Effectiveness and Complications of Sedation Regimens Used for Pediatric Dental Patients THESIS. Rachel Callie Gentz. Graduate Program in Dentistry

Transcription

1 Effectiveness and Complications of Sedation Regimens Used for Pediatric Dental Patients THESIS Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University By Rachel Callie Gentz Graduate Program in Dentistry The Ohio State University 2015 Masters Examination Committee: Dr. Homa Amini Dr. Paul Casamassimo Dr. Daniel Claman Dr. Megann Smiley

2 Copyright by Rachel Callie Gentz 2015

3 Abstract The objective of this study was to complete a retrospective chart review to determine the effectiveness and complications of different oral and nasal conscious sedation regimens used at Nationwide Children s Hospital (NCH) in the pediatric dental population. The most common regimens used at NCH oral midazolam, nasal midazolam, and other midazolam combinations were evaluated to determine their association with the outcome measures of effectiveness, patient behavior, work completed, and complications. In addition, the study sought to find any associations that exist between variables from the patients medical history and pre-sedation physical exam and the outcome, intra-operative, and post-operative morbidity of the sedation. Retrospective data was obtained from the electronic medical record used at NCH (Epic) for of all patients seen for dental sedation between the years of and from a post-sedation quality assurance survey (QAS) that is given to all parents following sedations. Data was available for a total of 701 sedation appointments. Practitioner rating of effectiveness for all sedation regimens combined is as follows: Effective (54.11%), somewhat effective (28.89%), ineffective (16.57%), and overly sedated (0.44%). Oral midazolam was the regimen most often rated as either effective or somewhat effective (88.8%). Most components of the medical history and physical examination were not ii

4 significantly associated with sedation outcome or complications. However, increased weight of the patient and obesity both were significantly associated with lower dosages given of both oral and nasal midazolam. This study showed that practitioners rate the majority of oral and nasal sedation appointments as effective for the most common sedation regimens used at NCH. This suggests that conscious sedation is a useful clinical adjunct for patients who require advanced behavior guidance techniques. iii

5 Dedication For everyone who helped me on my journey to become a pediatric dentist. iv

6 Acknowledgements I would like to thank my research committee for their guidance and support throughout the process. I would also like to thank Han Yin and Brent Merryman for their time and effort in assisting with the data and analysis. v

7 Vita May Chelsea High School Jan B.A. Biology, B.A. Psychology, Case Western Reserve University June D.M.D. Harvard School of Dental Medicine 2013 to present...dental Resident, Department of Pediatric Dentistry, The Ohio State University Fields of Study Major Field: Dentistry vi

8 Table of Contents Abstract... ii Dedication...iv Acknowledgments... v Vita.....vi List of Tables...x Chapter 1: Introduction....1 Review of Drug Classes and Regimens Safety and Emergency Considerations Complications Objective Chapter 2: Methods 14 Chapter 3: Results..21 Demographics Sedation Regimen Outcomes Medical History & Physical Examination Post-Sedation Complications Chapter 4: Discussion 33 Sedation Regimen.. 33 Medical History. 36 Complications vii

9 Future Research. 38 Chapter 5: Conclusions..40 References..51 Appendix A: Tables...45 Appendix B: Resident Handbook Guidelines...72 Appendix C: Quality Assurance Survey viii

10 List of Tables Table 1: Common Sedation Medication Regimens Table 2 Gender Table 3 Age Distribution of Subjects Table 4 Weight Distribution Table 5 Language Table 6 Interpreter Use Table 7 Race Table 8 Medical History Table 9 Duration of Sedation Table 10 Caregiver Missing Work Table 11 Type of Local Table 12 Block or Infiltration Table 13 Type of Restraint Table 14 Treatment Completed Table 15 Sedation Effectiveness Table 16 Behavior Table 17 Analgesic Use Table 18 Nausea and Vomiting Table 19 Complication Frequency ix

11 Table 20 Time Elapsed Until Normal Activity Resumed Table 21 Parent Satisfaction Table 22 Mallampati Score Table 23 ASA Status Table 24 Tonsil Assessment Table 25 Paradoxical Reaction and Complications Table 26 Medical Problems Table 27 Passive Smoke Exposure Table 28 Drug Regimens Table 29 Regimen and Post-Op Complications Table 30 Nausea and Regimen Table 31 Post-Op Complication and Number of Teeth Table 32 Number of Teeth Treated and Complications Table 33 Angry Child Syndrome Table 34 BMI and Post-Op Complications Table 35 LA Type Frequency Table 36 LA Type and Complications Table 37 Percentage of Biting Injuries Table 38 P Values for Drug Regimen Associations Table 39 Frequency of Drug Regimens and Outcomes Table 40 Drug Regimen and Number of Teeth Treated Table 41 P-Values for Outcomes Association with Medical History Table 42 Descriptive Statistics for Dosage and Outcome x

12 Table 43 Oral Midazolam Descriptive Statistics for Dose and Effectiveness Table 44 Logistic Regression Adjusting for Age and BMI Table 45 Nasal Midazolam Descriptive Statistics for Dosage and Effectiveness Table 46 Multiple Logistic Regression for Nasal Midazolam Adjusted for BMI and Age Table 47 P Values for the Association Between Nasal Midazolam and Outcomes and Complications Table 48 Descriptive Statistics of Weight Categories and Table 49 P Values of Medical and Outcome xi

13 Chapter 1: Introduction Each child presents a unique set dental, behavioral, and medical needs. As pediatric dentists we must to provide for all of these needs in in a way that ensures the safest, highest quality, least traumatic, and most cost effective dental treatment to our patient. Dental caries is most common chronic disease of childhood. By kindergarten, 40% children are affected by caries. 1 Despite a dentist s best efforts with communicative behavior guidance techniques, a portion of these patients will still exhibit a behavior management problem, and trying to complete restorative dental treatment in these situations can be unsafe and often unsuccessful. Additionally, the psychological impact that a negative dental experience can have on a child may influence future dental and medical experiences. 2 Behavior management problems in dentistry are closely related to dental fear and anxiety, but the two do not always coincide. Dental fear was found to be significantly associated with behavior management problems and with increased rate of dental caries. 3 A 1994 study reported a 10.5% incidence of behavior management problems among the 4-11 year old age group. 3 Age, gender and culture all have influences on the expression of dental anxiety as well as dental behavior in children. 4 So, for pediatric patients, it is important to identify all the factors contributing to behavior management and select a behavior guidance approach in attempts to complete the treatment safely, while minimizing the psychological impact. 1

14 There have been major changes in both patient behavior and in parental attitudes to behavior guidance techniques used in pediatric dentistry in recent decades. Parenting styles have changed to become more permissive. 5 Practitioners report that they believe these changes have resulted in worse patient behavior. With patient behavior and completion of dental treatment becoming more difficult overall, behavior can be a barrier to completion of dental treatment. Studies also show there is a greater acceptance of sedation and general anesthesia, but lower acceptance of hand over mouth technique, voice control, and passive restraint. 6 As a result sedation is increasing as an accepted form of behavior guidance over the more aversive techniques. In situations when the patient has inadequate cooperative ability or presents behavior problems, the practitioner is faced with the clinical decision to use mild to moderate sedation techniques or general anesthesia to complete necessary dental treatment. 7 Many factors are considered in the decision to use sedation including the amount and difficulty of dental treatment needed, treatment cost and insurance, parental preference, patients medical history, patients behavior and psychological needs, availability of an operating room for general anesthesia, and practitioner experience. 7, 8 Due to medical conditions precluding conscious sedation, extent of dental treatment required and other considerations some children will always require general anesthesia; however it should be avoided when not necessary due to the rare risk of death. In addition, its cost and the requirement for specialist facilities and staff in some cases limit its availability as an option. 3 In instances when the patient has behavior problems but GA can be avoided conscious sedation can be beneficial. Sedation is an advanced pharmacologic behavior 2

15 guidance technique approved by the American Academy of Pediatric Dentistry (AAPD) aimed at providing safe and effective dental treatment with the goals to: Guard the patient s safety and welfare; minimize physical discomfort and pain; control anxiety, minimize psychological trauma, and maximize the potential for amnesia; control behavior and/or movement so as to allow the safe completion of the procedure; return the patient to a state in which safe discharge from medical supervision, as determined by recognized criteria, is possible 9 While sedation offers many advantages, one disadvantage is that sedation is not always successful. Sedation medications do not always achieve the desired degree of sedation resulting in a non-sedated patient that is still not able to cooperate and may result in difficulty completing treatment, the need for passive or active restraint, or the need to abort treatment. Occasionally, patients have a paradoxical reaction in which they become even more combative than before sedation and treatment cannot be completed. When a sedation does not allow for the successful completion of all necessary dental care, the patient requires further treatment, often under general anesthesia. Levels of sedation range from minimal sedation to general anesthesia. The levels of sedation represent a continuum; therefore, the sedation practitioner must be prepared to rescue the patient who falls into a level of sedation deeper than intended. 10 Minimal sedation is defined in ASA guidelines as a minimally depressed level of consciousness where a patient has the ability maintain their own airway and provide normal responses to physical and verbal stimuli. Minimal sedation may affect cognitive function and motor coordination but ventilator and cardiovascular functions are unaffected. Moderate sedation is a depression of consciousness, in which the patient requires no intervention to 3

16 maintain a patent airway, has adequate spontaneous ventilation, and responds purposefully to verbal or tactile stimulation. 10 Deep sedation is a depression of consciousness when the patient cannot be easily aroused but responds purposefully to repeated or painful stimuli, and may need intervention to maintain a patent airway. Cardiovascular function is usually normal. 10 General anesthesia is a drug-induced loss of consciousness in which patients are not arousable even with painful stimuli ventilator function is often impaired, and cardiovascular activity may be impaired. 10 The levels of minimal sedation to moderate sedation were historically referred to as conscious sedation, but now the term minimal to moderate sedation is preferred. 3 Minimal to moderate procedural sedation is the area that is the focus of the sedations of this review and study, and the level of sedation that is typically used for procedural sedation in pediatric dentistry. During conscious sedation the patient can maintain an open mouth on their own, can maintain their airway and protective reflexes, and loss of consciousness is extremely unlikely. 3 It is important that we used evidence-based practice to support our clinical decisions on the best treatment modality for patients with behavior problems and/or dental anxiety. Currently, few valid clinical trials have investigated dental sedations, and research has not adequately determined which medications, dosages, and techniques are the most effective 11, 12 One 2007 meta-analysis attempted to summarize the relative efficacy of various sedation regimens, but was unable to be completed due to the variety of drug regimens and techniques used. The authors concluded it was difficult to isolate regimens for comparison and the studies reviewed were of poor quality and limited validity. 12 A 2012 Cochrane Review assessed 30 pediatric dentistry sedation clinical 4

17 trials and found 83% at high risk of bias. 3 Simple research studies investigating the doseresponse relationship of the most common sedation medications and combinations are absent from the literature. 13 For these reasons, a huge deficiency of research exists to support clinical decision of which regimens will be most effective and safe for the patient. The current sedation medications, combinations, techniques and adjuncts to sedation vary widely in the US and abroad; therefore, reviews and meta-analyses comparing sedations are difficult. Each residency program and practice uses different cocktails and techniques for sedations. 14 Sedation training at pediatric dentistry residency programs ranges from none to significant experience in a 2011 survey of program directors and residents at US programs. 13 This study reported that oral midazolam was the most frequently used sedation regimen and route of administration. 13 The majority of residency programs used forms of restraint including papoose boards during sedations. 13 The survey also concluded that efforts should be made to improve the consistency of training and competencies regarding sedation at residency training programs. 13 Review of Drug Classes and Regimens The ideal sedative agent or combination of agents would reduce anxiety and mitigate behavior while at the same time offer a wide margin of safety. 3 For those reasons, a favored class of drugs for pediatric dental sedation has become benzodiazepines such as midazolam (Versed). Benzodiazepines are relatively safe when used at therapeutic doses. 15 The mechanism of action of benzodiazepines involves gamma-aminobutyric acid (GABA), which is the major inhibitory neurotransmitter in the 5

18 central nervous system. Benzodiazepines bind to their receptor site on the GABA receptor and assist the inhibitory actions of GABA by enhancing the receptor s response to GABA. 16 The effects of different benzodiazepines at their receptor vary widely: midazolam has an onset time of only 10 minutes whereas diazepam, another sedation medication used in dentistry, has an onset of 60 minutes. 15 This difference lends them to very specific clinical applications, working and recovery times, and creates associated risks. They have the favorable effects of being amnestic, hypnotic, sedative, and anticonvulsant. Importantly, benzodiazepines are have a reversal agent available, Flumazenil. 15 A cautionary consideration to benzodiazepines such as midazolam is the occasional occurrence of a paradoxical excitement or agitation produced by the agent known as angry child syndrome. 15 Some of the best studies on the effectiveness of sedation regimens involve midazolam. A 2014 study comparing midazolam dosages of 0.5 mg/kg to 0.75 mg/kg concluded that the dosage of 0.75 mg/kg can enhanced the sedation, cooperation, and parent satisfaction for patients whose cooperation could not be achieved with the 0.5 mg/kg dose. 17, 18 A 2006 study found that children given a dose of 0.5 mg/kg oral midazolam were found to have significantly lower HR, systolic BP, and significantly more compliance during dental treatment and better amnesia after dental treatment. 19 The 2012 Cochrane review of dental sedation found that all placebo controlled trials of midazolam that were reviewed reported significant levels of behavior improvement as compared to placebo. 20 Another popular class of drugs for dental sedation is the antihistamines. Antihistamines, which are frequently given for other uses, have side effects of sedation 6

19 and hypnosis. This class of drugs has the advantage of not causing unconsciousness, respiratory, or cardiac depression like the other classes of sedation medications. 18 Promethazine (Phenergan) is typically used as a treatment for nausea. Promethazine is commonly used in pediatric dentistry both as a single sedation agent and in combination with other agents such as Demerol because its anti-nausea effect may counteract the nausea/ vomiting that opioids produce. 10 The most common side effect of antihistamines is usually benign extrapyramidal symptoms such as motor restlessness. The does in children is 2.2 mg/kg when used alone and 1.1 mg /kg when used in combination with other drugs. 10 Hydroxyzine (Vistaril or Atarax) dosage is 2.2 mg/kg when used alone and 1.1 when in combination with other drugs. 10 Opioids (or narcotics) are opioid receptor agonists that act as analgesics and also cause sedation and anxiolysis. As a result, they can be a good choice in dental sedation if a procedure is expected to be painful. Narcotics can, however, produce respiratory and cardiovascular depression, which can lead to serious life threatening complications including airway obstruction, hypoventilation, and hypotension. 21 It can also cause increased rates of nausea and vomiting compared to the other sedation medications commonly used. There is a narcotic reversal agent available, naloxone. 16 Historically, a very common medication used for dental sedations is chloral hydrate (CH). CH is a non-barbiturate sedative hypnotic of which the mechanism is not clearly understood. The 2012 Cochrane review of dental sedation found that the placebo controlled trial of CH found no statistically significant improvement in positive behavior in the CH group. 3 In this review, CH was used with nitrous oxide concurrently, and 4 children (27%) in the higher CH dose group (60 mg/kg) had airway issues or 7

20 obstruction. 3, 22 It can have a prolonged onset, long recovery time, and no reversal agent is available; as a result it has fallen our of favor with many practitioners. 16 Nitrous oxide is often used concurrently with dental sedations. Nitrous oxide is a safe and effective inhalation sedative/anxiolytic associated with very few medical concerns when used at therapeutic levels. 15 It can cause the mild anxiolysis, making the child receptive and suggestible to other traditional behavior guidance techniques such as tell-show-do (TSD) and distraction, and it can reduce the gag reflex and pain perception. 15 In pre-cooperative children under the age of 5 years, acceptance of a nasal hood to administer nitrous oxide is less likely. Additionally, a crying or upset child is breathing primarily through their mouth and nitrous oxide will be ineffective. 23 However, after receiving oral or nasal sedation with other agents, patients may be more likely to accept the nasal hood. Nitrous oxide serves as an important adjunct to oral or nasal sedation in behavior guidance and can serve as a titratable agent to help settle patients undergoing dental sedation. 15 Some patients are more anxious or fearful, less cooperative, or require a longer working time for dental sedation due to the amount of treatment to be completed. In this case very mild agents such as nitrous oxide or just midazolam may be inadequate to complete treatment. 15 In these cases, using a combination of sedation medications or cocktail can help the clinician complete treatment. The clinician must be aware of the increased risk of adverse events including respiratory depression when multiple agents are administered to a patient. 24 One combination that is commonly used currently is midazolam, meperidine, and hydroxyzine. It is important that the dose for each agent is well within the therapeutic dose range. 8

21 Route of administration is another area of sedation that has experienced changes in recent years. The popularity of intranasal (IN) administration has increased significantly because it can be administered to pre-cooperative or uncooperative children who do not tolerate the oral administration of sedation medication. 10 IN medications are absorbed into the systemic circulation via the nasal mucosa bypassing first-pass metabolism and resulting in a bioavailability similar to IV medication. 10, 25 Levels in the plasma peak at 10 minutes following IN administration. 10, 26 If the patient will tolerate oral administration, it is usually better accepted by the patient due to the initial IN administration that can cause irritation and the child to become upset. 10 Oral administration has been the most common route of administration for sedation medications in pediatric dentistry. Onset of clinical effectiveness is approximately 30 minutes. Disadvantages to this route of administration are long waiting period for effectiveness, unreliable absorption and inability to titrate, and patient nonacceptance of orally administered drugs. 10 IN midazolam is frequently used as a preinduction agent prior to general anesthesia at a dose of 0.2 mg/kg. When used as the only sedation for a procedure, higher doses of 0.35mg/kg- 0.5 mg/kg are typically used. 27 A 2001 study by Al-Rakaf compared 3 different dosages of IN midazolam and found that dental treatment was completed for 79% of children receiving 0.3 mg/kg, 96% of children receiving 0.4 mg/kg, and 100% of children receiving 0.5 mg/kg IN midzolam. 28 They also concluded that dental behavior was significantly better in the 0.5 mg/kg group compared to the two lower dosages. 28 Safety and Emergency Considerations 9

22 Of utmost importance to practitioners is the intraoperative and post-operative safety of dental sedation. Sedation is not without risks. Serious events such as hypoxemia, airway obstruction and laryngospasm, and allergy and even permanent neurologic damage and death are all real possibilities in sedation. 24, 29, 30 Most medical emergencies in dental sedation occur when young, small children are treated with sedation by a non-pediatric dentist. 11, 18 One 2000 study of adverse outcomes in dental sedation concluded that serious outcomes such as death and neurologic injury were associated with drug overdoses and were often attributable to prescription errors including decimal point errors. 30 These outcomes were also associated with combinations of sedation medications. The use of 3 or more medications as compared 1-2 medications was associated with adverse outcomes. 24 The practitioner must be aware of these risks and be prepared for emergencies and their appropriate interventions such as advanced airway management. These interventions require experience usually provided in advanced training programs. 15 In addition, practitioners as well as their staff, should have the appropriate training, and systems in place in the event of a medical emergency during sedation. These include basic life support (BLS), pediatric advanced life support (PALS), and an emergency team identified and a plan in place, and emergency drugs and equipment readily available. 18 Pre-operative history and physical (H & P) assessment are tools use to decide if a particular patient is appropriate for sedation. The purpose of the H & P is to rule out patients who are not safe to sedate due to medical conditions. In the healthy patient, the H & P identifies unrecognized medical or anatomical concerns that could increase the patient s risk during sedation. 31 Certain findings are clear contraindications to safe 10

23 sedation in the dental office, such as airway anatomic abnormalities, upper respiratory infection (URI), obstruction, or severe asthma. 31 Other aspects of the medical history that effect dental sedation are not as clear. For instance, obesity is a rapidly increasing medical condition in the pediatric population and is present in a significant portion of the patient population, now at approximately 17%. 31 Sedation concerns for obese patients include airway obstruction, increased GERD, delayed gastric emptying, increased risk of aspiration, and more difficult airway management and IV access. In addition obesity can modify the pharmacokinetics of sedative agents by prolonging absorption and distribution time and lengthening the elimination time due to the sequestering effect of fat on sedative medications. 32 Precautions for obese patients, such as avoiding narcotics which cause respiratory depression and paying close attention to patient positioning to minimize complications such as obstruction and reflux, have been suggested. 33 Due the high number of obese patients, the effects obesity has on sedation, and the incomplete understanding of its impact on sedation, caution should be taken with obese patients and efforts made to understand implications on sedation. Complications In addition to life threatening complications, there are a number of other morbidities can be associated with sedation. A 2014 study by Dosani et al. evaluated post-discharge events for 24 hours post sedation. They found that motor imbalance was significantly associated with midazolam: 66% of children slept in the car following pediatric dental sedation; 30% were supervised by only one driver; and 12% of those children were difficult to awaken. 34 These findings illustrate the need for close adult supervision following pediatric dental sedation. 11

24 Occasionally, rather than having a sedating effect, midazolam will evoke a paradoxical reaction and the child will become very agitated, hostile, angry, and even violent. 35, 36 Studies have reported that administration of the benzodiazepine reversal agent, Flumazenil, is effective in stopping midazolam-induced paradoxical reactions within 30 seconds. 35 A 2007 Danish study of oral midazolam administered to 687 children and adolescents reported the most common complications were double vision (6.1%) and paradoxical reaction (2.0%). 37 Nausea or vomiting was reported in %. Reduced respiration was found in 2 patients during treatment and none post-treatment. 37 Other studies report higher rates of some of these side effects. A review article of 16 pediatric dental sedation papers reported nausea and vomiting at 6% and paradoxical reaction at 3.8%. 38 Another side effect of midazolam that occurs regardless of route of administration is hiccups. The etiology of this side effect is not well understood. Studies have reported incidence of hiccups after midazolam to be 10-26%. 39 Patient selection for mild to moderate sedation is key for optimizing sedation safety, minimizing complications and the number of failed sedations, while maximizing the effectiveness of sedation. Determining the predictors of successful sedations will improve the clinician s patient selection criteria for sedation versus general anesthesia, and may also provide information for what specific drug regimens might be most successful for a specific type of patient. Objective The objectives of this study were to conduct a retrospective analysis to determine the association of variables from patients medical history, and pre-sedation history and 12

25 physical exam with the effectiveness of oral and nasal sedation regimens used at Nationwide Children s Hospital Dental Clinic. In addition, the study evaluated the frequency intra-operative and post-operative complications for the sedation regimens used, and any associations between patient characteristics identified in the history and physical examination with intra-operative and post-operative morbidity. 13

26 Chapter 2: Methods Inclusion criteria for this study were all patients seen for dental sedation appointments at the NCH dental clinic between July 2012 to June All patients were seen by any of 28 pediatric dentistry residents under the supervision of sedation certified attending dental faculty. According to protocol, patients referred for dental sedation must be at least 24 months of age, weight at least 10 kg, and not be greater than the 99 th percentile for BMI. Children are referred for sedation by residents and all referrals are reviewed by an attending pediatric dentist. Referral is based on cooperative ability, extent of treatment to be completed, medical history, and parental acceptance of sedation as a behavior guidance technique. All residents are trained on the appropriate selection criteria and contraindications to sedation according to the NCH Resident Handbook (Appendix A). When appropriate, consultation with the patient s pediatrician or medical specialists is obtained prior to sedation if any question arises regarding the risk of sedation. On the day of referral to sedation, the sedation procedure and pre-sedation instructions, including NPO instructions, are reviewed with the parent. In addition, parents are called the day before a sedation appointment to review all instructions. At all sedation appointments medical history, medications, and allergies are reviewed on the medical record (Epic) by the resident and attending, and with the parent. Baseline vital signs are obtained, NPO status, and any recent history of illness or URI are confirmed. A focused pre-sedation history and physical exam is completed, including same-day height and weight measurement, visual assessment of the airway, and auscultation of heart and breath sounds. Informed consent is obtained for sedation, dental 14

27 treatment, nitrous oxide, and possible use of protective immobilization, if necessary. History and physical exam are reviewed with the sedation-credentialed pediatric dental attending and the sedation regimen and route of administration are selected, dosages calculated and ordered in Epic, and dispensed from the Pyxis machine. Below are dosages used for the most common drug regimens, which comply with the NCH hospital maximum dosage guidelines: Drug(s) Concentration Dose (mg/kg) Max Dose (mg) Midazolam (oral) 2 mg/ml mg Midazolam (nasal) 5mg /ml mg Midazolam & Meperidine 2 mg/ml; 10 mg/ml Midazolam Meperidine 1-2 Mid 20 Dem 50 Midazolam & Hydroxyzine 2 mg/ml; 2mg/mL Midazolam Hydroxyzine Midazolam 20 Hydroxyzine 50 Midazolam, Meperidine & Promethazine 2 mg/ml; 10 mg/ml; Midazolam Meperidine 1-2 Midazolam 20 Meperidine mg/mL Promethazine 0.5 Promethazine 15 Promethazine 1.25 mg/ml , for adults Table 1: Common Sedation Medication Regimens 15, for children 15

28 A time out is completed by the dental attending prior to medication administration, to confirm patient identifiers, pertinent medical information, and procedure being completed. Sedation medication is administered by the resident. The caregiver waits with the child in the operatory with door closed and dim lighting during the latency period after medication administration. During dental treatment the parent waits in the waiting area. For most patients, a papoose board (used for protective immobilization) is placed beneath the child prior to the start of treatment and is used only if movement became disruptive to safe dental treatment. Prior to the start of treatment a blood pressure cuff and pulse oximeter is place on the child s arm and finger/toe, respectively. Pre-procedure and post-procedure vitals are recorded as well as at five minute intervals. A precordial stethoscope is used if the patient reaches a level of moderate sedation rather than minimal sedation. Nitrous oxide is titrated at the discretion of the pediatric dental resident as an adjunct to the sedation regimen. After dental treatment is completed, the caregiver returns to the treatment room while the patient recovers and is discharged after NCH sedation discharge criteria are met. Before the end of the sedation appointment, a trained dental sedation assistant completes the demographic and contact information portion of the QAS (Appendix 2). This includes type of restraint (if any) utilized and type of local anesthesia (block, infiltration, or both). Also recorded is the practitioner rating of sedation effectiveness (effective, somewhat effective, ineffective, or overly sedated) as determined by the pediatric dental resident who performed the sedation. If all treatment that was planned for the appointment was successfully completed, it is noted. Within 48 hours of the sedation appointment, a trained sedation assistant contacts the caregiver to complete the post- 16

29 operative complication and satisfaction portion of the QAS. This portion of the QAS has questions regarding post-operative analgesic use, lip/cheek/tongue biting injuries, nausea and vomiting, hiccups, and any other complications. Parents are asked to estimate the time post operatively that the child resumed eating, playing and sleeping normally. Lastly, the QAS asks if the caregiver considered the sedation successful, and if they would choose sedation, if necessary, again. Families who required an interpreter for the appointment were called by the assistant utilizing an interpreter. Patients whose caregivers could not be reached by phone were not included in the QAS data, but the data from the sedation appointment itself was still included in the analyses. For all patients seen for dental sedation during the specified time period of , retrospective data was obtained from patients electronic medical record used by NCH, Epic. Data extracted for analysis included demographic data, pertinent medical history findings, pre-sedation history & physical findings, medication and dosages, perioperative information, and postoperative information. To obtain data from Epic, the data extraction tool, SQL Developer, was used to export the following data queries from Clarity (Epic s Database) into an Excel database for each patient: o Dates of dental sedation(s) o Gender of patient o Age of patient o Race of Patient o First language of patient o First language of parent 17

30 o Medications o Medical Conditions Flagged in EPIC: o Seizure o Asthma o Autism o ADHD o Prematurity o Obesity o Passive smoke exposure o Weight (kg) on the date of the sedation appointment o Height (cm) on the date of the sedation appointment o Sedation regimen and dosage ordered (mg/kg) o Route of Administration (Cup/ syringe/intranasal) o Duration of procedure (from medication administration to patients discharge) o Behavior at sedation appointment (Frankl score +/+, +, -, -/-) o From Pre-Sedation History and Physical: o Family history of reaction to anesthesia? (y/n) o Personal history of reaction to anesthesia? (y/n) o Mallampati Score (1-4) o Airway anatomical abnormalities? (y/n) o ASA status (1-4) o Tonsil assessment (Brodsky score 1-4) o Complications: 18

31 o Sedation related complications? (y/n) o Paradoxical reaction/ angry-child syndrome? (y/n) Epic data was merged with the QAS, which is routinely given to all parents who can be reached by phone following sedation appointments. All QAS data was entered from paper records of the survey into an Excel database. The Epic Excel dataset was merged with the QAS dataset using vlookups in Excel to create a comprehensive database for analysis. All statistical analyses were performed using SAS 9.4 software. Descriptive statistics to summarize the database including patient demographics, comorbid medical conditions, parent satisfaction, and postoperative complications were reported as the frequency and percentage of the occurrence for each variable being examined. Also reported was the frequency missing for each variable. For each variable, a number of subjects had missing data. This is accounted for by the fact that when extracting data from Clarity (Epic s database) there were 51 patients for whom the sedation encounter could not be located using the query equation. This is due to the fact that the sedation visit was either coded as a different type of encounter, or the encounter was signed on a different date than the encounter. This resulted in 51 of the 650 patients having missing Epic data. In addition, any component of the medical history, pre-sedation history and physical exam that was either incomplete or entered incorrectly was included in the frequency missing. 19

32 Further analyses were completed to determine which variables from Epic have a significant association with the following outcome measures of sedation success. Analyses were completed for the most common sedation regimens used at NCH: Oral midazolam, nasal midazolam, and midazolam combination (midazolam plus one or more other sedation medications). 1) Practitioner rating of success of the sedation: a. Ineffective b. Somewhat effective c. Effective d. Overly sedated 2) Whether or not treatment was completed (y/n): 3) Patient behavior based on the Frankl scale: a. (+/+) b. (+) c. (-) d. (-/-) 20

33 Chapter 3: Results Demographics Data from all sedation encounters between July 2012 to June 2014 was included. This included a total of 701 sedation encounters. Of the 701 encounters, Epic data could not be matched to the sedation encounter for 51 of the data queries. QAS Data was available for 701 subjects. The frequency missing for all descriptive data is listed. This is accounted for by the 51 sedation encounters that were not able to be queried for data and any data missing or incorrectly entered. The sample was balanced with 333 male subjects (51.2%) and 317 female subjects (48.8%) (Table 2). Ages included 125 subjects in the 2-3 year old range, 161 in the 3-4 year old range, 125 in the 4-5 year old range, and 145 were 6 or older (Table 3). Weight data was available for 618 subjects. The majority of subjects (532, 86%) were kg. The remaining subjects were over 25 kg (Table 4). Demographic data such as preferred first language and race is by self-report/ caregiver report and is a part of the patients Epic data. The majority of patients were English speaking (553, 85%). The most common non-english first languages were Spainsh (55, 8.5%) and Somali (15, 2.3%) (Table 5.) Interpreters were utilized for 11.3% of sedation appointments (Table 6). A wide range of races were sedation patients, with the most common being Caucasian (347, 54%), followed by African American (163, 25%), Latino/Hispanic (57, 8.8%) and Biracial/multiracial (45, 7%) (Table 7.) 21

34 For 414 (60.2%) of the sedation encounters no caregiver needed to miss work. For 274 (39.8%) encounters one or more caregiver needed to miss work (Table 10). Caregivers were absent from the dental operatory for the dental treatment portion of the appointment in most sedations (631, 94.2%). Caregivers were present in the room for the duration of the sedation encounter for 39 sedations (5.8%) (Table 10). Most of these cases were patients with special healthcare needs. Data for type of immobilization (if any was used) was available from the QAS data for 483 encounters. The Papoose Board was used in 232(48%) of sedation appointments. Active restraint such as hand-holding or head stabilization was used in 100 (20.7%) of sedations (Table 13). Sedation Regimen Outcomes Practitioner rating of sedation effectiveness was the primary outcome measure for success of sedation. Practitioner rating of effectiveness was available for 682 sedation encounters. Residents ranked 369(54.11%) of sedations as effective, 197(28.89%) as somewhat effective, 113(16.57%) as ineffective, and 3(0.44%) as overly sedated (Table 15). The second outcome measure for the success of the sedation is whether the planned dental treatment for the appointment was completed. Data for the frequency of all treatment planned work being completed was available for 657 encounters. All work was completed in 607 (92.39%) of sedations. All planned treatment was not completed during 50 (7.6%) of sedations (Table 14). Third, behavior rating measured on the Frankl scale during the sedation appointment was available for 595 sedation encounters. Residents rated behavior during 22

35 the sedation appointment as (-/-) for 108 (18.15%) sedation, (-) for 144 (24.2%) sedations, (+) for 179 (30.08%) sedations and (+/+) for 164(27.56%) sedations (Table 16.) A total of 14 different sedation regimens were used for the 639 sedation encounters for which regimen was available (Table 28). For the purposes of analysis and discussion, the regimens were reclassified into three groups to reflect the most common regimens used as follows: Oral midazolam, which accounted for 181 sedations, nasal midazolam which accounted for 242 sedations, and combinations of midazolam plus one or more additional sedation medication, which numbered 181 (Table 28). The combinations included in all other midazolam combinations are oral midazolam + hydroxyzine, midazolam oral + promethazine, oral midazolam + meperidine, midazolam oral + meperidine + promethazine. To analyze the association among the three reclassified sedation regimens and the sedation outcome measures, the Pearson s chi-square test was used. Three primary outcome measures were analyzed; practitioner rating of sedation effectiveness, behavior rating (Frankl score), and treatment completed. In addition, if any form of immobilization was needed it was included in analysis, as was next dental visit type. Outcome measures were reclassified as dichotomous variables so that the chisquare test could be performed. Frankl score was reclassified as negative (- or -/-) and positive (+ or+/+). Effectiveness of sedation was reclassified as ineffective and effective (somewhat effective or effective being grouped together). Type of immobilization was re-classified as none used versus any type of immobilization used. A p-value < 0.05 was considered significant. Only the outcome measure All 23

36 treatment completed (p=0.0002) and practitioner rating of effectiveness (p=0.0458) were found to be significantly different among the different drug regimens. Patients who were given other midazolam combinations were more likely to not have all of their treatment completed compared to those who were given oral or nasal midazolam. Of patients who received midazolam combinations, 14.6% did not have all of their dental treatment completed. Treatment plans were most frequently completed in patients sedated with nasal midazolam with only 3.86% of patients not having treatment completed. For oral midazolam 5.95% of patients did not have treatment completed (Table 39). Sedation regimens of either oral or nasal midazolam were significantly more effective than the midazolam combinations. Oral midazolam was rated as either effective or somewhat effective in 158 of 178 sedations (88.76%). Nasal midazolam was rated as effective or somewhat effective in 200 of 238 sedations (84.03%). Other midazolam combinations were rated as effective or somewhat effective in 140 of 177 sedations (79.1%) (Table 39). The number of teeth treated during the sedation visit was compared among the three different drug regimens using Kruskal-Wallis Test, which tests the overall difference of number teeth treated between drug regimens. The number of teeth treated was found to be significantly different among regimens (p= ). Further pairwise comparison of number of teeth treated among each pair of drug regimens was done using Wilcoxon rank-sum test. P-values were adjusted based on Bonferroni-Holm s method for multiple comparison. Based on adjusted p-value, patients who received oral midazolam had significantly fewer teeth treated than those given nasal midazolam (p=0.16) and also had fewer teeth treated than those given midazolam combinations (p=0.0012). 24

37 The above analyses took only into account the three drug regimens, but did not consider the dosage (mg/kg) administered. To evaluate the effect of dosage on the outcome of sedations, the dosage in the effective group was compared to that in the ineffective group for the oral and nasal midazolam groups using the Wilcoxon rank-sum test. For oral midazolam the group of sedations that were rated as ineffective were administered significantly higher dosages in mg/kg than in the group of effective sedations (p=0.032). The mean dose of effective sedations was mg/kg and the mean dose for effective sedations was mg/kg. However, after multiple logistic regression was used to determine the effect of dosage of oral midazolam on effectiveness and adjusting for both age in years and BMI it was then determined that the dosage in mg/ kg was not statistically significantly different between the effective and ineffective groups (p=.3072), suggesting that age and BMI influence the effect of dosage on effectiveness (Table 44). For nasal midazolam, the Wilcoxon rank-sum test was again used to compare the dosage between the effective and ineffective groups with no significant difference in dosage between the ineffective group and the effective group (p= Wilcoxon ranksum test). Multiple logistic regression was used to determine the effect of dosage of nasal midazolam on effectiveness while adjusting for age in years and BMI. By adjusting for age and BMI, the dosage of nasal midazolam does have a significant effect on effectiveness (p=0.0437). Based on this model, the odds of being effective increase about 76% with 0.1mg/kg increase in dosage of nasal midazolam (Table 44, 45). For oral midazolam and nasal midazolam regimens the association between weight or obesity status was investigated to determine if dosage (mg/kg) differed 25

38 significantly in children in a heavier weight category or who are obese. Kruskal-Wallis Test was used to compare dosage (mg/kg) between the following weight categories of patients: 10-15kg, 15-20kg, 20-25kg, and 25+kg. The p-value < indicates that the dosage of oral midazolam was significantly different between the categories. The dosages show a downward trend as the weight category increases. The mean dosage in the kg group was 0.96 mg/kg while in the 25 kg+ group the mean dose was mg/ kg (Table 48). The same comparison was done for dosage (mg/kg) between obese patients and non-obese patients. The p-value was , which means dosage of oral midazolam was significantly higher in non-obese patients than in obese patients. Obese patients had a mean dose of mg/k while non-obese patients had a mean does of mg/kg (Table 48). The same analyses were completed to look at the relationship between nasal midazolam dosage and weight or obesity. The results were similar to what was seen with oral midazolam. For weight categories, the p-value was < , which means dosage of nasal midazolam was significantly different between different weight categories. The mean dose of nasal midazolam for the kg weight group was mg/kg while for the 25+ kg group it was mg/kg (Table 48). For obesity status the p-value was 0.037, showing the dosage of nasal midazolam was significantly higher in non-obese patients than in obese patients. Non-obese patients received a mean dose of nasal midazolam of mg/kg while obese patients received a mean dose of mg/kg (Table 48). Medical History & Physical Examination 26

39 The association between three measures of sedation outcome and a number of pertinent variables from the Epic medical history was determined to see if any elements from the patients medical history could be used as a predictor of sedation outcome. The sedation outcome measures used were; the re-classified practitioner rating of sedation effectiveness (effective versus ineffective), dental behavior during sedation appointment, and all planned treatment completed during sedation appointment. The variables from medical history analyzed for their association with outcome measure were gender, use of an interpreter, age, BMI, and positive history of seizures, autism, AHDH, prematurity, obesity or passive smoke exposure. Comparisons between the outcome measures and the medical history variables were done using the Chi-square test or Fisher exact test for categorical variables and Wilcoxon rank-sum test for continuous variables. Both effectiveness of sedation and all treatment completed as outcomes of the sedations were found not to be significantly associated with any of the medical history variables investigated (Table 41) For dental behavior which was re-classified into positive Frankl score versus negative Frankl score the only variable that showed significant difference between positive and negative behavior score was patient age (Table 41). Older patients were more likely to have positive behavior than younger patients (p= < 0.05) (Table 42). Caregiver reported medical history was a part of the QAS data. QAS medical history data was available for 687 subjects and 469 patients who had no reported medical history of illness or medical problems (68.3%). Of the subjects who reported medical history findings 51(7.4%) had asthma, 8(1.2%) had other respiratory illnesses, 5(.7%) 27

40 were born prematurely, 33 (4.5%) had autism spectrum disorders, 38 (5.5%) had multiple conditions, and 83(12.1%) reported other conditions (Table 8). Data from Epic from the pre-sedation history physical exam was available for 650 patients. None of these patients seen for sedation had any personal or family history of adverse reactions to sedation or general anesthesia. Medical history was positive for seizures in 15 (2.3%) of patients, Autism spectrum disorders in 28(4.3%) of patients, ADHD in 25 (3.9%) of patients, prematurity in 26(4%) of patients, and obesity in 58 (8.9%) of patients (Tables 26). Passive smoke exposure in was present 158 (34.9%) of the 452 patients for which smoke exposure data was available (Table 27). Mallampati score was available for 626 patients; 158(25.2%) were Mallampati I, 344(55.0%) were Mallampati II, 116(18.5%) were Mallampati III and 8(1.3%) were Mallampati IV (Table 22). The association between the patients Mallampati score and complications and the association between Mallampati score and the three outcome measures; effectiveness, work completed, and behavior, was evaluated using Pearson s chi-square test. None of the complications were significantly associated with Mallampati score (Table 41). Brodsky tonsil scores were available for 617 subjects; 128 (20.8%) were Grade I, 329 (63.5%) were Grade II, 90(15.0%) were Grade III, and 7 (1.1%) were grade IV (Table 24). The association between the patients Brodsky tonsil score and complications and the association between tonsil score and the three outcome measures; effectiveness, work completed, and behavior, was evaluated using Pearson s chi-square test. None of the complications were significantly associated with Brodsky tonsil score (Table 41). 28

41 Of 630 patients 520(82.5%) were ASA I, 107(17.0%) were ASA II, 2(0.5%) were ASA III, and no patients were ASA IV (Table 23). The association between the patients ASA status and the presence of complications and the association between ASA status and the three outcome measures; effectiveness, work completed, and behavior, was evaluated using Pearson s chi-square test. None of the complications were significantly associated with ASA status (Table 41). Data on the presence or absence of paradoxical reaction/angry child syndrome was available for 615 encounters. Of these patients 36 (5.9%) were reported by the practitioner as having angry child syndrome. Angry child syndrome was reported in 15(6.2%) of 243 patients sedated using nasal midazolam and 21(6.1%) of 346 patients given oral midazolam (Table 33). Pearson s chi-square test was used to determine the association between angry child syndrome and type of midazolam (oral versus nasal). The p-value was (>0.05) showing no significant difference in percentages of angry child syndrome between nasal and oral midazolam. Route of administration of midazolam does not appear to be associated with incidence of angry child syndrome. Post-Sedation Complications Data on post-operative complication and analgesic use was available from the QAS as was reported by the caregiver post-operatively the day of the sedation. Data on post-operative analgesic use was available for 394 encounters. No post-operative analgesics were given in 275 (69.8%) of encounters. Analgesics were given in 119 (30.2%) of sedation encounters (Table 17). Of data available for 401 encounters nausea or vomiting was experienced by 21(5.2%) of patients (Table 18). Lip biting occurred in 31(7.9%) out of 393 encounters. 29

42 Cheek biting occurred in 12(3.1%) of 392 encounters. Tongue biting occurred in 8(2.0%) of 393 encounters. Other biting occurred in 17(4.7%) out of 365 encounters (Table 19). Hiccups, either intraoperative reported by the resident or post-operatively reported by the parent, were present in 113(27.0%) out of 419 sedation encounters (Table 19). The association between the reclassified drug regimens (oral midazolam, nasal midazolam, and all other combinations) and each of the post-operative complications was determined using Pearson s chi-square test, which tests the overall distribution of each complication between the different sedation regimens. P-value <0.05 was considered as significant. Only nausea or vomiting showed a significant association with drug regimen (p=0.0486) (Table 29). Nausea and vomiting happens significantly more frequently in patients given the midazolam combinations as compared to either nasal midazolam or oral midazolam alone. Nausea or vomiting was present in 7.6% of patients given midazolam combinations as compared to 1.9% and 2.1% for oral and nasal midazolam, respectively (Table 30). Type of local anesthesia given was available for 659 encounters. The most common local anesthetic used was lidocaine, which was used in 375 (56.9%) sedations, followed by septocaine used in 116 (17.6%) of sedations. Both lidocaine and septocaine were used in 53 (7.9%) of sedations. No local anesthetic was used in 114 (17.3%) of sedations (Table 11). Data on type of local anesthesia injections given was available for 528 encounters. Infiltration anesthesia was given in 358 (67.8%) of cases. Nerve blocks were given in 70 (13.3%) of cases. Both block and infiltration was given in 100 (19.0%) of cases (Table 12). For analysis of post-operative complications and their association with type of local anesthesia, the groups were reclassified into infiltration only and 30

43 block or block and infiltration (Table 36). The association between local anesthesia type and each post-operative complication was determined using Pearson s chi-square test, which tests the overall distribution of the complications between the different LA groups. P-value <0.05 was considered as significant. Only lip biting (p=0.044) and cheek biting (p=0.022) showed significant association (Table 36). Lip biting occurred in 6.2% subjects with infiltration anesthesia and in in 16.33% of patients given a nerve block or a block and infiltration. Cheek biting occurred in 1.4% of patients given infiltration anesthesia and in 9.2% of patients given a block or infiltration and block (Table 37). Wilcoxon rank-sum test was used for comparison of number of teeth treated and the association with post-operative complications. All types of biting injuries were found to be significantly associated with a lower number of teeth treated during the sedation. Lip biting (p=0.039), cheek biting (p=0.034), tongue biting (p=0.017) and other biting (p=0.039) were associated with a lower number of teeth being treated. None of the other post- operative complications were found to be significantly associated with number of teeth treated. Wilcoxon rank-sum test was used to determine if patients BMI was significantly associated with post-operative complications. P-value <0.05 was considered as significant. None of the complications were found to be significantly associated with BMI (Table 41). The amount of time elapsed after the sedation appointment until the patient resumed normal activities was available as part of the QAS as reported by the caregiver. Out of 377 encounters, the majority of patients (225, 59.7%) resumed eating normally within 2-4 hours (Table 25). Out of data for 279 sedation encounters 196(70.3%) 31

44 resumed playing normally within 2-4 hours (Table 20). Of 262 encounters 144 (55.0%) were sleeping normally in less than 2 hours (Table 20). Data was available for 392 encounters on parent rating of sedation success. They rated 382(97.5%)of the encounters successful (Table 21). Of the caregiver satisfaction data available for 387 encounters 384 (99.2%) caregivers stated that they were satisfied with the sedation procedure (Table 21). Of the 402 caregiver responses for the question regarding if they would choose sedation again for their child 382(95.0%) of caregivers would choose sedation again (Table 31). 32

45 Chapter 4: Discussion The objective of this study was to complete a retrospective chart review of sedations at NCH to evaluate the effectiveness and complications of different oral and nasal conscious sedation regimens. The three most common midazolam sedation regimens were analyzed for their association with a number of sedation outcome measures and post-operative complications. In addition, subjects medical history and physical exam characteristics were evaluated for their relationship to sedation outcome and complications. The second purpose was to determine safety and efficacy of the regimens to help in the clinical decision of selecting a sedation regimen. Additionally, this study s results may help to determine which elements of the history and physical can help determine which patients sedation will more likely be safe and effective. Sedation Regimen One interesting finding regarding the sedation regimens was the fact that oral midazolam was found to be associated with significantly fewer teeth treated than either nasal midazolam or other midazolam combinations. This was a somewhat unexpected finding as oral midazolam was the regimen most frequently rated as effective or somewhat effective. One possible explanation for this is to consider contributing factors for patient selection for each drug regimen. Patients who are selected for combination regimens are often patients who have more treatment to complete; they may have several teeth or more than one quadrant of treatment to complete and therefore are judged to require an additional sedation medication to increase the level of sedation or working 33

46 time. Nasal administration is frequently used in younger children who are unable to cooperate to drink orally administered sedatives. One of the frequent procedures performed in these young children is the extraction of 2-4 maxillary anterior teeth due to caries. This could lead to an increase in the average number of teeth treated in the nasal midazolam if 4 teeth are frequently extracted. When analyzing the relationship between dosage and effectiveness, prior to adjusting for age and BMI, the dosage in the ineffective groups was higher than the effective group, which is seemingly paradoxical. It would be expected that a higher dosage would lead to a more effective sedation. After multiple logistic regressions that controlled for age and BMI, no significant relationship between dosage and effectiveness was found. This is still unexpected, as we would expect that with higher dosages we would see significantly more effective sedations. One possible explanation for why this was not observed is that patients who are either less cooperative at baseline or are planned for more difficult procedures may be given higher dosages in anticipation of a more difficult sedation. This may result in less effective sedations due to the patient selection of more difficult patients. Nonetheless, the statistical relationship observed is the opposite of what we would anticipate. Nausea and vomiting were found to be the only post-operative complications with a statistically significant association with drug regimen (p=0.486). Significantly more nausea and vomiting was noted in the patients given midazolam combinations than either oral or nasal midazolam alone. This is clinically significant because combinations are: (1) more likely to have the unpleasant and unwanted side effect of nausea and vomiting, (2) significantly less likely to have all planned treatment completed, (3) were less 34

47 frequently rated as either effective or somewhat effective by the sedation practitioner. Nausea and vomiting was found to be the only post operative complication that had a statistically significant association with drug regimen (p=0.486) with significantly more nausea and vomiting in the patient given midazolam combinations than either oral or nasal midazolam alone. The treatment plan was not completed in 14.6% of midazolam combination sedations compared with only 3.9% for nasal midazolam and 6.0% for oral midazolam sedations (Table 60). Sedation regimens of either oral or nasal midazolam were significantly more effective than the other midazolam combinations. Oral and nasal midazolam were effective in 88.8% and 84.0% of sedations, respectively. Other midazolam combinations were rated as effective 78.1% of sedations (Table 61). While combinations are sometimes chosen hoping to improve the outcome of sedation, in this study, the combinations had poorer outcomes as well as the increased post-operative nausea and vomiting. This may be a reason to more strongly consider single agent sedation. There may be a perception by clinicians that more sedation medications leads to more effective or deeper sedations leading practitioners down the path of choosing combination regimens for especially difficult patients. However, this study suggests that combinations are less effective and may lead to more complications. Important to note is the possible introduction of bias due to the fact that patients selected for combination drug regimens may be the patients that at baseline were less cooperative and were anticipated to require a higher level of sedation. This selection bias may account for the fact that despite the expectation that combination regimens would lead to a deeper sedation and better outcomes that this study indicates the opposite. 35

48 Randomized controlled trials that prospectively compare single agent sedation with oral and nasal routes compared to combinations compared to combination regimens are necessary to eliminate the potential for selection bias. This will be important if multiagent sedations have less positive outcomes and more complications such as nausea and vomiting as this study indicates. The wealth of literature supports the fact that serious adverse events such as obstruction, respiratory depression, and laryngospasm as well as death are significantly higher in combinations especially when 3 or more sedation medications are used. 30 Unless there is a very clear benefit from a dental treatment standpoint we do not want to increase the risk of sedation by using multiple agents unnecessarily. Medical History Most elements of the medical history and physical examination evaluated had no statistically significant association with sedation outcome or complications; however, patient age and patient weight are two factors that had interesting findings and clinical implications for sedation. Older patients were more likely to have positive behavior than younger patients (p= < 0.05) most likely due to the fact that in older children who have dental anxiety or behavior problems, a minimal level of sedation is able to help them cooperate and improve behavior. With pre-cooperative children, minimal sedation may not render them able to cooperate. This is consistent with numerous reports in the literature that state younger children may need a higher level of sedation to allow for dental treatment. Heavier patients and obese patients were found to have statistically significantly lower dosages of both oral midazolam and nasal midazolam. This finding could have 36

49 very significant implications when patients are either obese or if they are older and heavier patients. With the dosage in these groups being much lower, patients may be less likely to receive a dosage in mg/kg that can produce the level of sedation necessary. The reason for these lower dosages observed most likely is due to the maximum dosages set for the regimens by NCH. The maximum dosage for oral midazolam is 20 mg and for nasal midazolam is 10 mg. For a patient who is obese or who is in a heavier weight category, the dosage in mg/kg is significantly lower. As was seen in the analysis for nasal midazolam, the dosage of nasal midazolam is significantly associated with effectiveness. Heavier patients may benefit by having more effective sedations if the maximum dosage allowed is increased. However, it must be determined if the margin of safety will allow for such an increase in maximum dosage. Complications Some implications of the sedation-related complications analysis include the fact that parent-reported incidence of post-operative biting was found to be significantly associated with type of local anesthesia injection. Patents given block anesthesia or block and infiltration demonstrated significantly higher levels of post-operative biting. This is expected, and reinforces that when appropriate infiltration anesthesia should be used to minimize biting injuries. When looking at the association between number of teeth treated and complications, none of the complications investigated were significantly associated with having treated a greater number of teeth during the sedation. Biting injuries were not associated with a lower number of treated teeth. For this reason the clinician should not 37

50 worry about treating an increased number of teeth in a sedation appointment as it does not appear to increase the risk of post-operative complications. Future Research This study has several limitations. One limitation is missing data due to the retrospective nature of the study. Data was missing for a number of reasons; unanswered portions of the medical history or sedation encounter, unanswered questions from the QAS, and the inability to query data from 50 of the sedation encounters from Epic s database. All of these contributed to the frequency missing for each variable. Some variables had a significant number of missing data points. Another confounder is practitioner variability in determining the outcome measures such as sedation effectiveness and behavior. There was not clear standardization for how the practitioner classified the success of the sedation. Their determination of the effectiveness of the sedation was based on that practitioners personal impression and could have varied widely across residents and attendings. Additionally, whether or not treatment was able to be completed may vary widely based on practitioners clinical skills. The Frankl scale is a widely used behavior scale in pediatric dentistry and has specifications as to what behaviors should be classified at each level, but there may still be variability among clinicians in behavior rating, especially when the Frankl scale is applied to sedations. The Frankl score is traditionally applied to non-sedation dental treatment. There may be more appropriate scales to rate behavior and response to dental sedation. One consideration would be to change in the future to measuring behavior on a scale that is used in sedation research and is more relevant to sedation behavior. One such 38

51 scale rates behavior as excellent if a patient is calm, quiet, and treatment is performed easily, good if there are mild objections or whimpering but treatment is completed without difficulty, fair if there is crying but minimal movement or disruption to treatment, poor if there is struggling that interferes with treatment causing treatment to be completed with difficulty, and prohibitive it there is active resistance and treatment cannot be completed. 40 Effectiveness of sedation should also have more clearly defined characteristics or level of sedation with clear definitions and physiologic markers could be used. Improving these scales and definitions will help improve the consistency among providers and therefore improve the quality of data available for future study. Ultimately completing a true prospective randomized controlled trial to investigate the sedation regimens and dosages used at NCH needed to offer definitive clinical recommendations on sedation regimens. 39

52 Chapter 5: Conclusions Practitioners rate most oral and nasal sedation appointments as effective for the common midazolam sedation regimens used at NCH. Sedations using oral or nasal midazolam were significantly more effective than other midazolam combinations. Oral and nasal midazolam were significantly more likely to have positive behavior compared to other sedation regimens. No significant associations were found between any of the medical history variables and the effectiveness of the sedation. Heavier patients and those considered obese in Epic were given significantly lower dosages of oral or nasal midazolam during sedation. 40

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55 36. Golparvar M, Saghaei M, Sajedi P, Razavi SS. Paradoxical reaction following intravenous midazolam premedication in pediatric patients - a randomized placebo controlled trial of ketamine for rapid tranquilization. Paediatr Anaesth 2004;14(11): Uldum B, Hallonsten AL, Poulsen S. Midazolam conscious sedation in a large Danish municipal dental service for children and adolescents. Int J Paediatr Dent 2008;18(4): Papineni A, Lourenço-Matharu L, Ashley PF. Safety of oral midazolam sedation use in paediatric dentistry: a review. Int J Paediatr Dent 2014;24(1): Marhofer P, Glaser C, Krenn CG, Grabner CM, Semsroth M. Incidence and therapy of midazolam induced hiccups in paediatric anaesthesia. Paediatr Anaesth 1999;9(4): Padmanabhan MY, Pandey RK, Saksena AK, Chandra G. A comparative evaluation of agents producing analgo-sedation in pediatric dental patients. J Clin Pediatr Dent 2009;34(2):

56 Appendix A: Tables Demographics: Gender of Subjects Frequency Missing = 51 Gender Frequency Percent Male Female Table 2 Gender Total Age Distribution of Subjects Frequency Missing = 51 age (years) Frequency Percent 2-3 yo yo yo yo yo yo yo yo yo yo yo yo Table 3 Age Distribution of Subjects 44

57 Weight Distribution of Subjects Weight (kg) Frequency Percent kg kg kg kg kg kg kg Frequency Missing = 83 Table 4 Weight Distribution Language of Subjects Frequency Percent English Spanish Somali Nepali Arabic Hakha Chin Mandarin Other Frequency Missing = 51 Table 5 Language 45

58 Interpreter Use For Sedation Appointment Frequency Percent No Interpreter Interpreter Used Frequency Missing = 20 Table 6 Interpreter Use Race Frequency Percent Caucasian African American Biracial/Multiracial Latino/Hispanic Asian Other Race Frequency Missing = 59 Table 7 Race 46

59 Medical History Frequency Percent No Reported Medical History Asthma Respiratory Illness Prematurity Autism Spectrum Disorder Other Multiple Contitions Frequency Missing = 14 Table 8 Medical History Duration of Sedation (minutes) Frequency Percent Failed Sedation > Frequency Missing = 19 Table 9 Duration of Sedation 47

60 Frequency of One or More Caregiver Missing Work for the Sedation Frequency Percent No Work Missed Caregiver Missed Work Frequency Missing = 13 Table 10 Caregiver Missing Work Type of Local Administered Frequency Percent Lidocaine Septocaine No LA Both Type LA Not Recorded Frequency Missing = 42 Table 11 Type of Local

61 Block or Infiltration Local Anesthesia Frequency Percent Infiltration Block Both Frequency Missing = 173 Table 12 Block or Infiltration Type of Restraint Used Frequency Percent No Restraint Papoose only Legs/ Arms Papoose Lead Apron Active Restraint/ Hand Holding Other Frequency Missing = 218 Table 13 Type of Restraint 49

62 Frequency of Completion of Treatment Planned Work Frequency Percent Treatment Not Completed All Planned Treatment Completed Frequency Missing = 44 Table 14 Treatment Completed Practitioner Rating of Sedation Effectiveness Frequency Percent Ineffective Somewhat Effective Effective Overly Effective Frequency Missing = 19 Table 15 Sedation Effectiveness Behavior During Sedation Frankl Score Frequency Percent -/ / Frequency Missing = 106 Table 16 Behavior 50

63 Frequency of Post-Operative Analgesics Use Frequency Percent No Analgesic Given Analgesics Given Frequency Missing = 307 Table 17 Analgesic Use No Nausea/Vomiting Frequency of Nausea or Vomiting Frequency Percent Nausea or Vomiting Frequency Missing = 300 Table 18 Nausea and Vomiting 51

64 Frequency of Lip Biting Frequency Percent No Lip Biting Lip Biting Frequency of Cheek Biting Frequency Percent No Cheek Biting Cheek Biting Frequency of Tongue Biting Frequency Percent No Tongue Biting Tongue Biting Frequency of Hiccups Frequency Percent No Hiccups Hiccups Frequency of Other Biting Frequency Percent No Other Biting Other Biting Frequency Missing = 336 Table 19 Complication Frequency 52

65 Time Elapsed Until Patient Resumed Eating Normally Hours Frequency Percent <2 hr hr hr >6hr Frequency Missing = 324 Time Elapsed Until Patient Resumed Playing Normally Hours Frequency Percent <2 hr hr hr >6hr Frequency Missing = 422 Time Elapsed Until Patient Was Sleeping Normally Frequency Percent < hr hr Frequency Missing = 439 Table 20 Time Elapsed Until Normal Activity Resumed 53

66 Parent Rating of Sedation Success Was Sedation Sucessful? Frequency Percent No Yes Frequency Missing = 309 Parent Satisfaction With Sedation Frequency Percent Not Satisfied Satisfied Frequency Missing = 314 Frequency of Parents Who Would Choose Sedation Again Frequency Percent No Yes Frequency Missing = 299 Table 21 Parent Satisfaction 54

67 Frequency of Mallampati Score of Subjects Mallampati Frequency Percent Frequency Missing = 75 Table 22 Mallampati Score Frequency of ASA Status of Subjects Frequency Percent Frequency Missing = 71 Table 23 ASA Status Brodosky Score of Tonsil Assessment of Subjects Frequency Percent >25% % % >75% Frequency Missing = 84 Table 24 Tonsil Assessment 55

68 Frequency of Sedation Related Complications in Subjects Frequency Percent No Complication Recorded Complication Noted Frequency Missing = Dysphoric Child Syndrome Frequency of Paradoxical Reaction Frequency Percent Normal Frequency Missing = 86 Table 25 Paradoxical Reaction and Complications 56

69 Frequency of Positive Medical History of Seizures Frequency Percent Normal Seizures Frequency Missing = 51 Frequency of Positive Medical History of Autism Frequency Percent Normal Autism Frequency Missing = 51 Frequency of Positive Medical History of AHDH Frequency Percent Normal ADHD Frequency Missing = 51 Frequency of Positive Medical History of Prematurity Frequency Percent Normal Premature Frequency Missing = 51 Frequency of Positive Medical History of Obesity Frequency Percent Non- Obese Obese Frequency Missing = 51 Frequency of Positive Medical History of ADHD Frequency Percent Normal ADHD Table 26 Medical Problems 57

70 Frequency of Positive Medical History of Passive Smoke Exposure No Hx Smoke Exposure Passive Smoke Exposure Frequency Percent Frequency Missing = 249 Table 27 Passive Smoke Exposure Frequency of Drug Regimens Used Regemin Frequency Percent midazolam oral midazolam oral+midazolam nasal+meperidine midazolam oral+hydroxyzine midazolam oral+hydroxyzine+meperidine midazolam oral+meperidine midazolam oral+meperidine+promethazine midazolam oral+promethazine midazolam nasal midazolam nasal+hydroxyzine midazolam nasal+promethazine hydroxyzine hydroxyzine+meperidine meperidine meperidine+promethazine triazolam diazepam Total Reclassified Drug Regemins for Analysis Frequency Percent midazolam (oral) midazolam (nasal) all other midazolamn combinations Total Table 28 Drug Regimens 58

71 Re-Classified Drug Regimens Association with Post-Op Complications Post-op complications p-value Sedation Related Complications Dysphoric Child Syndrome Nausea or Vomiting Lip Biting Cheek Biting Tongue Biting Hiccups OTHER biting Table 29 Regimen and Post-Op Complications The Percentage of Nausea or Vomiting in Each Regimen Nausea_or_Vomiti ng Nausea_or_Vomiting no yes Total midazolam oral 101 (98.06%) 2 (1.94%) 103 other midazolam combinations 97 (92.38%) 8 (7.62%) 105 midazolam nasal 139 (97.89%) 3 (2.11%) 142 Table 30 Nausea and Regimen 59

72 Association Between Post-op Complications and Number of Teeth Treated Sedation Related N Mean Median Std Dev Minimum Maximum Complicat ions no yes Post Sedation Dysphoric N Mean Median Std Dev Minimum Maximum no yes Nausea or Vomiting N Mean Median Std Dev Minimum Maximum no yes Lip Biting N Mean Median Std Dev Minimum Maximum no yes Cheek N Mean Median Std Dev Minimum Maximum Biting no yes Tongue N Mean Median Std Dev Minimum Maximum Biting no yes Hiccups N Mean Median Std Dev Minimum Maximum no yes OTHER N Mean Median Std Dev Minimum Maximum biting no yes Table 31 Post-Op Complication and Number of Teeth 60

73 P-values for the Association Between Number of Teeth Treated and Complications p-value Sedation Related Complications Post-Sedation Dysphoric Child Syndrome Nausea or Vomiting Lip Biting Cheek Biting Tongue Biting Hiccups OTHER biting Table 32 Number of Teeth Treated and Complications Percentages of Dysphoric/Angry Child Syndrome for Oral and Nasal Midazolam midazolam type: Normal Angry Child Syndrome Total nasal 228 (93.83%) 15 (6.17%) 243 oral 325 (93.93%) 21 (6.07%) 346 Table 33 Angry Child Syndrome 61

74 Descriptive Statistics of the Association Between BMI and Post-Operative Complications Sedation Related N Mean Median Std Dev Minimum Maximum Complications no yes Post Sedation Dysphoric/Angry N Mean Median Std Dev Minimum Maximum Child no yes Nausea or Vomiting N Mean Median Std Dev Minimum Maximum no yes Lip N Mean Median Std Dev Minimum Maximum no yes Cheek Biting N Mean Median Std Dev Minimum Maximum no yes Tongue Biting N Mean Median Std Dev Minimum Maximum no yes Hiccups N Mean Median Std Dev Minimum Maximum no yes OTHER biting N Mean Median Std Dev Minimum Maximum no yes Table 34 BMI and Post-Op Complications Association between LA type and Post-operative Complications LA type Frequency Percent Infiltration Block/Both Infiltration and Block Table 35 LA Type Frequency 62

75 Values for the Association Between LA type and Post-operative Complications p-value Sedation Related Complications Post-Sedation Dysphoric/ Angry Child Syndrome Nausea or Vomiting Lip Cheek Biting Tongue Biting Hiccups OTHER biting Table 36 LA Type and Complications Percentage of Biting Injuries with LA Type Lip biting Lip biting LA type no yes Total infiltration 198 (93.84%) 13 (6.16%) 211 block/both 82 (83.67%) 16 (16.33%) 98 Cheek_Biting Cheek_Biting LA type no yes Total infiltration 207 (98.57%) 3 (1.43%) 210 block/both 89 (90.82%) 9 (9.18%) 98 Table 37 Percentage of Biting Injuries Tables 59. P-Values for the Association Between Drug Regimen and Other Factors p-value behavior rating all work completed effectiveness of sedation type of restraint next visit type Table 38 P Values for Drug Regimen Associations 63

76 Distribution of "All Treatment Planned Work Completed Among Different Drug Regimens Work Not Completed All Work Completed Total midazolam oral 10 (5.95%) 158 (94.05%) 168 other midazolam combinations 25 (14.62%) 146 (85.38%) 171 midazolam nasal 9 (3.86%) 224 (96.14%) 233 Distribution of Practitioner Rating of Sedation Effectiveness Among Different Drug Regimens Ineffective Effective Total midazolam oral 20 (11.24%) 158 (88.76%) 178 other midazolam combinations 37 (20.9%) 140 (79.1%) 177 midazolam nasal 38 (15.97%) 200 (84.03%) 238 Table 39 Frequency of Drug Regimens and Outcomes P-values for the Association Between Drug Regimen and Number of Teeth Treated adjusted p-value midazolam oral vs other midazolam oral vs midazolam nasal other vs midazolam nasal Table 40 Drug Regimen and Number of Teeth Treated 64

77 P-values for the Association between Effectiveness of Sedation Medical History Variables p-value statistical test gender Pearson's chi-square test interpreter Pearson's chi-square test medical Hx Pearson's chi-square test Seizures Fisher's exact test Autism >0.999 Fisher's exact test ADHD Fisher's exact test Obesity Pearson's chi-square test Prematurity >0.999 Fisher's exact test passive smoke exposure Pearson's chi-square test 2+ behavior health visits Fisher's exact test age Wilcoxon rank-sum test BMI Wilcoxon rank-sum test P-value for the Association Between Dental Behavior and Medical History Variables p-value statistical test gender Pearson's chi-square test interpreter Pearson's chi-square test medical Hx Pearson's chi-square test Seizures Pearson's chi-square test Autism Pearson's chi-square test ADHD Fisher's exact test Obesity Pearson's chi-square test Prematurity Pearson's chi-square test passive smoke exposure Pearson's chi-square test 2+ behavior health visits Pearson's chi-square test age Wilcoxon rank-sum test BMI Wilcoxon rank-sum test P-values for the Association between "all Treatment Planned Work Completed and Medical History Variables p-value statistical test gender Pearson's chi-square test interpreter Pearson's chi-square test medical Hx Pearson's chi-square test Seizures Fisher's exact test Autism Fisher's exact test ADHD >0.999 Fisher's exact test Obesity Fisher's exact test Prematurity Fisher's exact test passive smoke exposure Pearson's chi-square test 2+ behavior health visits >0.999 Fisher's exact test age Wilcoxon rank-sum test BMI Wilcoxon rank-sum test Table 41 P-Values for Outcomes Association with Medical History 65

78 Descriptive Statistics of the Association Between Dental Behavior and Age Behavior N Mean Median Std Dev Mini mum Maximum Negative Behavior (- or -/-) Positive Behavior (+ or +/+) Descriptive statistics for Dosage (mg/kg) between Ineffective and Effective Sedation N Mean Median Std Dev Minim Maxi um mum Ineffective Somewhat Effective/ Effective Table 42 Descriptive Statistics for Dosage and Outcome Descriptive statistics for Dosage (mg/kg) between Ineffective and Effective Sedation N Mean Median Std Dev Minimum Maximum Ineffective Somewhat Effective/ Effective Table 43 Oral Midazolam Descriptive Statistics for Dose and Effectiveness Multiple logistic regression to Determine the Effect of Dosage of Oral Midazolam on Effectiveness Adjusting for Age and BMI odds ratio: OR Point Estimate of OR 95% confidence interval of OR p-value Age (years) , BMI , Oral Midazolam Dose , Table 44 Logistic Regression Adjusting for Age and BMI Nasal Midazolam Descriptive statistics of Dosage (mg/kg) Between Ineffective and Effective Effectiveness N Mean Median Std Dev Minimum Maximum Ineffective Effective Table 45 Nasal Midazolam Descriptive Statistics for Dosage and Effectiveness 66

79 Multiple Logistic Regression to Determine the Effect of Dosage of Nasal Midazolam on Effectiveness Adjusting for Age and BMI odds ratio: OR Point Estimate of 95% confidence interval of OR OR p-value Age (years) , BMI , Oral Midazolam Dose , Table 46 Multiple Logistic Regression for Nasal Midazolam Adjusted for BMI and Age P-values of the Association Between the Dosage (mg/kg) of Oral Midazolam and Outcome Measures and Complications p-value effectiveness behavior work completed sedation related complications post sedation dysphoric/angry child syndrome Nausea or Vomiting Lip Cheek Biting Tongue Biting N/A Hiccups OTHER biting any complication Table 47 P Values for the Association Between Nasal Midazolam and Outcomes and Complications 67

80 Descriptive statistics of oral midazolam dosage (mg/kg) between different weight stratifications Weight (kg) N Mean Median Std Maximu Minimum Dev m 10-15kg kg kg kg Descriptive statistics of oral midazolam dosage (mg/kg) between obese patients and non-obese patients N Mean Median Std Maxim Minimum Dev um Non-Obese Obese Descriptive statistics of nasal midazolam dosage (mg/kg) between different weight categories weight_kg_gp1 N Mean Median Std Maxim Minimum Dev um 10-15kg kg kg kg Descriptive statistics of nasal midazolam dosage (mg/kg) between obese patients and non-obese patients N Mean Median Std Maxim Minimum Dev um Non-Obese Obese Table 48 Descriptive Statistics of Weight Categories and 68

81 P-Values for the association between any positive medical history & outcome measures and complications p-value effectiveness behavior work completed sedation related complications >0.999 post sedation dysphoric/angry child syndrome Nausea or Vomiting Lip Cheek Biting Tongue Biting >0.999 Hiccups OTHER biting any complication Table 49 P Values of Medical and Outcome 69

82 Appendix B: Resident Handbook Sedation Guidelines 70

83 71

84 Appendix C: Quality Assurance Survey (QAS) 72