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INTRODUCTION IN
ANESTHESIE, CRITICAL CARE
AND PAIN MANAGEMENT
Basic Course
1 ЯНВАРЯ 2016 Г.
VITEBSK STATE MEDICAL UNIVERSITY
Vitebsk
Content
Anesthesiology and Anesthesia .................................................................................................. 2
Type of anesthesia .................................................................................................................. 2
The History of Anesthesia ...................................................................................................... 3
Inhalation anesthesia .......................................................................................................... 4
Local & Regional Anesthesia ............................................................................................. 5
Intravenous Anesthesia ...................................................................................................... 6
Induction Agents ................................................................................................................ 6
Neuromuscular Blocking Agents ....................................................................................... 6
Opioids ............................................................................................................................... 7
The Scope of Anesthesia .................................................................................................... 7
Inhalation Anesthesia ............................................................................................................. 8
Theories of Anesthetic Action................................................................................................ 8
Mechanisms of Local Anesthetic Action ............................................................................. 10
Acute Pain Management .......................................................................................................... 13
Pain perception and nociceptive pathways ........................................................................... 13
Peripheral nociceptors .......................................................................................................... 13
Pain transmission in the spinal cord ..................................................................................... 14
Central projections of pain pathways ................................................................................... 16
Descending modulatory pain pathways ................................................................................ 16
Neuropathic pain .................................................................................................................. 19
Progression of acute to chronic pain .................................................................................... 19
Predictive factors for chronic postsurgical pain ................................................................... 20
Acute pain and the injury response. ..................................................................................... 21
Adverse physiological effects .............................................................................................. 22
Intensive (critical) care medicine ............................................................................................. 25
The history of intensive care ................................................................................................ 25
Critical Illness ...................................................................................................................... 27
Sources ..................................................................................................................................... 29
Anesthesiology and Anesthesia
Anaesthesiology (British English) or anesthesiology (American English) is a branch of
medicine that focuses on pain relief during and after surgery. This treatment is
called anesthesia. Practitioners of anesthesiology are called anesthesiologists or, in some
countries, anaesthetists. Anesthesiologists often also undertake non-surgical pain relief, critical
care and pain management.
In the practice of medicine anesthesia (or anaesthesia) is an induced, temporary state
with one or more of the following characteristics: analgesia (relief from or prevention
of pain), paralysis (extreme
muscle
relaxation), amnesia (loss
of
memory),
and unconsciousness. An anesthetic is an agent that causes anaesthesia.
Type of anesthesia
1. General Anesthesia. General anaesthesia (or general anesthesia) is a medically
induced coma and loss of protective reflexes resulting from the administration of one or
more general anesthetic agents. A variety of medications may be administered, with the
overall aim of ensuring unconsciousness, amnesia, analgesia, relaxation of skeletal
muscles, and loss of control of reflexes of the autonomic nervous system. The optimal
combination of these agents for any given patient and procedure is typically selected by
anesthesiologist.
2. Regional Anesthesia (including Epidural, Spinal and Nerve Block Anesthesia).
a. Neuraxial blockade. This is a shot of anesthetic near the spinal cord and the nerves
that connect to it. It blocks pain from an entire region of the body, such as the belly,
hips, or legs; include:

Spinal. Spinal Anesthesia also involves the injection of a local anesthetic,
with or without a narcotic, into the fluid that surrounds the spinal cord. This
type of anesthesia is commonly used for genitourinary procedures and
procedures of the lower extremities.

Epidural. Epidural Anesthesia involves the injection of a local anesthetic,
usually with a narcotic, into the epidural space, through either a needle or
catheter. The epidural space is outside of the spinal cord. This type of
anesthesia is commonly used in labor and delivery and for procedures of the
lower extremities. An epidural block can be performed at the lumbar,
thoracic, or cervical level.

Caudal. The caudal space is the sacral portion of the epidural space.
b. Nerve Block Anesthesia (Peripheral nerve blocks). This is a shot of anesthetic to
block pain around a specific nerve or group of nerves. Blocks are often used for
procedures on the hands, arms, feet, legs, or face.
3. Combined General with Regional Anesthesia. This is a combination technique that puts you
to sleep and provides pain control, not only during the procedure, but afterwards as well.
4. Conscious Sedation or Monitored Anesthesia Care. This involves the injection of
medications through an IV catheter to help the patient relax, as well as to block pain. A
combination of sedative and narcotic medications are used to help to tolerate a procedure
that otherwise would be uncomfortable.
The History of Anesthesia
The Greek philosopher Dioscorides first used the term anesthesia in the first century AD to
describe the narcotic-like effects of the plant mandragora. The term subsequently was defined in
Bailey’s An Universal Etymological English Dictionary (1721) as “a defect of sensation” and again in
the Encyclopedia Britannica (1771) as “privation of the senses.” Oliver Wendell Holmes in 1846 was
the first to propose use of the term to denote the state that incorporates amnesia, analgesia, and narcosis
to propose use of the term to denote the state that incorporates amnesia, analgesia, and narcosis to make
painless surgery possible. In the United States, use of the term anesthesiology to denote the practice or
study of anesthesia was first proposed in the second decade of the twentieth century to emphasize the
growing scientific basis of the specialty.
The specialty of anesthesia began in the midnineteenth century and became firmly
established less than six decades ago. Ancient civilizations had used opium poppy, coca leaves,
mandrake root, alcohol, and even phlebotomy (to the point of unconsciousness) to allow
surgeons to operate. Ancient Egyptians used the combination of opium poppy (containing
morphine) and hyoscyamus (containing scopolamine); a similar combination, morphine and
scopolamine, has been used parenterally for premedication. What passed for regional anesthesia
in ancient times consisted of compression of nerve trunks (nerve ischemia) or the application
of cold (cryoanalgesia). The Incas may have practiced local anesthesia as their surgeons chewed
coca leaves and applied them to operative wounds, particularly prior to trephining for headache.
The evolution of modern surgery was hampered not only by a poor understanding of disease
processes, anatomy, and surgical asepsis but also by the lack of reliable and safe anesthetic
techniques. These techniques evolved first with inhalation anesthesia, followed by local and
regional anesthesia, and finally intravenous anesthesia. The development of surgical anesthesia
is considered one of the most important discoveries in human history.
Inhalation anesthesia
Because the hypodermic needle was not invented until 1855, the first general anesthetics
were destined to be inhalation agents. Diethylether (known at the time as “sulfuric ether”
because it was produced by a simple chemical reaction between ethyl alcohol and sulfuric acid)
was originally prepared in 1540 by Valerius Cordus. Ether was used for frivolous purposes
(“ether frolics”), but not as an anesthetic agent in humans until 1842, when Crawford W. Long
and William E. Clark independently used it on patients for surgery and dental extraction,
respectively. However, they did not publicize their discovery.
Four years later, in Boston, on October 16, 1846, William T.G. Morton conducted the
first publicized demonstration of general anesthesia for surgical operation using ether. The
dramatic success of that exhibition led the operating surgeon to exclaim to a skeptical audience:
“Gentlemen, this is no humbug!”
Von Leibig, Guthrie, and Soubeiran independently prepared chloroform in 1831.
Although first used by Holmes Coote in 1847, chloroform was introduced into clinical practice
by the Scot Sir James Simpson, who administered it to his patients to relieve the pain of labor.
Ironically, Simpson had almost abandoned his medical practice after witnessing the terrible
despair and agony of patients undergoing operations without anesthesia.
Joseph Priestley produced nitrous oxide in 1772, and Humphry Davy first noted its
analgesic properties in 1800. Gardner Colton and Horace Wells are credited with having first
used nitrous oxide as an anesthetic for dental extractions in humans in 1844. Nitrous oxide’s
lack of potency (an 80% nitrous oxide concentration results in analgesia but not surgical
anesthesia) led to clinical demonstrations that were less convincing than those with ether.
Nitrous oxide was the least popular of the three early inhalation anesthetics because of its low
potency and its tendency to cause asphyxia when used alone. Interest in nitrous oxide was
revived in 1868 when Edmund Andrews administered it in 20% oxygen; its use was, however,
overshadowed by the popularity of ether and chloroform. Ironically, nitrous oxide is the only
one of these three agents still in widespread use today.
Chloroform superseded ether in popularity in many areas (particularly in the United
Kingdom), but reports of chloroform-related cardiac arrhythmias, respiratory depression, and
hepatotoxicity eventually caused practitioners to abandon it in favor of ether, particularly in
North America.
Even after the introduction of other inhalation anesthetics (ethyl chloride, ethylene,
divinyl ether, cyclopropane, trichloroethylene, and fluroxene), ether remained the standard
inhaled anesthetic until the early 1960s. The only inhalation agent that rivaled ether’s safety
and popularity was cyclopropane (introduced in 1934). However, both are highly combustible
and both have since been replaced by a succession of nonflammable potent fluorinated
hydrocarbons: halothane (developed in 1951; released in 1956), methoxyflurane (developed in
1958; released in 1960), enflurane (developed in 1963; released in 1973), and isoflurane
(developed in 1965; released in 1981).
Two newer agents are now the most popular in developed countries. Desflurane
(released in 1992), has many of the desirable properties of isoflurane as well as more rapid
uptake and elimination (nearly as fast as nitrous oxide). Sevoflurane has low blood solubility,
but concerns about the potential toxicity of its degradation products delayed its release in the
United States until 1994. These concerns have proved to be largely theoretical, and sevoflurane,
not desflurane, has become the most widely used inhaled anesthetic in the United States, largely
replacing halothane in pediatric practice.
Local & Regional Anesthesia
The medicinal qualities of coca had been used by the Incas for centuries before its
actions were first observed by Europeans. Cocaine was isolated from coca leaves in 1855 by
Gaedicke and was purified in 1860 by Albert Niemann.
The original application of modern local anesthesia is credited to Carl Koller, at the time
a house officer in ophthalmology, who demonstrated topical anesthesia of the eye with cocaine
in 1884. Later in 1884 William Halsted used cocaine for intradermal infiltration and nerve
blocks (including blocks of the facial nerve, brachial plexus, pudendal nerve, and posterior tibial
nerve).
August Bier is credited with administering the first spinal anesthetic in 1898. He was
also the first to describe intravenous regional anesthesia (Bier block) in 1908.
Procaine was synthesized in 1904 by Alfred Einhorn and within a year was used
clinically as a local anesthetic by Heinrich Braun. Braun was also the first to add epinephrine
to prolong the duration of local anesthetics.
Ferdinand Cathelin and Jean Sicard introduced caudal epidural anesthesia in 1901.
Lumbar epidural anesthesia was described first in 1921 by Fidel Pages and again
(independently) in 1931 by Achille Dogliotti.
Additional local anesthetics subsequently introduced include dibucaine (1930),
tetracaine (1932), lidocaine (1947), chloroprocaine (1955), mepivacaine (1957), prilocaine
(1960), bupivacaine (1963), and etidocaine (1972). The most recent additions, ropivacaine and
levobupivacaine, have durations of action similar to bupivacaine but less cardiac toxicity.
Intravenous Anesthesia
Induction Agents
Intravenous anesthesia required the invention of the hypodermic syringe and needle by
Alexander Wood in 1855. Early attempts at intravenous anesthesia included the use of chloral
hydrate (by Oré in 1872), chloroform and ether (Burkhardt in 1909), and the combination of
morphine and scopolamine (Bredenfeld in 1916).
Barbiturates were first synthesized in 1903 by Fischer and von Mering. The first
barbiturate used for induction of anesthesia was diethylbarbituric acid (barbital), but it was not
until the introduction of hexobarbital in 1927 that barbiturate induction became popular.
Thiopental, synthesized in 1932 by Volwiler and Tabern, was first used clinically by John
Lundy and Ralph Waters in 1934 and for many years remained the most common agent for
intravenous induction of anesthesia. Methohexital was first used clinically in 1957 by V. K.
Stoelting and is the only other barbiturate used for induction of anesthesia in humans.
After chlordiazepoxide was discovered in 1955 and released for clinical use in 1960,
other benzodiazepines — diazepam, lorazepam, and midazolam—came to be used extensively
for premedication, conscious sedation, and induction of general anesthesia.
Ketamine was synthesized in 1962 by Stevens and first used clinically in 1965 by
Corssen and Domino; it was released in 1970 and continues to be popular today, particular
when administered in combination with other agents.
Etomidate was synthesized in 1964 and released in 1972. Initial enthusiasm over its
relative lack of circulatory and respiratory effects was tempered by evidence of adrenal
suppression, reported after even a single dose.
The release of propofol in 1986 (1989 in the United States) was a major advance in
outpatient anesthesia because of its short duration of action. Propofol is currently the most
popular agent for intravenous induction worldwide.
Neuromuscular Blocking Agents
The introduction of curare by Harold Griffith and Enid Johnson in 1942 was a milestone
in anesthesia. Curare greatly facilitated tracheal intubation and muscle relaxation during
surgery. For the first time, operations could be performed on patients without the requirement
that relatively deep levels of inhaled general anesthetic be used to produce muscle relaxation.
Such large doses of anesthetic often resulted in excessive cardiovascular and respiratory
depression as well as prolonged emergence. Moreover, larger doses were often not tolerated by
frail patients.
Succinylcholine was synthesized by Bovet in 1949 and released in 1951; it has become
a standard agent for facilitating tracheal intubation during rapid sequence induction. Until
recently, succinylcholine remained unchallenged in its rapid onset of profound muscle
relaxation, but its side effects prompted the search for a comparable substitute.
Other neuromuscular blockers (NMBs) — gallamine, decamethonium, metocurine,
alcuronium, and pancuronium — were subsequently introduced. Unfortunately, these agents
were often associated with side effects, and the search for the ideal NMB continued. Recently
introduced agents that more closely resemble an ideal NMB include vecuronium, atracurium,
rocuronium, and cis-atracurium.
Opioids
Morphine, isolated from opium in 1805 by Sertürner, was also tried as an intravenous
anesthetic. The adverse events associated with large doses of opioids in early reports caused
many anesthetists to avoid opioids and favor pure inhalation anesthesia. Interest in opioids in
anesthesia returned following the synthesis and introduction of meperidine in 1939.
The concept of balanced anesthesia was introduced in 1926 by Lundy and others and
evolved to include thiopental for induction, nitrous oxide for amnesia, an opioid for analgesia,
and curare for muscle relaxation.
In 1969, Lowenstein rekindled interest in “pure” opioid anesthesia by reintroducing the
concept of large doses of opioids as complete anesthetics. Morphine was the first agent so
employed, but fentanyl and sufentanil have been preferred by a large margin as sole agents. As
experience grew with this technique, its multiple limitations—unreliably preventing patient
awareness, incompletely suppressing autonomic responses during surgery, and prolonged
respiratory depression—were realized.
Remifentanil, an opioid subject to rapid degradation by nonspecific plasma and tissue
esterases, permits profound levels of opioid analgesia to be employed without concerns
regarding the need for postoperative ventilation.
The Scope of Anesthesia
The practice of anesthesia has changed dramatically since the days of John Snow. The
modern anesthesiologist is now both a perioperative consultant and a primary deliverer of care
to patients. In general, anesthesiologists manage nearly all “noncutting” aspects of the patient’s
medical care in the immediate perioperative period. The “captain of the ship” doctrine, which
held the surgeon responsible for every aspect of the patient’s perioperative care (including
anesthesia), is no longer a valid notion when an anesthesiologist is present. The surgeon and
anesthesiologist must function together as an effective team, and both are ultimately answerable
to the patient rather than to each other.
The modern practice of anesthesia is not confined to rendering patients insensible to
pain. Anesthesiologists monitor, sedate, and provide general or regional anesthesia outside the
operating room for various imaging procedures, endoscopy, electroconvulsive therapy, and
cardiac catheterization. Anesthesiologists have traditionally been pioneers in cardiopulmonary
resuscitation and continue to be integral members of resuscitation teams.
An increasing number of practitioners pursue a subspecialty in anesthesia for
cardiothoracic surgery, critical care, neuroanesthesia, obstetric anesthesia, pediatric anesthesia,
and pain medicine. Anesthesiologists are actively involved in the administration and medical
direction of many ambulatory surgery facilities, operating room suites, intensive care units, and
respiratory therapy departments. They have also assumed administrative and leadership
positions on the medical staffs of many hospitals and ambulatory care facilities. They serve as
deans of medical schools and chief executives of health systems.
Inhalation Anesthesia
Five inhalation agents continue to be used in clinical anesthesiology: nitrous oxide,
halothane, isoflurane, desflurane, and sevoflurane. The course of a general anesthetic can be
divided into three phases: (1) induction, (2) maintenance, and (3) emergence.
Inhalation anesthetics, such as halothane and sevoflurane, are particularly useful in the
induction of pediatric patients in whom it may be difficult to start an intravenous line. Although
adults are usually induced with intravenous agents, the nonpungency and rapid onset of
sevoflurane make inhalation induction practical for them as well.
Regardless of the patient’s age, anesthesia is often maintained with inhalation agents.
Emergence depends primarily upon redistribution from the brain and pulmonary
elimination of these agents. Because of their unique route of administration, inhalation
anesthetics have useful pharmacological properties not shared by other anesthetic agents. For
instance, administration via the pulmonary circulation allows a more rapid appearance of the
drug in arterial blood than intravenous administration.
Theories of Anesthetic Action
General anesthesia is an altered physiological state characterized by reversible loss of
consciousness, analgesia, amnesia, and some degree of muscle relaxation.
The multitude of substances capable of producing general anesthesia is remarkable: inert
elements (xenon), simple inorganic compounds (nitrous oxide), halogenated hydrocarbons
(halothane), ethers (isoflurane, sevoflurane, desflurane), and complex organic structures
(propofol).
A unifying theory explaining anesthetic action would have to accommodate this
diversity of structure. In fact, the various agents probably produce anesthesia by differing sets
of molecular mechanisms. Inhalational agents interact with numerous ion channels present in
the CNS and peripheral nervous system. Nitrous oxide and xenon are believed to inhibit N-
methyl-D -aspartate (NMDA) receptors. NMDA receptors are excitatory receptors in the brain.
Other inhalational agents may interact at other receptors (e.g., gamma-aminobutyric acid
[GABA]-activated chloride channel conductance) leading to anesthetic effects.
Additionally, some studies suggest that inhalational agents continue to act in a
nonspecific manner, thereby affecting the membrane bilayer. It is possible that inhalational
anesthetics act on multiple protein receptors that block excitatory channels and promote the
activity of inhibitory channels affecting neuronal activity, as well as by some nonspecific
membrane effects. There does not seem to be a single macroscopic site of action that is shared
by all inhalation agents.
Specific brain areas affected by various anesthetics include the reticular activating
system, the cerebral cortex, the cuneate nucleus, the olfactory cortex, and the hippocampus;
however, to be clear, general anesthetics bind throughout the CNS.
Anesthetics have also been shown to depress excitatory transmission in the spinal cord,
particularly at the level of the dorsal horn interneurons that are involved in pain transmission.
Differing aspects of anesthesia may be related to different sites of anesthetic action. For
example, unconsciousness and amnesia are probably mediated by cortical anesthetic action,
whereas the suppression of purposeful withdrawal from pain may be related to subcortical
structures, such as the spinal cord or brain stem. One study in rats revealed that removal of the
cerebral cortex did not alter the potency of the anesthetic! Indeed, measures of minimal alveolar
concentration (MAC), the anesthetic concentration that prevents movement in 50% of subjects
or animals, are dependent upon anesthetic effects at the spinal cord and not at the cortex.
Past understanding of anesthetic action attempted to identify a unitary hypothesis of
anesthetic effects. This hypothesis proposes that all inhalation agents share a common
mechanism of action at the molecular level. This was previously supported by the observation
that the anesthetic potency of inhalation agents correlates directly with their lipid solubility
(Meyer–Overton rule). The implication is that anesthesia results from molecules dissolving at
specific lipophilic sites. Of course, not all lipid-soluble molecules are anesthetics (some are
actually convulsants), and the correlation between anesthetic potency and lipid solubility is only
approximate.
Neuronal membranes contain a multitude of hydrophobic sites in their phospholipid
bilayer. Anesthetic binding to these sites could expand the bilayer beyond a critical amount,
altering membrane function (critical volume hypothesis). Although this theory is almost
certainly an oversimplification, it explains an interesting phenomenon: the reversal of
anesthesia by increased pressure. Laboratory animals exposed to elevated hydrostatic pressure
develop a resistance to anesthetic effects. Perhaps the pressure is displacing a number of
molecules from the membrane or distorting the anesthetic binding sites in the membrane,
increasing anesthetic requirements. However, studies in the 1980s demonstrated the ability of
anesthetics to inhibit protein actions, shifting attention to the numerous ion channels that might
affect neuronal transmission and away from the critical volume hypothesis.
General anesthetic action could be due to alterations in any one (or a combination) of
several cellular systems, including voltage-gated ion channels, ligand-gated ion channels,
second messenger functions, or neurotransmitter receptors. For example, many anesthetics
enhance GABA inhibition of the CNS. Furthermore, GABA receptor agonists seem to enhance
anesthesia, whereas GABA antagonists reverse some anesthetic effects. There seems to be a
strong correlation between anesthetic potency and potentiation of GABA receptor activity.
Thus, anesthetic action may relate to binding in relatively hydrophobic domains in channel
proteins (GABA receptors). Modulation of GABA function may prove to be a principal
mechanism of action for many anesthetic drugs.
The glycine receptor α1-subunit, whose function is enhanced by inhalation anesthetics,
is another potential anesthetic site of action. The tertiary and quaternary structure of amino
acids within an anesthetic-binding pocket could be modified by inhalation agents, perturbing
the receptor itself, or indirectly producing an effect at a distant site.
Other ligand-gated ion channels whose modulation may play a role in anesthetic action
include nicotinic acetylcholine receptors and NMDA receptors. Investigations into mechanisms
of anesthetic action are likely to remain ongoing for many years, as many protein channels may
be affected by individual anesthetic agents, and no obligatory site has yet been identified.
Selecting among so many molecular targets for the one(s) that provide optimum effects
with minimal adverse actions will be the challenge in designing better inhalational agents.
Mechanisms of Local Anesthetic Action
Neurons (and all other living cells) maintain a resting membrane potential of −60 to −70
mV by active transport and passive diffusion of ions. The electrogenic, energy-consuming
sodium–potassium pump (Na +-K +-ATPase) couples the transport of three sodium (Na) ions
out of the cell for every two potassium (K) ions it moves into the cell. This creates an ionic
disequilibrium (concentration gradient) that favors the movement of K ions from an
intracellular to an extracellular location, and the movement of Na ions in the opposite direction.
The cell membrane is normally much more “leaky” to K ions than to Na ions, so a relative
excess of negatively charged ions (anions) accumulates intracellularly. This accounts for the
negative resting potential difference (–70 mV polarization).
Unlike most other types of tissue, excitable cells (e.g., neurons or cardiac myocytes)
have the capability of generating action potentials.
Membranebound, voltage-gated Na
channels in peripheral nerve axons can produce and transmit membrane depolarizations
following chemical, mechanical, or electrical stimuli. When a stimulus is sufficient to
depolarize a patch of membrane, the signal can be transmitted as a wave of depolarization along
the nerve membrane (an impulse). Activation of voltage-gated Na channels causes a very brief
(roughly 1 msec) change in the conformation of the channel, allowing an influx of Na ions and
generating an action potential.
The increase in Na permeability causes temporary depolarization of the membrane
potential to +35 mV. The Na current is brief and is terminated by inactivation of voltagegated
Na channels, which do not conduct Na ions. Subsequently the membrane returns to its resting
potential.
Baseline concentration gradients are maintained by the sodium–potassium pump, and
only a minuscule number of Na ions pass into the cell during an action potential. Na channels
are membrane-bound proteins that are composed of one large α-subunit, through which Na ions
pass, and one or two smaller βsubunits. Voltage-gated Na channels exist in (at least) three
states—resting (nonconducting), open conducting), and inactivated (nonconducting).
Local anesthetics bind a specific region of the α-subunit and inhibit voltage-gated Na
channels, preventing channel activation and inhibiting the Na influx associated with membrane
depolarization. Local anesthetic binding to Na channels does not alter the resting membrane
potential. With increasing local anesthetic concentrations, an increasing fraction of the Na
channels in the membrane bind a local anesthetic molecule and cannot conduct Na ions. As a
consequence, impulse conduction slows, the rate of rise and the magnitude of the action
potential decrease, and the threshold for excitation and impulse conduction increases
progressively.
At high enough local anesthetic concentrations and with a sufficient fraction of local
anesthetic-bound Na channels, an action potential can no longer be generated and impulse
propagation is abolished. Local anesthetics have a greater affinity for the channel in the open
or inactivated state than in the resting state. Local anesthetic binding to open or inactivated
channels, or both, is facilitated by depolarization. The fraction of Na channels that have bound
a local anesthetic increases with frequent depolarization (e.g., during trains of impulses).
This phenomenon is termed use-dependent block. Put another way, local anesthetic
inhibition is both voltage and frequency dependent, and is greater when nerve fibers are firing
rapidly than with infrequent depolarizations. Local anesthetics may also bind and inhibit
calcium (Ca), K, transient receptor potential vanilloid 1 (TRPV1), and many other channels and
receptors.
Conversely, other classes of drugs, most notably tricyclic antidepressants
(amitriptyline), meperidine, volatile anesthetics, Ca- channel blockers, and ketamine, also may
inhibit Na channels. Tetrodotoxin is a poison that specifically binds Na channels but at a site
on the exterior of the plasma membrane. Human studies are under way with similar toxins to
determine whether they might provide effective, prolonged analgesia after local infiltration.
Sensitivity of nerve fibers to inhibition by local anesthetics is determined by axonal
diameter, myelination, and other anatomic and physiological factors. In comparing nerve fibers
of the same type, small diameter increases sensitivity to local anesthetics. Thus, larger, faster
Aαfibers are less sensitive to local anesthetics than smaller, slower-conducting Aδfibers, and
larger unmyelinated fibers are less sensitive than smaller unmyelinated fibers. On the other
hand, small unmyelinated C fibers are relatively resistant to inhibition by local anesthetics as
compared with larger myelinated fibers. In spinal nerves local anesthetic inhibition (and
conduction failure) generally follows the sequence autonomic >sensory >motor, but at steady
state if sensory anesthesia is present all fibers are inhibited.
Pain is defined by the International Association for the Study of Pain (IASP) as ‘an
unpleasant sensory and emotional experience associated with actual or potential tissue damage,
or described in terms of such damage’ (Merskey & Bogduk, 1994).
Acute pain is defined as ‘pain of recent onset and probable limited duration. It usually
has an identifiable temporal and causal relationship to injury or disease’. Chronic pain
‘commonly persists beyond the time of healing of an injury and frequently there may not be
any clearly identifiable cause’ (Ready & Edwards, 1992).
Acute Pain Management
Pain perception and nociceptive pathways
The ability of the somatosensory system to detect noxious and potentially tissuedamaging stimuli is an important protective mechanism that involves multiple interacting
peripheral and central mechanisms. The neural processes underlying the encoding and
processing of noxious stimuli are defined as ‘nociception’ (Loeser & Treede, 2008). In addition
to these sensory effects, the perception and subjective experience of ’pain’ is multifactorial and
will be influenced by psychological and environmental factors in every individual.
Peripheral nociceptors
The detection of noxious stimuli requires activation of peripheral sensory organs
(nociceptors) and transduction into action potentials for conduction to the central nervous
system. Nociceptive afferents are widely distributed throughout the body (skin, muscle, joints,
viscera, meninges) and comprise both medium-diameter lightly myelinated A-delta fibres and
smalldiameter, slow-conducting unmyelinated C-fibres. The most numerous subclass of
nociceptor is the C-fibre polymodal nociceptor, which responds to a broad range of physical
(heat, cold, and pressure) and chemical stimuli. A range of transient receptor potential (TRP)
channels (Patapoutian et al, 2009) detects thermal sensation. A number of receptors have been
postulated to signal noxious mechanical stimuli, including acid-sensing ion channels (ASICs),
TRPs and potassium channels (Woolf & Ma, 2007).
Tissue damage, such as that associated with infection, inflammation or ischaemia,
produces disruption of cells, degranulation of mast cells, secretion by inflammatory cells, and
induction of enzymes such as cyclo-oxygenase-2 (COX-2). Ranges of chemical mediators act
either directly via ligand-gated ion channels or via metabotropic receptors to activate and/or
sensitise nociceptors. Endogenous modulators of nociception, including proteinases (Russell &
McDougall, 2009), pro-inflammatory cytokines (e.g. TNFα, IL-1β, IL-6) (Schafers & Sorkin,
2008), anti-inflammatory cytokines (e.g. IL-10) (Sloane et al, 2009) and chemokines (e.g.
CCL3, CCL2, CX3CL1) (Woolf & Ma, 2007; White & Wilson, 2008), can also act as signalling
molecules in pain pathways. Following activation, intracellular kinase cascades result in
phosphorylation of channels (such as voltage-gated sodium and TRP channels), alterations in
channel kinetics and threshold, and sensitisation of the nociceptor. Neuropeptides (substance P
and calcitonin generelated peptide) released from the peripheral terminals also contribute to the
recruitment of serum factors and inflammatory cells at the site of injury (neurogenic oedema).
This increase in sensitivity within the area of injury due to peripheral mechanisms is termed
peripheral sensitisation, and is manifest as primary hyperalgesia (Woolf & Ma, 2007). Nonsteroidal anti-inflammatory drugs (NSAIDs) modulate peripheral pain by reducing
prostaglandin E2 (PGE 2) synthesis by locally induced COX-2. Inflammation also induces
changes in protein synthesis in the cell body in the dorsal root ganglion and alters the expression
and transport of ion channels and receptors, such as TRPV1 and opioid receptors respectively,
to the periphery (Woolf & Ma, 2007). The latter underlies the peripheral action of opioid
agonists in inflamed tissue (Stein et al, 2009).
Sodium channels are important modulators of neuronal excitability, signalling and
conduction of neuronal action potentials to the central nervous system (CNS) (Cummins et al,
2007; Momin & Wood, 2008; Dib-Hajj et al, 2009). A rapidly inactivating fast sodium current
that is blocked by tetrodotoxin is present in all sensory neurons. This is the principal site of
action for local anaesthetics, but as the channel is present in all nerve fibres, conduction in
sympathetic and motor neurons may also be blocked. Subtypes of slowly activating and
inactivating tetrodotoxin-resistant sodium currents are selectively present on nociceptive fibres.
Following injury, changes in sodium channel kinetics contribute to hyperexcitability, and
specific alterations in the expression of sodium channels (up-regulation or down-regulation)
occur in different pain states. The importance of sodium channels in pain sensitivity is reflected
by the impact of mutations in the SCN9A gene encoding the Na(v)1.7 channel: loss-of-function
results in insensitivity to pain whereas gain-of-function mutations produce erythromelalgia and
severe pain (Dib-Hajj et al, 2008). However, subtype-selective drugs are not yet available
(Momin & Wood, 2008).
The cell bodies of nociceptive afferents that innervate the trunk, limbs and viscera are
found in the dorsal root ganglia (DRG), while those innervating the head, oral cavity and neck
are in the trigeminal ganglia and project to the brainstem trigeminal nucleus. The central
terminals of C and A-delta fibres convey information to nociceptive-specific neurons within
laminae I and II of the superficial dorsal horn and to wide dynamic range neurons in lamina V,
which encode both innocuous and noxious information. By contrast, large myelinated A-beta
fibres transmit light touch or innocuous mechanical stimuli to deep laminae III and IV.
Pain transmission in the spinal cord
Primary afferent terminals contain excitatory amino acids (e.g. glutamate, aspartate),
peptides (e.g. substance P, calcitonin gene-related peptide [CGRP]) and neurotrophic factors
(e.g. brain-derived neurotrophic factor [BDNF]), which act as neurotransmitters and are
released by different intensity stimuli (Sandkuhler, 2009). Depolarisation of the primary
afferent terminal results in glutamate release, which activates postsynaptic ionotropic alphaamino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors and rapidly signals
information relating to the location and intensity of noxious stimuli. In this ‘normal mode’ a
high intensity stimulus elicits brief localised pain, and the stimulus-response relationship
between afferent input and dorsal horn neuron output is predictable and reproducible (Woolf &
Salter, 2000).
Summation of repeated C-fibre inputs results in a progressively more depolarised
postsynaptic membrane and removal of the magnesium block from the N-methyl-D-aspartate
(NMDA) receptor. This is mediated by glutamate acting on ionotropic NMDA receptors and
metabotropic glutamate receptors (mGluR), and by substance P acting on neurokinin-1 (NK1)
receptors. A progressive increase in action potential output from the dorsal horn cell is seen
with each stimulus, and this rapid increase in responsiveness during the course of a train of
inputs has been termed ‘wind-up’. Long-term potentiation (LTP) is induced by higher
frequency stimuli, but the enhanced response outlasts the conditioning stimulus, and this
mechanism has been implicated in learning and memory in the hippocampus and pain
sensitisation in the spinal cord (Sandkuhler, 2009). Behavioural correlates of these
electrophysiological phenomena have been seen in human volunteers, as repeated stimuli elicit
progressive increases in reported pain (Hansen et al, 2007).
Intense and ongoing stimuli further increase the excitability of dorsal horn neurons.
Electrophysiological studies have identified two patterns of increased postsynaptic response:
‘windup’ is evoked by low frequency C-fibre (but not A-beta fibre) stimuli and is manifest as
an enhanced postsynaptic response during a train of stimuli; and ‘LPT’ is generated by higher
frequency stimuli and outlasts the conditioning stimulus. Increases in intracellular calcium due
to influx through the NMDA receptor and release from intracellular stores activate a number of
intracellular kinase cascades. Subsequent alterations in ion channel and/or receptor activity and
trafficking of additional receptors to the membrane increase the efficacy of synaptic
transmission. Centrally mediated changes in dorsal horn sensitivity and/or functional
connectivity of A-beta mechanosensitive fibres and increased descending facilitation contribute
to ‘secondary hyperalgesia’ (i.e. sensitivity is increased beyond the area of tissue injury).
Windup, LTP and secondary hyperalgesia may share some of the same intracellular
mechanisms but are independent phenomena. All may contribute to ‘central sensitisation’,
which encompasses the increased sensitivity to both C and A-beta fibre inputs resulting in
hyperalgesia (increased response following noxious inputs) and allodynia (pain in response to
low intensity previously non-painful stimuli) (Sandkuhler, 2009).
The intracellular changes associated with sensitisation may also activate a number of
transcription factors in both DRG and dorsal horn neurons, with resultant changes in gene and
protein expression (Ji et al, 2009). Unique patterns of either up-regulation or down-regulation
of neuropeptides, G-protein coupled receptors, growth factors and their receptors, and many
other messenger molecules occur in the spinal cord and DRG in inflammatory, neuropathic and
cancer pain. Further elucidation of changes specific to different pain states may allow more
accurate targeting of therapy in the future.
In addition to the excitatory processes outlined above, inhibitory modulation also occurs
within the dorsal horn and can be mediated by non-nociceptive peripheral inputs, local
inhibitory GABA-ergic and glycinergic interneurons, descending bulbospinal projections, and
higher order brain function (e.g. distraction, cognitive input). These inhibitory mechanisms are
activated endogenously to reduce the excitatory responses to persistent C-fibre activity through
neurotransmitters such as endorphins, enkephalins, noradrenaline (norepinephrine) and
serotonin, and are targets for many exogenous analgesic agents.
Thus, analgesia may be achieved by either enhancing inhibition (e.g. opioids, clonidine,
and antidepressants) or by reducing excitatory transmission (e.g. local anaesthetics, ketamine).
Central projections of pain pathways
Different qualities of the overall pain experience are subserved by projections of
multiple parallel ascending pathways from the spinal cord to the midbrain, forebrain and cortex.
The spinothalamic pathway ascends from primary afferent terminals in laminae I and II, via
connections in lamina V of the dorsal horn, to the thalamus and then to the somatosensory
cortex. This pathway provides information on the sensory-discriminative aspects of pain (i.e.
the site and type of painful stimulus). The spinoreticular (spinoparabrachial) and
spinomesencephalic tracts project to the medulla and brainstem and are important for
integrating nociceptive information with arousal, homeostatic and autonomic responses as well
as projecting to central areas mediating the emotional or affective component of pain.
The spinoparabrachial pathway originates from superficial dorsal horn lamina I neurons
that express the NK1-receptor and projects to the ventromedial hypothalamus and central
nucleus of the amygdala. Multiple further connections include those with cortical areas
involved in the affective and motivational components of pain (e.g. anterior cingulate cortex,
insular and prefrontal cortex), projections back to the periaqueductal grey (PAG) region of the
midbrain and rostroventromedial medulla (RVM), which are crucial for fight or flight responses
and stress-induced analgesia, and projections to the reticular formation, which are important for
the regulation of descending pathways to the spinal cord (see Figure 1.1) (Hunt & Mantyh,
2001; Tracey & Mantyh, 2007; Tracey, 2008).
Descending modulatory pain pathways
Descending pathways contribute to the modulation of pain transmission in the spinal
cord via presynaptic actions on primary afferent fibres, postsynaptic actions on projection
neurons, or via effects on intrinsic interneurons within the dorsal horn. Sources include direct
corticofugal and indirect (via modulatory structures such as the PAG) pathways from the cortex,
and the hypothalamus, which is important for coordinating autonomic and sensory information.
The RVM receives afferent input from brainstem regions (PAG, parabrachial nucleus and
nucleus tractus solitarius) as well as direct ascending afferent input from the superficial dorsal
horn, and is an important site for integration of descending input to the spinal cord (Millan,
2002). The relative balance between descending inhibition and facilitation varies with the type
and intensity of the stimulus and with time following injury (Vanegas & Schaible, 2004;
Heinricher et al, 2009; Tracey & Mantyh, 2007). Serotonergic and noradrenergic pathways in
the dorsolateral funiculus (DLF) contribute to descending inhibitory effects (Millan, 2002) and
serotonergic pathways have been implicated in facilitatory effects (Suzuki et al, 2004).
Figure 1 The main ascending and descending spinal pain pathways
Notes: (a) There are 2 primary ascending nociceptive pathways. The spinoparabrachial pathway (red)
originates from the superficial dorsal horn and feeds areas of the brain concerned with affect. The spinothalamic
pathway (blue) originates from deeper in the dorsal horn (lamina V) after receiving input from the superficial
dorsal horn and predominantly distributes nociceptive information to areas of the cortex concerned with
discrimination.
(b) The descending pathway highlighted originates from the amygdala and hypothalamus and terminates
in the PAG. Neurons project from here to the lower brainstem and control many of the antinociceptive and
autonomic responses that follow noxious stimulation. Other less prominent pathways are not illustrated.
The site of action of some commonly utilised analgesics are included.
Legend. A: adrenergic nucleus; bc: brachium conjunctivum; cc: corpus collosum; Ce: central nucleus
of the amygdala; DRG: dorsal root ganglion; Hip: hippocampus; ic: internal capsule; LC: locus coeruleus; PAG:
periaqueductal grey; PB: parabrachial area; Po: posterior group of thalamic nuclei; Py: pyramidal tract; RVM:
rostroventrmedial medulla; V: ventricle; VMH: ventral medial nucleus of the hypothalamus; VPL: ventral
posterolateral nucleus of the thalamus; VPM: ventral posteromedial nucleus of the thalamus.
Source: Modified from Hunt (Hunt & Mantyh, 2001).
Neuropathic pain
Neuropathic pain has been defined as ‘pain initiated or caused by a primary lesion or
dysfunction in the nervous system’ (Merskey & Bogduk, 1994; Loeser & Treede, 2008).
Although commonly a cause of chronic symptoms, neuropathic pain can also present
acutely following trauma and surgery. The incidence has been conservatively estimated as 3%
of acute pain service patients and often it produces persistent symptoms (Hayes et al, 2002).
Similarly, acute medical conditions may present with neuropathic pain (Gray, 2008).
Nerve injury and associated alterations in afferent input can induce structural and
functional changes at multiple points in nociceptive pathways. Damage to peripheral axons
results in loss of target-derived growth factors and marked transcriptional changes in DRG of
injured neurons (including down-regulation of TRP and sodium channels) and a differing
pattern in non-injured neighbouring neurons that contributes to spontaneous pain (Woolf & Ma,
2007). In the spinal cord, activation of the same signal transduction pathways as seen following
inflammation can result in central sensitisation, with additional effects due to loss of inhibition
(Sandkuhler, 2009). Central neurons in the RVM were sensitised after peripheral nerve injury
(Carlson et al, 2007) and structural reorganisation in the cortex after spinal cord injury (Wrigley
et al, 2009), and changes in cerebral activation have been noted in imaging studies of patients
with neuropathic pain (Tracey & Mantyh, 2007).
Progression of acute to chronic pain
The importance of addressing the link between acute and chronic pain has been
emphasised by recent studies. To highlight this link, chronic pain is increasingly referred to as
persistent pain. A survey of the incidence of chronic pain-related disability in the community
concluded that patients often relate the onset of their pain to an acute injury, drawing attention
to the need to prevent the progression from acute to chronic pain (Blyth et al, 2003 Level IV).
The association between acute and chronic pain is well defined, but few randomised
controlled studies have addressed the aetiology, time course, prevention or therapy of the
transition between the two pain states. Acute pain states that may progress to chronic pain
include postoperative and post-traumatic pain, acute back pain and herpes zoster.
Chronic pain is common after surgery (Kehlet et al, 2006; Macrae, 2008) and represents
a significant source of ongoing disability, often with considerable economic consequences.
Such pain frequently has a neuropathic element. For example, all patients with chronic
postherniorrhaphy pain had features of neuropathic pain (Aasvang et al, 2008 Level IV).
Predictive factors for chronic postsurgical pain
A number of risk factors for the development of chronic postsurgical pain have been
identified A systematic review of psychosocial factors identified depression, psychological
vulnerability, stress and late return to work as having a correlation to chronic postsurgical pain.
Very young age may be a protective factor as hernia repair in children under 3 months age did
not lead to chronic pain in adulthood.
Risk factors for chronic postsurgical pain.
1. Preoperative factors:
 Pain, moderate to severe, lasting more than 1 month
 Repeat surgery
 Psychological vulnerability (e.g. catastrophising)
 Preoperative anxiety
 Female gender
 Younger age (adults)
 Workers’ compensation
 Genetic predisposition
 Inefficient diffuse noxious inhibitory control (DNIC)
2. Intraoperative factors:
 Surgical approach with risk of nerve damage
3. Postoperative factors:
 Pain (acute, moderate to severe)
 Radiation therapy to area
 Neurotoxic chemotherapy
 Depression
 Psychological vulnerability
 Neuroticism
 Anxiety
The pathophysiological processes that occur after tissue or nerve injury mean that acute
pain may become persistent. Such processes include inflammation at the site of tissue damage
with a barrage of afferent nociceptor activity that produces changes in the peripheral nerves,
spinal cord, higher central pain pathways and the sympathetic nervous system.
After limb amputation, reorganisation or remapping of the somatosensory cortex and
other cortical structures may be a contributory mechanism in the development of phantom limb
pain. There is preclinical and clinical evidence of a genetic predisposition for chronic pain,
although one study found that an inherited component did not feature in the development of
phantom pain in members of the same family who all had a limb amputation.
Descending pathways of pain control may be another relevant factor as patients with
efficient diffuse noxious inhibitory control (DNIC) had a reduced risk of developing chronic
postsurgical pain.
Acute pain and the injury response.
Acute pain is one of the activators of the complex neurohumoral and immune response
to injury and both peripheral and central injury responses have a major influence on acute pain
mechanisms. Thus, acute pain and injury of various types are inevitably interrelated and if
severe and prolonged, the injury response becomes counterproductive and can have adverse
effects on outcome.
Although published data relate to the combination of surgery or trauma and the
associated acute pain, some data have been obtained with experimental pain in the absence of
injury.
Electrical stimulation of the abdominal wall results in a painful experience (visual
analogue scale [VAS] 8/10) and an associated hormonal/metabolic response, which includes
increased cortisol, catecholamines and glucagon, and a decrease in insulin sensitivity.
Adverse physiological effects
Clinically significant injury responses can be broadly classified as inflammation,
hyperalgesia, hyperglycaemia, protein catabolism, increased free fatty acid levels (lipolysis)
and changes in water and electrolyte flux (Liu & Wu, 2008; Carli & Schricker, 2009) (Figure
1.3). In addition, there are cardiovascular effects of increased sympathetic activity and diverse
effects on respiration, coagulation and immune function (Liu & Wu, 2008).
Hyperglycaemia
Hyperglycaemia is broadly proportional to the extent of the injury response. Injury
response mediators stimulate insulin-independent membrane glucose transporters glut-1, 2 and
3, which are located diversely in brain, vascular endothelium, liver and some blood cells.
Circulating glucose enters cells that do not require insulin for uptake, resulting in
cellular glucose overload and diverse toxic effects. Excess intracellular glucose nonenzymatically glycosylates proteins such as immunoglobulins, rendering them dysfunctional.
Alternatively, excess glucose enters glycolysis and oxidative phosphorylation pathways,
leading to excess superoxide molecules that bind to nitric oxide (NO), with formation of
peroxynitrate, ultimately resulting in mitochondrial dysfunction and death of cells served by
glut-1, 2 and 3. Myocardium and skeletal muscle are protected from this toxicity because these
two tissues are served by glut-4, the expression of which is inhibited by injury response
mediators (Figure 1.3) (Carli & Schricker, 2009).
Even modest increases in blood glucose can be associated with poor outcome
particularly in metabolically challenged patients such as people with diabetes (Lugli et al, 2008
Level II). Fasting glucose levels over 7 mmol/L or random levels of greater than 11.1 mmol/L
were associated with increased inhospital mortality, a longer length of stay and higher risk of
infection in intensive care patients (Van den Berghe, 2004). Tight glycaemic control has been
associated with improved outcomes following coronary artery bypass graft (CABG) in patients
with diabetes (Lazar et al, 2004 Level II), but the risks and benefits of tight glycaemic control
in intensive care patients (Wiener et al, 2008 Level I) continues to be debated (Fahy et al, 2009
Level IV).
Lipotoxicity
Free fatty acid (FFA) levels are increased due to several factors associated with the
injury response and its treatment and can have detrimental effects on cardiac function. High
levels of FFA can depress myocardial contractility (Korvald et al, 2000), increase myocardial
oxygen consumption (without increased work) (Oliver & Opie, 1994; Liu et al, 2002), and
impair calcium homeostasis and increase free radical production leading to electrical instability
and ventricular arrhythmias (Oliver & Opie, 1994).
Protein catabolism
The injury response is associated with an accelerated protein breakdown and amino acid
oxidation, in the face of insufficient increase in protein synthesis. Following abdominal surgery,
amino acid oxidation and release from muscle increased by 90% and 30% respectively, while
whole body protein synthesis increased only 10% (Harrison et al, 1989 Level IV). After
cholecystectomy 50 g of nitrogen may be lost (1 g nitrogen = 30 g lean tissue) which is
equivalent to 1500 g of lean tissue. Importantly, the length of time for return of normal physical
function after hospital discharge has been related to the total loss of lean tissue during hospital
stay (Chandra, 1983).
Protein represents both structural and functional body components, thus loss of lean
tissue may lead to delayed wound healing (Windsor & Hill, 1988 Level III-3), reduced immune
function (Chandra, 1983) and diminished muscle strength (Watters et al, 1993 Level III-3) —
all of which may contribute to prolonged recovery and increased morbidity (Watters et al, 1993;
Christensen et al, 1982).
An overall reduced ability to carry out activities of daily living (ADLs) results from
muscle fatigue and muscle weakness. Impaired nutritional intake, inflammatory–metabolic
responses, immobilisation, and a subjective feeling of fatigue may all contribute to muscle
weakness (Christensen et al, 1990). Such effects are broadly proportional to the extent of injury
but there are major variations across populations, with durations also varying up to 3 to 4 weeks.
Pain from injury sites can activate sympathetic efferent nerves and increase heart rate,
inotropy, and blood pressure. As sympathetic activation increases myocardial oxygen demand
and reduces myocardial oxygen supply, the risk of cardiac ischaemia, particularly in patients
with pre-existing cardiac disease, is increased. Enhanced sympathetic activity can also reduce
gastrointestinal (GI) motility and contribute to ileus. Severe pain after upper abdominal and
thoracic surgery contributes to an inability to cough and a reduction in functional residual
capacity, resulting in atelectasis and ventilation-perfusion abnormalities, hypoxaemia and an
increased incidence of pulmonary complications. The injury response also contributes to a
suppression of cellular and humoral immune function and a hypercoagulable state following
surgery, both of which can contribute to postoperative complications. Patients at greatest risk
of adverse outcomes from unrelieved acute pain include very young or elderly patients, those
with concurrent medical illnesses and those undergoing major surgery (Liu & Wu, 2008).
Intensive (critical) care medicine
Intensive care medicine or critical care medicine is a branch of medicine concerned
with the diagnosis and management of life-threatening conditions requiring sophisticated organ
support and invasive monitoring.
Patients
requiring
(hypertension/hypotension),
intensive
care
may
airway
require
or respiratory
support
for
instability
compromise (such
as ventilator support), acute renal failure, potentially lethal cardiac arrhythmias, or the
cumulative effects of multiple organ failure, more commonly referred to now as multiple organ
dysfunction syndrome. They may also be admitted for intensive/invasive monitoring, such as
the crucial hours after major surgery when deemed too unstable to transfer to a less intensively
monitored unit. Intensive care is usually only offered to those whose condition is potentially
reversible and who have a good chance of surviving with intensive care support. A prime
requisite for admission to an intensive care unit (ICU) is that the underlying condition can be
overcome. It is the most expensive, technologically advanced and resource-intensive area of
medical care.
The history of intensive care
There are several key figures and events commonly associated with the origin of critical
care medicine and development of ICUs, although many other unrecognized individuals have
certainly contributed to the development of this field.
During the Crimean War in the 1850s, Florence Nightingale demanded that the most
seriously ill patients were placed in beds near to the nursing station so that they could be
watched more closely, creating an early focus on the importance of a separate geographical area
for critically ill patients. In 1923, Dr.Walter E Dandy opened a special three-bed unit for the
more critically ill postoperative neurosurgical patients at the Johns Hopkins Hospital in
Baltimore, MD, USA, using specially trained nurses to help monitor and manage them. In 1930,
Dr. Martin Kirschner designed and built a combined postoperative recovery/intensive care ward
in the surgical unit at the University of Tubingen, Germany. Other surgical units followed these
examples, such that by 1960 almost all hospitals had a recovery unit attached to their operating
rooms. During the Second World War, specialized shock units were used to provide efficient
resuscitation for the large numbers of severely injured soldiers.
The polio epidemic in Copenhagen resulted in 316 patients developing respiratory
muscle paralysis and/or bulbar palsy, with subsequent respiratory failure and pooling of
secretions. The Blegham Hospital, the hospital in Copenhagen for communicable diseases, had
only one tank respirator and six cuirass respirators at the time. This was completely inadequate
to support the hundreds of polio patients with respiratory failure and bulbar palsy. The mortality
rate from polio with respiratory failure and bulbar involvement was historically 85–90% and,
as the epidemic progressed, the situation looked desperate.
Professor Lassen, chief physician at the Blegdam Hospital, had a strong desire to
provide treatment for all polio victims, despite insufficient respirators, and therefore consulted
with Dr. Bjorn Ibsen, a Copenhagen anaesthetist. Professor Lassen hoped that positive pressure
ventilation, as used in modern anaesthesia at that time, might be a solution.
Two days later, a 12-year-old girl with polio and resultant respiratory failure and bulbar
palsy had a tracheostomy formed just below the larynx: a rubber cuffed tracheostomy tube was
inserted and positive pressure ventilation successfully delivered manually with a rubber bag.
Tracheostomies had been performed in Copenhagen for 4 years before this, but with little
beneficial effect on outcome. As a result of this success, it became possible for the medical
team in Copenhagen to treat potentially every patient admitted with polio. At the height of the
epidemic, over 300 such patients were admitted per week, 30–50 per day, with approximately
10% either ‘suffocating or drowning in their own secretions.’ At times, there were over 70
patients in the hospital requiring respiratory support. Teams of medical students were drafted
in and paid £1.50 per shift: 250 medical students came in daily and worked shifts with 35–40
doctors. By using such a strategy, mortality from polio in Copenhagen decreased from over
80% to approximately 40%.
Dr. Ibsen had the idea of caring for all such patients in a dedicated ward, where each
patient could have their own nurse. Thus, in December 1953, the specialty of intensive care was
born. Dr. Henning Sund Kristensen took over the running of this Copenhagen intensive care
unit (ICU) following the epidemic; many patients did not regain respiratory function and
required long-term ventilation. Adjusting such ventilation, using blood gas analysis, was made
possible by the invention of the first pH, pCO2 and pO2 electrodes by Astrup, SiggardAnderson and Severinghaus. That the technology of pH monitoring was developed by the
Danish brewing industry and, in particular, by the Carlsberg factory in Copenhagen, greatly
helped Dr. Kristensen and his team.
This, together with regular involvement of physiotherapists, improved survival rates
further for patients requiring long-term ventilation. It rapidly became clear that teamwork was
a vital component of high quality intensive care.
Max Harry Weil is considered widely as the ‘father of modern intensive care’ – he
established a four-bed ‘shock ward’ at Los Angeles County/University of Southern California
Medical Center in the USA during the early 1960s.
During the 1960s and 1970s, ICUs were established in the UK. This was aided by rapid
expansion in consultant anaesthetists during the late 1950s, together with an increase in junior
anaesthetists who could staff such units around the clock. In the UK, the first full-time intensive
care clinician was Professor Ron Bradley, who ran the ICU at St Thomas’ Hospital, London.
This ICU, known as Mead Ward, had initially been set up by Dr. Geoffrey Spencer in 1966.
Professor Bradley worked there with Dr. Margaret Branthwaite, who herself went on to
lead the ICU at the Royal Brompton Hospital, and together they developed the first pulmonary
artery catheter.
The first microprocessorcontrolled ventilator was developed in 1971 and this, along
with the development of a multitude of new equipment and drugs, stimulated a rapid growth of
intensive care medicine.
Many of the initial critical care units were staffed by physicians whose primary
specialties were in anesthesiology or internal medicine. Often hospitals had separate surgical
and medical ICUs, and some, particularly in the USA, also developed specialty respiratory,
cardiac, and neurosurgical ICUs. The majority of units were open, with patients managed by
their primary admitting physician, so that different patients on a single ICU would be managed
by different physicians. Later, it was realized that many ICU patients had similar problems,
regardless of the reason for their critical illness, and that closed units, in which patients were
managed by a team of specially qualified intensive care physicians and nurses, provided patients
with better care and were associated with improved outcomes. The important role of the
intensivist in maximizing patient outcomes was also recognized, and specialist-training
programs began to develop, as intensive care medicine became a specialty in its own right.
Critical Illness
Critical illness is the impairment of vital organ function or the presence of instability,
or the risk of serious and potentially preventable complications.
Intensive care is a specialty that deals in uncertainty. Where the patient is certain to
survive the current illness there is no requirement for intensive care. Where the patient is certain
to die, palliative care outside the intensive care unit offers a better quality of death. Between
these two groups lies a varying degree of uncertainty and it is the function of the intensivist to
attempt to quantify both the likely prognosis and the likely impact of intensive care on that
prognosis.
Critically ill patients may be encountered in all areas of the hospital, from the Accident
and Emergency department to medical or surgical wards, operating theatres, recovery wards or
critical care units. Patients may be referred by other doctors, ward nurses, physiotherapists or
critical care outreach teams. Some may be acutely unwell to the point of requiring immediate
resuscitation, whereas others may be relatively stable and require assessment and the
formulation of a management plan to ensure continued progress towards full recovery. In either
case, the aim is to use a systematic approach to assessment to ensure that all immediately lifethreatening problems are recognized and the correct treatment is started immediately. Critically
ill patients often have multiple problems, and the use of a systematic approach reduces the risk
of missed diagnoses and provides a framework for treatment when working under stressful
conditions. You are interested in all the patient’s problems and their responses to the treatments
instigated. Documentation is vital, as shift working and frequent handovers provide many
opportunities for failures in communication. Each entry in the notes should be dated and timed,
and the person making the entry should sign it legibly.
Sources
1. John F. Butterworth IV, David C. Mackey, John D. Wasnick - Morgan &
Mikhail’s Clinical Anesthesiology. 5th Edition - Copyright © 2013, 2006,
2002 by McGraw-Hill Education, LLC.
2. Ronald d. Miller - Miller’s Anesthesia. Eighth edition - Copyright © 2015 by
Saunders, an imprint of Elsevier Inc.
3. Agamemnon Despopoulos, Stefan Silbernagl - Color Atlas of Physiology © 2003 Thieme
4. Macintyre PE, Schug SA, Scott DA, Visser EJ, Walker SM; APM:SE Working
Group of the Australian and New Zealand College of Anaesthetists and Faculty
of Pain Medicine (2010) - Acute Pain Management: Scientific Evidence(3rd
edition) - ANZCA & FPM, Melbourne.
5. Adam Brooks, Keith Girling, Bernard Riley & Brian Rowlands - Critical Care
for Postgraduate Trainees - © 2005 Edward Arnold (Publishers) Ltd.
6. Fiona E Kelly, Kevin Fong, Nicholas Hirsch and Jerry P Nolan - Intensive
care medicine is 60 years old: the history and future of the intensive care unit Clinical Medicine 2014 Vol 14, No 4: 376–9.
7. Jean-Louis Vincent. - Critical care – where have we been and where are we
going? Review. - Critical Care2013, 17(Suppl 1):S2.