Practical Conscious Sedation PDF

 Quintessentials of Dental Practice – 15 Oral Surgery and Oral Medicine – 2 Practical Conscious Sedation Authors: David Craig Meg Skelly Editors: Nairn H F Wilson...

 Quintessentials of Dental Practice – 15 Oral Surgery and Oral Medicine – 2 Practical Conscious Sedation Authors: David Craig Meg Skelly Editors: Nairn H F Wilson John G Meechan Quintessence Publishing Co. Ltd. London, Berlin, Chicago, Copenhagen, Paris, Milan, Barcelona, Istanbul, São Paulo, Tokyo, New Dehli, Moscow, Prague, Warsaw 2 British Library Cataloguing in Publication Data Craig, David Practical conscious sedation. - (Quintessentials of dental practice series; Oral surgery and oral medicine; 2) 1. Anesthesia in dentistry 2. Conscious sedation I. Title II. Skelly, Meg III. Wilson, Nairn H. F. 617.9′676 ISBN 1850973113 Copyright © 2004 Quintessence Publishing Co. Ltd., London All rights reserved. This book or any part thereof may not be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, or otherwise, without the written permission of the publisher. ISBN 1-85097-311-3 3 Inhaltsverzeichnis Titelblatt Copyright-Seite Foreword Acknowledgements Chapter 1 Historical Development of Conscious Sedation Aim Outcome Introduction Relative Analgesia Barbiturate-based Techniques The Jorgensen Technique Methohexitone Benzodiazepine-based Techniques Diazepam Diazemuls Midazolam Flumazenil Propofol-based Techniques Equipment Conclusions Further Reading Chapter 2 Basic Physiology and Anatomy: A Whistle-stop Tour Aim Outcomes Introduction Respiratory Physiology Mechanics, volumes, capacities and flow rates Pulmonary gas exchange Control of Respiration Cardiovascular Physiology Factors affecting heart rate 4  Factors affecting stroke volume Factors affecting blood pressure Airway Obstruction Superficial Veins of the Forearm and the Dorsum of the Hand Some Differences Between Adults and Children Conclusions Further Reading Chapter 3 Pharmacology Aim Outcome Introduction Routes of Administration Pharmacokinetics Pharmacodynamics Properties of the Ideal Sedative Drug Intravenous Agents The benzodiazepines Diazepam Midazolam Temazepam Flumazenil Mechanism of action of benzodiazepines Respiratory Effects Cardiovascular Effects Propofol Opioids Inhalational Agents Nitrous oxide Disadvantages of Nitrous Oxide Sevoflurane Conclusion Further Reading Chapter 4 Initial Assessment and Treatment Planning Aim Outcome Introduction The Assessment Visit 5  What is the Problem? Medical History and Investigations Dental History Social Factors Dental Examination Treatment Planning The First Sedation Visit Conclusions Further Reading Chapter 5 Equipment for Conscious Sedation Aim Outcome Inhalational Sedation Gas supply Equipment checking Intravenous Sedation Using Midazolam Drugs and syringes Pulse Oximetry Equipment for Airway Management Conclusions Further Reading Chapter 6 Clinical Techniques Aim Outcome Introduction Presedation Preparation Inhalational Sedation with Nitrous Oxide and Oxygen Administration of nitrous oxide Nitrous oxide pollution and scavenging Other inhalation sedation methods Intravenous Sedation with Midazolam Method of administration Venepuncture Midazolam Administration Titration Regimen: Monitoring the Sedated Patient Recovery and Discharge 6  Reversal of Midazolam Sedation Other Sedation Techniques Intravenous midazolam preceded by an opioid Intravenous propofol by operator-controlled infusion Intravenous sedation by patient-controlled infusion Oral sedation with benzodiazepines Intranasal sedation using midazolam Conclusions Further Reading Chapter 7 Complications: Avoidance and Management Aim Outcome Introduction Complications of Sedation and their Management Respiratory depression Airway obstruction Hypotension Problems with Venepuncture Hiccups Allergy Nausea and vomiting Prolonged recovery Failure of sedation Paradoxical effects Disinhibition Oversedation Undersedation Sexual fantasies Record Keeping Conclusions Useful Website Chapter 8 Sedation in Special Circumstances Aim Outcome Introduction Medically Compromised Patients Conditions in which sedation is beneficial 7  Conditions where the technique might require modification Conditions where caution is required Medical Risk Assessment Special Care Patients Paediatric Patients Failed Sedation Recognition Management Conclusions Further Reading Chapter 9 Standards of Good Practice and Medicolegal Considerations Aim Outcome Introduction Training Undergraduate education and training Postgraduate education and training Environment and Equipment for Sedation Inhalational sedation Intravenous sedation Indications for Conscious Sedation Patient selection Patient preparation Consent Clinical Records and Procedures Aftercare Medicolegal Requirements for Specific Sedation Techniques and Circumstances Inhalation sedation Intravenous sedation Oral and intranasal sedation Conscious Sedation for Children Complications Clinical Governance and Audit Conclusions Further Reading 8 Foreword The ability to provide effective, safe conscious sedation is a tremendous attribute for a dental team. Patients with a real fear of dentistry and individuals with other conditions which make it extremely difficult if not impossible for them to be treated under normal conditions rightfully expect conscious sedation treatment to be available to assist them obtain the treatment they require. In addition, patients faced with the prospect of an unpleasant, possibly distressing dental procedure, such as a difficult surgical extraction, should have the option of conscious sedation to help them through the difficult phase of their treatment. As a consequence, conscious sedation is considered to be an integral element of the control of pain and anxiety in the delivery of dental care. In other words, conscious sedation is an important fundamental aspect of the modern practice of dentistry. Practical Conscious Sedation, Volume 15 of the highly acclaimed Quintessentials of Dental Practice Series, is a succinct authoritative text on the provision of conscious edition in the primary dental care setting. As with all the books in the Quintessentials of Dental Practice Series, Practical Conscious Sedation presents, in a generously illustrated text, a wealth of information for all members of the dental team. For the practitioner reluctant to make conscious sedation available, this book provides the necessary knowledge, guidance and encouragement to expand their range of methods for the control of pain and anxiety. For the dental team already providing conscious sedation, this book promotes and gives lots of practical advice on good practice and the safety of patients. Although not primarily intended for students, they too can learn a great deal from this easy-to- read book. Nairn Wilson Editor-in-Chief 9 Acknowledgements We wish to thank Andrew Dyer and Ted Dawson for their patient and meticulous preparation of the photographs for this book. 10 Chapter 1 Historical Development of Conscious Sedation Aim The aim of this chapter is to describe the historical development of conscious sedation techniques for dentistry. Outcome After reading this chapter you should have an understanding of the way conscious sedation techniques have evolved. You will also understand the close historical links between conscious sedation and general anaesthesia. Introduction The ability of twenty-first century dentists to provide comfortable treatment for their patients has its origin in the discovery and development of general anaesthetic drugs in the nineteenth century. Before the advent of these drugs, the dental patient was expected to endure considerable pain and distress. The most commonly performed surgical procedure was the extraction of teeth. Grim stoicism and occasional self- medication with alcohol were the only ways of coping. Dentists contributed in no small measure to the early development of general anaesthesia and, later, to the introduction of local anaesthesia and conscious sedation techniques. In the USA, Horace Wells used nitrous oxide for the first time in 1844 and William Morton administered ether for dental extractions in October 1846. Both these men were dental surgeons. In England, another dentist, James Robinson, was the first to administer ether to a patient in London only two months after Morton. Carl Koller pioneered the use of topical and injected cocaine for local anaesthesia in ophthalmology in 1884. Twenty years later, procaine was available for use in dental patients. This was superseded by lidocaine (lignocaine) in the late 1940s. Reports of dentists using nitrous oxide to provide inhalational conscious sedation, rather than general anaesthesia, started to appear in the early 1900s. By the 1930s, an intravenous barbiturate, hexobarbitone, was in use in UK dental practices for sedation. 11  Over the course of the second half of the twentieth century, there were further developments in the drugs and techniques used for dental conscious sedation. These are shown in Table 1-1. Table 1-1 Chronological development of dental conscious sedation. Year Developments 1940s “Relative Analgesia” (nitrous oxide/oxygen) 1945 The Jorgensen Technique 1960s IV methohexitone (Brietal®) 1966 IV diazepam (Valium®) 1970s IV diazepam (Diazemuls®) 1983 IV midazolam (Hypnovel®) 1988 IV flumazenil (Anexate®) 1990s IV propofol (Diprivan®) Relative Analgesia Joseph Priestley discovered oxygen in 1771 and nitrous oxide in 1772. The analgesic properties of nitrous oxide were discovered by Humphry Davy in 1798. It appears that Davy inhaled nitrous oxide in order to determine its effects, whilst suffering pain from a partially erupted wisdom tooth. He noticed that his painful pericoronitis was relieved. In 1800, Davy published a treatise on nitrous oxide in which he suggested that the gas “may probably be used with advantage during surgical operations”. No further progress was made until 1844, when Horace Wells had one of his own teeth extracted under nitrous oxide anaesthesia. Edmund Andrews, a Chicago surgeon, reasoned that the asphyxia often seen during nitrous oxide anaesthesia was due to the oxygen in nitrous oxide not being available to oxygenate the blood. In 1868 he demonstrated that a mixture of 20% oxygen and 80% nitrous oxide was satisfactory for safe and effective anaesthesia. In 1881 nitrous oxide was first used as an analgesic during childbirth in St Petersburg. In 1889 nitrous oxide was used to provide analgesia for a dental procedure in Liverpool. By current standards, the machines used to deliver nitrous oxide and oxygen were crude and the gases far from pure. Many dentists manufactured their own nitrous oxide! During the first half of the twentieth century interest in nitrous oxide sedation came and went. Success was variable, partly as a consequence of the use of inappropriate equipment, but also because of a misunderstanding about the 12 properties of the gas and the best way to use it. Hitherto, the main emphasis had been placed on the analgesic properties of nitrous oxide, but attempts to achieve total analgesia in every patient often led to failure. Many patients experienced nausea, vomiting and excitement-stage symptoms. Appreciation of the excellent sedative properties of nitrous oxide came later following the work of Harry Langa (USA), Ulla Hoist (Denmark) and Paul Vonow (Switzerland) during the 1940s and 1950s. The change in use of nitrous oxide from analgesia to sedation led to alterations in technique, dosage and in the approach to the patient. Langa used the term “Relative Analgesia” to describe his sedation technique. The technique involved the administration of low to moderate concentrations of nitrous oxide in oxygen (using a specially designed machine) accompanied by a steady stream of reassuring and encouraging talk. The technique, with some minor modifications, has now been in use for over fifty years. Barbiturate-based Techniques Barbiturates Key Dates 1912 phenobarbitone 1930s hexobarbitone and thiopentone 1940s The Jorgensen Technique 1960s IV methohexitone (Brietal®) The Jorgensen Technique In 1945 Niels Jorgensen used a cocktail of intravenous agents as “premedication” for patients about to undergo dental procedures under local analgesia. The method, also known as the Loma Linda technique, took advantage of the hypnotic and tranquillising effects of pentobarbitone, the analgesic action of pethidine and the amnesic properties of hyoscine. It allowed prolonged treatment to be carried out, but the method was unsuitable for procedures lasting less than two hours. Recovery could be prolonged. Methohexitone Barbituric acid was first prepared in 1864 by Adolph von Baeyer – a research assistant to Kekule in Ghent. The first hypnotic barbiturate, diethylbarbituric acid (barbitone), was introduced into medicine by Fischer and von Mering in 1903. Barbitone had excellent hypnotic properties and was used for many years. 13 Phenobarbitone (Luminal) was introduced in 1912. Hexobarbitone, thiopentone and methohexitone were classified as ultra-short-acting drugs and, therefore, the most likely to be of use for dental sedation. In the 1930s, Stanley Drummond-Jackson, a Huddersfield dentist, used intravenous hexobarbitone (and later thiopentone) to produce “insensibility” in patients undergoing not only extractions but also more lengthy conservative procedures. He used a singledose technique which was calculated on the basis of the estimated length of the procedure. If the procedure took longer, the anaesthesia was maintained by the use of inhalational agents. The technique was satisfactory in the skilled hands of a fast worker, but there were few dentists who possessed sufficient knowledge and competence in the use of these drugs and, as a consequence, the technique did not gain popularity. The situation did not change until the introduction of methohexitone (Brietal). In the mid-1960s Drummond-Jackson pioneered a method to produce a controlled level of unconsciousness by administering increments of the drug via an indwelling intravenous needle. Drummond-Jackson’s technique became known as “ultra-light anaesthesia” or “minimal increment methohexitone”. The technique was widely adopted, especially in the UK and in the USA. It was, however, a subject of controversy, and over the next two decades an increasing amount of evidence was produced in an attempt to undermine the confidence of both the dental profession and the patients. There was much discussion about whether the technique produced anaesthesia or sedation and whether protective laryngeal reflexes were dangerously compromised. There were discussions about the meaning of sedation and the definition of anaesthesia. There was polarisation of views, hostility between medical and dental anaesthetists and, finally, a lengthy and hugely expensive libel action in the UK. The outcome was a rapid decline in the use of ultra-light methohexitone in dentistry. Benzodiazepine-based Techniques Benzodiazepines – Key Dates 1959 chlordiazepoxide (Librium®) 1966 diazepam (Valium®) 1970s diazepam (Diazemuls®) 1983 midazolam (Hypnovel®) 1988 flumazenil (Anexate®) 14  Diazepam Benzodiazepine compounds were first synthesised in 1933. Early animal tests indicated that chlordiazepoxide had interesting muscle-relaxant properties. In 1960 Randall reported that it produced “taming” of a number of species of animals in doses much lower than those producing measurable hypnosis. It was this taming effect (later observed in monkeys) which led to the clinical trials of the drug in humans for the determination of its antianxiety potential. Chlordiazepoxide (Librium®) was the first compound introduced for clinical use. Diazepam (Valium®) was first used to provide dental sedation by Davidau in France in 1966. It rapidly became the most commonly used intravenous sedation agent for dental procedures. A single titrated dose of 10-20 mg produced approximately 30 minutes of good quality sedation, without loss of consciousness. Although diazepam is an easy-to-use, safe and effective intravenous sedative, it has two important disadvantages. First, Valium preparations for intravenous injection contain propylene glycol as a vehicle. This proved to be an irritant to tissues and caused some degree of discomfort during injection in 75% of cases. Thrombophlebitis was also a problem. Second, diazepam has a long half-life and an active metabolite which means that recovery may not be complete for up to 72 hours. Diazemuls Diazemuls was introduced in the 1970s. This preparation used soya bean oil as a vehicle which was much less of an irritant to veins than propylene glycol, but the problems associated with a relatively slow recovery remained. Many dentists supplemented diazepam sedation with an opioid drug. The most commonly used agent was pentazocine (Fortral®). The indications for a multidrug technique were poorly defined. Some practitioners claimed that diazepam alone did not produce sufficiently deep sedation for treatment to be carried out comfortably. In some cases, this was true, but it may also have been the result of the desire of both the patient and the dentist to produce the same level of sedation as had previously been achieved with general anaesthesia. Midazolam Midazolam (Hypnovel®) became available in 1983. Although it has properties very similar to diazepam, there are four principal differences that make midazolam a better agent for dental sedation: non-irritant solution 15  a much shorter half-life no clinically significant active metabolites increased potency (approximately two to three times that of diazepam). Despite its excellent properties, midazolam is not always the ideal intravenous drug for dental sedation. Its relatively long period of action makes it inefficient for isolated procedures of short duration, e.g. removal of a single tooth. Sometimes there are indications for the use of midazolam in combination with other drugs, e.g. opioids or ketamine (see Chapter 6). Flumazenil Flumazenil (Anexate®) was introduced in 1988. It is a specific benzodiazepine antagonist which reverses most of the agonistic effects of benzodiazepines. It is used electively and to manage severe benzodiazepine-induced respiratory depression. Propofol-based Techniques Di-isopropyl phenol (Diprivan®) was introduced in 1977. It is insoluble in water and was originally solubilised in Cremophor-EL. Following a number of anaphylactic reactions to Cremophor-EL, the vehicle was changed to soya bean oil. Owing to its very short half-life, propofol soon became the intravenous induction agent of choice for day-case general anaesthesia. It has become a very popular sedative agent which produces safe, controllable anxiolysis/sedation with rapid and clear-headed recovery. Equipment No account of the historical development of sedation would be complete without a mention of some of the changes in technology which have also taken place. In some cases, the availability of new or modified hardware has improved the ease of administration and the safety of conscious sedation. On other occasions, the introduction of a novel sedation agent has led to the design and manufacture of a new item of equipment. The following developments are representative: Fail safe Relative Analgesia machines (Fig 1-1). Active waste gas scavenging (Figs 1-2 and 1-3). Disposable indwelling needles and cannulae (Figs 1-4 and 1-5). Pulse oximetry (Fig 1-6). 16 Automatic sphygmomanometry (Fig 1-7). Operator – patient-controlled infusion pumps (Fig 1-8). Fig 1-1 Examples of modern Relative Analgesia machines. Fig 1-2 Active scavenging mask assembly. 17 Fig 1-3 Active scavenging suction control. Fig 1-4 Butterfly needles. Fig 1-5 Y-Can and Venflon type cannulae. 18  Fig 1-6 Datex Ohmeda pulse oximeter. Fig 1-7 Electronic sphygmomanometer. Fig 1-8 Graseby 3100 syringe pump. Conclusions Conscious sedation techniques have been used in dentistry for over fifty years. Many techniques have evolved from general anaesthetic practice. The development of new drugs and equipment continues. 19 Further Reading Langa H. Relative Analgesia in Dental Practice: Inhalation Analgesia and Sedation with Nitrous Oxide. Philadelphia: Saunders, 1976. Sykes P (Ed.). Drummond-Jackson’s Dental Sedation and Anaesthesia. London: Society for the Advancement of Anaesthesia in Dentistry, 1979. 20 Chapter 2 Basic Physiology and Anatomy: A Whistle-stop Tour Aim The aim of this chapter is to outline the basic principles of physiology and anatomy which are relevant to conscious sedation. Outcomes After reading this chapter you should have an understanding of: relevant respiratory and cardiovascular physiology airway obstruction anatomy of commonly used venepuncture sites differences between adult and paediatric patients. Introduction To understand fully the principles of safe sedation practice, it is necessary to review certain aspects of physiology, in particular, those relating to the respiratory and cardiovascular systems. A knowledge of the anatomy of the upper airway assists in airway management. Familiarity with the pattern of veins in the antecubital fossa and on the dorsum of the hand is essential for the administration of intravenous sedation. Respiratory Physiology The major function of the respiratory system is to ensure continuous effective gas exchange so that oxygen enters the bloodstream and carbon dioxide is removed. Mechanics, volumes, capacities and flow rates Quiet breathing is characterised by the rhythmic expansion and relaxation of the lungs and thorax. The diaphragm is the most important muscle of respiration but the intercostal muscles contribute to the increase in the volume of the thorax during inspiration. The accessory muscles of inspiration are not used during quiet breathing. Expiration is normally a passive process resulting from the elastic recoil of the lungs. Active expiration, primarily involving the muscles of the anterior abdominal 21 wall and the intercostal muscles, is seen during exercise and hyperventilation. The size of the thorax and lungs determines the lung capacities whilst lung volumes are determined by inspiratory and expiratory effort (Fig 2-1). Tidal volume (Vt) is the volume of gas inhaled during a normal inspiration. A fit adult patient at rest normally has a tidal volume of approximately 500 ml. The residual volume (RV) is the volume of air remaining in the lungs at the end of a maximal expiratory effort. RV increases with age and with any decrease in elastic recoil of the lungs. Vital capacity (VC) is the volume of gas entering the lungs following a maximal inspiratory effort. Functional residual capacity (FRC) is the volume of the gas remaining in the lungs at the end of a normal expiration. Functional residual capacity is important because it is a measure of oxygen reserve. Fig 2-1 Lung volumes and capacities.VC, vital capacity; IC, inspiratory capacity; EC expiratory capacity; FRC, functional residual capacity; IRV, inspiratory reserve volume; ERV, expiratory reserve volume, RV, residual volume; Vt, tidal volume. Minute volume is the product of the tidal volume and the respiratory rate. A normal adult at rest breathes approximately 12 times per minute. Thus, the minute volume for an adult is usually about 6 litres. These figures provide the sedationist with a physiological basis for estimating the initial fresh gas flow required when using inhalational sedation techniques. The dead space volume refers to the portion of the airways which is not available for the exchange of gases. Dead space increases with age and reduction in cardiac output. The term alveolar ventilation is used to describe the volume of gas entering the alveoli each minute and taking part in gas exchange. It is important to recognise that a patient who has very shallow breathing (where the tidal volume is less than the 22 dead space volume) is effectively not breathing at all. Hypoventilation is common following the administration of central nervous system (CNS) depressant drugs such as benzodiazepines and opioids. Pulmonary gas exchange Gas exchange occurs at the alveolar-capillary membrane, where only two or three cells separate alveolar gas from the bloodstream. Oxygen and carbon dioxide cross the alveolar membrane by diffusion. The rate of diffusion depends upon the: concentration gradient of each gas across the alveolar membrane area available for diffusion rate of removal of oxygen and carbon dioxide. Oxygen is removed by capillary blood and its rate of transfer is also dependent upon the rate of its chemical combination with haemoglobin. The rate of diffusion of carbon dioxide from capillary blood into the alveolus is 20 times more rapid than that of oxygen in the reverse direction. Most of the oxygen is transported to the periphery of the body in combination with haemoglobin. Only a very small amount of oxygen is transported dissolved in plasma. Normal adult haemoglobin consists of four protein chains with a haem group attached. The bonding between the chains determines the shape of the haemoglobin molecule which, in turn, influences the affinity of the haemoglobin molecule for oxygen. The affinity of haemoglobin for oxygen is also affected by other variables, e.g. body temperature and pH. Oxygen combines loosely and reversibly with haemoglobin. Each molecule of haemoglobin can combine with four atoms of oxygen, but the association of each atom alters the affinity of the haemoglobin molecule for subsequent oxygen atoms. This results in the characteristic sigmoid shape of the oxygen dissociation curve (Fig 2-2). The shape of the curve means that large amounts of oxygen are released to the tissues in response to relatively small falls in alveolar oxygen tension, thus maintaining optimum oxygenation of the tissues. 23  Fig 2-2 Oxygen-haemoglobin dissociation curve. The oxygen dissociation curve shows the oxygen saturation of haemoglobin on the y- axis and the partial pressure of oxygen (oxygen tension) on the x-axis. The plateau at the top of the curve results from the saturation of the binding sites with oxygen. This provides a potential reserve of oxygen when the partial pressure of oxygen falls. The steep vertical section of the curve allows for optimum loading and unloading of oxygen. During sedation a pulse oximeter is used to estimate the patient’s arterial oxygen saturation (the y-axis on the oxygen dissociation curve). However, the unremitting hunger of all the cells of the body for oxygen is only satisfied by a continuous supply and adequate partial pressure of oxygen (the x-axis on the curve). The shape of the dissociation curve determines the precise relationship of the axes and thus the relationship between the displayed arterial oxygen saturation (SaO2) and the quantity of oxygen available for cellular respiration. Careful consideration of the curve and the underlying biochemistry will demonstrate the significance of the recommendation that the SaO2 must be maintained above 90% throughout sedation and the immediate recovery period. Carbon dioxide is carried in the blood in solution, in the form of bicarbonate and attached to protein as carbamino compounds. Carbon dioxide is much more soluble than oxygen and so the quantity of carbon dioxide carried in solution is significant. Most of the carbon dioxide carried in the blood is present in the form of bicarbonate. Bicarbonate is formed as a result of the hydration of carbon dioxide with the production of carbonic acid which, in turn, is ionised to form a hydrogen ion and a bicarbonate ion: 24 Control of Respiration Respiration is an automatic process under the control of the brain’s respiratory centre (Fig 2-3). The respiratory centre receives a large number of inputs, including those from the central and peripheral chemoreceptors, lung mechanoreceptors and the higher centres of the CNS. Changes in the rate and depth of breathing are produced by alterations in the firing rate in the nerves supplying the muscles of respiration. Fig 2-3 Control of respiration. At rest, at least 60% of the respiratory drive is derived from the central chemoreceptors in the medulla. The central chemoreceptors respond to changes in the pH (H+ ion concentration) of the cerebrospinal fluid (CSF). When the level of carbon dioxide in the blood rises, carbon dioxide diffuses into the CSF from the cerebral blood vessels, liberating H+ ions (see above) which stimulate the chemoreceptors. Thus, the carbon dioxide level in blood regulates ventilation by its effect on the pH of the CSF. Under normal circumstances the body maintains the pH of CSF within very narrow limits. The initial response to a rise in carbon dioxide is an increase in tidal volume followed by an increase in respiratory rate – that is, the patient first takes deeper breaths and then breathes more rapidly. Certain sedatives agents (particularly benzodiazepines and opioids) reduce the respiratory drive and cause a reduction in chemoreceptor sensitivity. They reduce the rate and depth of breathing (causing carbon dioxide levels to rise and oxygen levels to fall) and diminish the normal ventilatory response to these changes. This is why monitoring with a pulse oximeter is considered to be essential during intravenous sedation and high dosage oral sedation using benzodiazepines. 25  The peripheral chemoreceptors are located in the carotid body and in the aortic arch. They respond rapidly to changes in oxygen saturation (and, to a lesser extent, carbon dioxide saturation and pH), as occurs during the normal respiratory cycle. Cardiovascular Physiology The main purpose of the circulatory system is to deliver a continuous supply of oxygen and nutrients to the cells of the body and to remove the waste products of cellular metabolism (carbon dioxide and water). The circulatory system comprises the heart, arteries, arterioles, capillary bed and veins. The distensible arteries convert the pulsatile flow of blood leaving the heart into a steady flow. The arterioles are the site of greatest vascular resistance. Veins act as capacitance vessels and normally contain between 60% and 70% of the circulating blood volume. The heart receives a sympathetic and a parasympathetic nerve supply. Sympathetic stimulation increases the heart rate and also the force of contraction of the myocardial muscle. An increase in sympathetic drive is part of the body’s normal response to fear and anxiety. Parasympathetic stimulation reduces the heart rate. The sympathetic nervous system is almost entirely responsible for the control of the vascular system, with the exception of the coronary, cerebral, pulmonary and renal circulations. The average adult has a blood volume of 5-6 litres and a resting cardiac output of 5.5 1/min. Cardiac output is usually described as being the product of heart rate and stroke volume. Factors affecting heart rate Heart rate (normally 60-80 beats per minute) is generated by the activity of the sino- atrial node; but this rate is modified by: autonomic tone higher-centre responses to pain and anxiety baroreceptor mechanisms chemoreceptor responses to hypoxia and hypercarbia circulating hormones, e.g. catecholamines, thyroxine Autonomic tone depends on the balance between sympathetic and parasympathetic 26 nervous systems. At rest, the heart beats at a rate which is mostly dependent upon vagal (parasympathetic) tone. Input from higher centres, for example in response to anxiety and pain, increases sympathetic tone and hence heart rate. Specialised stretch receptors (baroreceptors) located in the heart and major blood vessels provide a negative feedback mechanism for the control of systemic arterial pressure. A fall in arterial blood pressure is associated with a decrease in the firing rate in the baroreceptor nerve supply. This results in a reflex increase in the heart rate and vice versa. Heart rate is also influenced by hypoxia and hypercarbia. In normal circumstances the oxygen and carbon dioxide chemoreceptors exert little effect, but in hypoxic conditions their powerful discharge helps to maintain systemic blood pressure. Factors affecting stroke volume Stroke volume depends on the size of the heart, the contractility of the myocardium and on the venous return. The size of heart is dependent on blood volume and vascular capacity. In normal circumstances, blood volume is constant with the result that it is changes in vascular capacity which mainly influence the size of the heart. Venous pooling is associated with an increased volume of blood in the veins with less available for return to the heart. This reduction in venous return results in a fall in cardiac output. The contractility of the myocardium is affected by an increase in the initial length of the cardiac muscle fibres (Starling’s law) and by increasing the power of contraction of the fibres. The latter is usually the result of an increase in the activity of the sympathetic nervous system, or the level of circulating catecholamines. The normal heart never expels the whole of the end-diastolic volume. There is a small residual volume (approximately 50 ml). The amount of blood ejected in systole is called the ejection fraction (approximately 70 ml). Certain drugs, including digitalis and beta-sympathomimetic agents, increase myocardial contractility, whilst hypoxia, trauma and most anaesthetic drugs, including midazolam, decrease myocardial contractility. Venous return is influenced by a number of factors including: gravity (related to patient positioning) muscle pumps vascular tone blood volume. Factors affecting blood pressure 27 The amount of blood ejected by the heart (cardiac output) balanced against the resistance to blood flow offered by the peripheral circulation (peripheral resistance) determines the pressure generated in the major blood vessels: Blood vessel size relates to arteriolar tone which is controlled by the sympathetic nervous system and circulating catecholamines. Sympathetic control is regulated by the vasomotor centre which receives input from the higher centres, baroreceptors, chemoreceptors, sensory nerves and the respiratory centre. The vasomotor centre also responds directly to hypoxia and hypercarbia. Increased sympathetic activity results in vasoconstriction and decreased activity results in vasodilatation. Blood viscosity depends on body temperature, changes in the haematocrit and plasma protein concentration. In normal circumstances blood viscosity may be regarded as constant. Airway Obstruction Airway obstruction may occur if a patient becomes unconscious following either a gross overdosage of sedative drugs or a nonsedation-related sudden collapse. The most common cause of airway obstruction is obliteration of the oropharynx due to the relaxed tongue falling backwards (Fig 2-4). This may occur regardless of whether the patient is in a supine, lateral, or even prone position. The obstruction is caused by the loss of tone in the muscles of the tongue and the neck which fail to lift the base of the tongue away from the posterior pharyngeal wall. Fig 2.4 Obstructed airway. Obstruction of the upper airway may be partial or complete. Partial airway obstruction is recognised by noisy air flow which is often described as either snoring or crowing depending upon the site of obstruction. Snoring suggests that the 28 partial obstruction is hypopharyngeal; crowing suggests laryngospasm. Snoring is not uncommon in patients being treated under conscious sedation. Complete airway obstruction is indicated by the absence of air movement at the mouth and is silent. Although this may be confused with apnoea, inspection of the chest for movement (or attempts at movement) will usually clarify the diagnosis. The initial – and the most important – step in managing airway obstruction involves opening the airway by head tilt; that is, extending the head at the atlanto- occipital joint (Fig 2-5). However, this may not, in itself, be sufficient to ensure a patent airway and additional measures are frequently necessary. These include chin lift, neck lift, or the “triple airway manoeuvre”. This involves displacement of the mandible anteriorly, by lifting at the angles, whilst maintaining both head tilt and a slightly opened mouth. It is necessary to keep the jaws slightly apart in a significant proportion of unconscious patients as expiratory nasopharyngeal obstruction may occur when the mouth is closed. Oral (Guedel) airways lift the tongue away from the posterior pharyngeal wall and also keep the jaws slightly apart (Fig 2-6). Fig 2-5 Patent airway Fig 2-6 Guedel oral airways (sizes 1-4). Airway obstruction occurring during sedation MUST be managed promptly and effectively. All treatment must cease whilst the above measures are being instigated. Ineffective management of serious airway obstruction causes hypoxia and hypercarbia which, if uncorrected, may lead to cardiorespiratory arrest. 29 Superficial Veins of the Forearm and the Dorsum of the Hand Successful intravenous cannulation calls for an accessible vein. The dorsum of the hand and the flexor surface of the forearm generally provide a choice of suitable veins but other sites may need to be considered, in particular, in those individuals who have received numerous intravenous injections from healthcare professionals or by themselves. The pattern of veins varies enormously so the following diagrams and notes must be interpreted with caution. Venepuncture cannot be learned from a book, but a little anatomical knowledge will greatly increase the chances of success. There is no single best site for venepuncture. Sedationists should avoid falling into the trap of using the same area (dorsum of hand or antecubital fossa) on every patient. The ideal vein for venepuncture is one which is of medium size (very large veins are sometimes difficult to enter with a small cannula), visible and reasonably well tethered to the underlying tissues. It is sensible to survey both the dorsum of the hand (Fig 2-7) and the antecubital fossa (Fig 2-8) on both arms before making a final decision. Some patients express a preference but, unfortunately, this is not always for the most accessible vein. Other patients appear to enjoy the challenge offered by their “difficult” veins. Intravenous drug users are often particularly difficult to cannulate and it is sometimes better to let them have a go, but be prepared for some unusual approaches. Fig 2-7 Dorsal hand veins. 30  Fig 2-8 Forearm and ante-cubital fossa veins. In the antecubital fossa, the large median basilic vein is a tempting target, but it is often quite mobile and easily slips away from the tip of the cannula. Stabilisation of the vein may flatten it and make a clean entry into the lumen difficult. This vein overlies the brachial artery and the median nerve, either of which may be entered or 31 damaged if the angle of approach is too steep and the cannula penetrates too deeply. The median cephalic vein is usually smaller, but is less mobile and does not overlie any important structures. The cephalic vein is often visible and is another safe choice. There are few hazards associated with the dorsum of the hand, but the veins are sometimes quite small and tortuous. There is often marked variation between the veins of the left and right hands. It is probably sensible to avoid using these veins in patients whose professional activity might be affected by a failed venepuncture and the resulting haematoma. Concert pianists, television presenters and even dentists come to mind! The veins on the flexor surface of the wrist are sometimes useful when other sites have proved difficult or impossible. These veins are usually very narrow but reasonably well tethered and so venepuncture (using a very small-gauge cannula or even a butterfly needle) is often relatively straightforward. Contrary to popular belief, venepuncture at this site is no more (or less) uncomfortable than at other, more conventional, sites. The great (long) saphenous vein, as it passes in front of the medial malleolus, may also be considered, although patients may be surprised when asked to remove their shoe and sock in preparation for dental treatment. Some Differences Between Adults and Children Children, in particular very young ones, should not be thought of as small adults. There are a number of important anatomical and physiological differences between the child and the adult patient which are relevant to the use of sedation for paediatric dental patients. Metabolism: Children have a higher metabolic rate than adults. This leads to increased oxygen consumption and increased carbon dioxide production. The younger the child, the higher is the metabolic rate. Airway: The head and tongue are relatively large. The neck is shorter and the larynx located higher and more anteriorly. The trachea is proportionately narrower compared with adults. Children tend to breathe through the mouth rather than through the nose. Respiration: Tidal volume is usually smaller than in adults, but the respiratory rate is increased. The respiratory rate for young children is normally between 15 and 20 breaths per minute. This means that the minute volume (the product of the tidal 32 volume and the respiratory rate) of children and adults is much more similar than might be expected from a simple comparison of size. An initial fresh gas flow rate of 61/min is therefore a reasonable starting point for the administration of inhalational sedation for both adults and children (see Chapter 6). The inspiratory phase of breathing tends to be more diaphragmatic as the ribs are horizontal, reducing the lateral expansion of the chest. Circulation: Children between 5 and 12 years of age have a higher heart rate (80- 120 beats per minute) than adults although arterial blood pressure is lower (typically 90-110 mmHg, systolic). Haemoglobin levels are increased. The superficial veins are smaller than in adults and may have more fatty tissue covering them. This may make venepuncture difficult. The brachial pulse is often more easily palpated than the radial or even the carotid pulse. Arterial oxygen saturation measurements and pulse oximeter alarm limits are similar for adults and children. Conclusions A knowledge of basic cardiorespiratory physiology is important for practising safe, effective conscious sedation. Efficient airway management and cannulation depend on a sound knowledge of the relevant anatomy. Children should not be regarded as small adults. Further Reading Adams AP, Cashman JN. Anaesthesia, Analgesia and Intensive Care. London: Edward Arnold, 1991. Last RJ. Superficial veins of the forearm: the surgical anatomy in relation to intravenous injection. In: Sykes P (Ed.). Drummond-Jackson’s Dental Sedation and Anaesthesia. London: Society for the Advancement of Anaesthesia in Dentistry, 1979. 33 Chapter 3 Pharmacology Aim The aim of this chapter is to describe the pharmacology of the drugs used for conscious sedation, with emphasis on their clinical effects. Outcome After reading this chapter you should have a basic understanding of the pharmacology of inhalational, intravenous and oral drugs used in conscious sedation. Introduction The safe administration of any drug requires a knowledge of its pharmacology, which is classically considered under the headings of pharmacokinetics and pharmacodynamics. These subjects are potentially highly complicated and confusing to the non-expert. Fortunately, dental sedationists need only a basic working knowledge of sedative agents and the drugs with which the agents may interact (Table 3-1). Table 3-1 Useful definitions. Term Definition description of drug absorption, distribution, redistribution, pharmacokinetics metabolism and excretion. How the body affects drugs description of the effects of drugs. How drugs affect the pharmacodynamics body products of drug breakdown which have pharmacological active metabolites effects of their own, usually similar in nature to that of the parent drug certain drugs are short-acting because of redistribution within the body – if repeated doses are given they cumulative effects accumulate in the body and their duration of action increases time for the plasma concentration of a drug to fall to half its original value. Complete elimination involves removal 34  of the drug from the receptor sites (sometimes called the half-life redistribution half-life or alpha-phase) and then metabolism and excretion (the elimination half-life or beta-phase). Redistribution time is usually shorter than elimination time the portion of a dose of drug which is broken down by the first-pass metabolism liver on first passage through the portal circulation (applies only to orally administered drugs) the affinity of a drug for lipids. As biological membranes lipid solubility are mostly lipid in composition, lipid-soluble drugs reach the site of action quickly the alveolar concentration of an inhalation agent which minimum alveolar will prevent movement to a reproducible surgical stimulus concentration (MAC) in 50% of subjects (= potency). High value = low potency determines the rate at which the concentration of gas in the blood gas solubility CNS equilibrates with that being inhaled (= the speed of induction and recovery). Low value = rapid effects in the context of dental sedation this refers to the recovery of the motor and mental functions impaired by sedation. recovery This means regaining the ability to stand and walk unaided, coordinate fine movements and judge distance and time correctly the ratio between the dose of a drug which produces therapeutic index unwanted effects and the dose which produces therapeutic effects. A safe drug has a high therapeutic index The drugs most commonly used for dental sedation are the benzodiazepines for intravenous sedation and nitrous oxide and oxygen for inhalational sedation. These will be described in detail. Reference, however, will also be made to other agents and routes of administration which are being used and/or investigated for use in dentistry, including propofol and transmucosal benzodiazepines. Routes of Administration Drugs which produce conscious sedation and analgesia may be administered by a variety of methods. The choice of route depends on the drug itself, how quickly a response is required, and whether the effect is required locally or systemically. The various routes are: 35  inhalational intravenous oral sublingual intranasal intramuscular rectal. Drugs administered by inhalation are absorbed by the pulmonary circulation. Parenteral (by injection) administration is, by contrast, much faster acting – emergency drugs are almost all given by this route. Oral administration may be more pleasant for a needle-phobic patient, but absorption is unpredictable and time- consuming because the rate of gastric emptying is altered by anxiety, disease, other drugs and the presence of food. Oral drugs are also subject to first-pass metabolism. It is important to remember that whatever the route of administration, all sedative drugs travel to their target sites via the systemic circulation. Pharmacokinetics A consideration of the pharmacokinetics and pharmacodynamics of available sedative drugs is important when choosing the most appropriate agent for each individual patient. The degree of protein binding of a drug alters its availability. A portion of the drug administered is dissolved in plasma (the active form) whilst the rest is bound to plasma proteins and is not free to combine with receptor sites. Some disease processes change the proportion of bound drug. Similarly, two drugs can compete for the same binding site and thereby increase the free concentration of one or both agents. Either of these mechanisms may alter the expected clinical effects. Drugs are eliminated by a variety of routes. Most of the inhalational agents used for sedation are excreted through the lungs. For benzodiazepines, the most important organs are the liver and the kidneys which metabolise and excrete these drugs. The measure of elimination of a drug is the half-life (see Table 3-1). The properties and route of administration of different drugs determine the speed of absorption and distribution and hence the speed of onset of the sedative effect. A drug with rapid metabolism and excretion produces a swift recovery and earlier discharge for the patient. 36 Pharmacodynamics Pharmacodynamics describes the effect the drug has on the patient and includes both desirable and undesirable effects. The definitions of both types of effect are not fixed, but depend upon individual circumstances and what one is trying to achieve. For example, midazolam can produce unconsciousness. In the case of conscious sedation, this pharmacodynamic property is clearly undesirable and potentially harmful. In contrast, an anaesthetist might choose midazolam to induce anaesthesia slowly and gently for a patient who has severe cardiac disease to avoid the cardiodepressant actions of other induction agents. Most sedative drugs elicit a response via receptors which are specific to each drug. Receptors are located in cell membranes. When drugs bind to receptors in the CNS these are altered and the activity of the cell is either stimulated or inhibited. These drugs are called agonists. Midazolam is a benzodiazepine agonist. Drugs which act to displace agonists from the receptor sites thus terminating their effects are known as antagonists. Flumazenil is a benzodiazepine antagonist. A drug which binds to the receptor site to produce the opposite effect to an agonist is known as an inverse agonist. An example would be a drug which acts at benzodiazepine receptors to induce anxiety and alertness. However, it is doubtful that there would be much of a market for such an agent. Properties of the Ideal Sedative Drug Comfortable, non-threatening method of administration rapid onset predictable sedative/anxiolytic action controllable duration of action produces analgesia no side effects rapid and complete recovery. Intravenous Agents Properties of an Ideal Intravenous Sedation Agent Injection characteristics Painless 37  Anxiolysis Yes Analgesia Yes Cardiorespiratory stability Stable Ease of titration Easy Induction and recovery rate Rapid Metabolism 0% Potency Weak Speed of change in sedation level Rapid Reversibility Yes Systemic toxicity None Storage/shelf-life Stable/long The benzodiazepines The first clinically useful benzodiazepine, chlordiazepoxide (Librium®) was synthesised in the late 1950s by F Hoffman-La Roche & Co Ltd (Fig 3-1). All benzodiazepines have a common core structure with individual differences which determine their solubility and precise actions (Fig 3-2). Diazepam (Valium®) was introduced in clinical practice in 1963 and was first used for dental sedation in 1966 (Fig 3-3). Midazolam (Hypnovel®) became available in 1983 (Fig 3-4). Its advantages over diazepam soon made it the drug of choice for intravenous sedation for dentistry. Other benzodiazepines – for example, temazepam and lorazepam, have also been used to produce conscious sedation. Fig 3-1 Chlordiazepoxide. 38  Fig 3-2 Core benzodiazepine molecule. Fig 3-3 Diazepam. Fig 3-4 Midazolam. The benzodiazepine group of drugs has a number of desirable pharmacodynamic properties which make these agents useful for conscious sedation. These include: anxiolysis 39  sedation muscle relaxation anterograde amnesia. Another desirable therapeutic property of benzodiazepines is their anticonvulsant action. For the sedationist, the most significant undesirable property of these drugs is respiratory depression, which, is usually easily managed but requires careful monitoring. Benzodiazepines have the potential to produce dependency as a result of long-term use or abuse. This is not a problem when midazolam is used for conscious sedation. Diazepam Diazepam produces excellent sedation and was for many years the drug of choice for dental sedation. However, it has a number of disadvantages which have resulted in its being superseded by midazolam. Diazepam is insoluble in water and the first commercially available preparation, Valium®, was made soluble by mixing it with the organic solvents propylene glycol, ethyl alcohol and sodium benzoate in benzoic acid. Intravenous administration of Valium® was frequently painful due to the presence of these solvents which sometimes also caused thrombophlebitis. An alternative preparation, Diazemuls® contains an oil-in-water emulsion, is non- irritant and does not damage veins. Many practitioners considered that diazepam on its own was not sufficiently potent for extremely anxious patients or for those undergoing surgical procedures which led to the practice of adding an opioid to enhance the sedative effect. The most commonly used drug was pentazocine, marketed as Fortral®. This technique should now be regarded as of historical interest only since adequate sedation is usually easily achieved with midazolam alone. Midazolam is at least twice as potent a sedative as diazepam on a weight for weight basis. Midazolam Midazolam (Hypnovel®) is currently available as two injectable preparations in 2 ml and 5 ml ampoules, each of which contains 10 mg of the drug (Fig 3-5). It is stable in aqueous solution and is non-irritant on injection. The advantage of using the 10 mg in 5 ml preparation is that it is easier to administer by titration. Titration 40 means administering the drug slowly in small volume increments whilst assessing the patient’s response. This mode of administration ensures that patients receive an adequate but not excessive dose of the sedative agent. It is absolutely impossible to predict the correct sedative dose of intravenous midazolam for any individual patient on the basis of their weight, height, Body Mass Index (BMI) or the apparent degree of anxiety. Fig 3-5 Midazolam ampoules (10 mg/5 ml and 10 mg/2 ml). Midazolam: Properties Water soluble Yes Solvent Aqueous Irritant No Presentation 10 mg/5 ml or 10 mg/2 ml Distribution half-life 6–15 mins Elimination half-life 1.5–2 hours Usual dose 2–7.5 mg Late active metabolites None Analgesia No In the UK midazolam is only available in a form suitable for parenteral administration. However, this formulation has been successfully mixed with other liquids (for example, fruit juices) for oral use. Similarly, the 10 mg in 2 ml formulation has been used as an intranasal spray. These methods of administration have proved useful for those patients who refuse or cannot be given intravenous 41 injections. Temazepam Temazepam is no longer considered to be the drug of choice as an oral alternative to intravenous or inhalational sedation in the dental surgery. It may, however, have a place in the management of pre-appointment anxiety. For example, temazepam may be prescribed to ensure a satisfactory night’s sleep prior to a dental visit. Temazepam is a minor metabolite of diazepam which is impossible to solubilise and is therefore not available in an injectable form. It has been produced in various forms: tablet, gel-filled capsule and an elixir for oral administration (Fig 3-6). However, the capsule formulation has now been withdrawn due to inappropriate intravenous use by recreational drug users. Fig 3-6 Temazepam elixir (10 mg/5 ml). As a result of this misuse it is now categorised as a UK Schedule 3 Controlled Drug. The different formulations have different rates of absorption, but temazepam is reasonably rapidly absorbed following oral administration. The sedative effects are usually clinically apparent for at least 45 minutes. Temazepam has a relatively short elimination half-life (5–11 hours) which makes it a useful drug for conscious sedation. Flumazenil Flumazenil (Anexate®) is a specific benzodiazepine antagonist (Fig 3-7). It has the 42 same core structure as all other benzodiazepines (Fig 3-8). However, as it has a stronger affinity for the receptors than most agonists, including midazolam, it will displace them. Flumazenil reverses the anxiolytic, sedative and respiratory depressant effects of midazolam but has no clinically apparent sedative or stimulant effects. It does not reverse the anterograde amnesia induced by midazolam. Therefore, the loss of memory of unpleasant events which took place before reversal with is retained. Flumazenil is useful for both elective and emergency reversal of sedation. Fig 3-7 Flumazenil ampoule (500 micrograms/5 ml) Fig 3-8 Flumazenil. Flumazenil has a shorter half-life than midazolam. When it was first introduced, in 1988, there was a suggestion that administering flumazenil to a sedated patient would result in a short period of reversal followed by “resedation” some 50–60 minutes after the flumazenil was given. This is not true. The displaced midazolam continues to be redistributed and metabolised independently of the presence of flumazenil. The cessation of action of flumazenil (approximately 50 minutes) coincides with the point at which most patients would normally be expected to be fit for discharge after a single dose of midazolam. 43  Allergy to the benzodiazepines is rare. However, as the common core structure of these drugs is almost identical, a patient who exhibits an allergic reaction to any benzodiazepine must not be managed with flumazenil, which would only worsen the situation. Mechanism of action of benzodiazepines Benzodiazepines act throughout the CNS. Specific benzodiazepine receptors are located on nerve cells within the brain. All benzodiazepine molecules have a common core shape, which enables them to attach to these receptors. The effect of attaching benzodiazepines to cell membrane receptors is to alter an existing physiological filter. The normal passage of information from the peripheral senses to the brain is filtered by the GABA (gamma aminobutyric acid) system. GABA is an inhibitory neurotransmitter which is released from sensory nerve endings as a result of nerve stimuli passing from neurone to neurone. When released, GABA attaches to receptors on the cell membrane of the postsynaptic neurone. This stabilises the neurone by increasing the threshold for firing. In this way, the number of sensory messages perceived by the brain is reduced. Benzodiazepine receptors are located on cell membranes close to GABA receptors (Fig 3 -9). The effect of having a benzodiazepine in place on a receptor is to prolong the effect of GABA. This further reduces the number of stimuli reaching the higher centres and produces pharmacological sedation, anxiolysis, amnesia, muscle relaxation and anticonvulsant effects. Benzodiazepines must cross the blood-brain barrier to reach their target receptors. 44  Fig 3-9 GABA (gamma aminobutyric acid) and BDZ (benzodiazepine) receptors. Highly lipophilic agents such as midazolam reach the CNS receptors quickly and easily. All benzodiazepines which are CNS depressants have a similar shape with a ring structure on the same position of the diazepine part of each molecule. By contrast, flumazenil, the benzodiazepine antagonist, does not have this ring structure and has a neutral effect on the GABA system. Flumazenil is an effective antagonist, as it has a greater affinity for the benzodiazepine receptor than the active drugs and therefore displaces them. Paradoxical or unusual effects are exhibited by some patients when sedated with benzodiazepines. Patients who misuse CNS active drugs are often difficult to sedate. This may be due to altered activity at the receptor level. This may be manifest as failure to achieve sedation, an unusually short period of effective sedation or hyperactivity. The greater sensitivity to even small doses of drug seen in older people may be the result of a reduction in the number or effectiveness of CNS receptors and/or a slower circulation. For this reason, the rate of titration and the size of the increments must be reduced. Metabolism of benzodiazepines occurs in the liver. Some drugs are broken down to metabolites which have a longer elimination half-life than the parent drug. An example of this is diazepam. Diazepam is degraded to several metabolites including desmethyldiazepam, which has sedative properties and a half-life of several days. Midazolam has no metabolites which are active once the parent drug has been 45 eliminated. This is a major advantage of midazolam and is the principal reason for its being considered the drug of choice for outpatient conscious sedation. The water- soluble metabolites of the benzodiazepines are excreted via the kidneys. The anterograde amnesia produced is a desirable effect in terms of reducing the patient’s memory of treatment but, paradoxically, is less helpful when trying to “wean” patients away from treatment under sedation. It is important to remember that there is no loss of memory of events which take place before the injection of midazolam. The most profound amnesia occurs immediately after induction, but some disturbance to short-term memory may persist for several hours or even until the following day. Midazolam-induced amnesia may be prolonged. It is therefore essential to warn both patients and their escorts of this possibility. It is advisable not to guarantee complete amnesia as this effect varies between patients and in the same patient on different occasions. The effect of anterograde amnesia is often misinterpreted by patients with the result that they believe that they have been unconscious. This may lead to difficulties. When the patient returns for treatment under sedation they may insist that they are under-sedated or more awake than before. The muscle relaxant effect of benzodiazepines contributes to the difficulty in standing, walking or maintaining balance experienced by many patients following treatment. Respiratory Effects Benzodiazepines produce respiratory depression. This is usually mild in healthy patients if the drug is administered intravenously by slow titration. It can, however, be a significant problem in unwell or elderly people. Even in a fit healthy individual, a fast injection or a large quantity of midazolam has the potential to depress respiration to the point of apnoea. There are two mechanisms by which ventilation is depressed. First, relaxation of the muscles of respiration causes a dose-related reduction in the rate and depth of breathing. Second, the reduction in sensitivity of the central carbon dioxide and oxygen chemoreceptors decreases the ability of the respiratory centre to increase the respiratory drive in the presence of hypercarbia and/or hypoxia (see Chapter 2). Benzodiazepine-induced respiratory depression affects all patients who are sedated with these drugs by any route of administration. For this reason it is important to monitor respiration throughout sedation particularly with intravenous sedation but also after the oral administration of benzodiazepines. Respiration 46 should be monitored clinically by observation of the rate and depth of breathing; however, since it is not always easy to detect small changes in respiratory function a pulse oximeter is mandatory. Cardiovascular Effects Benzodiazepines have few significant cardiovascular effects in healthy people. There is a decrease in mean arterial pressure, cardiac output, stroke volume and systemic vascular resistance. This may present as a small fall in arterial blood pressure immediately following induction of sedation. However, this is normally compensated by the baroreceptor reflex and is of negligible clinical significance except in people with compromising cardiovascular disease. Propofol Propofol (Diprivan® 1%) is a synthetic phenol anaesthetic induction agent which was introduced for clinical use in the late 1970s (Fig 3-10). It is the induction agent of choice for day-case surgery due to its rapid onset, short duration and fast recovery. Fig 3-10 Propofol ampoules (200 mg/20 ml). Propofol: Properties Injection characteristics Painful in small veins Anxiolysis Yes Cardiorespiratory stability Stable Ease of titration Infusion Induction and recovery rate Very rapid Metabolism Yes Potency High 47  Speed of change in sedation level Very rapid Reversibility No Systemic toxicity Low Storage/shelf-life Stable/long Analgesia No Propofol is extremely lipid soluble but virtually insoluble in water. Like Diazemuls it is solubilised in an oil-in-water emulsion. Each 20 ml ampoule contains 200 mg of propofol (10 mg/ml). The solution is sometimes painful on injection particularly when a small vein is used. However, injecting into a large vein and/or adding 1 ml of 1% plain lidocaine (approximately 0.1 mg/kg) to each 20 ml (200 mg) of propofol helps to reduce pain. The pharmacokinetics of propofol which make it an ideal agent for day-case general anaesthesia also make it suitable, in lower doses, for sedation. The redistribution half-life is approximately two to four minutes. In order to maintain sedation at a constant level, it is therefore necessary to administer propofol by continuous infusion. Metabolism takes place in the liver and metabolites of propofol are excreted by the kidneys. The elimination half-life is about 60 minutes in fit patients. Propofol is very useful for short procedures when sedation is required for only a few minutes, for example, for the extraction of a single tooth. Recovery occurs rapidly after the drug is discontinued. The short redistribution half-life prevents the accumulation of drug in the body and, as a consequence, propofol is also an appropriate agent for much longer cases – for example, implant surgery. There has been some discussion in the literature as to the appropriateness of using propofol in people with epilepsy. Propofol has been reported to be capable of inducing grand mal seizures in patients with no history of epilepsy. Conversely, propofol has also been used to suppress convulsions! Until this situation is clarified, it is wise to avoid selecting this drug for patients with any history of epilepsy. As with midazolam, propofol tends to depress respiration. The frequency of hypersensitivity reactions is similar to that of other anaesthetic induction agents. Opioids For some patients, the use of a single agent does not provide an adequate degree of sedation to enable treatment to be provided. In these cases a combination of agents may make treatment possible, thereby avoiding the need for general anaesthesia. The 48 most frequently used combination of agents is an opioid and midazolam. Individual opioids, like benzodiazepines, act through CNS receptors and have either agonist or antagonistic actions. These drugs produce a number of therapeutic effects including analgesia, sedation and euphoria. Their undesirable effects include cardiorespiratory depression and nausea and vomiting. The most important of these in relation to conscious sedation is respiratory depression. Great care must always be taken when a combination of an opioid and a benzodiazepine is used for sedation. In dental sedation the most frequently used opioid is nalbuphine but fentanyl and its derivatives are also used. Nalbuphine (Nubain®) has the advantage that it is not a controlled drug and so, unlike other opioids, special security precautions are not required. Nalbuphine (Fig 3-11) must be given before midazolam is titrated. The incidence of vomiting is about 30% with this technique – it is sometimes necessary to administer an antiemetic. Fig 3-11 Nalbuphine (10 mg/ml) and naloxone (400 micrograms/ml). If any opioid is used for sedation the opioid antagonist naloxone (Narcan®) must be available (Fig 3-11). Naloxone is a pure opioid antagonist and reverses respiratory depression, analgesia and sedation. Inhalational Agents Inhalational agents are commonly used for dental sedation. Traditionally nitrous oxide has been the only gas used, but volatile anaesthetic agents are now being investigated and may have a role to play in the future. No currently available agent is ideal. The greatest potential danger when using inhalational sedation is the failure to deliver an adequate supply of oxygen to the patient, due to inappropriate or faulty equipment. No correctly maintained Relative Analgesia machine should be capable of administering less than 30% oxygen. 49  Properties of an Ideal Inhalational Sedation Agent Induction characteristics Smooth Anxiolysis Yes Cardiorespiratory stability Stable Ease of titration Easy Induction and recovery rate Rapid Metabolism 0% Ease of breathing Non-pungent Blood gas solubility Low Potency (MAC) Weak (high) Speed of change in sedation level Rapid Systemic toxicity None Environmental effects None Analgesia Yes The minimum alveolar concentration (MAC) is a value obtained experimentally which represents the potency of an inhalational agent. A high MAC indicates an agent of low potency which is ideal for conscious sedation. Nitrous oxide Nitrous oxide is rapidly absorbed. The rate of absorption depends on a number of factors, including the solubility of the drug in blood. Agents with low solubility produce rapid onset of sedation because the concentration of drug in blood, and therefore in the brain, rapidly equilibrates with the inspired concentration. When the agent is discontinued, recovery occurs quickly as the concentration of the agent falls. Nitrous oxide has a high MAC compared with most volatile anaesthetic agents. The nitrous oxide molecule is excreted unchanged almost exclusively by the lungs. It is therefore suitable for patients with (even advanced) liver or kidney disease. It has little effect on the respiratory system as it is non-irritant and does not increase bronchial secretions or depress respiration centrally. The cardiovascular effects ofnitrous oxide are insignificant in healthy patients. The inspired concentration ofnitrous oxide at which sedation occurs varies from patient to patient. In some people 70% nitrous oxide has no effect whereas in others (especially the elderly) 25% may produce unconsciousness, with loss of airway-protective reflexes. Traditionally, three planes of Relative Analgesia are described (Table 3-2). Planes I 50 and II are clinically useful for dental sedation. Plane III is generally considered to be too close to anaesthesia to be safe in the dental outpatient setting. Properties of Nitrous Oxide Induction characteristics Smooth Anxiolysis Yes Cardiorespiratory stability Stable Ease of titration Easy Induction and recovery rate Rapid Metabolism