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-
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Uncle Fester - The Father of Home Cooked Methamphetamine If Albert Hofmann was the "Father Of LSD," it's probably appropriate to call Steve Preisler the "Father Of Modern Meth-Making." "Uncle Fester" is the pseudonym, or "pen name," used by Steve Preisler to write his books. In the early 1980's, he gained cult status after publishing his first book "Secrets o
PRODUCT INFORMATION ACHROMYCIN DESCRIPTION Composition ACHROMYCIN Tetracycline HCl is a broad spectrum antibiotic isolated from Streptomyces aureofaciens . It is a yellow, crystalline, hygroscopic powder soluble 1 in 10 parts of water. CLINICAL PHARMACOLOGY Tetracycline is rapidly but incompletely absorbed from the stomach and small intestine. Absorption is impaired by admini