PAEDIATRIC MEDICINES RESEARCH GROUP DIVISION OF GRADUATE ENTRY MEDICINE AND HEALTH SCHOOL OF MEDICINE UNIVERSITY OF NOTTINGHAM THE USE OF PROCEDURAL SEDATION IN CHILDREN BADRIYAH SHADID ALOTAIBI BPharm, MSc. THESIS SUBMITTED TO THE UNIVERSITY OF NOTTINGHAM FOR THE DEGREE OF DOCTOR OF PHILOSOPHY SEPTEMBER, 2016 DEDICATION DEDICATED WITH LOVE TO MY PARENTS, MY HUSBAND, MY CHILDREN AND ALL MY FAMILY MEMBERS IN SAUDI ARABIA. I ABSTRACT The use of sedation for diagnostic and therapeutic procedures in children is common and leads to considerable debate. Evaluating this subject is complicated by differences in the methods and the outcomes used for sedation assessment in children reported in the literature which are large. This thesis used systematic literature reviews, a prospective study and a national survey to evaluate several aspects of paediatric sedation. A systematic review of the safety and effectiveness of chloral hydrate in three categories of procedural sedation was conducted. For painless procedural sedation, chloral hydrate was more effective for shorter imaging procedures, such as CT scanning. The incidence of adverse events was 1,951 occurring in 14439 patients (13.5%), with hypoxia the most frequent. Moderate hypoxia (SpO2 85%–90%) was seen in 281 cases of 14439 patients (1.9%) of children. For painful procedural sedation, the success rate of chloral hydrate was variable (35%–100%). Hypoxia was the most common adverse event, occurring in 95 of 1810 patients (5.2%). Most (66 cases/1810 patients, 3.6%) were mild however moderate hypoxia occurred in 29 of 1810 patients (1.6%). The incidence of adverse events was higher during painful procedures than during painless procedures: 313AEs/1810 patients (17.3%) versus 1,951AEs/14439 patients (13.5%). The most frequent use of chloral hydrate as a treatment was to reduce agitation during mechanical ventilation, followed by treatment of neonatal diseases and treatment of neurological disorders. The reported success rate was high throughout all treatment procedures (86%–100%). The incidence of hypoxia was found to be the II highest, when it was used for the treatment of agitation 71 cases/438 patients (16.2%). Due to the heterogeneity between the studies it was not possible to perform meaningful statistical analysis. The effectiveness and safety of triclofos (a chloral hydrate derivative) was evaluated for procedural sedation in children, in a systematic review of the literature. The success rate was variable (ranging from 50 to 100%), shorter procedures such as CT scanning were more likely to be successful. Vomiting and hypoxia were the most frequently reported adverse events, 10% (62/613) and 7.8% (48/613) respectively. A systematic literature review of the safety and effectiveness of paraldehyde as a sedative agent for children was performed, as it was named as a second line agent in the sedation policy of the Derbyshire Children's Hospital. The literature is scant; only five studies were located and involved 157 patients. The reported effectiveness of paraldehyde ranged from 75- 93%. Vomiting was the most commonly reported adverse event (2 cases/8 patients, 25%). Due to the small numbers of patients and poor methodology of studies, its clinical use cannot be supported. A further systematic literature review of 29 studies involving 6342 children on the safety and effectiveness of midazolam for imaging procedures was conducted. The procedural success rate was variable (0%–100%, median 82%). Hypoxia was the most commonly reported adverse event (74 cases/2046 patients, 3.6%) with (32 cases/2046 patients) 1.6% of cases being reported as moderate hypoxia. Palatability of the two most commonly used sedative agents, chloral hydrate and midazolam, was evaluated by conducting a literature review and a prospective study at the Derbyshire Children's Hospital. Only 9 studies were identified during the literature review. Of these, 8 studies evaluated the palatability of midazolam, while only 2 evaluated the palatability of chloral hydrate. Midazolam was reported as more III acceptable to patients than chloral hydrate. The prospective study supported this, and showed that patient acceptance of midazolam was good, while it was poor for chloral hydrate. The success rate of procedures was lower with midazolam, then chloral hydrate. A further literature review evaluated the use of sedation in Middle Eastern countries. Limited numbers of reports were found. Of the 37 studies, the majority (43%) were conducted in Turkey, within single centres and only examined a single procedure. Very limited evidence on the use of sedation guidelines was reported. Further exploration of the current sedation practice in the Kingdom of Saudi Arabia was done using a national survey. The questionnaires were completed by 81 health care professionals. Only 61% documented the use of sedation guidelines, although 91% reported monitoring of patients during procedural sedation. The most commonly reported agents for both painless and painful procedures were chloral hydrate and midazolam. This research aimed to add to the evidence base for paediatric sedation. The results suggest a need for future research to cover further areas, including the safety and effectiveness of other drugs, worldwide practice and patient monitoring. IV PUBLICATIONS, PRESENTATIONS AND AWARDS RELATED TO THIS THESIS Publications and presentations related to this thesis Paper: 1. Alotaibi B, Choonara I, Sammons H. Safety of Chloral Hydrate for Dental Procedural Sedation in Children: A Systematic Review of the Literature (Paper submitted to International Journal of Paediatric Dentistry). Conference abstracts: 1. Alotaibi B, Choonara I, Sammons H. Safety and Clinical Effectiveness of Chloral Hydrate for Painless Procedural Sedation in Children. Arch Dis Child 2014, 99:1, a169. 2. Alotaibi B, Choonara I, Sammons H. Midazolam for Imaging Procedural Sedation in Children: A Systematic Review. Arch Dis Child 2015, 100:e1. 3. Alotaibi B, Choonara I, Sammons H. Safety and clinical effectiveness of triclofos for procedural sedation in children: a systematic review. Arch Dis Child 2015, 100:e1. Oral presentation: 1. Safety and Clinical Effectiveness of Chloral Hydrate for Painless Procedural Sedation in Children, Oral presentation at National Child Health Workshop, September 18th, 2013, Derby, United Kingdom and at 7th Saudi Students Conference-UK, February 1st 2014, Edinburgh, United Kingdom. V 2. Safety and Clinical Effectiveness of Chloral Hydrate for Painful Procedural Sedation in Children, Oral presentation at National Child Health Workshop, 16 September 2014, Derby, United Kingdom. Poster presentation: 1. Safety and Clinical Effectiveness of Chloral Hydrate for Painless Procedural Sedation in Children, RCPCH Annual Conference, April 8th to 10th, 2014. Birmingham, UK. 2. Midazolam for Imaging Procedural Sedation in Children: A Systematic Review, at NPPG 20th Annual Conference and Exhibition, 7-9 November 2014, Nottingham, UK and at the 15th ESDPPP Congress, Belgrade, Serbia. 3. Safety and Clinical Effectiveness of Triclofos for Procedural Sedation in Children: A Systematic Review, NPPG 20th Annual Conference and Exhibition, 7-9 November 2014, Nottingham, UK. 4. Safety and Clinical Effectiveness of Paraldehyde for Procedural Sedation in Children, the 8th Saudi Students Conference-UK, February 1st 2015, London, UK. Rewards/Awards: 1. Best scientific presentation, 7th Saudi Students Conference, Edinburgh, 01 February 2014. For Safety and Clinical Effectiveness of Chloral Hydrate for Painless Procedural Sedation in Children VI ACKNOWLEDGEMENTS Praise be to Allah and may His peace and Blessings be upon all the prophets. Thanks, first and foremost, to Allah for granting me the chance and the ability to complete this thesis. This research would not have been accomplished successfully without the support and help of the following people to whom I am extremely grateful and obliged. First, Gratefulness, admiration and appreciation all go to my supervisors: Dr. Helen Sammons and Prof. Imti Choonara. I can confidently say that without their help and support, I would have never made it this far. Not only have they been a source of inspiration, but also a tremendous academic resource as I have learnt so much from their vast experience and knowledge. They have always been there to respond to any queries I had or any issues I experienced with any aspect of my research. I must say that I owe them so much. Second, I would like to thank my parents who have provided all sorts of encouragement for me to complete my studies successfully. Their care and trust instilled so much drive and determination in me to tackle life challenges head on. I would also like to give my gratitude to my husband, children and my friend Mrs/Thavalamar for their valuable and extensive support throughout this arduous but worthwhile academic journey in the UK. No words can describe my appreciation for other family members and friends who have been a source of inspiration and guidance. I would also like to thank all researchers, men and women, in all disciplines and wish them all success in their respective professions. VII A tremendous salute should be finally given to the Medical Services Department in the Saudi Armed Forces for believing in me and for assuming the financial costs of this postgraduate course. Without excluding anyone, I thank all those involved in this research endeavour for their comments and feedback, all of which contributed to moulding this dissertation into what it presently