Pharmacokinetics in the elderly

The elderly are an expanding population of patients presenting for anaesthesia. The pharmacokinetics of anaesthetic agents in the elderly deserves special attention because the normal ageing process and the effect of age-related diseases affect organ systems in a heterogeneous way with unpredictable consequences. The pharmacokinetics of each drug is also affected by these changes in a specific way and, together with the pharmacodynamic consequences, makes drug use and drug dosing challenging in this population. Although a decrease in bolus and infusion rates is a common theme, only pharmacokinetic modelling of drug disposition in the elderly will provide accurate dosing guidelines and increase the margin of safety.     

Ökonomische Aspekte beim Einsatz moderner Inhalationsanästhetika am Beispiel des Sevofluran

The economic impact of the new German health care laws requires an awareness of cost-effectiveness when using newer drugs. The main goal in patient care, i.e., effective treatment, must be achieved by the rational use of restricted resources at a maximum degree of effectiveness. Economic aspects of the new inhalational anaesthetics such as sevoflurane are discussed in this article. The cost of inhalational anaesthetic agents accounts for up to 5% of all the running expenses of an anaesthesia department. The consumption and cost of an inhalational agent depend on fresh gas flow, vapour setting, and duration of anaesthesia. Comparing the cost for 1 MAC-h of anaesthesia, desflurane is more expensive at current market prices than sevoflurane and isoflurane. However, at low or minimal fresh-gas flows, the price for one MAC-h is almost the same for these volatile anaesthetics. Total intravenous anaesthesia using propofol is even more expensive, partly due to wastage, i.e., opened ampoules with a remainder of propofol that has to be discarded after each case. When choosing an anaesthetic agent, the price of 1?ml liquid anaesthetic is an important factor. However, the overall cost-effectiveness analysis must balance the cost of the agent with its pharmacodynamic advantages such as more rapid recovery from anaesthesia. Furthermore, the indirect costs of side effects have to be taken into account. For example, nausea and vomiting lead to a prolonged stay in the recovery room after anaesthesia for outpatient surgery, which in turn incurs additional costs for antiemetic drugs and the extra time for nursing care. Therefore, a lower incidence of nausea and vomiting and a more rapid recovery from anaesthesia leading to earlier discharge from the recovery room may compensate for the higher price. Volatile agents account for up to 1% of the total intraoperative costs. In analysing the costs of 1?h of anaesthesia, other products such as plasma substitutes and blood products account for a much higher proportion than anaesthetic agents, and reductions or increases in costs pertaining to these products have a bigger impact on overall costs than do volatile anaesthetics. We conclude that volatile anaesthetics account for only a minor portion of the anaesthesia department budget and the cost of anaesthesia delivery. The higher market price of the new agents may be compensated for by the economic impact of fewer side effects and a shorter post-anaesthesia stay in the hospital. In analysing data for sevoflurane, this agent may be cost-effective, for example, for outpatient anaesthesia.     

Clinical applications of intravenous anaesthetics pharmacology: the example of hypnotics and opioids

OBJECTIVE: To review the general principles of pharmacokinetics and pharmacodynamics models by focusing on intravenous anaesthetics (hypnotics and opioids). DATA SOURCES: Medline references, lectures from the French congress of anaesthesiology and intensive care medicine, abstracts. DATA SYNTHESIS: Pharmacokinetic and pharmacodynamic modelling allows simple estimation of becoming of anaesthetic drugs in the body, instead of classical pharmacologic approach. However, pharmacokinetic as well as pharmacodynamic parameters are often considered as resulting from complex mathematic approaches and remain then poorly used in practice by physicians. The aim of this article is to simply expose concepts underlying PK-PD models building and to explain significance of the main PK-PD parameters (first-order rate constants, k(e0), T(1/2)k(e0), T(peak), context-sensitive half-time, context-sensitive decrement times). Clinical consequences for using intravenous anaesthetic drugs (hypnotics and opioids) are exposed either during bolus injection or continuous infusion, when injected alone or co-administered.     

Age-related pharmacology

Paediatric patients display different pharmacokinetic and pharmacodynamic responses to anaesthetic drugs. These drugs can be used safely in neonates and children if their altered pharmacology is understood.The physiological differences in each body system that lead to this altered drug handling are described. They include the staged maturation of hepatic and renal elimination pathways, depending on gestational and post-natal age. Body water forms a greater proportion of the neonate than the adult and these differences are illustrated. The commonly used classes of anaesthetic drugs are discussed in more detail, including induction agents, volatile agents, opioids, neuromuscular blocking agents, non-steroidal anti-inflammatory drugs and local anaesthetics. Pharmacological handling at different ages and dosing implications are covered.     

Pharmacological models and their use in clinical anaesthesia

Intravenous agents used in anaesthesia belong to a variety of chemical classes and cover a number of different pharmacodynamic responses. Compared to inhalational anaesthesia the combined administration of intravenous agents offers a greater degree of freedom because different pharmacodynamic effects can be controlled separately. This greater degree of freedom, however, requires a more detailed insight into the pharmacology of the drugs to allow control of drug administration and to meet the therapeutic optimum. This review considers the combination of pharmacokinetics and pharmacodynamics as a pharmacological model. The general principles of these two subunits relevant for dosing of intravenous agents are reviewed. In establishing a model of the non-linear system relating dosing to effect, pharmacokinetics introduces an intermediate step which describes the time course of drug concentrations as a function of dosing. It is thought that incorporating the entire dependence of the effect upon time is, in most cases, linear. Pharmacodynamics relate concentration to effect in a non-linear but time-independent manner. It embodies the entire non-linearity of the system, but is assumed to be a static relation. Special attention is given to those principles which apply to any intravenous agent irrespective of its particularities. The impact of distribution and elimination, hysteresis, and ceiling on the induction, maintenance and recovery of anaesthesia, and on improving anaesthesia techniques and drug delivery are considered.     

Balanced anaesthesia today

An 'ideal' anaesthetic can be approached by using a combination of different compounds. A variety of anaesthetic techniques has been described to ensure safe administration and an early recovery with high patient satisfaction. In particular, the inhalational anaesthetics desflurane and sevoflurane, with their rapid pharmacokinetics, re-established the notion of balanced anaesthesia as an equivalent, well-controllable technique. With the choice of anaesthetics and anaesthetic adjuvants clinically available today, especially the combination of a volatile anaesthetic with a short-acting opioid, balanced anaesthesia represents a big step towards an ideal anaesthetic.     

Inhalational anaesthetic agents

The continued development of anaesthetic agents since the late 18th century has paved the way for the progression of surgical techniques. Inhalational agents are used worldwide for the delivery of safe, effective anaesthesia. These include the volatile agents halothane, isoflurane, sevoflurane and desflurane, in addition to the anaesthetic gases nitrous oxide and xenon. Although the newer volatiles have an improved safety profile in comparison to older agents, the ideal anaesthetic agent remains elusive. It is vital for anaesthetists to understand the physical properties, pharmacodynamics and pharmacokinetics of the individual inhalational anaesthetic agents so that the most appropriate agent for a patient or procedure is selected and administered correctly.     

The pharmacology of anaesthetics in the neonate

Neonatal anaesthesia dosing needs to be based on physiological characteristics of the newborn, pharmacokinetic/pharmacodynamic considerations and the adverse effects profile. Disease processes and treatments in this group are distinct from adults. Absorption, distribution and clearance are altered because of immaturity of enzyme, anatomical or physiological systems resulting in extensive variability of drug disposition in neonates. This is further compounded by pharmacogenomic influences. Population and physiological-based pharmacokinetic modelling have improved understanding of maturation and subsequent dose approximation. Postmenstrual age is a reasonable measure for maturation, although postnatal age may also have an impact. The neonatal response to drugs is also altered. Although neuromuscular monitoring is robust, there remains a need for other clinically applicable tools to assess pharmacodynamics that can provide effect feedback. In neonatal anaesthesia, a specific focus of interest is tools to assess depth of anaesthesia, sedation and pain. These tools have potential to improve effectiveness and safety.     

Cost-effectiveness and high patient satisfaction in the elderly: sevoflurane versus propofol anaesthesia

BACKGROUND AND OBJECTIVE: The use of propofol compared with isoflurane is associated with improved patient comfort and decreased costs. However, as the cost saving, the quicker recovery time and patient comfort may not be evident if sevoflurane is substituted for isoflurane; these two anaesthetic agents were analysed in elderly patients. METHODS: In a prospective randomized study, 96 patients undergoing elective ophthalmic surgery received either total intravenous anaesthesia with propofol (Group P), propofol for induction and sevoflurane for maintenance (Group P/S) or sevoflurane for inhalation induction and maintenance (Group S). Analyses focussed on haemodynamics, the quality of recovery, and the costs for the anaesthetic and the entire procedure. RESULTS: Bradycardia or hypotension, mainly registered in Groups P and P/S, did not influence patients' recovery. In Group S, postoperative nausea and vomiting occurred frequently, and 50% of patients complained of discomfort during induction. In Group P/S, the costs for anaesthetics and total costs were lower than those in Groups P and S. CONCLUSIONS: Propofol- and sevoflurane-based maintenance of anaesthesia were similar with regard to patient comfort and recovery in the elderly. Cost analysis revealed that it was less expensive to use propofol for induction and sevoflurane for maintenance than to use either propofol or sevoflurane as sole agents for anaesthesia.     

Anaesthesia in patients with Parkinson's disease

The neurodegenerative death of dopaminergic neurons of the pars compacta of the substantia nigra leads to the classical triad of resting tremor, muscle rigidity, and bradykinesia of Parkinson's disease. Parkinson's disease is a common disease of elderly patients requiring perioperative anaesthesia. Particular anaesthetic problems are neurological, respiratory, and cardiovascular. The clinical features and the interaction of common anaesthetics with the drug therapy of the patient present an anaesthetic challenge and directly influence perioperative morbidity and mortality.     

Modélisation et programme en Basic de la cinétique des agents anesthésiques par inhalation

The pharmacokinetics of inhaled anaesthetics has been well described by Eger's model using a monoalveolar lung with continuous alveolar ventilation and four extrapulmonary compartments defined by their blood supply and anaesthetic solubility. The model is presented with its equations. A Basic microcomputer programme is proposed for this model : expected concentrations of anaesthetic in various conditions of administration, ventilation or cardiac output are shown, such as the uptake and distribution of nitrous oxide during anaesthesia. Different inhaled anaesthetics were compared for induction and recovery times in standardized conditions of administration.     

Characteristics of children less than 2 years of age undergoing anaesthesia in Denmark 2005–2015: a national observational study

There are few data available that describe the current anaesthetic management of children. We have analysed anaesthetic practice and peri‐operative complications for children in Denmark aged less than two years. We conducted a population‐based observational cohort study using the Danish Anaesthesia Database to identify children who received anaesthesia in hospital from 1 January 2005 until 31 December 2015. Data were combined with that from the Danish National Patient Registry and the Danish Civil Registration System. Age, sex, height, weight, ASA physical status, days in hospital before anaesthesia, number of anaesthetics per child, indications for anaesthesia, methods of anaesthesia, airway management and complications were all recorded. A total of 17,436 children (64% of whom were male) received 27,653 anaesthetics during the study period. In 58% of cases, the child had an ASA physical status score of 1. Thirty‐seven percent had a previous anaesthetic episode. Seventy‐nine percent were anaesthetised at a university hospital. The indications for anaesthesia were surgery (70%), diagnostic radiology (16%), non‐surgical care (11%) and other indications (3%). General anaesthesia combining intravenous and inhalational agents was the most common approach for surgery (68%) and diagnostic radiology (47%). For non‐surgical care, general anaesthesia using inhalational agents was the most common method (42%). Neuraxial blocks were used infrequently. The most common regional anaesthetic nerve block was an infraclavicular brachial plexus block (11%). Peri‐operative complications occurred in 1.71% of cases. A large proportion of anaesthetics were conducted in children with comorbidities. Non‐surgical indications for anaesthesia were frequent and peri‐operative complications were rare.     

Nitrous oxide: a unique drug of continuing importance for anaesthesia

Early attempts to use nitrous oxide as a sole anaesthetic foundered because of its low potency. It has been used successfully as an adjunct to more potent anaesthetics, however, since 1868. By enabling reduced doses of more potent anaesthetics, nitrous oxide reduces the cost of anaesthesia and limits cardiorespiratory side effects. Nitrous oxide does increase the incidence of postoperative nausea and vomiting in cases where risk of this side effect is increased, but it seems likely that use of antiemetics prophylactically will negate this factor. Perhaps the greatest argument for the continued use of nitrous oxide is that it reduces the incidence of recall of intraoperative awareness. Reduced pharmacokinetic variability compared with other anaesthetics, especially intravenous agents, is likely to be a most important reason for this, although evidence is emerging that nitrous oxide also has pharmacodynamic advantages. There are specific situations in which nitrous oxide should not be used, but in the absence of these, its use can be favourably recommended.     

Laboratory animal anaesthesia: influence of anaesthetic protocols on experimental models

The use of experimental animals requires anaesthesia to provide immobility and analgesia. Animals require anaesthesia not only for ethical reasons but also because pain and stress can alter the quality of research results. Recognition of pain, and its treatment is important throughout the procedure. Before anaesthesia, animals are acclimated and rehydrated. Except in small rodents and in ruminants, in order to avoid vomiting, a fast of 8 to 12 hours before anaesthesia is recommended. In order to protect animals against suffering and distress during transfer, restraint and management, a premedication is administered. Most human anaesthetic products can be used in animals. There are some specific veterinary anaesthetics. Moreover, the anaesthetic effects could be different from specie to an other. In most big animals, induction is realized by intravenous administration. In small rodents, venous puncture and contention could be difficult, and anaesthetic agents may be injected via intraperitoneal or intramuscular way. The principal inconvenient of these administration routes is the impossibility to adjust dose to animal response. In large animals, human anaesthesia material can be used. Some technical adaptations could be necessary in smaller animals. In rodents or in neonatology, specific devices are recommended. ECG, arterial pressure, tidal volume, expired CO(2) and oxygen saturation monitoring assess quality of, and tolerance to anaesthesia. If animals are awaked after anaesthesia, postoperative management is closed to human clinical problems. During animal experimentations, anaesthesia may interact with results. All anaesthetic drugs alter normal physiology in some way and may confound physiologic results. In the literature, most publications do not mention this possible interaction. Investigators need to understand how animals are affected by anaesthetic drugs in order to formulate anaesthetic protocols with minimal effects on data. Extrapolation between different animal species and human and animals about the effects of anaesthetic agents are very hazardous. Great differences exist between the effects observed in vitro and in whole animals. The effects of the anaesthetics could be totally different if they are used alone or in association. The same anaesthetic could have opposite effects from an organ to another. For results validation, the anaesthesia side effects (hypoventilation, hypotension, cooling em leader ) have to be minimized. All new experimental models should require discussing the possible interferences between anaesthesia and results and to compare results obtained with different anaesthetic protocols.     

Spinal anaesthesia: local anaesthetics and adjuncts in the ambulatory setting

Intrathecal lidocaine remains a popular choice for ambulatory spinal anaesthesia due to its reliability, rapid onset and predictable rapid recovery profile. However, concerns with transient neurological symptoms (TNS) and their significant association with lidocaine have generated interest in alternative local anaesthetic agents to provide adequate spinal anaesthesia with the briefest possible recovery period. This chapter updates current data on drug dose-response relationships for local anaesthetics and the increasing use of intrathecal adjuncts to improve the anaesthetic and recovery profile for ambulatory spinal anaesthesia. Newer spinal anaesthetic techniques for common ambulatory procedures highlight the success of combining subclinical doses of local anaesthetics and intrathecal adjuncts. Controversies regarding the possible lower risk of TNS with newer spinal anaesthetic techniques and new discharge criteria are reviewed. The final section provides technical pearls to optimize ambulatory spinal anaesthetic outcomes.     

Ligand Gated Ion channels: crucial targets for anaesthetics?

Anaesthetic agents range from simple inert gases to complex synthetic compounds. It is difficult to envisage a unifying mechanism by which all of these agents induce anaesthesia. This review is focused on ligand-gated ion channels. We introduce the molecular classification (plus the concept of superfamilies and receptor isomerism) and nomenclature of the pore-forming proteins, then overview the large body of recent data suggesting they may be selective anaesthetic targets. A wide variety of anaesthetics (volatiles, propofol, etomidate, neurosteroids and barbiturates) have been shown to interact with GABA_A receptors. Point mutations in membrane spanning subunits comprising circa 450 amino acids can ablate the sensitivity of recombinant channels suggesting that the site of action is not in bulk membrane or interfacial lipids. Such drugs act stereoselectively to enhance the amplitude and or duration of inhibitory synaptic currents. In contrast, ketamine, nitrous oxide and xenon produce their anaesthetic effects (and untoward side effects) by depressing activity in the glutamatergic NMDA receptor. A minority of energetic researchers suggest that NMDA receptor activity is crucial for arousal (plays a more pivotal role in anaesthesia) and others suggest that voltage-gated channels are equally important in depressant drug action. Molecular biology and electrophysiology have been crucial for our understanding of channel function, but no concensus mechanism for anaesthetic action has yet emerged.     

Increased sensitivity to etomidate in the elderly: initial distribution versus altered brain response

To determine the effect of aging on the pharmacokinetics and pharmacodynamics of etomidate, we administered etomidate (5 to 10 mg/min) by intravenous infusion to 21 healthy surgical patients, age 22 to 82 yr. Etomidate produced progressive slowing of the EEG to an easily recognized pattern (stage 3) that determined the dosage endpoint. Subsequent power-spectrum analysis of the EEG gave the median frequency. Median frequency values and simultaneous measurements of blood etomidate concentration were incorporated into a sigmoid Emax pharmacodynamic model that permitted an estimate of IC50, the blood etomidate concentration which produced a 50% reduction in the median frequency. The dose of etomidate required to reach the uniform EEG endpoint decreased significantly with increasing age (r2 = .68) as did the dose needed to produce maximal median frequency depression (r2 = .69). None of the parameters of the pharmacodynamic effect model, including IC50, correlated with age, suggesting that increased brain sensitivity in the elderly does not cause the age-related change in dose requirement. The initial distribution volume for etomidate decreased significantly with increasing age (r = .56), implying that a higher initial blood concentration in the elderly following any given dose of etomidate is part of the cause of the lower dose requirement in the elderly patient. A contracted initial distribution volume in the elderly may result from well described physiologic changes of age. Etomidate clearance also decreased with age. Age-dependent changes in etomidate pharmacokinetics rather than altered brain responsiveness may be the basis for the decreased etomidate dose requirement in the elderly.     

Bispectral index and anaesthesia in the elderly

BACKGROUND: Due to pharmacokinetic and pharmacodynamic reasons, the elderly are at particular risk of incurring unwanted side effects of drugs commonly used in anaesthesia. The bispectral index (BIS) is an EEG-derived value that measures the sedative component of the anaesthetic state. The BIS could be useful in guiding titration of anaesthetic drugs in the elderly. METHODS: A review of the published data was performed by the authors in order to assess the suitability of BIS technology application to the geriatric population. RESULTS: Age-related EEG differences exist in the normal population but they do not affect the BIS. The BIS correlates with depth of sedation independently of age. Senile dementia may be associated with significantly lower BIS values. CONCLUSIONS: The BIS is a useful guidance for titration of anaesthetic drugs in the elderly. The presence of senile dementia may be a confounding factor in the interpretation of the BIS values during anaesthesia.     

Induction and maintenance of intravenous anaesthesia using target-controlled infusion systems

Total intravenous anaesthesia (TIVA) has several potential advantages: (i) each component of anaesthesia can be regulated independently and adapted to changes in the stimulus during surgery, (ii) lack of pollution, (iii) ease of use in ‘remote locations’, (iv) quality of recovery. The main drawback of TIVA is that it is difficult to use. Target-controlled infusion (TCI) is a new technique for the administration of intravenous agents based on real-time pharmacokinetic and pharmacodynamics simulations. Its aim is to control and maintain a steady therapeutic level of drugs with a narrow margin of safety. TCI is intended to be similar to the vaporizer of volatile anaesthetics. TCI has been used for more than 15 years for research purposes but the recent availability of a marketed system dedicated to propofol (Diprifusor) is a landmark in the dissemination of the technique. TCI can be used with other hypnotic drugs (midazolam, ketamine, etomidate) and also with opioids. Sedation and post-operative analgesia are also indications for TCI administration. TCI makes it possible to apply more easily certain tedious pharmacokinetic and pharmacodynamic concepts at the bedside at a low cost with potential clinical benefits for the patient. Clinical studies have demonstrated that TCI is as safe as manual infusion techniques but is preferred by anaesthesiologists because it reduces the workload. The main limit of this method at the present time is the large interindividual pharmacokinetic and pharmacodynamic variability and the lack of marketed systems for opioids. Population pharmacokinetics, effect compartment control and even closed-loop systems or Bayesian forecasting are possible directions for future improvements.     

Repeat anaesthesia: hepatic injury

Hepatic injury following repeat anaesthesia is a very rare but potentially fatal complication. The halogenated anaesthetic agents have been implicated in hepatic injury. Predisposing factors include repeat exposure to halogenated anaesthetics, genetic factors, middle age, female gender and liver enzyme induction. Halothane is a well-known cause of halothane hepatitis, but isoflurane, enflurane and desflurane have also been implicated with this clinical syndrome. A cross-sensitivity has been shown that is potentiated by the use of nitrous oxide. Although sevoflurane is metabolized differently, cases of hepatic injury following sevoflurane anaesthesia have been reported. The diagnosis of halothane hepatitis can be made only once other causes have been eliminated. Halogenated anaesthetics should be avoided for patients who have survived halothane hepatitis. Total intravenous anaesthetics and or regional techniques may be used instead.