INTRODUCTION

Flexible bronchoscopy is the gold standard tool to visualize both upper and lower airway in human (1). Hence, its popularity in the assessment of airway has increased gradually and now it has evolved into an essential diagnostic and therapeutic modality in the field of pulmonology (2). In addition, advancement of technology and physician’s experience with this tool has established it as a safe procedure with very low mortality and minimum morbidity (3). The feasibility of flexible bronchoscopy in infants and small children was first described in 1978 (4). Since then the utility of flexible bronchoscopy in children also shows a rising trend (5).

However, introduction of a bronchoscope a foreign body, through the airway is an invasive procedure. It would be an unpleasant and painful experience for the patient. It is also potential to stimulate protective airway reflexes like cough. In addition, it could induce vagal stimulation leading to laryngeal spasms, bronchospasms and bradycardia (6). Hence, provision of an adequate level of anaesthesia to the patient’s airway is a must for a successful bronchoscopy. This requirement is more highlighted in paediatric practice because a bronchoscopy with inadequate level of anaesthesia might be a huge trauma to children.

Due to all these reasons, paediatric flexible bronchoscopy in children was usually done under deep sedation or general anaesthesia during the early part of its introduction (7). In contrast, the use of conscious sedation and adequate tropical anaesthesia to airway have taken the bronchoscopy procedure out from the operating theatre and now it is an outpatient procedure which is done at a day care setup in most centres around the world(7). Introduction of a bronchoscope through the airway, especially through the larynx is a strong stimulus to arouse a sedated child. Therefore, application of an adequate tropical anaesthesia to the airway is the key to a successful bronchoscopy which is done under sedation. (8) It also abolish laryngeal reflexes and gaging which finally ensure patient’s as well as physician’s comfort during the procedure (9). 

Lignocaine is the most commonly used medication for the topical anaesthesia of airway, not only for bronchoscopy but all procedures involving the airway (10). Although there is no controversy regarding the use of lignocaine in bronchoscopy as a topical anaesthetic agent, there is no consensus about the mode of administration. Direct administration of lignocaine to the airway via working channel of the bronchoscope in “spray as you go” fashion is the commonly practising procedure (11). This might lead to a potentially toxic level of lignocaine in serum (12,13). Similarly, direct application of a liquid to unanaesthetised larynx might produce intense cough and vagal stimulation (8).

Nebulization of medications are commonly practice in children and generally it is well tolerated. Nebulization of lignocaine prior to the procedure might deliver the drug to upper as well as lower airways without inducing gag reflex. Then the bronchoscope can introduce in to an already anaesthetized airway. Additional doses could be instilled while going in if it is required. Studies in adults have shown that nebulized lignocaine produce similar anaesthetic effect in comparison to local instillation method and more patient tolerance and acceptance (14,15,16). Nebulized lignocaine might have equivalent or more benefits in comparison to routine direct instillation technique in children also.

REVIEW OF LITERATURE

Since the introduction of flexible bronchoscopy in paediatric practice, almost four decades have elapsed now (4). The use of this tool has extended the diagnostic as well as therapeutic capabilities of physicians in a wide spectrum of respiratory disorders in children. Now it is a routine practice in every paediatric pulmonology unit. However, still there is no consensus about the sedation and mode of topical anaesthesia for paediatric bronchoscopy in children(17).

Lignocaine which is chemically designated as acetamide, 2-(diethylamino)-N-(2,6-dimethylphenyl)-, monohydrochloride is the most commonly used drug for the topical anaesthesia of airway  due to its rapid onset and relatively shorter duration of action and lesser toxicity in comparison with other medications (18). Lignocaine inhibits the ionic fluxes required for the propagation of impulses (initiation and conduction) and hence, stabilizes the neuronal membranes, producing a local anaesthetic action (19). Lignocaine is metabolized by the liver rapidly. Its metabolites and unchanged molecules are excreted by kidneys. The elimination half-life of lignocaine is about 2 hours (19). Life-threatening and fatal events have been reported in infants and young children with the use high or more frequent doses of lignocaine. Even though, it has a potential to induce cardiac arrhythmias, seizures and even cardiac arrest, the cautious use of recommended doses with adherence to guidelines reported to be safe in routine practice because its toxicity is directly related to its serum levels (11). A plasma level above 5 µg/ml which usually achieved with a dose more than 8.2mg/kg is considered to be toxic (20).

Lignocaine is rapidly absorbed to the systemic circulation following the administration to airway locally (11). Few studies were found which assessed the safety and serum levels of lignocaine after local application to the airway in adults and children.

In one study to assess the serum levels of topical lignocaine in fibre optic bronchoscopy Sucena et al demonstrated that even some patient’s serum levels have exceeded the toxic levels they did not show any adverse effect (20). Serial blood samples were taken before and after the administration of lignocaine as 2% gel, 10% spray and 2% liquid respectively during the procedure (cumulative dose of 11.6 +/- 3.1 mg/kg). Six out of 30 participants showed higher serum levels than the toxic level but without any untoward effects. Hence, the author suggested that even higher doses of topical lignocaine would be safe in flexible bronchoscopy. Similarly, Loukides et al demonstrated that although the total dose of local lignocaine used in the study has exceeded the recommended highest dose in all 12 adult participants, none of them reached the toxic serum level and no one developed an adverse effect during the flexible bronchoscopy (21). They also demonstrated that peak plasma lignocaine concentration could be achieved within 20-30min of administration. However, the study population was only 12. Therefore, the applicability of this study to practical setup is limited.     

Efthimiou et al also studied the plasma concentration of lignocaine during the fibreoptic bronchoscopy (22). They recorded lignocaine concentration of 41 adult patients who received tropical application during fibreoptic bronchoscopy. Average total dose of  9.3 +/- 0.5 mg/kg was used. All achieved adequate level of anaesthesia and mean plasma concentration reached was 2.9 +/- 0.5 mg/l. All patients including 2 who have exceeded the toxic level did not show any complication. This study also demonstrated that peak plasma concentration depends only on the mg/kg dose. Other factors which might influence the mucosal absorption like airflow obstruction, sputum production and smoking did not show any significant association. Similar observation published by Milman et al in 1998 after studding the serum lignocaine concentration during fibreoptic bronchoscopy of 16 patients (23). Total dose of lignocaine 2.4-8.0 mg/kg were used, including nebulized dose 1.6-6.6 mg/kg. Serum lignocaine concentration was correlated only with the total mg/kg dose and no complications were detected. This team of investigators also concluded that lignocaine could be used safely as a local anaesthetic agent for flexible bronchoscopy with a total dose which maintaining below 6-7 mg/kg body weight.

Scieszka et al studied the serum level of lignocaine following nebulization via a high frequency jet ventilator during flexible bronchoscopy (24). All 12 adult participants achieved adequate level of anaesthesia while, none of them developed untoward effects and none of them required additional lignocaine doses. Therefore, this team concluded that nebulized lignocaine is also effective and safe for flexible bronchoscopy.

Amitai et al studied the serum lignocaine concentration during flexible bronchoscopy in children and published the results in 1990 (25). In this study, lignocaine was given to the airway via bronchoscope. Serial blood samples were drawn to assess the lignocaine serum concentration in 15min intervals. 15 children (3months – 9.5year) were participated and total lignocaine dose was ranged from 3.5 to 8.5mg/kg. Peak serum lignocaine concentration was 1-3.5µg/ml and it was well correlated with the total lignocaine dose. Despite, some children exceeded the total recommended dose and potential toxic serum level, none has developed a complication. Hence, they concluded that the use of tropical lignocaine up to 8.5mg/kg appear to be safe in children. Gjonaj et al also did a similar kind of study to assess lignocaine concentration during flexible bronchoscopy in children. However, in this study nebulized lignocaine was used instead of direct local application through the bronchoscope (11). In this prospective randomized double blind study 20 children (1.5 – 192 months) received either 4mg/kg or 8mg/kg dose of lignocaine via a nebulizer. Intravenous midazolam and additional doses of lignocaine via bronchoscope were given while doing the procedure by a blinded bronchoscopist if it was needed. Fifty percent of children in both groups tolerated the procedure only with nebulized lignocaine and they did not require any additional doses via bronchoscope. The highest serum level of lignocaine achieved following nebulization was 0.62µg/ml, a level far below the toxic level. The supplemental lignocaine which needed was 1.2-3.3mg/kg in 4mg/kg nebulized group and 1.8-11.6mg/kg in 8mg/kg nebulized group. However, none has developed a feature of lignocaine toxicity. Furthermore, those children also did not develop any adverse effect like bronchospasms due to the use of nebulized route. Finally, the authors concluded that nebulized lignocaine up to 8mg/kg doses appears to be safe in paediatric flexible bronchoscopy and it was moderately effective as a tropical agent in anaesthesia for this procedure.

The safety of lignocaine as a topical anaesthetic agent for flexible bronchoscopy in both adults and children has been proven objectively by many studies and few of them have mentioned above. Lignocaine topical application to achieve anaesthesia for bronchoscopy could be done in several ways. Direct tracheal injection through cricothyroid membrane, local spray to pharynx and larynx with the use of a plastic cannula, local application of lignocaine as a gel, direct application of the liquid form in to airway through the working channel of bronchoscope in “spray as you go” fashion and nebulization of the medication via a jet or ultrasonic nebulizer are the mostly used methods (26). Each of these method has its own advantages and disadvantages. There were some studies done to assess the effectiveness of lignocaine as a topical anaesthetic agent, while, they also compared the effectiveness of different modalities of local application of lignocaine. Most of these studies done in adults.

Stolz  et al did a prospective, double blind, randomized controlled trail to evaluate the additional benefits of nebulized lignocaine in flexible bronchoscopy. One hundred and fifty adult patients were participated in this study (26). Patients were sedated using intravenous hydrocodone and midazolam boluses. All received nebulization of either 4 mL of 4% lignocaine or 4 mL of normal saline as a placebo. Both groups received 10% lignocaine spray to nasopharynx 4times and to oropharynx 2times. Additional lignocaine doses were given through the bronchoscope while doing the procedure as decided by the bronchoscopist. Following the procedure both bronchoscopist and patient gave a rating for their perception of cough during the procedure using a 100mm visual analogue scale. There were no difference in cough scores of both physician and patients in both groups. Other outcome parameters like duration of procedure and haemodynamic findings were also similar in both groups. Mean lignocaine dose used for the nebulized group was significantly higher than the placebo group. Therefore, additional nebulized lignocaine for flexible bronchoscopy under combined sedation was not recommended by the authors. It seems that a significant level of anaesthesia in the upper airway has been achieved with 10% lignocaine spray in both groups during this study. Hence, the place for additional nebulized lignocaine has dropped. However, in paediatric practice local spray of lignocaine to nasopharynx and oropharynx cannot be achieved as in adults because this need a very good patient cooperation. It is virtually impossible in small children and infants as they are unable to keep their mouth open according to instructions until local spray is being carried out. Therefore, in children still there would be a place for nebulized lignocaine.

There are some studies in adults which proved the effectiveness of nebulized lignocaine as similar as the local instillation via bronchoscope. Perhaps, more patient satisfaction was achieved with the nebulized route. The tendency to stimulate cough while instilling a liquid directly in to highly innervated larynx might be the reason for this. Isaac PA et al did a single blinded study to compare the effectiveness of nebulized lignocaine via an inexpensive and portable jet nebulizer with other two method of local lignocaine application namely, cricothyroid puncture and direct instillation through bronchoscopy (27). The main outcomes of the study, physician’s and patient’s assessment of the overall condition of the procedure were done using a 100mm visual analogue scale. Nebulization method was used successfully in 46 of 48 (96%) patients. The cricothyroid injection has produced better condition than nebulization. However this method is not practising in children. Nebulization method was as satisfactory as local instillation method. Nebulization was safe, effective and both bronchoscopist and patient accepted it well. No adverse effects were recorded even though higher than the recommended dose was used in some patients. Keane et al also did a similar kind of study to compare the efficacy of nebulized lignocaine with local spray technique (14). All 54 adult patients received 100mg of lignocaine either via nebulization (2.5ml of 4% solution) or via a standard spry device (10mg/spray in 10 times). All patients received additional total 100mg of lignocaine to the vocal cords, trachea and main bronchi via bronchoscope. Cough frequency which assessed after listening to an audio record of the procedure was the main outcome. No significant difference was observed in overall cough frequency of both groups. However, most patients in spry group reported that the spray was unpleasant. Therefore the investigators concluded that nebulized lignocaine as effective as local spray in flexible bronchoscopy and patient preference towards the nebulized route.   

Korttila et al compared the ultrasonic nebulizer and laryngotracheal administration of lignocaine for bronchoscopy under conscious sedation (15). Bronchoscopist rated the adequacy of local anaesthesia and patient cooperation using a 100mm visual analogue scale. Both ratings were higher in the local spray group. Peak plasma concentration of lignocaine achieved earlier in nebulization group and it was lower than the local spray group. Even though, the ratings were higher for local spray group, nebulized group also achieved adequate anaesthesia to carry out the procedure and no adverse effects were recorded. Hence, the study group concluded that bronchoscopy can be conducted using nebulization as successfully and safely as local spray of lignocaine. Nebulization route would be more important in children because local spray in to larynx is not feasible, especially in younger ones. A somewhat similar kind of study was done by Giriraj et al in 2014 to assess the effectiveness of nebulized lignocaine as a topical anaesthetic agent in diagnostic transnasal tracheoscopy, a similar procedure as flexible bronchoscopy done by ENT surgeons (14). A retrospective chart review and prospective case series were used. Eight patient received both modalities in two different occasions. 11 of 16 patients (69%) who received local instillation of lignocaine to the larynx via the working channel of tracheoscopy resulted in strong cough, whereas, 98% of patients who received nebulized lignocaine have completed the procedure comfortably. 100% of patients who have the experience of both modalities preferred local anaesthesia with nebulizer alone. Gove et al compared the use of nebulized lignocaine with local instillation in fibreoptic bronchoscopy under conscious sedation in 1985(28). The authors noted that nebulized lignocaine alone could be used for bronchoscopy because it provided adequate level of anaesthesia and procedure were performed more quickly. They finally concluded that nebulized lignocaine alone or with diazepam premedication is effective, safe and acceptable method of induction of topical anaesthesia for flexible bronchoscopy. Kaur et al demonstrated that with the use of nebulized and local spray of lignocaine prior to the procedure, there were no significant difference between the effectiveness of 1% or 2% lignocaine instillation during the procedure to achieve topical anaesthetic effect during flexible bronchoscopy (29). Hence, when combined with prior nebulization, 1% lignocaine would be sufficient to achieve adequate level of anaesthesia instead of using 2% solution.     

A systemic review done by Mihara et al in 2014 demonstrated that topical lignocaine reduce the possible laryngospasms in children during upper airway procedures (30). However, Nielson  et al. demonstrated that direct application of lignocaine solution in to larynx might affect the assessment laryngomalacia in children during flexible bronchoscopy because, it induce increase in signs of laryngomalacia (31). Hence, local lignocaine might exaggerates the clinical findings of laryngomalacia during bronchoscopy.

Even tough, there is no consensus about the safe dose of lignocaine for topical anaesthesia of the airway, 4mg/kg is generally consider as the cut off. However, in practical setup this dose limit is usually exceeding and up to 8mg/kg proven as safe (10). 

RATIONALE OF THE STUDY

Nebulization of medications believed to produce more even and through application of medication along the entire mucosa of the airway. Even if it is an off labelled use, the safety and effectiveness of nebulized lignocaine as a mode of topical anaesthesia in flexible bronchoscopy has been proven (32). Even though, one of the primary objective of using topical lignocaine during bronchoscopy is to reduce cough, direct application of liquid form in to unanaesthetised highly innervated airway itself potential to induce intense cough. In addition, assessment of some conditions like laryngomalacia might be adversely affected by direct local instillation. However, nebulization of the medication likely to be less irritant to the mucosa of the airway in comparison to the direct tropicalization via bronchoscope (10). Most of the adults preferred nebulization route than direct local instillation route in above mentioned studies. As nebulized medications are frequently used in children and it seems well tolerated by them, nebulized lignocaine also could be used in children undergoing flexible bronchoscopies under conscious sedation. This might enhance the topical anaesthesia in nasal passage, larynx, trachea and bronchi at the same time. Common practices which done in adults, prior to the bronchoscopy procedure to achieve topical anaesthesia, like tropical application of lignocaine gel in to nasal passage and spray of lignocaine to pharynx and larynx are not feasible in children as this need good patient cooperation. Perhaps, that kind of measures might scare children more. On the other hand, prior preparation of children with nebulized topical anaesthesia at the bedside, before sending to the bronchoscopy suite might reduce the cumulative time taken for the procedure. Due to all these reasons, there would be a place for nebulized lignocaine as a topical anaesthetic agent for flexible bronchoscopy done in children under conscious sedation. Hence, assessment of the effectiveness of nebulized route in comparison to the routine local instillation through the working channel of the bronchoscope “spray as you go fashion” would be important. Unfortunately, no study was found which compared these two methods in children indicating a gap in knowledge of this field. Therefore, we planned a randomized open labelled control trail to compare these two modalities of lignocaine tropicalization in paediatric flexible bronchoscopy.     

 RESEARCH QUESTION:

•      Is nebulized lignocaine efficacious topical anaesthetic agent in paediatric flexible bronchoscopy done under conscious sedation when compared to conventional locally instilled lignocaine directly through the bronchoscope in a "spray as you go" fashion? 

•      Nebulized lignocaine is not inferior to locally instilled lignocaine directly through the bronchoscope in a "spray as you go" fashion, as a topical anaesthetic agent in paediatric flexible bronchoscopy done under conscious sedation. 

•      To compare the efficacy of nebulized lignocaine and locally instilled lignocaine directly through the bronchoscope in a "spray as you go" fashion, as a topical anaesthetic agent in flexible bronchoscopy done under conscious sedation in children aged 1moth to 16 years.

 SECONDARY OBJECTIVES-

•      To compere the following parameters to assess the safety and easiness of the procedure while using these two modalities of topical anaesthesia.

Patient’s safety

•      Intensity of cough and stridor which developed or worsened due to the procedure

•      Adverse events during the procedure (Oxygen desaturations, Tachy or Bradycardia)

•      Total dose of lignocaine used for the procedure

•      Need of top up doses of sedative drugs and cumulative dose of each medication used during the whole procedure.

•      Older children’s (more than 5y) felling about the maximum pain they perceived during the procedure.  

Easiness of the procedure

•      Time taken to enter in to the lower airway through larynx

•      Total duration of the procedure

•      Physician’s and bronchoscopy nursing sister’s overall felling about the easiness of the procedure

OUTCOME MEASURES

• Primary Outcome

Secondary Outcomes

1. Patient’s safety

2. Easiness of the procedure

METHODOLOGY

Study design:  Randomized open labelled control trial

Study period: July 2016 to January 2017

Place of study:  Bronchoscopy suite, Division of Pediatric Pulmonology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi

Study population: Children aged 1 month to 16 years with respiratory diseases, who have an indication for a flexible bronchoscopy as already decided by the   in-charge consultant paediatric pulmonologist of the unit.

Inclusion criteria:

Children aged 1 month to 16y with respiratory diseases and already selected for a flexible bronchoscopy under conscious sedation at the paediatric bronchoscopy suite, AIIMS. No healthy volunteer will be included.

Exclusion criteria:

1. History of any kind of adverse reaction to lignocaine given by any route
2. History of any adverse reaction to any other medication which use in the procedure (Atropine, Midazolam, Fentanyl)
3. Children who are already given sedative drugs or lignocaine within 72hours of the procedure.
4. Children who are already on ventilatory support via ETT or tracheostomy
5. Children with SpO2 <92% with 5l/min O₂ at the time of enrolment
6. Children with GCS <15/15 at the time of enrolment, due to any reason
7. Already diagnosed children with cardiac arrhythmias
8. Already diagnosed children with acute or chronic, liver or renal failure 
9. Not consented

Children who are followed up at out patient’s clinic will be admitted to C5 day care unit for bronchoscopy on the day of the procedure, if they were selected for a bronchoscopy by the in-charge consultant paediatric pulmonologist of the unit if there is a medical indication.

Bronchoscopy will be done in some children who are on inward treatment at AIIMS if there is an indication.

First, all these children will be assessed with a routine bronchoscopy check list of the unit according to the unit policy to confirm the fitness and preparation for the procedure at the day of the procedure (annexure-01).  Bronchoscopy will be done only in children who fulfil the criteria according to that checklist and those who have been selected will be evaluated for the enrolment. All children of 1month to 16years, who have been selected for bronchoscopy will be evaluated with a pre prepaid enrolment form (annexure-02) to assess the eligibility for the study. Children who fulfil any exclusion criteria will be excluded.

If the patient is eligible, parent’s information sheet will be given (Annexure-03) and informed written consent (Annexure-04) will be taken from parents by the chief investigator.  Consented children will be enrolled to the study. 

Computer generated Variable Blocked randomization will be used to allocate equal number of children randomly for both arms of the study. Randomization will be performed by a person not involved in the study.

ALLOCATION CONCEALMENT

Sequentially numbered opaque envelops will be used for allocation concealment. Each patient will be given a serial number according to the order of enrolment. All the envelopes will be kept inside the bronchoscopy room in a locker and envelopes will be taken out according to the serial number. The allocated envelop to a particular serial number will be opened by the bronchoscopy nurse and randomly allocated study arm of that particular serial number will be disclosed to the in charge senior resident for bronchoscopy on that day.

As one arm use nebulization and the other arm use local instillation of liquid form through the bronchoscope, the project will be carried out as an open labelled study. Local instillation of N.saline alone in to larynx as a placebo in nebulization arm might induce intense cough and nebulization of N.saline alone as a placebo in local instillation arm might produce, bronchospasms. Hence, a use of a placebo to facilitate blindness was not considered.  

INTERVENTION

Arm 01 :  Nebulization of 4mg/kg lignocaine 15min prior to bronchoscopy + IV Atropine 0.01mg/kg,  IV Midazolam 0.1mg/kg and IV Fentanyl  2 µg/kg +  (Additional Midazolam 0.1mg/kg + additional Lignocaine 1mg/kg local instillation via bronchoscopy 1-2 times if required)

Arm-02 : IV Atropine 0.01mg/kg,  IV Midazolam 0.1mg/kg and IV Fentanyl  2 µg/kg + Local instillation of lignocaine 2mg/kg via bronchoscope to larynx + 2mg/kg at carina. +  (Additional Midazolam 0.1mg/kg + additional Lignocaine 1mg/kg local instillation via bronchoscopy 1-2 times if required)

PROCEDURE:

First, children at day care or paediatric ward who are already prepared for the bronchoscopy will be assessed again with the routine bronchoscopy check list of the unit to confirm the preparation and suitability for the procedure on that day. Then children who have been selected for bronchoscopy, will be assessed with the enrolment form to select them for the study. Parents of the children who do not meet the exclusion criteria will be explained about the study and consent form will be given by the chief investigator. If parents give the informed written consent for the participation, children will be enrolled to the study. Once a patient is enrolled a serial number will be given according to the order of the enrolment.

The envelop which is already allocated to child’s serial number will be opened by the bronchoscopy nurse and randomly allocated study arm for that particular child will be revealed to the in charge senior resident for bronchoscopy on that day.

Then child’s pulse rate, respiratory rate and SpO2 on room air or with O2 <5l/min will be recorded at the bedside. (Children with SpO2 <92% with 5l/min O2 already excluded from the study). Presence of stridor before the procedure will be recorded. Children who have been randomly allocated to the nebulization arm will be nebulized with lignocaine 15min prior to the procedure at bedside using a jet nebulizer and appropriate sized well-fitting face mask according to the age.

Lignocaine dose for nebulization will be 4mg/kg and 2% lignocaine solution (20mg/ml) will be used. The dose for a 10kg child will be 2ml. The minimum dose used in the study will be 1ml and maximum dose will be 5ml of 2% lignocaine solution. (All children below 5kg receive 1ml and all children above 20kg will receive 5ml of 2% lignocaine solution. Children between 5-20kg will receive 1-5ml of 2% lignocaine solution according to the weight). Nebulized salbutamol solution 0.1mg/kg also will be added to the nebulizer in children who has a history of wheezing. Then, normal saline up to 4ml will be added if necessary to make the final volume of nebulization solution 3ml for children below 10kg and 5ml for children above 10kg to facilitate effective nebulization through the jet nebulizer. Total time for nebulization expected to be 10-15min. Following nebulization, children will be shifted to the bronchoscopy suite which is situated in the same floor of the same premises of paediatric ward and day care.

Children who have been randomly allocated to local instillation arm will be nebulized with 0.1mg/kg salbutamol solution if there is a history of wheezing 15min before sending to bronchoscopy suite. (Nebulization of salbutamol for children with a history of wheezing before the procedure is a routine practice of the unit). Other children who does not have a history of wheezing and have been allocated randomly to study arm-02 will be sent to the bronchoscopy room directly without any prior medication. All these children’s pulse rate, respiratory rate and SpO2 on room air or with O2 <5l/min, presence of stridor will be recorded at the bedside before sending.

At the bronchoscopy room child’s pulse rate, respiratory rate, SpO2 and presence of stridor will be documented again. Child will be connected to a pulse oxymeter and monitoring continued throughout the procedure and 2h following the procedure or till child become fully awake, whichever comes last. Then all the children in the study (both arms) will receive following medications to achieve conscious sedation. IV- Atropine 10µg/kg, IV-Midazolam 0.1mg/kg, IV-Fentanyl 2µg/kg respectively. All the IV injections will be followed by a flush with 1-2ml N. Saline. Closure of eyes will be considered as the sign of sedation. Usually children achieve sedation with this combination. If child does not sleep 3min after IV fentanyl injection, IV-Midazolam 0.1mg/kg will be repeated. If child wakeup during the procedure, an additional midazolam 0.1mg/kg will be used. All the used drugs will be recorded and final total dose will be calculated.

Child will be continuously monitored using a pulse oxymeter as mentioned above. All the medications and equipment required for an emergency resuscitation will be kept in the bronchoscopy room. All the medical staff working in the bronchoscopy room have completed the Paediatric Life Support Course and competent in resuscitation of children if they develop any complication due to medications or procedure.

Lignocaine solutions for mandatory instillation in study arm-02 and additional instillation, if it is required in both arms will be prepared before the procedure and will be kept in labelled sterile syringes separately. For a patient in study arm-2, two aliquots of 2mg/kg lignocaine and additional 2 aliquots of 1mg/kg will be prepared. For a 10kg child, 2 aliquots of  2% lignocaine solution 1ml and 2 aliquots of 2% lignocaine 0.5ml will be taken and all diluted 1:1 with normal saline. For study arm-01, only 2 aliquots of  1mg/kg lignocaine solution (2% lignocaine 1:1 diluted with normal saline) will be prepared and will be kept in labelled sterile syringes separately.   

A free flow of O₂ 5l/min will be given to all children throughout the procedure despite their preprocedure O₂ saturation values. Once the child sleeps (indicated by eye closure) and maintain SpO2 >92% with spontaneous respiration and HR >60/min bronchoscopy procedure will be started. A video camera will be started to record child’s cough. This camera will be focussed only to child’s face and hence, use of medications during the procedure will not be recorded to maintain blindness during the assessment of cough frequency later. The camera will be kept in the same place for all procedures and the bronchoscopy bed also will be kept in the same place for all procedures. Same video camera and same settings will be used for all recordings.       4% lignocaine gel will be applied to the distal 10cm of the bronchoscope prior to insertion in both arms of the study to facilitate the passage through the airway. Nasal route will be used to advance the bronchoscope. Two stop watches will be activated once the tip of the bronchoscope inserted to a nostril of the child to advance it through the airway. One will be stopped when tip of the bronchoscope advance through the vocal cords and other will be stopped when tip of the bronchoscope remove from the nostril after completion of whole procedure. Both times will be recorded and those will be taken as the time taken to advance the bronchoscope through larynges and total duration of the procedure respectively.

Once the bronchoscope is advanced through the nasal passage of a child and enter in to the larynx rest of the procedure will be differed according to the study arm.

Study arm 01: Nebulization group.

No local instillation of lignocaine through the bronchoscope will be done at larynx. However, while advancing the bronchoscope to larynx if child develop cough and if cough persisted more than 10 seconds, 1mg/kg lignocaine will be instilled to the larynx through the bronchoscope (Already prepared 1:1 diluted solution will be used). Similarly, while passing the scope through trachea and if child develop cough and if it is persisting for more than 10seconds another 1mg/kg already prepared lignocaine solution will be instilled in to carina through the bronchoscope.

Study arm 02 : Local instillation group

Lignocaine 2mg/kg will be instilled to the larynx through the working channel of the bronchoscope for all children who have been randomly allocated to study arm 02. Then the bronchoscope will be advanced through vocal cords. If child develop cough and if it is persisting for more than 10 seconds preventing the access through the vocal cords additional 1mg/kg lignocaine will be instilled to vocal cords. Then all children of study arm 02 will received 2mg/kg of lignocaine to the carina through the bronchoscope in “as you go fashion”. If child develop cough during the examination of trachea and bronchi after this mandatory dose and if cough persisting continuously more than 10seconds, an additional dose of already prepared lignocaine 1mg/kg will be given to lower airway.

 Criteria for additional doses-

For both arms, consideration for additional doses of topical lignocaine to be done if child’s cough persisting continuously for more than 10 seconds only. Intermittent cough during the procedure will not be consider as an indication for additional doses. All the topical anaesthesia used for the procedure will be documented and total dose, including additional doses will not be exceed 6mg/kg.

All the children will be given free flow of 5l/min O₂ throughout the procedure and O₂ flow will be increased if SpO₂ drops <92% or >5% of the baseline value for more than 10s.

The cumulative time duration which child develop desaturations (SpO₂ drop >5% from pre-procedure value) during and 1h after the procedure will be recorded in seconds, using another stop watch. The minimum SpO₂ level which child develops will also be recorded.

Child minimal heart rate and maximum heart rate during and 1h after the procedure will be recorded to calculate the deviation from pre procedure value later.

After completion of the procedure child will be sent back to the paediatric ward or day care and SpO2 and Pulse rate will be monitored with a pulse oxymeter continuously for 2h or  till child become fully awake, whichever comes last.

Assessment of the frequency of child’s cough and intensity of child’s cough and stridor

This will be done later by watching the video of the child’s face during the procedure by two independent observers who are blinded for the mode of topical anaesthesia. Ten recordings will be assess at a time. While, playing the video, two observers will count the number of time child cough during the procedure. The two observers will do this independently and chart it while, unrevealing to each other. The mean count of both observers will be taken and it will be divided by the total duration of the procedure (already measured with a stopwatch) to get the rate. After watching the video record the same observers will give an overall rating for the intensity of child’s cough independently. For this 100mm visual analogue scale will be used according to the ERS guidelines on assessment of cough (33). Same visual analogue scale will be used in same manner to give an overall rate about stridor, if child developed or worsened it due the procedure. Both observers will give these rating independently unrevealing to each other and average will be taken as the value for that particular child. Same room and same time of the day will be used to play the recordings.

Same level of volume and same audio and video settings will be kept for all assessments.

Same two individuals who are not participating for the study directly will do all the blinded assessments.   

Assessment of “Easiness of the procedure”-Physicians and nurse’s view 

A rating for overall easiness of the procedure will be given by the bronchoscopist and bronchoscopy nurse within 10min after completion of the procedure using a 100mm VAS.

Assessment of Child’s overall perception of pain during the procedure

Wong-Baker FACES® Pain Rating Scale (http://www.wongbakerfaces.org/)will be given to children >5y to rate their feeling of pain during the procedure (Annexure-05). The way of rating will be explained to children in simple language. Assessment will be done 2h after the procedure or when they are fully awake, whichever comes last. Even though, this scale has been validated for the assessment of pain in children above 3years, children over 5year will be taken to obtain more accurate assessment. 

SAMPLE SIZE

There is no published study which compared these two method of local anesthesia of airway for bronchoscopy in children. Therefore, 50 patients will be enrolled for the trail at the beginning. Then, an interim analysis will be done after 30 patients to calculate sample size and study will be proceed to obtain that sample size.

DATA COLLECTION

Data will be collected using a pre-prepared data collection sheet by the principal investigator

This will include- Identification and demographic data, base line vital signs and outcome variable measures.

STATISTICAL ANALYSIS

Data will be analyzed according to the intention to treat principal. Add- Data will presented as median (IQR) if data not normally distributed and will be compared using MannWhitney test. The mean frequency of cough (number of cough episodes per a minute) in two groups will be calculated and expressed as mean+ SD. Statistical significance will be assessed using student’s t test.  Score for intensity of cough, stridor, assessment of easiness by the physician and nurse,  assessment of perceived pain by children>5y using the pain score, total  doses of midazolam and lignocaine (expressed as mg/kg), total duration of the procedure and time taken to enter through vocal cords (expressed in seconds), minimum heart rate, maximum heart rate and deviation of heart rate from pre-procedure value, total duration of time which SpO₂ drop >5% from pre-procedure value will also analyzed in a similar way. Chi-squared test will be used for assess the number of children who develop stridor during the procedure, number of children who develop bradycardia (heart rate <60/min) during the procedure.  

ETHICAL ISSUES:

Children already selected for bronchoscopy due to a medical indication will be taken for the study. No new or additional drug will be used. Only the route of administration of a routinely used drug will be changed. The safety and effectiveness of the nebulized route for the administration of topical lignocaine has been proven in adults. Even a higher doses of nebulized lignocaine has been used, the plasma levels proven to be well below the toxic level. (According to the studies in adult bronchoscopies and upper airway procedures in children other than flexible bronchoscopy). Nebulized lignocaine up to 8mg/kg for bronchoscopy has been proven to be safe in children. We use lignocaine 4mg/kg for this study and go up to maximum 6mg/kg if it is needed only during the procedure. Children will be monitored closely during and after the procedure. If a child develops any adverse effect it will be managed appropriately by a competent medical team at AIIMS. This trial will be conducted only after obtaining the approval from AIIMS ethics committee.

Costs Involved

Drugs will be supplied in the hospital. There will be no charges for the study procedures or participation

DSMB

A committee of three persons not involved in the trial or data collection will be formed to supervise the trial.

Dissemination of Results

The data will be analysed and manuscript will be prepared by Dr S.S.C.de Silva  and he will be the lead author. All supervisors will be co-author for the manuscript.

REFERENCE

1. Casal RF, Ost DE, Eapen GA. Flexible bronchoscopy. Clin. Chest Med. 2013;34(3):341–352.

2. Du Rand IA, Blaikley J, Booton R, et al. British Thoracic Society guideline for diagnostic flexible bronchoscopy in adults Thorax 2013;68:i1–i44.

3. Dooms C, Seijo L, Gasparini S, Trisolini R, Ninane V, Tournoy KG. Diagnostic bronchoscopy: state of the art. Eur Respir Rev 2010; 19: 117, 229–236

4. Wood RE, Fink RJ. Applications of flexible fiberoptic bronchocopes in infants and children, Chest 1978; 73:737.

5. American Thoracic Society. Flexible endoscopy of the pediatric airway. American review of respiratory disease 1992;145:233-235

6. de Blic H, Marchac V, Scheinmann P. Complications of flexible bronchoscopy in children: prospective study of 1,328 procedures. Eur Respir J 2002; 20: 1271–1276

7. Morris MJ, Kwon HP, Zanders TB. Monitoring, Sedation, and Anesthesia for Flexible Fiberoptic Bronchoscopy, Global Perspectives on Bronchoscopy.2012. Dr. Sai P. Haranath (Ed.), InTech, DOI: 10.5772/47917.

8. Sharma GK, Verma SP. Is Nebulized Lidocaine Adequate Topical Anesthesia for Diagnostic Transnasal Tracheoscopy? Ann Otology, Rhinology & Laryngology 2015; 124:545–549

9. Jose RJ, Shaefi S, Navani N. Sedation for flexible bronchoscopy: current and emerging evidence. Eur Respir Rev 2013; 22: 128, 106–116

10. Roberts MH, Gildersleve CD. Lignocaine topicalization of the pediatric airway. Pediatric Anesthesia 2016;26: 337–344

11. Gjonaj ST, Lowenthal DB, Dozor AJ. Nebulized lidocaine    administered to infants and children undergoing flexible bronchoscopy. Chest 1997;112:1665-9 

12. Efthimiou J, Higgenbottam T, Holt T, et al. Plasma concentrations of lignocaine during fibreoptic bronchoscopy. Thorax 1982; 37:68-71

13. Jakobsen CJ, Ahlburg P, Holdgard HO, et al. Comparison of intravenous and topical lidocaine as a suppressant of coughing after bronchoscopy during general anaesthesia. Acta Anaesth Scand 1991; 35:238-41

14. Keane D, McNicholas VT. Comparison of nebulized and sprayed topical anaesthesia for fibreoptic bronchoscopy. Eur, Respir J 1992; 5:1123-25

15. Kortilla K, Tarkkanen J, Tarkkanen L. Comparison of laryngotracheal and ultrasonic nebulizer administration of lidocaine in local anaesthesia for bronchoscopy. Acta Anaesth Scand 1981; 25:161-65

16. Graham DR, Hay JG, Clague J, et al. Comparison of three different methods used to achieve local anesthesia for fiberoptic bronchoscopy. Chest 1992; 102:704-07

17. Somu N, Vijayasekaran D, Ashok TP, Balachandran A, Subramanyam L.  Flexible fibreoptic bronchoscopy in 582 children-value of route, sedation and local anesthetic. Indian Paediatrics 1995; 32:543-547

18. Cox B , Durieux ME , Marcus MA. Toxicity of local anaesthetics . Best Pract Res Clin Anaesthesiol . 2003;17: 111 - 136 .

19. Thomson AH, Elliott HL, Kelman AW, Meredith PA, Whiting B. The pharmacokinetics and pharmacodynamics of lignocaine and MEGX in healthy subjects. J Pharmacokinet Biopharm. 1987;15:101-15

20. Sucena M, Cachapuz I, Lombardia E, Magalhães A, Tiago Guimarães J. Plasma concentration of lidocaine during bronchoscopy. Rev Port Pneumol. 2004;10:287-96

21. Loukides S, Katsoulis K, Tsarpalis K, Panagou P, Kalogeropoulos N. Serum concentrations of lignocaine before, during and after fiberoptic bronchoscopy. Respiration. 2000;67:13-7.

22. Efthimiou J, Higenbottam T, Holt D, Cochrane GM. Plasma concentrations of lignocaine during fibreoptic bronchoscopy. Thorax. 1982;37:68-71.

23. Milman N, Laub M, Munch EP, Angelo HR. Serum concentrations of lignocaine and its metabolite monoethylglycinexylidide during fibre-optic bronchoscopy in local anaesthesia. Respir Med. 1998;92(1):40-3.

24. Scieszka S, Droste H, Mayer M, Schlenkhoff D. Serum levels of lidocaine as affected by high frequency jet ventilation during bronchoscopies under local anaesthesia. Anaesthesist. 1988;37:420-4.

25.Amitai Y, Zylber-Katz E, Avital A, Zangen D, Noviski N. Serum lidocaine concentrations in children during bronchoscopy with topical anesthesia. Chest 1990;98:1370-1373

26. Stolz D, Prashant N, Leuppi J, Pflimlin E, Tamm M. Nebulized Lidocaine for Flexible

Bronchoscopy. Chest 2005;128:1756–1760

27. Isaac PA, Barry JE, Vaughan RS, Rosen M, Newcombe RG. A jet nebuliser for delivery of topical anesthesia to the respiratory tract. A comparison with cricothyroid puncture and direct spraying for fibreoptic bronchoscopy. Anaesthesia. 1990; 45:46-48.

28. Gove RI, Wiggins J, Stableforth DE. A study of the use of ultrasonically nebulized  lignocaine for local anaesthesia during fibreoptic bronchoscopy. Br J Dis Chest. 1985 Jan;79:49-59

29. Kaur H, Dhooria S, Aggarwal AN, Gupta D, Behera D, Agarwal R. A Randomized Trial of 1% vs 2% Lignocaine by the Spray-as-You-Go Technique for Topical Anesthesia During Flexible Bronchoscopy. Chest 2015;148:739 – 745

30. Mihara T, Uchimoto K, Morita S et al. The efficacy of lidocaine to prevent laryngospasm

in children: a systematic review and meta-analysis. Anaesthesia 2014; 69: 1388–1396.

31. Nielson DW, Ku PL, Egger M. Topical lidocaine exaggerates laryngomalacia during flexible bronchoscopy. Am j respir crit care med 2000;161:147–151.

32. Shirk MB, Donahue KR, Shirvani J. Unlabeled uses of nebulized medications. Am J Health Syst Pharm. 2006;63:1704-16.

33. Morice AH Et al. ERS guidelines on the assessment of cough. Eur Respir J 2007; 29: 1256–1276