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ANAESTHESIA AND ANALGESIA: CONTRIBUTION TO SURGERY, Department of Anaesthesia, Christchurch School of Medicine, University of Otago, Christchurch, New Zealand Anaesthetists provide comprehensive perioperative medical care to patients undergoing surgical and diagnostic procedures, includingpostoperative intensive care when needed. They are involved in the management of perioperative acute pain as well as chronic pain.
This manuscript considers some of the recent advances in modern anaesthesia and their contribution to surgery, from the basicmechanisms of action, to the delivery systems for general and regional anaesthesia, to the use of new drugs and new methods ofmonitoring. It assesses the resulting progress in acute and chronic pain services and looks at patient safety and risk management.
It speculates on directions that may shape its future contributions to the management of the patient undergoing surgery.
Key words: anaesthesia, analgesia, contribution to surgery.
Abbreviations: AEP, auditory-evoked potentials; COX-2, cyclo-oxgenase 2; CSA, continuous spinal anaesthesia; CSE, combined spinal and epidural; EEG, electroencephalograph; GABAA, gamma-aminobutyric acid-A; PONV, postoperativenausea and vomiting; TCI, target-controlled infusion; TOE, transoesophageal echocardiography.
William Morton first publicly showed inhalational anaesthesia in How do anaesthetics work? Despite the widespread presence of 1846 with the use of diethyl ether. At the end of the nineteenth clinical anaesthesiology in surgical practice, the mechanisms by century, August Bier discovered that a class of drugs (local anaes- which diverse inhalational agents give general anaesthesia remain thetics) could stop neural transmission. Since those humble begin- unknown. There are complex multisite, multilevel (molecular, nings, the application of anaesthesia and analgesia has advanced subcellular, cellular, local microcircuit) interactions.1 Binding rapidly particularly in the past 50 years, making surgery much sites for general anaesthetics have been identified on several safer and allowing more sophisticated surgery to take place. The ion channels, including the nicotinic acetylcholine and gamma- explosion hazard with anaesthetic gases was largely conquered aminobutyric acid-A (GABAA) receptors.2 At clinically effective with the development of the halogenated agents in the 1950s.
concentrations, a broad variety of general anaesthetics increase Introduction of sevoflurane and desflurane during the last decades apparent GABA sensitivity and prolong inhibitory post-synaptic offered new perspectives to clinical anaesthesia, characterized by current mediated by GABAA receptors. Advancement in mol- rapid onset of and recovery from anaesthesia.
ecular techniques has allowed greater understanding of the action Anaesthetists provide comprehensive perioperative medical of anaesthetic agents through the use of the ‘knock-in’ mice care to patients undergoing surgical and diagnostic procedures, model.3 Conception of the mechanisms of action of many drugs including postoperative intensive care when needed. They are routinely given in the operating room can be improved by the use involved in the management of perioperative acute pain as well of protein biomarker technology (such as protein microarray as chronic pain. This manuscript considers some of the recent chips).4 A greater understanding of the mechanisms of anaesthe- advances in modern anaesthesia and their contributions to the sia will allow the development of more selective anaesthetics to management of the surgical patient. They range from the ‘basic achieve maximal clinical efficacy with minimal adverse effects.
mechanisms of action’, the delivery systems for general andregional anaesthesia, the use of new drugs to the new methodsof monitoring. The resulting progress in acute perioperative and chronic pain services is assessed in addition to patient safety and Regional anaesthesia provides a substitute for general anaesthe- risk management. It speculates on directions that may shape any sia. Alternatively, it can be used to supplement general anaesthe- sia and provide postoperative analgesia. There is continuousdevelopment and refinement of regional anaesthetic techniquesfor various types of surgery, as well as for continuous regional E. Shipton DM, FANZCA, FFPMANZCA; A. Lin MBChB.
analgesia.5 The quality of blockade and analgesia depends on Correspondence: Professor Edward Shipton, Department of Anaesthesia, accurate administration of local anaesthetic around the intended Christchurch School of Medicine, University of Otago, PO Box 4345, Christ- nerve structures. The use of nerve stimulation and insulated needles plus the development of ultrasound guidance (with an accurate depiction of the underlying anatomy) allows for Accepted for publication 15 October 2007.
precise needle placement.6 Ultrasound helps monitor the real-time Ó 2008 The AuthorsJournal compilation Ó 2008 Royal Australasian College of Surgeons administration of local anaesthetics or analgesics.6 Ultrasound or New drugs in clinical and research development in anaes- even computed tomography-guided nerve block techniques are particularly useful when the underlying anatomy is complex.7–10 Regional anaesthesia precludes the disadvantages seen with general anaesthesia (intubation, long recovery, postoperative nau- sea and vomiting (PONV), impaired oxygenation and depressed ventilation), It has been successfully used in the fields of obstet- rics and in lower-extremity, cardiothoracic,11–13 breast 14 and laparoscopic surgeries.15 The risks of anaesthetic and surgical complications are not any higher with regional anaesthesia than with general anaesthesia.14 However, it is not without its risks, including drug adverse effects, such as cardiovascular toxicity and Combining the use of spinal and epidural techniques (CSE) has been gaining popularity over recent years.16 It provides rapid onset of anaesthesia without increasing the complications.17 Recent evidence shows that lower doses provide adequate anal- gesia while reducing the incidence of motor block.18,19 The spinal needle can be used as a guide for the advancement of epidural needle and prevent the epidural catheter from puncturing the dura.20 A lower incidence of unintentional ‘wet tap’ has been shown with this technique. Fetal/neonatal bradycardia is occa- sionally seen with CSE technique, but is not associated with increased rates of emergency caesarean sections.21 In elderly and frail patients, in whom general or epidural anaes- thesia may be too risky,22 continuous spinal anaesthesia (CSA) has recently regained popularity.23 CSA offers haemodynamic stability, as hypotension is less likely with CSA when compared with CSE.24,25 However, with any neuraxial administration, hypotension and haematoma formation remain concerns that deserve further attention and research.24 In neuraxial opioid analgesia, opioid phys- icochemical properties determine efficacy and safety. Intrathecal morphine, fentanyl and sufentanil are most commonly used.26 Other analgesic adjuvants include clonidine, dexmedetomidine and adren-aline, all working through a-adrenergic receptors.26 Other agents inthe early stages of investigation for neuraxial analgesia include neo- stigmine, ketamine, midazolam, adenosine and ziconotide.26 The availability of the stereoisomer of ketamine with its increasedpotency and lower incidence of psychomimetic adverse effects in equianalgesic doses (compared with the racemate) has increased The quest for safety has long been a central part of the search for its non-anaesthetic use as an adjunct analgesic.31 new anaesthetic/analgesic agents. Recent fields examined includethe inert gases, the racaemic mixtures (ketamine, ropivacaine, levobupivacaine), the coxibs and the cyclodextrins (Table 1).
Provided there are no contraindications, the use of the cyclo-oxgenase 2 (COX-2) inhibitors (the coxibs) preoperatively show clear benefits in terms of reduced postoperative pain, analgesicconsumption and patient satisfaction.32 With their chronic use, Of all the inert gases, only xenon has considerable anaesthetic peptic ulceration remains a reduced but significant adverse properties under normobaric conditions.27 Xenon’s anaesthetic effect.33 Their lack of antiplatelet effects is important in patients effect is possibly achieved through the non-competitive antagonism on anticoagulants and in neuraxial blockade.33 COX-2 inhibitors of N-methyl-D-aspartate receptor.25 It is highly lipid soluble with may not produce bronchospasm (at analgesic doses), but may have a very low blood/gas partition coefficient (0.14)28 that makes induc- similar adverse effects as general non-steroidal anti-inflammatory tion of and emergence from anaesthesia more rapid compared with drugs on renal function.33 More trials are needed to determine other inhalational anaesthetic agents.27 Xenon has also been shown their possible prothrombotic effect.
to possess cardioprotective and neuroprotective effects.29,30 It mayprove beneficial in patients at high risk for neurological or cardiac damage during surgery. With the advancement in anaesthetic deliv-ery systems, the cost–benefit of using xenon gas may in future With regard to local anaesthetics, the main focus has been on the justify its use in high-risk surgical patients.
development of the enantiomer-specific compounds, ropivacaine Ó 2008 The AuthorsJournal compilation Ó 2008 Royal Australasian College of Surgeons and levobupivacaine. These provide similar efficacy to bupiva- ation of tumour and certain neurodegenerative disease proteins.54 caine in peripheral and central nerve blockade, but with reduced Local anaesthetics in turn have been shown to have potent anti- risk of severe cardiotoxicity.34 Human studies have borne this out inflammatory properties.54 Some of the new synthetic opioids are with levobupivacaine having fewer effects than bupivacaine on devoid of immunosuppressive functions seen with morphine.55 QRS prolongation, central nervous system symptoms and electro- There remains a need to examine how genetic diversity or acquired defects alter the immune response to tissue injury and There has been no effective antidote for toxic doses of local infection.53 This will improve risk stratification and create pos- anaesthetics. Recently, intralipid was shown to effectively reverse local anaesthetic toxicity in the animal model by hastening theloss of bupivacaine from cardiac tissue.35,36 Several human case reports using a bolus of 20% intralipid followed by an intralipidinfusion show promising efficacy.37,38 As other effective alterna- Progress in computing technology has allowed the development tives have not been found, the use of intralipid is worth consid- of target-controlled infusion (TCI) devices, with drugs delivered ering in the management of local anaesthetic toxicity.39 to achieve specific predicted target blood drug concentrations.56A set of pharmacokinetic parameters is selected using computer simulation of a known infusion scheme. The selected model isincorporated into a computer-compatible infusion pump. Clinical Adenosine-1 receptors play a role in antinociception in the spinal trials with such systems provide appropriate target concentra- cord.40 The direct administration of adenosine reduces the amount tions.56 TCI allows for the administration of small doses of of intraoperative volatile anaesthetic required and contributes to short-acting anaesthetic drugs, such as opioids (remifentanil and postoperative pain relief.41 An additional advantage of adenosine fentanyl) and propofol.57 The use of TCI has been extended to is its cardioprotective effect, making it an attractive future option include paediatric anaesthesia and sedation.
as part of a balanced anaesthetic technique.42 Continuous electronic physiological monitoring is core to the safe Over the past decades, the search for short termination of action of delivery of anaesthesia during surgery. Devices are being devel- non-depolarizing muscle relaxants has continued. Sugammadex oped that can assess depth of sedation and anaesthesia, stroke (Org 25969) is a cyclodextrin.43 It forms a tight complex with volume, cardiac output, systemic vascular resistance, cerebral aminosteroid-based non-depolarizing muscle relaxants (rocuro- haemodynamic and metabolic variables.58 Some new ventilators nium, pancuronium, vecuronium). Animal and human studies are capable of monitoring lung mechanics and of automatically show a rapid dose-dependent decrease in the concentration of free adjusting the ventilator settings to prevent ventilator associated and bound non-depolarizing muscle relaxants.44,45 It is devoid of lung injury or to aid weaning.58 New monitors include cerebral the cardiovascular side-effects associated with acetylcholinester- microdialysis to provide online analysis of tissue biochemistry.58 ase inhibitors such as neostigmine. Continued research is required Novel imaging methods include positron emission tomography to clarify the role of sugammadex before this termination tech- and functional magnetic resonance imaging.58 nique can replace the standard use of succinylcholine for short-term muscle relaxation.46 Non-invasive monitoring is increasingly being developed for use inanaesthesia. For example, the use of continuous cerebral oximetry Anaesthetic agents interact with the underlying pathological protects against the risk of intraoperative cerebral ischaemia.59 Aor- mechanisms of ischaemia reperfusion injury and protect the myo- tic blood flow can be determined with the use of non-invasive cardium by a preconditioning mechanism.47 Volatile anaesthetics oesophageal echo-Doppler monitoring.60 Thoracic bioimpedance activate ATP-sensitive potassium channels (similar to ischaemia- has been used as well to investigate haemodynamic changes.61 induced preconditioning) thereby providing a cardioprotectiveeffect.48–50 Preconditioning by volatile anaesthetics involves the activation of protein kinase C and mitogen-activated proteinkinases. Transcription factors are activated, resulting in the induc- Over the past 10 years, depth of anaesthesia monitoring has tion of specific genes in the heart.51 The effects are most evident emerged to aid anaesthetists by the development of processed elec- when the volatile agent is given throughout the entire procedure.52 troencephalographic methods, such as bispectral index, mid-latency The anaesthetist may therefore substantially influence the critical auditory-evoked potentials (AEP), and spectral entropy.62–64 These situation of ischaemia-reperfusion during surgery by choosing the correlate well to clinical observed level of consciousness.62–64 These monitoring techniques improve the titration of both inhaled andi.v. anaesthetic agents by avoiding excessive anaesthesia and aware-ness, promoting faster emergence from anaesthesia, and managing Knowledge of the host immune response to anaesthesia/analgesia Auditory evoked potentials form an electrical manifestation of and surgery needs to be integrated with the role of immunity in the brain response to an auditory stimulus. Mid-latency auditory general in the progression of many of the chronic diseases.53 evoked potentials as well as the coherent frequency of the auditory Volatile anaesthetics appear to suppress effector functions of both evoked potential are useful for monitoring depth of anaesthesia.66 the innate and adaptive immunity and may facilitate the prolifer- It is possible to acquire and process raw electroencephalograph Journal compilation Ó 2008 Royal Australasian College of Surgeons (EEG) and frontal electromyogram signals and produce two spec- tral entropy-based indices (namely response entropy and state Postoperative nausea and vomiting remains problematic to every entropy).67 The M-Entropy module provides useful information anaesthetist and surgeon. There is strong evidence that volatile on the cortical state of the patient during general anaesthesia. It anaesthetics (like opioids) are emetogenic with no meaningful acts as an indirect measure of the adequacy of analgesia.68 With the differences between halothane, enflurane, isoflurane, sevoflurane use of these new monitoring technologies, closed loop anaesthesia and desflurane.78 Various anti-emetic strategies are associated in the true sense has finally emerged.
with a reduction rate of approximately 25–30%.79 However, whena propofol technique is substituted for a volatile anaesthetic tech- nique, the risk for PONV is reduced by approximately one-fifth.78 In closed or rebreathing circuits, fresh gas supply matches uptake.
Interestingly, all anti-emetics (dexamethasone, droperidol and A lower fresh gas flow rate is therefore used. Humidity and tem- ondansetron) work independently, so a combination benefit can perature are conserved. In recent years, new computer-assisted be derived.80 If PONV is a serious problem, general anaesthesia control of gas delivery has dramatically improved the gas com- can be avoided by using a regional, opioid-free anaesthetic position in closed circuits. Fast gas analysers and appropriate algorithms regulate the exact amount of volatile and fresh gasinjected into the system. This minimizes the difference between the actual volatile gas concentration and vaporizer setting seen inthe traditional closed loop low-flow system. Closed loop systems Anaesthesia was one of the first medical professions to treat are able to reach and maintain a preset target.69 The computer patient safety as an independent problem. Preoperative evaluation program takes over the role of dose administration while the carried out by anaesthetists aims primarily to estimate the risk of anaesthetist only enters the desirable level to be maintained.
perioperative complications and to create opportunities to opti- Closed-loop feedback allows the realization of ‘quantitative mize the patient’s condition before surgery.81 Patient safety is closed-system anaesthesia’ in the operating room.70,71 primarily determined by quality of systems of care. There has To monitor muscle relaxation, a closed-loop muscle relaxation been steady progress in anaesthesia safety because of the devel- system can be formed by the connection of a muscle relaxation opment of performance standards, an increase in error reporting, monitor (TOF Watch SX; Organon Schering-Plough, Kenilworth, integration of information technology and improved safety sys- NJ, USA) to a laptop computer.72 A controller algorithm pro- tems.82 This has led to a 10-fold reduction in anaesthesia-related gramme then communicates with a syringe pump.72 deaths over the past few decades, despite the increase in more The linking of EEG monitoring to TCI for closed loop anaes- challenging operations and the number of older and sicker thesia remains a research tool. Nunes et al. recently developed patients. According to the Institute of Medicine’s 1999 report a fuzzy relational classifier that uses AEP features to classify the entitled To err is human, ‘. anesthesiology has successfully depth of anaesthesia.73 It is a machine-learning model based on reduced anesthesia mortality rates from two deaths per 10 000 fuzzy clustering and fuzzy relationship that somehow mimics anesthetics administered, to one death per 200 000 to 300 000 In addition to fibre-optic airway devices, supraglottic airway devi-ces have revolutionized airway management in anaesthesia over The occurrence of postoperative pain remains problematic. In the last 15 years. Examples include the classic, intubating and 2003, Apfelbaum found that 80% of patients still experience post- Proseal (LMA North America, Inc., San Diego, CA, USA) laryn- operative pain.84 Acute pain management services first entered geal mask airway, the Combitube (Tyco-Kendall, Mansfield, MA, clinical practice in the late 1980s.85 Anaesthetists have played USA), the laryngeal tube, and laryngeal tube sonda mark I and II.74 an important role in this interdisciplinary approach to managing The Glidescope (Verathon Inc., Bothell, WA, USA) is a new vid- postoperative pain.86 Evidence of earlier discharge with the use of eolaryngoscope.75 It has a digital camera incorporated in its blade an acute pain service has been shown.87,88 that displays a view of the vocal cords on a monitor. This allows Inadequately relieved postoperative pain leads to complica- visual placement of a tracheal tube. Improved designs include the tions, such as deep vein thrombosis, lung infections and myocar- paediatric ProSeal–Laryngeal mask airway76 and the Microcuff dial ischaemia, which may extend hospital stay.89 New analgesics (Kimberly-Clark Health Care, Roswell, GA, USA) paediatric endo- and analgesic drug delivery systems are being developed. For example, the use of i.v. paracetamol avoids absorption and bio-availability variability and produces more predictable plasma par-acetamol concentrations than the oral route.90 Nitroxyparacetamol (or nitroacetaminophen) is a new, potent nitric oxide-releasing Transoesophageal echocardiography (TOE) has proved useful to version of paracetamol that has analgesic and anti-inflammatory anaesthetists in guiding therapy in haemodynamically unstable properties.33,91 It should prove a useful analgesic for patients with patients in the operating room and intensive care unit. TOE provides paracetamol-induced liver damage. The anticonvulsant gabapen- real-time dynamic information about the anatomy and physiology tin has shown analgesic efficacy in several surgical procedures, of the whole heart.77 It is of value in the management of patients particularly to reduce post-surgical neuropathic pain.92 Early undergoing procedures (including cardiac valvular repair), in sur- studies with its successor, pregabalin are in progress.
gery for endocarditis and in surgery of the thoracic aorta. It con- Advances in neurobiology and clinical medicine have estab- tributes useful information in a wide range of cardiac pathologies.77 lished that the fetus and newborn may experience acute and even Ó 2008 The AuthorsJournal compilation Ó 2008 Royal Australasian College of Surgeons chronic pain.93 Many scales have been developed in an attempt to standardize pain measurement in neonates.93 Recently, attention How could anaesthetists aid the patient undergoing surgery in has been paid to the short-term and long-term outcomes of pre- future? Software could be developed to integrate patient monitor- mature infants and newborns exposed to noxious stimuli. These ing and response to anaesthesia and surgery, resulting in an early include simple heel prick, invasive intubation and surgery.
warning system that alerts the anaesthetist to impending disas- Repeated or prolonged painful experiences are linked to deleteri- ter.107 New techniques like nanotechnology could enable precise ous outcomes in preterm neonates.93 It could alter the develop- timing and site of drug delivery.107 Delivery systems under devel- ment of the nervous system and lead to abnormal pain behaviour opment could deposit drugs at the desired site of action, control in later life.94,95 This shows the importance of good analgesia their rate of release, and to neutralize overdose, bind and elimin- ate previously given drugs.107 Emerging applications could bedeveloped by pharmacogenomic research as well. In post-surgicalpain medicine, Anaesthetists could make use of new molecular targets, such as sodium channel blockers (Nav 1.3, Nav 1.7 andNav 1.8) 108; potassium channel openers in sensory neurons109; Anaesthetists often lead the medical specialist team involved in N-type calcium channels (Cav 2.2) blockers109; P2X4 and chronic pain management. In some patients, the hyperphenomena P2X7 receptor antagonists in microglia110; vanilloid receptor-1 (primary and secondary hyperalgesia, mechanical allodynia) that antagonists111,112; and the cannabinoid-2 receptor agonists.111,113 are normal in the first days or weeks after surgery, do not regress,but persist beyond the usual course of an acute surgical injury.96Acute persistent pain soon becomes chronic pain.96 Chronic pain demands a greater use of the health resources and has proved to be Anaesthesia historically grew out of surgery and the two disci- a major public health burden.97 Unrelieved postoperative pain and plines continue to work in close partnership. Anaesthetists and severe perioperative pain have been shown to be risk factors for surgeons form an integrated team linking together to do their the development of chronic pain.98 This emphasizes the need for utmost for the good of the patient. This relationship plays an effective perioperative pain management.
important role in enabling patient safety and avoiding errors. Of There has been tremendous progress in pain medicine (parti- importance to the surgeon are the recent developments in anaes- cularly interventional pain medicine) enhancing the contribution thetic technology and the advances in drugs and monitoring of the anaesthetist in managing post-surgical pain syndromes.
methods. As illustrated in this manuscript, these developments Advances in neuroimaging techniques (positron emission tomog- have accelerated and altered the work carried out in the operating raphy, functional magnetic resonance imaging) help identify brain room. In addition, evidence is just beginning to emerge on the mechanisms for more effective treatments for chronic pain. Rapid relation between specific anaesthetics and anaesthetic techniques progress is being made towards the development of gene ther- and long-term clinical outcomes after surgery.114 apy.80 For example, viral vector-mediated gene transfer achievesfocal production of short-lived analgesic peptides (or growth fac-tors). This prevents disc degeneration and promotes chondrocyte and disc regeneration.99 This should soon have clinical applica- 1. Urban BW. Current assessment of targets and theories of anaes- tion for both the anaesthetist and the surgeon involved in pain thesia. Br. J. Anaesth. 2002; 89: 167–83.
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Ó 2008 The AuthorsJournal compilation Ó 2008 Royal Australasian College of Surgeons


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