Sedative and Anxiolytic Drugs
Sedation is best considered as a continuum between normal consciousness and general anaesthesia. The most frequently cited description of the varying levels of sedation utilized in clinical practice is that from the American Society of Anesthesiologists (Table 7.1).
There is a seamless progression from minimal sedation to deep sedation, in which verbal contact and protective airway reflexes may be lost. It is very difficult to predict how an individual patient will respond to a sedative agent. The ability of the patient to maintain a patent airway independently is one characteristic of moderate or conscious sedation, but even at this level of sedation it cannot be assumed that protective airway reflexes are intact. Deep sedation may progress easily to be indistinguishable from general anaesthesia, and a higher level of skill is needed to ensure the safe management of the patient. The degree of apparent sedation is related to the stimulation from the procedure, and patients can move rapidly between levels of sedation due to procedural effects without any change in drug dosage. It is therefore important that healthcare professionals delivering sedation have the necessary skill set to cope with sedation which is deeper than intended. Similarly, patients having sedation should be fasted in an identical manner to patients having a general anaesthetic.
The difference between sedative and anaesthetic drugs is largely one of usage. Many anaesthetic drugs may be used at reduced dosage to produce sedation and, similarly, agents used primarily as sedatives will produce a form of anaesthesia if given in sufficiently high doses. The usual target is to produce conscious sedation, i.e. to titrate drug therapy so the patient is free of anxiety, free of pain and responding purposefully to command. In adults, this corresponds to the levels of sedation from anxiolysis to moderate sedation as described in Table 7.1.
Over recent years, there has been an increased focus of safe sedation practice by regulatory agencies. When sedation is used in areas outside the operating theatre environment, and by non-anaesthetic personnel, there is a particular need to ensure adequate provision of facilities, equipment and competent personnel. An audit of sedation for over 14 000 upper gastrointestinal endoscopies published in 1995 demonstrated a 30-day mortality of 1:2000 and a morbidity rate of 1:2003, primarily due to respiratory and cardiovascular problems. As a result, several practice guidelines have been published to address these issues. Examples include guidance on sedation for upper gastrointestinal endoscopy, procedures in the emergency department and dental surgery, and the sedation of children. Many of these documents share key messages: the requirement of a trained individual solely responsible for monitoring the patient during sedation; the mandatory use of pulse oximetry; the importance of supplementary oxygen therapy during sedation; the need for comprehensive resuscitation equipment which must be immediately available; and the need for personnel who are trained to recognize, and are competent to manage, cardiorespiratory complications. This guidance relates solely to conscious sedation. If deep sedation is required, the patient requires a level of care identical to that needed for general anaesthesia.
This is defined as the administration of sedative(s) (with or without analgesics) to induce a state which allows a patient to tolerate unpleasant procedures whilst maintaining cardiorespiratory function and the ability to maintain airway control independently and continuously. Procedural sedation may be used for a variety of interventions including radiological investigations, gastrointestinal endoscopy and transoesophageal echocardiography. However, there is no absolute indication for the use of sedation and many procedures for which sedation was felt previously to be mandatory can now be undertaken without the need for systemic drug therapy. The requirement for procedural sedation should be determined by a combination of patient, procedural and operator factors. It is always important to ensure that the benefits of procedural sedation (such as greater patient satisfaction and better tolerance of the procedure) outweigh the associated risks. Sedation should never be used for the convenience of the individual performing the procedure.
The commonest reasons for the use of procedural sedation are to provide anxiolysis for the concerned patient, analgesia for painful procedures and to allow longer procedures (e.g. interventional radiology) to be better tolerated. In individuals with significant cardiac comorbidity, sedation may also attenuate the cardiovascular stimulation (and increase in myocardial oxygen demand) associated with some procedures. It is important that the sedative agent used will target the specific undesirable symptom. For example, sedatives such as benzodiazepines have no analgesic action and will not provide effective sedation for painful procedures. Great care must be taken when co-administering sedative drugs and systemic opioids. The synergism between these two groups of drugs significantly increases the risks of airway obstruction and respiratory depression.
Sedative drugs may be given in the preoperative period to reduce the apprehension experienced before undergoing anaesthesia and surgery. Sedation may be particularly useful in young children, patients with learning difficulties and individuals who are very anxious. Sedative drugs given in this way augment the actions of anaesthetic agents. The choice of drug depends on the patient, the proposed surgery and the prevailing circumstances; for example, requirements for patients undergoing ambulatory surgery are different from those scheduled for major surgery as an inpatient. The oral route of administration is preferred and benzodiazepines are the drugs used most commonly for this purpose. Nasal administration may be useful in children.
The synergy between sedative drugs and intravenous induction agents is used in the technique of co-induction. The administration of a small dose of sedative may result in a significant reduction in the dose of induction agent required, and therefore in the frequency and severity of side-effects. Patients undergoing regional anaesthetic techniques (e.g. for joint arthroplasty) may also receive supplemental sedation to help alleviate anxieties regarding hearing or seeing parts of the surgery, or to help maintain comfort for prolonged surgery. A target-controlled infusion of propofol is used increasingly for this purpose. Studies in the elderly have found that sedation regimens can relatively frequently produce a deeper level of sedation than intended, resulting in unplanned general anaesthesia.
Sedation is often used to supplement the use of topical local anaesthesia when awake fibreoptic intubation is necessary. Because mask ventilation or tracheal intubation may be difficult or indeed impossible in some of these cases, great caution must be taken not to depress consciousness or respiratory drive. For this reason, an infusion of remifentanil (either manual or target-controlled) is used frequently for sedo-analgesia.
Most critically ill patients require sedation to facilitate mechanical ventilation and other therapeutic interventions in the intensive care unit (ICU). With the increasing sophistication of mechanical ventilators, the modern approach is to titrate adequate analgesia with sufficient sedation to maintain the patient in a tranquil but rousable state. The pharmacokinetic profiles of individual drugs should be considered because sedatives are inevitably given by infusion for prolonged periods in patients with potential organ dysfunction and impaired ability to metabolize or excrete drugs. Many different drugs and regimens have been used to provide short-term and long-term sedation in the ICU, including benzodiazepines, anaesthetic agents such as propofol, opioids, and most recently, α2-adrenergic agonists. There is no evidence supporting the use of any particular regimen or combination of agents.
The value of sedation titration by such measures as the Ramsay Sedation Score or Richmond Agitation Sedation Scale during critical care has been recognized for many years, but more attention has focused recently on the importance of daily sedation ‘holds’. These daily interruptions in the sedative and analgesic infusions of selected patients help avoid the accumulation of these agents and this now forms part of the ventilator care bundle package. This has been shown to decrease the incidence of some complications associated with mechanical ventilation during critical illness, such as ventilator-associated pneumonia. In addition, sedation ‘holds’ may facilitate weaning from mechanical ventilation, thereby decreasing the length of stay in critical care and the need for tracheostomy.
The administration of sedative drugs requires skill and vigilance, not least because of the seamless progression from light sedation to general anaesthesia. Traditionally, sedative drugs have been administered by intermittent intravenous bolus doses titrated to effect. There is considerable variability in the individual response to a given dose and there are many circumstances in which medical practitioners without anaesthetic training administer sedatives. Recent technological advances in microprocessor-controlled infusion pumps have improved the safety of administration of sedatives. Patient-controlled analgesia systems have been programmed for patient-controlled sedation, usually to maintain sedation after an initial bolus dose administered by the physician. When the system is wholly patient-controlled, the mean dose of sedative drug decreases while the range increases. In target-controlled infusion (TCI), an adapted syringe driver is programmed with the pharmacokinetic model of a drug and designed to rapidly achieve (and subsequently maintain) a prescribed ‘target’ plasma concentration. The individual using a TCI system is able to set (and alter) the desired concentration based on the clinical assessment of the patient. There are several different pharmacological models, each specific for an individual drug. Examples include Marsh and Schnider (propofol), Minto (remifentanil) and Maitre (alfentanil). All these models adjust for variations in pharmacokinetics due to gender, age and weight.
Most sedative drugs may be categorized into one of three main groups: benzodiazepines, antipsychotics and α2-adrenoceptor agonists. Drugs classified more usually as intravenous anaesthetic agents, particularly propofol and ketamine, are also used as sedatives in subanaesthetic doses; the pharmacology of these drugs is discussed in Chapter 3. Similarly, remifentanil, which is used increasingly as part of a sedative regimen, is described fully in Chapter 5. Inhaled anaesthetics (see Ch 2) are also used occasionally as sedatives (e.g. sevoflurane to an end-tidal concentration of 0.3–0.5 kPa, or nitrous oxide).
The term benzodiazepine originates from the structure of the molecule, which consists of the fusion of a benzene and diazepine ring. These drugs were developed initially for their anxiolytic and hypnotic properties and largely replaced oral barbiturates in the 1960s due to their favourable pharmacological profile: minimal cardiorespiratory effects, the production of anterograde amnesia and a lower incidence of physical dependence. As parenteral preparations became available, they rapidly became established in anaesthesia and intensive care. All benzodiazepines have similar pharmacological effects; their therapeutic use is determined largely by their potency and the available pharmaceutical preparations. Benzodiazepines are often classified by their duration of action as long-acting (e.g. diazepam), medium-acting (e.g. temazepam) or short-acting (e.g. midazolam).
Benzodiazepines exert their actions by high-affinity binding to a specific benzodiazepine binding site, which is part of the γ-aminobutyric acid (GABA) receptor complex. GABA is the major inhibitory neurotransmitter in the central nervous system (CNS), with most neurones undergoing GABA-ergic modulation. The benzodiazepine site is an integral part of the GABAA receptor subtype. Binding of the agonist increases the affinity of the GABAA receptor to GABA, producing an increased frequency of the opening of the chloride ion channel, and thus an increase in intracellular chloride transmission. This causes hyperpolarization of the postsynaptic membrane, which makes the neurone resistant to excitation. Benzodiazepine binding sites are found throughout the brain and spinal cord, with the highest density in the cerebral cortex, cerebellum and hippocampus, and with a lower density in the medulla. The absence of GABAA receptors outside the CNS is consistent with the good cardiovascular safety profile of these drugs.
The GABAA receptor is a large structure which also contains separate binding sites for other drugs including barbiturates, alcohol and propofol. The binding of other compounds to the benzodiazepine binding site explains the synergistic effects seen with some other drugs. This synergy may lead to dangerous depression of the CNS if drugs are used in combination and also results in pharmacological cross-tolerance, e.g. with alcohol. It is also consistent with the use of benzodiazepines to manage the symptoms associated with acute withdrawal or detoxification from alcohol or other drugs. Elderly patients are particularly sensitive to the effects of benzodiazepines and dosage should be reduced accordingly.
The benzodiazepine antagonist flumazenil occupies the benzodiazepine binding site but produces no activity. Benzodiazepine compounds have been developed which are ligands at the benzodiazepine binding site but have inverse agonist activity, resulting in cerebral excitement. These compounds are also antagonized by flumazenil. This mirrors the way in which paradoxical reactions to benzodiazepines in the elderly are reversed by flumazenil and exacerbated by increasing the dose of the original drug. Other more sinister causes of restlessness, such as hypoxaemia and local anaesthetic toxicity, should always be excluded first.
Benzodiazepines are relatively small lipid-soluble molecules. Unlike diazepam and lorazepam, which are dissolved in solvents (polyethylene and propylene glycol previously, now lipid emulsions), midazolam is water-soluble. This is due to the presence of an imidazole ring in its structure, which allows midazolam to act as a structural isomer demonstrating tautomerism (isomerism triggered by a change in the physical environment). Midazolam is prepared in a solution buffered to a pH of < 4. At this pH, the imidazole ring is open and the molecule is ionized and therefore water-soluble. When the molecule is exposed to the higher pH of the body, the molecule forms the unionized ring, resulting in high lipid solubility.
The characteristic CNS effects seen with all benzodiazepines are anxiolysis, sedation, anterograde amnesia and antiepileptic activity. The degree to which individual benzodiazepines produce these effects is variable, and is thought to be related to their affinity for particular subunits of the GABAA receptor. For example, benzodiazepines with high activity at the α1 and/or α5 subunits tend to have more sedative and amnesic effects, whilst those with activity at α2 and/or α3 subunits produce more anxiolysis.