving the legs and the torso that tensioned the restraining straps. These were considered absent when the legs were relaxed or involved in phasic movements. The three items were shown to be reliably scored by the observers in a preliminary analysis. From these data, the duration of each behavioral state was further computed and values were summed over time within a given time period of the procedure. Each procedure was divided into five periods: baseline represented the period just before the procedure, when the child was positioned on the operating table without a facemask; induction represented the inhalation of the mixture without any stimulation; the local anesthesia corresponded to the administration of topical anesthesia to the upper airways; the endoscopy examination itself; and the recovery was a 5-min observation period after the procedure. Data were expressed as a percentage of time that the child exhibited the particular behavioral element during a given period of the procedure, ranging from 0 to 100%. In cases of treatment failure, missing values were replaced by means of carrying forward the last available response.

Side Effects
Respiratory side effects such as desaturation, defined arbitrarily by pulse oximetric saturation < 94% for > 30 s, bronchospasm, or persistent cough after the procedure, as well as GI (nausea, vomiting) side effects or the occurrence of nightmares, were evaluated during and after the procedure.

Statistical Analysis
An independent statistician performed the analysis. The number of patients necessary was estimated with the following statistical assumptions: failure of sedation for 30% of the patients of the nitrous oxide group and 60% in the control group. Fifty-six patients per treatment group were needed in order to reach a 90% statistical power with an risk (two sided) equal to 0.05. Patients were classified in two groups, without and with BAL. Fisher exact tests were used to test differences in the proportions of failures between the two treatment arms. In case of quantitative variables (VAS, CHEOPS, behavioral items), differences between the two treatment arms were tested with nonparametric Wilcoxon rank-order tests. All statistical analyses were performed with SAS version 6.12 (SAS Institute; Cary, NC).

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

 
One hundred five patients were included in the study. The characteristics of the patients are shown in Table 1 . There were no significant differences in age, underlying disease, treatment, and number of BAL and bronchial biopsy procedures. The mean duration of inhalation of the blinded (and eventually the open premixed 50% nitrous oxide and oxygen) including the 3-min inhalation before the bronchoscopy was 4 min (229 s) for a simple FB and 9 min (533 s) for FB with BAL.

View larger version (20K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Comparison of vocalizations and body movements displayed by the children throughout the procedure. Vocalizations and body movements were assessed from video recordings of the procedure using a digital image indexation software. Vocalizations (top) were defined by audible sounds, cries or screams. Phasic body movements (middle) were defined by short-lived squirming and kicking movements that did not tension the restraining straps. Tonic body movements (bottom) were defined by more tonic movements involving the legs and the torso that tensioned the restraining straps. Values indicate the percentage of time that the child exhibited the particular behavioral element during the particular period of time, ranging from 0 to 100%. Data are plotted as mean ± SEM. *Comparison of nitrous oxide vs control group (p < 0.05).

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

 
The main finding of this prospective, randomized, double-blind, controlled study was that premixed 50% nitrous oxide and oxygen, combined with sedation and local anesthesia, has a greater efficacy in terms of quality of sedation and pain control than 50% nitrogen and oxygen during FB with and without BAL in children. Children in the nitrous oxide group experienced less pain than children in the control group as evidenced by three independent sources of assessment, namely the endoscopy team, the patients themselves, and the behavioral analysis. In addition, the tolerance of premixed 50% nitrous oxide and oxygen was excellent with only minor side effects observed.

Premixed 50% nitrous oxide and oxygen has been proposed to provide sedation and analgesia in a large variety of pediatric procedures, including lumbar puncture, bone marrow aspiration, laceration repair, dressing changes, various diagnostic punctures, and dental care.^{8 9 10 15 16} However, to our knowledge, the efficacy of premixed 50% nitrous oxide and oxygen has been investigated in the pediatric population in only one randomized controlled trial.¹⁶ Although nitrous oxide has been proved efficacious during GI endoscopy in children,¹¹ the premixed 50% nitrous oxide and oxygen was inhaled before the endoscopy in all the patients but inhaled during the procedure only in a minority of the 37 patients. Furthermore, this study was not placebo controlled, and no objective analysis of comfort was performed.

The efficacy of premixed 50% nitrous oxide and oxygen in increasing the comfort of FB was demonstrated in this study by the agreement between the evaluations of pain by the endoscopy team, by the patient, and by the analysis of the videotape recording by two independent observers. The onset of the sedative effect of premixed 50% nitrous oxide and oxygen was rapid, within 3 min, as shown in this study by a significant difference between the two groups as early as the local anesthesia period (Fig 1) . This mixture was also short acting, as evidenced by the loss of significant effect in the recovery period. This is a major advantage of premixed 50% nitrous oxide and oxygen, making it useful for moderately painful procedures of short duration, such as FB.¹⁰ BAL was performed only in a few patients, which could explain the lack of a significant difference between the two groups. However, there was a trend in favor of premixed 50% nitrous oxide and oxygen (Table 2) .

Thirty eight percent of the patients tolerated the FB under premixed 50% nitrogen and oxygen (Table 2) . This suggests that in approximately one third of the patients, the procedure can be performed with sedative agents, local anesthesia, and oxygen. It has to be underlined that the psychological preparation and condition of the patient before the FB, as a result of the premedication and local anesthesia, could also have contributed to this result. It has been shown in adults undergoing FB, that the improvement of the information provided to the patients can in itself achieve greater levels of comfort.⁷ An additional study would be warranted to assess the effect of psychological preparation on pain during FB in children.

The rate of failure with premixed 50% nitrous oxide and oxygen was 21% for the total population and reached 30% in patients 2 years of age and 24% in patients undergoing FB without BAL. This implies that a small subgroup of patients express pain or discomfort during the procedure despite premedication, topical anesthesia, and premixed 50% nitrous oxide and oxygen. A younger age, increased pain perception, and/or a nonoptimal inhalation of premixed 50% nitrous oxide and oxygen could be possible explanations for this negative result. Further studies are warranted to identify the patients that would benefit most from general anesthesia.

The rate of failure with premixed 50% nitrous oxide and oxygen was greater in patients 2 years of age. This age-dependent effect has been observed in previous studies.^{10 17} However, it is more difficult to assess pain in these younger children, and this could contribute to our observation. It is also more difficult in infants to separate the discomfort induced by the physical restraints from that induced by the bronchoscopic examination of the airways itself. Also, the higher minimal alveolar concentration of anesthetic gases in this age could explain the reduced effectiveness of nitrous oxide in this group.¹⁸

The purpose of this study was to reduce the pain and discomfort during FB. Indeed, we found it unethical to continue the procedure with premixed 50% nitrogen and oxygen if the patient experienced pain. For this reason, we choose as the primary outcome the rate of failure of the first blinded inhalation mixture with the hypothesis that, in case of premixed 50% nitrous oxide and oxygen, a smaller number of patients would switch to the open administration of this mixture. We did not compare premixed 50% nitrous oxide and oxygen with general anesthesia. FB is a relatively safe, although invasive, procedure that is commonly performed in pediatric pulmonary care. We perform in our department between 400 FBs and 600 FBs without general anesthesia per year. Thus, the aim of this study was an attempt to further improve the comfort of this already reasonably well-tolerated technique, which we routinely perform under sedation and local anesthesia; therefore, we reasoned that to compare with general anesthesia would be unethical. In addition, the improved ease, reduced risk, and cost for a FB performed without general anesthesia, compared to a procedure under general anesthesia, must also be highlighted. The simultaneous administration of a high concentration of oxygen by premixed 50% nitrous oxide and oxygen is also beneficial to patients with a lung or airway disease to prevent the relatively common transient desaturations.

With regard to the behavior reactions analyzed on the videotape recording, the tonic body movements seemed to be more discriminating than vocalizations or phasic body movements to assess the pain induced during bronchoscopy. Indeed, the percentage of time that the child exhibited vocalizations and phasic body movements were globally similar during the local anesthesia and the bronchoscopy period. This observation is worth emphasizing for future studies evaluating pain control during invasive procedures in young children. Although this relatively small study observed no serious side effects with premixed 50% nitrous oxide and oxygen, this concurs with two previous large-scale studies^{10 19} that showed that premixed 50% nitrous oxide and oxygen is a safe analgesic in children.

In conclusion, this study demonstrates improved efficacy of sedation and pain control with premixed 50% nitrous oxide and oxygen in children undergoing FB with or without BAL. The results of this prospective, double-blind, randomized, controlled study are of great importance for the pediatric community and premixed 50% nitrous oxide and oxygen combined with premedication and local anesthesia should be considered as a safe and effective method to facilitate routine FB in children.

	Acknowledgements

 
The authors thank Sophie Brenon for her assistance, Dr. Nicholas Hart for reviewing the manuscript, and all the patients and their parents for their enthusiastic participation.

	Footnotes

 
Abbreviations: CHEOPS = Children’s Hospital of Eastern Ontario Pain Score; FB = fiberoptic bronchoscopy; NS = not significant; VAS = visual analog scale

This study was supported by Assistance Publique-Hôpitaux de Paris and Air Liquide Santé International.

Received for publication December 30, 2002. Accepted for publication June 30, 2003.

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