2017 CSPD/WSPD Annual Meeting “WOW” session

Program: When laughing gas becomes Not so funny - A blurred line between use and abuse

Presenter: Dr. Yawen Peng, DMD Western University of Health Sciences Course objectives

Upon completion, the attendance will be able to:

• Recall the indications and contraindications of Nitrous Oxide usage from the AAPD guidelines

• Describe the anesthetic properties of Nitrous Oxide

• Understand the study reports of the potential toxic from Nitrous Oxide

• Identify the best practice of Nitrous Oxide usage in pediatric dentistry

About the speaker- Dr. Yawen Peng

• DMD from Boston University Goldman School of Dental Medicine • Certificate in Pediatric Dentistry from Tufts University • Masters of Arts in Health Professions Education from University of the Pacific • Diplomate, American Board of Pediatric Dentistry

• Practice in Los Angeles, California • Faculty for Pre-doctoral education in Pediatric Dentistry at the College of Dental Medicine at Western University of Health Sciences

Tell us about yourself! What is Nitrous Oxide?

• Colorless and odorless gas with a faint sweet smell

• Heavier than air or oxygen o Spilled/wasted gas that is not scavenged from the room ends up on the floor

• Anxiolytic agent: o Used to calm a nervous but cooperative patient without inducing the loss of consciousness o Indirectly relax skeletal muscle (relief of anxiety) o CNS mild depression (cerebral cortex) and euphoria Laughing gas! o Decrease the fear for future dental treatment

• Analgesic properties o Mild analgesic effect at sub-anesthetic concentrations  Local Supplement

• Amnestic

History of Nitrous Oxide

• 1776- Joseph Priestley and Karl Scheele discovered N2O

• Early 1800s- Sir Humphrey Davy recommended N2O used as a recreational drug o Excited and euphoric o Loss all inhibitions and laughed “laughing gas” History of Nitrous Oxide

• 1844- Dr. (dentist from Connecticut) o Attend demonstration by Dr. Gardner Colton- No pain in the attendance’s injured leg

o Explored the use in general and dental surgery Founder of Anesthesia

o Extract his own decayed molar under 100% N2O (may become unconscious and hypoxic) (less than 20% oxygen could be fatal)

History of Nitrous Oxide

• 1868- Dr. Edmund Andrews o Recommend 20% O2 and 80% N2O combo  modern dentistry

o Paul Bert developed N2O/O2 delivery equipment

• 1976 ADA o Adopted standards for the manufacture of inhalation sedation units

Mechanism of Action

• Inhaled N2O is insoluble in the blood without binding with hemoglobin and diffuse into brain through crossing the Blood Brain Barrier (BBB) • Change membrane protein structure of neurons

• Analgesic action: o Neuronal release of endogenous opioid peptides o Produce “relative analgesia” (Langa) • Anxiolytic effect: o Activation of gamma-aminobutyric acid type A receptor through benzodiazepine binding site

David, E., Longnecker, M.D., Frank, L., Murphy, M.D., Introduction to Anesthesia. Saunders 1996 Pharmacokinetic properties

• Onset o Quick! (A few seconds to 3-5 minutes) o Rapidly diffuse from lungs to blood and cross BBB in brain rapidly

• Elimination o Quick! (99% in 5-10 minutes) o Unchanged with exhalation from the lungs o No metabolism in liver or kidneys o Exits faster than traces of nitrogen that replace it • Need 100% O2 to washout the residuals in anatomic dead space

How do you use Nitrous Oxide?

• Practice type o Solo, group, hospital, academics, etc.. o Urban, suburban, etc..

• N2O/O2 system o Portable vs Central o Removing and monitoring ambient gases o Monitoring system

• Patient type o Medicaid, insurance, etc.. o Age group and frequency o Combine with sedation

How is Nitrous Oxide used by other pediatric dentists?

• Significant difference in the distribution of respondents indicating the percentage of patients requiring N2O as a function of the years in practice (<10 yrs vs. >10 yrs ).

Why or why not use N2O/O2?

• Dr. Wilson et al. found that 97 % of respondents use N2O/O2 in the offices

• Reason for use: • Reason for not using Calms patient (98%) o Less difficult to use general anesthesia o (58%) o Helps with gaggers (81%) Aids in distraction (73%) o Better manage patients without it (48%) o Patients do not need it (39%) o More patients require sedation (70%) o More prepared to use sedation (48%) o State legislation made sedation difficult o (21%)

o “I don’t like it” (18%) o “Slows me down too much” (16%)

AAPD guidelines

• Last revision in 2013

• Indications o A fearful, anxious, or obstreperous patient o Certain patients with special health care needs o A patient whose gag reflex interfere with dental care o A patient for whom profound local anesthesia cannot be obtained o A cooperative child undergoing a lengthy dental procedure

• Contraindications o Some chronic obstructive pulmonary diseases (COPD) o Severe emotional disturbances or drug-related dependencies o First trimester of pregnancy o Treatment with bleomycin sulfate (cancer therapy) o Methylenetetrahydrofolate reductase deficiency Patient o Cobalamin (Vitamin B12) deficiency Can you use N2O/O2 on an Asthmatic patient?

• Benefit from increased concentration of oxygen administered. • Same concepts apply to Sickle-Cell trait/disease, , liver and kidney disorders Why is there a shift in N2O/O2 usage?

• Younger practitioners preferring N2O/O2 management o Older generations may prefer a more disciplinary approach o Younger generations may rely more on a deferment-style of management • Increased parental acceptance of this behavior guidance technique

• Changing parental styles o Increased disruptive behavior in children?

How does parents think about N2O/O2?

In US, N2O/O2 sedations ranks high in parental acceptance. However, Dr. Wilson et al. in 2016 found in their survey:

• Over half of the parents expressed concern over N2O/O2

• Parents are growing more concerned about their children’s safety, including vaccinations or anesthesia

• Practitioners will benefit from being familiar with evidence-based studies and educate parents through conversations Parents from around the world

• In UK o N2O/O2 is the most popular form of sedation o Significantly more dentists than parents believe that the child could have been managed without sedation and would not require it for further dental treatment

• In Spain o Popular behavior techniques are tell-show-do, voice control and active restraint

• In Arab o N2O/O2 is the “Least approved technique”

A global perspective of pediatric dentistry training

• Frequency of sedation type received in the advanced education training: o General anesthesia (52%) o Nitrous oxide (46%) o Oral sedation (44%)

• Conclusion: Our profession moves toward a philosophy of managing children who o Cope easily with dental procedures using tell-show-do, or o Using a definitive fail-safe pharmacological method for most other who do not cope well. Nitrous Oxide - the safest drug on earth?! Side effects

• Most common: o Nausea (2.2%), Vomiting (1.6%) o Diffusion hypoxia

• Over-sedation

• Others

Nausea and Vomit

• Before appointment o Light meal 2 hours prior to administration (No NPO required) o Wear loosely fitting clothes for comfort

• During appointment: o Avoid drastic and constant changes in the concentration  Roller coaster effect o Increase or decrease at an increment of 1L/minute every 1 minute interval

• Early signs of vomiting: o Hyperventilation, sweating, nausea

• Management o Remove everything on patient’s fact and in oral cavity o Turn patient’s head and body away to the side opposite to the operator o Remove vomitus pooled in the checks o Use emesis basin and high pressure suction tip to remove vomitus o Administer 100% O2 for 3-5 minutes Diffusion Hypoxia

• Occur as the sedation is reversed at the termination of the procedure

• N2O escapes into alveoli and dilute O2 inside  O2-CO2 exchange disrupted  Hypoxia created

• Management o Use pulse oximeter to monitor O2 level • (>90% is danger due to rapid loss of O2 into brain) o Oxygenate for 5 miuntes after termination of N2O N2O diffuses into air-filled spaces

• N2O enters into gas-filled spaces 30x faster than nitrogen exit o Increase volume and pressure in the space

• The effect is in any concentration of N2O/O2 administered

• The magnitude of the effect is proportional to o Blood supply of the cavity o Concentration of N2O inhaled o Length of time the patient is exposed to N2O

• Dangerous in patient s with bowel obstruction, pheumothorax middle ear and sinus diseases, and retinal surgery o In eyes may lead to blindness

Over-sedation

• 30-50% N2O (dissociation sedation and analgesia): o Recommended concentrations for most dental procedures o Patient are relaxed, “floating, warm and tingling”, somnolent, dissociated and easily susceptible to suggestions o Some may experience amnesia but no alteration of learning or memory o Analgesic effect of 30% N2O is as effective as 10-15 mg of morphine, 50% N2O is equally effective as EMLA o Supplementatio with local anesthesia for operative dentistry and oral surgery

• >60% N2O (Total analgesia): o Patient experience dis-coordination, ataxia, giddiness, increased sleepiness and loss of consciousness o Loose the ability to maintain open mouth never use mouth prop! o More likely experience nausea and vomiting

• If over-sedated, decrements of N2O concentration by 5- 10% for 2 minutes or remove nasal hood and allowed breathing ambient air Latex allergy

Anesthetic carpule (latex stopper and Nitrous oxide masks and hoses diaphragm) Bite block Gloves Orthodontic bands and elastics Blood pressure cuff Polishing wheels and points Endodontic stops Prophy cups Mixing bowls Rubber dams Gutta percha Instrument bands Hoses (saliva ejector and HVE) Widgets Toys, balloons, prizes Have you experience any

emergency with N2O/O2 usage?

• Type o Airway o Cardiac o Others

• Combine with sedation

• Need emergency medical service

• Follow-up management Let’s see other practitioners’ experience

Dr. Wilson et al. in 2016 found in their survey: • No significant changes in the percentage of practitioners who reported compromised airway with N2O/O2 and sedatives (30% in 2015 versus 28% in 1996)

• There is a decrease for the need of EMS resulting from sedation (5% in 1996 to 3% in 2015)

• Almost 50% of the practitioners will conduct emergency drills in the office at least once a year Is your patient the only person

inhaled N2O in the room? How much N2O is actually delivered to your patient?

• The reading of N2O/O2 from the apparatus is never identical to the actual inspired concentration of

N2O reaches the alveoli

• Leakage may be from: o Poorly fitted nasal masks o Dead space o Mouth breathing

• With inspired concentration set at 50-70%, only 30- 50% is actually delivered to alveoli Occupational exposure from N2O • Spontaneous abortion, reduced fertility and congenital abnormality o Vaisman 1968 and Askrog 1970: 7 out of 31 birth were complication free in Russian female anesthesiologists

o Unscavenged N2O for 3 hours or more in a week have a 2.5 fold increase in the rate of spontaneous abortion

o Animal study showed exposure to N2O during gestation leads to teratogenic effects and reduced fetal weight • Bone marrow suppression

• Lassen 1956: prolonged N2O treatment for tetanus • Sweeney 1985: 3 out of 20 dentists • Vitamin B12 activity DNA synthesis RBC Pernicious anemia • Sickness in other systems o Renal and hepatic (1. 7 fold increase) disorders o 4x higher incidence in neurological disorders (numbness, tingling and muscle weakness)

Quarnstrom, F. Nitrous Oxide Analgesia: What is safe exposure levels in staff? Dentistry Today. 2002 21(4): 104-09. How does chronic exposure of

N2O affects fertility?

• Kugel et al. found in their experiment rats that N2O interfere with “Hypothalamic-pituitary-gonadal axis” by decreasing the release of luteinizing hormone releasing hormone (LHRH) from the hypothalamus.

Hematologic diseases

• Lassen et al first describes the observation in Lancet 1956 th o Granulocytopenia developed on the 4 day (of 50% N2O) followed by Thrombocytopenia o Aplastic Anemia developed after several days o Hematologic diseases resolved after discontinuation of N2O

• Burman et al had similar discovery in their patient in 1978 o 6 hours exposure- Mild Megaloblastic changes o 24 hours exposure- Severe Megaloblastic changes Neuropathology

• Layzer et al (1978) reported sensory polyneuropathy in dentists and a hospital technician

• Polyneuropathy is linked to Vitamin B12 deficiency

• Heavy occupational exposure to N2O  Irreversibly oxidize cobalt atom of Vitamin B12  Vitamin B12 transfer from active Co(I) to inactive Co (II or III)  Reduce Iron concentration  Covert hemoglobin to methemoglobin (cannot bind O2 85% SpO2 the most)

• Symptoms include weakness, numbness, and burning pain from hands and feet and progress to the arms and legs Metabolic diseases

• Inactivation of Vitamin B12 from N2O may cause inhibition of Methionine metabolism

• Methionine is an essential amino acid for angiogenesis (growing new blood vessels), a methyl donor for many reactions including myelin sheath assembly, neurotransmitter synthesis and DNA synthesis

• Vitamin B12 is a cofactor for Methionine synthetase enzyme, which involves in a pathway for DNA synthesis and repair.

• Deficiency in this enzyme manifests with megaloblastic changes, growth retardation, psychomotor retardation and neurologic problems. N2O Patient with potential Vitamin B12 deficiency • Felmet et al. (2000) and McNeely et al. (2000) reported breast-fed infants who developed anemia

and/or neuropathy after N2O exposure

• Both infants were Vitamin B12 deficiency from deficiency of intrinsic factor and a vegan diet mother

• Vitamin B12 deficiency can result secondary to conditions such as pernicious anemia or dietary restrictions, most commonly vegan. Nitrous oxide and brain development

• Animal studies in several species have shown that N2O is associated with apoptosis in the developing brain

• Nitrous oxide can inhibit major enzymatic pathways and repeated exposure may lead to neurologic damage

• Further study in human is needed for better understanding of the impact

What are the FDA’s concerns?

• Potential risks for procedures in children under age 3 o Longer than three hours o Multiple procedures

• Effects are subtle and may include learning, memory, or behavior problems

• IV or inhaled anesthetic and sedation drugs that block N-methyl-D-aspartate (NMDA) receptors and/or potentiate gamma-aminobutyric acid (GABA) activity Other uses for N2O

• Propellant in whipped cream o Dissolves readily in fats o Foams and dissolves at release of pressure

• Oxidizing agent in race cars o Supports combustion better than regular air o Molecule breaks at low temperature leaving pure oxygen and nitrogen in the engine o Boosts horsepower up to 50% o May cause explosion if used improperly

Popular Science magazine 1949

-How to DIY N2O at home~ A sign advertising laughing gas is prominently displayed in the party island of Ko Phangan, Thailand Nitrous Oxide Abuse

• Early 1800s - Sir Humphrey Davy recommended N2O used as a recreational drug

• 1961- Case report of N2O abuse in the literature • 1980s~1990s – Debates about clinical consequences and implications of N2O misuse, such as hematologic, neurological and psychiatric effects

• Most N2O abuse observed in adolescents and young adults (4- 10% population) Be careful when patients “ASKING” for it!

• N2O is not regularly considered as a possible etiology in the emergency department, leading to misdiagnosis and significantly underreported How can we better serve our patients? The right method for the right patient

• Follow AAPD guideline

• Thorough evaluation of medical, allergy, dental, family and any sedation history

• Fully discuss the pros and cons of N2O/O2 therapy and offer any alternatives when possible

• Always consider the least invasive behavior guidance techniques before moving up the ladder Indications

• A fearful, anxious, or obstreperous patient • Certain patients with special health care needs • A patient whose gag reflex interfere with dental care • A patient for whom profound local anesthesia cannot be obtained • A cooperative child undergoing a lengthy dental procedure

• , Sickle-Cell trait/disease, epilepsy, liver and kidney disorders • Minor surgical procedures (medical journals) o Nitrous Oxide sedation is not recommended for procedures longer than one hour

AAPD Guideline on use of Nitrous Oxide for Pediatric Dental Patients Contraindications

• Some chronic obstructive pulmonary diseases (COPD) • Severe emotional disturbances or drug-related dependencies (psychosis or addition) • First trimester of pregnancy • Treatment with bleomycin sulfate • Methylenetetrahydrofolate reductase deficiency (DNA peoduction) • Cobalamin (Vitamin B12) deficiency

• Current upper respiratory tract infection • Phobic individuals • Potential air-filled spaces expansion from N2O: o Pneumothorax o Middle ear surgery o Recent eye surgery o Maxillofacial injuries

AAPD Guideline on use of Nitrous Oxide for Pediatric Dental Patients ADA House of Delegates October 2016 meeting

• Updates from 2012 guideline for nitrous oxide and oxygen used in minimum sedation: o When used in combination with a sedative agent, the agent may produce “Minimum, moderate, deep sedation, or general anesthesia”

• Charles J. Coté, Stephen Wilson. o “Guidelines for monitoring and management of pediatric patients before, during, and after sedation for diagnostic and therapeutic procedures: update 2016”, Pediatrics June 2016 (AAP/AAPD)

Administration technique

• Proper training of practitioners and staff is mandatory!

• Select appropriately sized nose hood

• Flow rate: 5-6 L/min (watch for reservoir bag refill) o 100% O2 for 1-2 minutes o Add N2O at 10% interval or 1L/minute every 1 minute interval o Usually 30-40% N2O is ideal for most patients (DO NOT exceed 50%) o Nitrous Oxide sedation is not recommended for procedures longer than one hour

• May GRADUALLY adjust the concentration depending on the procedure: (avoid roller coaster effect!) o Decrease for restorations o Increase for injection of local anesthesia and extractions

• Continue basic behavior guidance techniques during treatment for psychological reassurance

• Termination of N2O  100% O2 for 5 minutes

AAPD Guideline on use of Nitrous Oxide for Pediatric Dental Patients Best practice

recommendation for N2O/O2

• Occupational exposure below 100ppm over a time- weighted average (TWA) period of 8 hrs (Control of substances Hazardous to Health (COSHH) regulations 2002)

• However, 70% of practitioners do not use monitors with N2O alone, and more than 75% of practitioners do not use methods to monitor N2O in ambient air (Wilson S. et al., 2016)

How to decrease chronic

exposure of N2O?

• Exposure of inhalation sedation is measured by the Time Weighted Average (TWA) exposure

• National Institute for Occupational Safety and Health (NIOSH) USA 1994 recommended TWA exposure of below 50 ppm for dental staffs over an 8-hr period

• Use appropriate mask size and discourage patient talking

• Use Scavenging system!!! (80 ltr/min) o Active system keeps N2O below 50 ppm (TWA) o Up to 7000 ppm (TWA) in place without scavenging system

• Increase air exchange rate to 10 per hour o Reduce N2O exposure level to below 25 ppm (TWA)

• Calibrate flow meters every 2 years It is our legal responsibility

• The Control of Substances Hazardous to Health (COSHH) Regulation 2002: o It is a legal requirement to produce a Risk Assessment into the use of nitrous oxide in regards to occupational exposure, including when and where it is being used and monitoring the levels produces. o Risk assessment will help identify sources of excess production and enable reducing measures to be instigated. o The monitoring include: leak testing of equipment, monitoring of air in the workers’ personal space and room air monitoring o The monitoring must be maintained on a periodic basis

Vitamin B12 supplements

• Consider in people who have risk factors to become severely Vitamin B12 deficiency

• Takes up to 40 mg/day before and after dental procedure for extended periods of time

• There is no guidelines as to the “right” amount to take or the amount that will counteract the Vitamin B12 deficiency that will experienced during dental procedure Better alternative to Nitrous Oxide • Tell your patient NOT to get dental disease in the first place!!! Questions? • Contact Dr. Yawen Peng @ o [email protected] o (909)706-3841

References

• AAPD Policy on minimizing occupational health hazards associated with Nitrous Oxide. 2013 • Wilson S, Alcaino EA., Survey on sedation in paediatric dentistry: a global perspective. Int Paediatr Dent 2011 Sep;21(5): 321- 32. • Wilson S, Gosnell ES., Survey of American academy of pediatric dentistry on nitrous oxide and sedation: 20 years later. Pediatr Dent 2016 Oct 15;38(5):385-92 • Wilson S, Houpt M., Project USAP 2010: Use of sedative agents in Pediatric Dentistry- a 25-year Follow-up Survey. Pediatr Dent 2016 Mar-Apr;38(2):127-33. • Quarnstrom, F. Nitrous Oxide Analgesia: What is safe exposure levels in staff? Dentistry Today. 2002 21(4): 104-09. • Kugel G et al., Nitrous oxide and infertility. Anesth Prog. 1990 Jul;37(4): 176-80 • Amess JA and Burman JF, Megaloblastic haemopoiesis in patients receiving nitrous oxide. Lancet 1978 Aug 12;2(8085):339-42. • Baum VC., When Nitrous Oxide is no laughing matter. Peds anesthesia 2007; 17”824-30 • Tobias JD. Applications of nitrous oxide for procedural sedation in the pediatric population. Pediatr Emer Care Feb 2- 13;29(2):245-65 • Schmitt EL and Baum VC. Nitrous oxide in pediatric anesthesia: friend or foe? Current opinion in Anesthesiology 2008. 21:356- 59 • Lorenc JD, Inhalant abuse in the pediatric population: a persistent challenge. Current Opinion in Pediatrics 2003.15:204-09 • Henretig F. Inhalant abuse in children and adolescents. Pediatric Annals Jan 1996; 25(1):47-52 • Pedersen RS et al., Nitroux oxide provides safe and effective analgesia for minor paediatric procedures- a systemic review. Dan Med J 2013;60(6):A4627 • Guelmann M et al., Effect of continuous versus interrupted administration of nitrous oxide-oxygen inhalation on hehavior of anxious pediatric dental patients: A pilot study. J Clin Pediatr Dent 2012; 37(1):77-82 • Andreas D et al. The hematological effects of nitrous oxide anesthesia in pediatric patients. Pediatr Anesthe June 2015; 120(6): 1325-30 • Nagele P et al., Nitrous Oxide anesthesia and plasma homocysteine in adolescents, Anesth Analg Oct 2011;113(4):843-48 • Brodsky JB and Cohen EN., Adverse effects on nitrous oxide. Med Toxicol. Sep-Oct 1086;1(5):362-74 • Sethi NK et al., Nitrous oxide “Whippit” abuse presenting with Cobalamin responsive psychosis. J Med Toxicol June 2006;2(2): 71-74 • Garakani A et al., Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: A systematic review of the case literature. Am J Additions 2017;25:358-69 • Samir PV and Fere SS., Nitrous oxide-oxygen inhalation sedation: A light on its safety and efficacy in pediatric dentistry. Int J Advan Health Sci Aug 2015;2(4):4-10 • Paterson SA and Tahmassebi JF., Paediatric dentistry in the new millennium: 3. Use of inhalation sedation in paediatric dentistry. Dent Update Sep 2003;30(7):350-8 • Klein U., Ch. 15- N2O/O2 sedation in pediatric dentistry. Pocket dentistry- fastest clinical dentistry insight engine. Jan 2015