Advanced therapy in thoracic surgery - part 1 pot

1
CHAPTER 1
POSTOPERATIVE
A
NALGESIA FOR
THORACOTOMY
PATIENTS:A
C
URRENT REVIEW
PETER H. NORMAN,
MD, FRCPC
M. DENISE DALEY, MD, FRCPC
ALICIA KOWALSKI, MD
It is natural to want to relieve pain and suffering. None are
more aware of this than those professionals who have
devoted their lives to the provision of anesthesia, yet we
have often been prevented from alleviating pain by not
understanding its pathogenesis or by a lack of appropriate
tools to deal with it. Intraoperative pain is now only of
historic concern. It is our fervent hope that postoperative
pain will follow intraoperative pain into the history books.
Not so long ago, certainly within the professional
experience of some of us, a minimalist approach was
taken to the management of pain after thoracic surgery.
Anesthesiology residents and faculty alike were admon-
ished to keep total opioid dosage low so the patient
would “want to breathe” after surgery. During this era,
the classic thoracotomy patient would be nearly apneic
from pain in the postanesthesia care unit. Hypoxic and
hypercarbic, diaphoretic and hypertensive, patients

would gradually improve to the point at which they
could actually breathe and complain of pain only after
large doses of opioids. Frequent arterial blood gas analy-
ses often demonstrated the unusual observation that the
administration of opioids led to a decrease in carbon
dioxide tension and an increase in oxygen tension in this
setting.
In 1973 Gibbons and colleagues suggested that
thoracic epidural blockade was the treatment of choice
for relief of pain after a chest injury.
1
The major limitation
was sympathetic blockade causing hypotension. To
prevent this complication, they advocated intercostal
blockade for fractures at or above the fifth rib. The
modern era of pain management after thoracic surgery
began with the introduction of epidural narcotic tech-
niques for post-thoracotomy pain.
2,3
Soon continuous
infusions were advocated,
4
and the effect of better postop-
erative analgesia on pulmonary function was investigated.
5
This led to an increased ability to control post-thoraco-
tomy pain and also stimulated the overall interest in find-
ing other useful modalities for post-thoracotomy pain
relief. Older or abandoned techniques were investigated
with renewed interest and used singly or in combinations.

For at least the past 10 years, the immediate postopera-
tive pain of most thoracotomy patients has been well
handled. There are occasional patients whose pain is diffi-
cult to manage because of coexisting disease processes
that contraindicate epidural analgesia, anatomic factors,
and/or pre-existing chronic pain, but currently there are
techniques to help even these patients. As an uninten-
tional consequence of relieving the severe, acute incisional
pain of surgery, we may have unmasked other sources of
equally troubling pain such as referred pain and sympa-
thetically mediated pain. Much research is focused on
treating these “new” modalities. This unbundling of post-
operative pain has been termed disaggregation.
6
Another
area of increasing interest is the pathogenesis of chronic
postoperative pain. Whether we can affect or even prevent
this unhappy outcome remains to be seen.
Post-Thoracotomy Pain
Acute Pain
Pain in the first few weeks after a thoracotomy arises
from a variety of different mechanisms. The best charac-
terized mechanism is somatic pain, which is localized to
the area around the incision and chest tube insertion
sites. It is produced by direct injury to the skin and
underlying subcutaneous tissues, fasciae, ligaments,
muscles, and ribs. Damaged tissue releases a variety of
algesic substances, including substance P, prostaglandins,
and serotonin, which stimulate the peripheral nerve
endings.

7
Intercostal nerves from the area conduct these
pain impulses to the spinal cord and thence to the brain
via the spinothalamic and spinoreticular tracts. Somatic
pain is responsible for the sharp, severe postoperative
pain that is exacerbated by movement and is believed to
be primarily mediated by type A delta nerve fibers.
8
Visceral, or nonincisional, pain is responsible for the dull,
nauseating, diffuse thoracic wall “aching” sensation expe-
rienced after a thoracotomy. It is mediated by type C
nerve fibers, which travel with the autonomic nerves.
Both the vagus and sympathetic nerves probably
contribute to this type of pain.
8
Another form of pain frequently reported in post-
thoracotomy patients is localized to the ipsilateral shoul-
der region. Although it is often moderate to severe in
intensity and present in 75 to 85% of patients who have
had a thoracotomy,
9–11
this type of pain has received little
attention in the literature. It has been attributed to a vari-
ety of factors, including distraction of the posterior
thoracic ligaments or shoulder joint due to patient posi-
tioning; stretching of the brachial plexus, also as a conse-
quence of intraoperative positioning; transection of a
major bronchus; and referred pain from the phrenic
nerve.
9

As the latter provides sensory innervation to the
pericardium and pleura, mechanical trauma to these
regions during surgery and irritation of the pleural
surfaces by chest tubes postoperatively can result in
phrenic nerve stimulation, with referral to the shoulder.
Scawn and colleagues have demonstrated a reduction in
the incidence of post-thoracotomy shoulder pain from
85 to 33% with the injection of 10 mL of 1% lidocaine
into the periphrenic fat at the level of the diaphragm.
9
In
this same study, there was a small but insignificant
increase in arterial partial pressure of carbon dioxide
(PaCO
2
) in the first 2 postoperative hours in patients
receiving a phrenic nerve block, thereby suggesting the
possibility of diaphragmatic paresis. The technique may
thus be inappropriate in patients with severely compro-
mised respiratory function. The lack of efficacy of supras-
capular nerve blockade in relieving post-thoracotomy
shoulder pain demonstrated by Tan and colleagues
provides further evidence that distraction of the shoulder
joint does not play a major role in the generation of this
type of pain.
11
The extent to which the surgical approach contributes
to the severity of post-thoracotomy pain is unclear.
Anteroaxillary and anterior limited thoracotomies are
less painful procedures than are posterolateral thoraco-

tomies.
12,13
When muscle-sparing thoracotomies have
been compared with traditional posterolateral thoraco-
tomies (involving a transection of the latissimus dorsi
muscle), some studies have demonstrated less postopera-
tive pain with the former,
14
whereas others have revealed
no difference between the two techniques.
15,16
It is well
appreciated that thoracoscopic procedures result in less
pain than do traditional thoracotomies in the early post-
operative period, but Nomori and colleagues have
demonstrated this benefit to be lost by 14 days after
surgery.
17
The lack of a consistent and/or persistent
decrease in post-thoracotomy pain with less extensive
surgical incisions provides further evidence that the
actual surgical incision is just one of several mechanisms
responsible for post-thoracotomy pain.
Chronic Pain
Post-thoracotomy pain syndrome is defined as “pain that
recurs or persists along a thoracotomy scar at least two
months following the surgical procedure.”
18
There is
“usually tenderness, sensory loss, and absence of sweating

along the thoracotomy scar.”
18
The incidence is variable,
ranging from 2 to 67%.
19
Dajczman and colleagues stud-
ied 59 of 206 sequential patients who had undergone a
unilateral thoracotomy; all procedures were performed
by one surgeon over a period of 5 years.
20
Thirty to 73%
of the patients available for evaluation were experiencing
pain (Table 1-1), which most rated at a visual analog
scale (VAS) of two to four (Figure 1-1).
These results were confirmed by Perttunen and
colleagues,
21
who found an incidence of post-thoracotomy
pain of 80% at 3 months, 75% at 6 months, and 61% after
1 year. More than 50% of these patients had limitations of
their activities of daily living imposed by the chronic pain.
There was also a 3 to 5% incidence of severe pain.
Intriguingly, early consumption of larger quantities of
nonsteroidal anti-inflammatory drugs (NSAIDs) was
associated with an increased incidence of long-term prob-
lems. As suggested by Perttunen and colleagues, this could
2
/ Advanced Therapy in Thoracic Surgery
TABLE 1-1. Frequency of Post-Thoracotomy Pain at Various
Intervals following Surgery

Time since No. of Total No. of Percentage of
Thoracotomy Patients Patients Evaluable
(yr) with Pain Evaluable Patients with Pain
≤ 1* 6 12 50
1–2 11 15 73
2–3 7 13 54
3–4 3 6 50
4–5 3 10 30
Total 30 56 —
Adapted from Dajczman E et al.
20
*At least 2 months post-thoracotomy.
influence of the variable permeability of the skin is
decreased. Nevertheless, there is a significant variability
in the systemic drug levels and analgesic effects. As well,
there is an accumulation of fentanyl under the patch,
providing appreciable serum levels for up to 24 hours
after patch removal.
25
Because of the possibility of apnea
owing to high serum levels in opioid-naive patients,
26
transdermal fentanyl is not currently recommended for
acute postoperative pain. One approach that may permit
its use in the future is to combine a low-dose transder-
mal fentanyl patch with an NSAID.
27
Another possibility
is to add electrical control to enhance the rate of
fentanyl absorption across the skin. This iontophoretic

route of administration is currently experimental but
may offer the possibility of patient-controlled transder-
mal fentanyl in the future.
28
Fentanyl can be delivered across the mucous mem-
branes of the mouth. Oral transmucosal fentanyl citrate
(OTFC, Actiq Abbott Laboratories, Abbott Park, IL) has
been used for breakthrough chronic cancer pain as well
as acute postoperative pain.
29,30
It would be a good choice
if the intravenous route was temporarily unavailable for
acute postoperative analgesia. Fentanyl, sufentanil, butor-
phanol, heroin, oxycodone, and meperidine have been
administered through the nasal mucosa, and morphine,
codeine, fentanyl, heroin, and hydromorphone have been
administered by inhalation.
31
Ketamine
Ketamine is a phencyclidine derivative occasionally
employed as an anesthetic induction agent. Uniquely
among induction agents, it produces what has been
termed dissociative anesthesia.The analgesia does outlast
the anesthetic effects and occurs at lower serum levels, so it
can be useful in a decreased dosage as a postoperative anal-
gesic. Ketamine may be given by intravenous, subcuta-
neous, epidural (see below), oral, and transdermal routes.
32
Ketamine produces analgesia by multiple mecha-
nisms, including inhibition of N-methyl-

D-aspartate
(NMDA) receptors, depression of the thalamus while
activating the limbic system, and direct spinal effects.
NMDA receptors are involved in hyperalgesia or neuro-
pathic pain, which suggests that ketamine would be a
good choice for analgesia for these patients.
33
A recent
study in rats demonstrated that ketamine had different
mechanisms of action depending on the presence or
absence of inflammation. Antinociceptive effects were
created by activation of the monoaminergic descending
inhibitory system, whereas in a hyperalgesic state
induced by inflammation, inhibition of NMDA activa-
tion was the likely mechanism of the antihyperalgesia.
34
Ketamine is a useful agent when narcotics and neurax-
ial agents are contraindicated or working poorly. Chow
and colleagues described a patient undergoing multiple
thoracotomies whose pain management was complicated
by infection and the development of neuropathic pain.
35
Low-dose ketamine was used to decrease the need for
narcotics after his fourth thoracotomy, with good results.
It has also been suggested that ketamine should have pre-
emptive effects because of its action at NMDA receptors.
A landmark study in cholecystectomy patients found less
postoperative pain, as measured by VAS scores and
morphine consumption, in the group given low-dose
intraoperative ketamine.

36
An alternative explanation for
the observed improved analgesia is that ketamine
prevents the development of acute tolerance to opioids.
37
Nonsteroidal Anti-inflammatory Drugs
NSAIDs have proven to be a useful component of postop-
erative pain relief. Many oral NSAIDs have been used
including ibuprofen, naproxen, and ketoprofen. The only
currently available parenteral NSAID is ketorolac
tromethamine (Toradol, Roche Laboratories, Nutley, NJ).
The addition of ketorolac to a patient-controlled epidural
analgesia (PCEA) regimen employing hydromorphone
alone significantly decreased the incidence of noninci-
sional pain.
38
Ketorolac is also employed in the treatment
of breakthrough pain with otherwise satisfactory epidural
analgesia. Ketorolac has several other features that make it
useful in postoperative thoracotomy patients. These
include its moderate potency (equivalent to morphine in
some studies
39
); ease of administration by the intravenous
and intramuscular routes; lack of acute tolerance, which
may occur with even a single dose of opioid
40
;and lack of
significant cardiorespiratory or central nervous system
side effects.

NSAIDs inhibit cyclooxygenase (COX), the enzyme
that regulates the conversion of arachidonic acid to
prostaglandins. There are two isoenzyme forms of COX.
COX-1 is always present (constitutive). It modulates
platelet activity and gastrointestinal cytoprotection and
is involved in maintaining renal function in hypo-
volemic states. COX-2 is thought to be inducible by
inflammatory stimuli and is involved with inflamma-
tion and pain. Conventional NSAIDs, such as
indomethacin and ketorolac, which inhibit both COX-1
and COX-2, have been implicated in postoperative
bleeding and gastric ulceration. They also may predis-
pose to renal failure if the patient is concomitantly hypo-
volemic or even just relatively “dry,” as post-thoracotomy
patients often are. Specific inhibitors of COX-2 were
developed in an attempt to prevent the side effects of
conventional NSAIDs while maintaining the benefits.
Current selective COX-2 inhibitors still exhibit some
predilection for causing renal failure and gastric ulcera-
tion but debatably to a lesser extent than conventional,
4
/ Advanced Therapy in Thoracic Surgery
nonselective NSAIDs.
41–43
The selective COX-2 inhibitors
do not affect platelet function and have not been shown
to increase postoperative blood loss. As a result they can
be used perioperatively with relative impunity from
hemorrhage. As of this writing, there is no parenteral
COX-2 inhibitor available, although one is in US Food

and Drug Administration trials.
Regional Analgesia Techniques
In the past two decades, regional analgesia techniques
have become the primary means of providing optimal
pain relief after a thoracotomy. Although the type C
nerve fibers responsible for autonomically mediated
visceral pain have abundant opioid receptors, type A
delta nerve fibers, which mediate somatic incisional pain,
contain a paucity of these receptors.
44
Accordingly,
systemically administered opioids have limited efficacy in
controlling acute post-thoracotomy pain, especially that
associated with activity. In contrast, local anesthetics,
which are an integral component of most regional anal-
gesia techniques, are very effective in blocking conduc-
tion in both type A delta and C nerve fibers.
The main blocks used for thoracotomy patients are
intercostal nerve blocks, interpleural analgesia, thoracic
paravertebral nerve blocks (TPVBs), and epidural analge-
sia. Characteristics of these blocks are summarized in
Table 1-5. Each may be performed as a single injection
through a needle, but owing to the prolonged period of
substantial pain experienced after a thoracotomy, catheter
techniques are used more commonly (with the possible
exception of intercostal nerve blocks, as discussed below).
A standard 18- or 20-gauge epidural catheter may be
placed through a hollow needle into the appropriate area
for each block, and analgesic medication is administered
through this catheter either as intermittent boluses or a

continuous infusion. The former has the disadvantage of
supplying fluctuating levels of analgesic in the area of the
block and thus providing varying degrees of pain relief for
the patient. The latter has the disadvantages of providing
more analgesic than is necessary during periods of less
painful stimulation, and promoting the accumulation of
analgesic medication over time,
45
unless appropriate
decrements in infusion rates are made. With the goal of
minimizing the disadvantages of both methods, low
continuous (“basal”) infusion rates have been combined
with intermittent boluses administered on an as-needed
basis (which is usually patient controlled).
Regional analgesia use in thoracotomies has several
unique features compared with use in other types of
surgery. First, all techniques except epidurals may be
performed under direct vision from an internal approach
before the chest is closed. This not only increases the ease
with which the blocks are performed, but may also improve
their success rate when compared with blocks performed
via percutaneous techniques (although no studies have
directly addressed this issue). As well, the risk of developing
a pneumothorax, which is a potentially limiting factor for
intercostal nerve blocks and interpleural analgesia, is irrele-
vant because the thoracic cavity is open intraoperatively
and chest tubes are used postoperatively. Finally, hypov-
olemia is a relatively common occurrence in patients after
thoracotomy because extensive fluid administration has
been implicated in the development of postoperative

pulmonary edema, especially after pneumonectomy.
46
Therefore, regional analgesia techniques producing exten-
sive blockade of the sympathetic nervous system and
peripheral vasodilation may be accompanied by a signifi-
cant risk of hypotension, and are often avoided.
Postoperative Analgesia for Thoracotomy Patients: A Current Review
/
5
TABLE 1-5. Summary of Factors Related to Regional Analgesia Techniques*
Technique Ease of Analgesic Preservation Modification Hypotension Motor Blockade Urinary Retention Respiratory
Insertion Efficacy of Pulmonary of Stress Depression
Function Response
Intercostal
nerve blocks +++ + + ϪϪ Ϫ Ϫ Ϫ
Interpleural
analgesia ++++ ± ± ϪϪ Ϫ Ϫ Ϫ
Thoracic
paravertebral
block ++ + ++ + ϪϪϪϪ
Epidural
analgesia
†
++ + + ϪϪ ±++±
Ϫ = not a factor; ± = sometimes a factor; + to ++++ = degrees of being somewhat a factor to being an important factor.
*For post-thoracotomy pain.
†
With opioid/low-dose local anesthetic infusions.
Of the four types of regional analgesia discussed in
this chapter, epidural analgesia is the only technique for

which agents other than local anesthetics have been
successfully used. This is not surprising because the
intercostal nerve block, interpleural analgesia, and
paravertebral nerve block techniques depend primarily
on blocking impulse transmission within somatic nerves.
By contrast, blockade of pain pathways within the spinal
cord may be accomplished by other drugs, most
commonly opioids, delivered into the epidural space.
Although several local anesthetic agents are available,
bupivacaine has been the most popular choice for post-
thoracotomy blocks over the past couple of decades,
primarily because of its prolonged duration of action.
Concentrations of 0.25 to 0.5% are necessary to provide
adequate sensory blockade with most of the blocks
discussed below, although lower concentrations have been
used in the epidural space, when combined with opioids.
Since its release in 1996, ropivacaine has been used
increasingly for a variety of intraoperative and postopera-
tive situations, and although the current literature regard-
ing post-thoracotomy regional analgesia focuses on
bupivacaine, ropivacaine will probably play a major role
in clinical practice and the literature in the future. It is an
amide local anesthetic structurally similar to bupivacaine
that has the unique quality of being supplied as the pure
S-(Ϫ)-enantiomer. This contrasts with the other local
anesthetics, which exist as racemic mixtures of both the
R-(+)- and S-(Ϫ)-enantiomers. Consequently, ropiva-
caine produces less cardiovascular and central nervous
system toxicity,
47,48

similar analgesia, and a less intense and
shorter duration of motor blockade than does bupiva-
caine when administered into the epidural space.
49,50
Low concentrations of epinephrine
(1:100,000–1:400,000) are frequently added to the solu-
tion used for the regional analgesia techniques to decrease
the quantity of medication absorbed into the systemic
circulation. This should extend the duration and possibly
improve the degree of analgesia, and decrease the risk of
systemic toxicity from the drug. Lower peak plasma
concentrations have been convincingly demonstrated
when epinephrine has been added to the solutions used in
intercostal nerve blocks,
51
interpleural analgesia,
52
and
epidural analgesia,
53,54
but data regarding the duration and
quality of analgesia and systemic toxicity are more vari-
able. There is even evidence that the addition of epineph-
rine to epidural opioid solutions may increase the
incidence of some opioid-related side effects, especially
pruritus.
55–57
Epinephrine may also directly contribute to
the pain relief achieved with epidural analgesic techniques
by stimulation of ␣

2
-adrenergic receptors in the dorsal
horn of the spinal cord.
58
Ultralong-acting local anesthetics and opioids cur-
rently under development have been advocated as a
means of providing prolonged analgesia from a single
dose. However, their eventual role in the management of
acute post-thoracotomy pain is unclear because prolon-
gation of analgesic effects is accompanied by a prolonga-
tion of the duration of adverse events, which has
particular relevance in the case of life-threatening cardio-
vascular and respiratory depression.
Despite their apparent usefulness in post-thoracotomy
patients, regional analgesia techniques are not appropriate
for all individuals. Absolute contraindications for all types
of regional analgesia include patient refusal, an allergy to
the medication to be used, a lack of resuscitative equip-
ment, a lack of ability to use the resuscitative equipment,
and an infection or tumor at the site of injection. Relative
contraindications are often specific for the type of block
and are discussed below for the individual techniques.
Knowledge of the contraindications may be critical in
choosing the specific block for a particular patient.
Intercostal Nerve Block
definition and technique
Intercostal nerve block is a technique in which a local
anesthetic is injected into the immediate vicinity of the
intercostal nerve as it lies in the costal groove on the
internal surface of the rib. In this position, the intercostal

nerve traverses between the internal intercostal and inter-
costalis intimus muscles and is located just caudad to the
intercostal artery and vein. Local anesthetic is injected 7
to 8 cm from the posterior midline, proximal to the
origin of the lateral cutaneous branch in the midaxillary
line.
59
Because there is a considerable overlap of sensory
innervation of the thoracic dermatomes, it is necessary to
block at least one level above and below the desired
dermatomal level.
Intercostal nerve blocks are often performed by a
“single-shot” injection through a needle. There is limited
spread of local anesthetic from one intercostal space to
the next; therefore, separate injections at each level are
usually necessary. For posterolateral thoracotomy inci-
sions, intercostal nerve blocks are usually performed at
T3 to T7. Three to 5 mL of local anesthetic is adminis-
tered with each block; thus, a total of 20 to 25 mL of local
anesthetic is used. Analgesia persists for 5 to 12 hours
after a single injection,
60–63
and intercostal nerve blocks
may be repeated as necessary. A variety of catheter tech-
niques have also been described,
62,64,65
although most of
these studies involved the use of more than one catheter,
which creates a cumbersome situation.
6

/ Advanced Therapy in Thoracic Surgery
mechanism of action
Intercostal nerve blocks produce analgesia by direct
blockade of the intercostal nerves. There is usually mini-
mal or no spread of anesthetic proximally to the dorsal
rami of the intercostal nerves or the sympathetic chain.
efficacy
Intercostal nerve blocks are moderately effective for
post-thoracotomy pain. For example, Kolvenbach and
colleagues detected “adequate” analgesia in approxi-
mately 76% of their group of patients, as measured by
the lack of need for supplemental opioids.
62
When
compared with placebo or parenteral opioids, intercostal
nerve blocks have usually been shown to produce better
pain control with lower pain scores and/or fewer supple-
mental opioids.
64–68
Only two studies have compared intercostal nerve
blocks with other regional techniques for post-thoracotomy
pain. Asantila and colleagues compared intercostal nerve
blocks with epidural analgesia with either bupivacaine or
morphine, and found no significant differences between
treatments with respect to pain scores or supplemental
parenteral opioid requirements.
69
More recently, Perttunen
and colleagues randomized 45 patients to receive intercostal
nerve blocks (performed at T3–T7 via an internal approach

and administered as a single injection just prior to wound
closure), TPVBs, or continuous epidural analgesia with
bupivacaine.
70
In the first 4 hours after surgery, pain scores
during coughing were significantly lower in the intercostal
nerve block group than in the other two groups. No differ-
ences were noted in supplemental morphine consumption,
pain scores at rest, or pain scores with coughing after the
initial 4-hour period. However, the authors emphasize that
pain relief in all patients was only fair (VAS pain scores of
28–62/100 at rest and 62–91/100 with coughing), and opti-
mizing the management of these techniques may have
produced different results.
Analgesic efficacy may be limited in intercostal nerve
blocks owing to a lack of blockade of the dorsal rami,
which can result in persistent pain at the medial edge of
the incision, and muscles and ligaments in the surround-
ing area. Failure to block the sympathetic chain, vagus,
and phrenic nerves may further limit the ability of inter-
costal nerve blocks to provide optimal pain relief after
thoracotomy.
Intercostal nerve blocks also appear to be moderately
effective in improving pulmonary function. This is
suggested in several,
64,66,71,72
but not all,
65
studies by higher
values of forced expiratory volume in 1 second (FEV

1
),
forced vital capacity (FVC), and/or peak expiratory flow
rate (PEFR) in patients receiving these blocks compared
with values in patients receiving a placebo or parenteral
opioids. Compiling the results of several studies,
Richardson and colleagues demonstrated an overall 55%
preservation of spirometric function (vs preoperative
values) with intercostal nerve blocks by 48 hours post-
thoracotomy.
8
Despite the above observations, most stud-
ies have failed to demonstrate that intercostal nerve
blocks decrease the incidence of postoperative complica-
tions in post-thoracotomy patients. Furthermore,
although Deneuville and colleagues showed that inter-
costal nerve blocks were associated with fewer postopera-
tive respiratory complications than was as-needed
parenteral opioid, the incidence of complications with
intercostal nerve blocks was identical to that with “fixed-
schedule” intramuscular opioid injections.
65
advantages and disadvantages
The main advantage of intercostal nerve blocks is the ease
with which they can be performed.
61
They require little
training and no special equipment. The technique is quite
safe, and any significant complication usually occurs
within 30 minutes of performing the block. As such, no

special monitoring is necessary for patients with these
blocks beyond the immediate post-block time period.
The main disadvantages of intercostal nerve blocks are
the necessity of performing separate blocks at multiple
levels, and the relatively short duration of analgesia
achieved via the single-injection techniques.
adverse effects
The most common adverse effect associated with the use
of intercostal nerve blocks for thoracotomy is the devel-
opment of high systemic blood levels of local anesthetic.
This is a consequence of both the volume needed for
injections at multiple levels and the vascularity of the
area of injection. Peak blood levels of local anesthetic
occur at 5 to 20 minutes,
61,64,73
and they are higher than
with interpleural analgesia, TPVBs, and epidural analge-
sia.
70,74
Case reports of spinal anesthesia associated with
the use of intercostal nerve blocks have also been
reported.
75,76
This has been postulated to be due to retro-
grade intraneural spread of local anesthetic to the
subarachnoid space. Most cases have involved intercostal
nerve blocks performed by an internal approach during
thoracotomy, possibly because of the more medial injec-
tion of the local anesthetic in these circumstances.
contraindications

There are no absolute contraindications specific to inter-
costal nerve blocks. The main relative contraindication of
intercostal nerve blocks when used for post-thoracotomy
analgesia is in patients for whom the effects of high
Postoperative Analgesia for Thoracotomy Patients: A Current Review
/
7
systemic blood levels of local anesthetic may be particu-
larly detrimental, which includes patients with cardiac
conduction defects and seizure disorders.
Interpleural Analgesia
definition and technique
The term interpleural analgesia refers to a technique
whereby local anesthetic is placed into the interpleural
space, located between the visceral and parietal pleurae.
The term intrapleural analgesia is often used interchange-
ably with interpleural analgesia,but the former is
anatomically incorrect. For thoracotomy patients, a
multiorifice epidural catheter is usually inserted into the
interpleural space under direct vision by the surgeon
prior to chest closure, and a local anesthetic is adminis-
tered either as a continuous infusion or intermittent
bolus doses. Some authors emphasize suturing the inter-
nal tip of the catheter high in the interpleural space (in
the cranial portion of the thoracic cage) to prevent
dislodgment,
77
whereas others recommend placing the tip
at the level of the incision.
78

Ta ble 1-6 presents examples
of dosage regimens. None has been demonstrated to be
superior to the others.
mechanism of action
Interpleural analgesia produces pain relief primarily by
diffusion or bulk flow of local anesthetic through the
parietal pleura, into the subpleural space, and finally to
the intercostal nerves. The resultant effect is a multilevel
intercostal nerve block.
79
Interpleural analgesia tech-
niques may also block other nervous structures including
the vagus and phrenic nerves as they traverse through the
interpleural space,
77
pain receptors in the parietal pleura,
and the thoracic sympathetic chain, by diffusion of local
anesthetic into the paravertebral space. The clinical
importance of blockade at these secondary sites is
unclear and may contribute to the variable results in
studies examining the efficacy of interpleural analgesia.
efficacy
The efficacy of interpleural analgesia for post-thoracotomy
pain is controversial.
80
Compared with placebo or
parenteral opioids, interpleural analgesia has been shown
to improve analgesia in some studies,
81,82
and to have

minimal or no effect in others.
83–85
Interpleural analgesia
has also been demonstrated to produce a degree of anal-
gesia similar to TPVB and thoracic epidural analgesia
with bupivacaine in some studies,
78,86
but less than
thoracic epidural bupivacaine, lumbar epidural hydro-
morphone, and lumbar epidural morphine in others.
74,87,88
The lack of consistent efficacy for post-thoracotomy
pain has been primarily attributed to the loss of local
anesthetic by drainage through chest tubes. Ferrante and
colleagues documented a 30 to 40% loss of an injected
dose of bupivacaine over a 4-hour period through the
chest tubes.
89
For interpleural analgesia administered via
the bolus method, clamping the chest tubes for 15 to 30
minutes after each dose has been advocated to help
circumvent this problem,
77
although the safety and effi-
cacy of such a maneuver has been questioned.
8
Other factors that may contribute to the lack of anal-
gesic efficacy are dilution of local anesthetic with pleural
exudate, and uneven distribution of local anesthetic
throughout the pleural space. The latter may occur

because of inflammation of the pleura by the current
surgical procedure and/or the presence of fibrous tissue
from previous pleural disease or thoracotomy. As well,
the distribution of local anesthetic within the inter-
pleural space is gravity dependent.
90
The upright position
assumed by post-thoracotomy patients, because of its
beneficial effects on pulmonary function, encourages
pooling of the local anesthetic in the inferior thoracic
cage, thereby contributing to lesser analgesia at the more
cranial thoracic dermatomes. Finally, the dorsal rami of
the thoracic spinal nerves are not blocked by interpleural
techniques; thus, patients may experience pain in the
medial part of the incision and paravertebral surround-
ing muscles and ligaments.
64
The effects of interpleural analgesia on postoperative
pulmonary function are likewise unimpressive. Most
studies have failed to demonstrate an improvement in
FEV
1
,FVC,PEFR, arterial blood gas values, and/or
pulmonary complications compared with these effects
when placebo or parenteral opioids are used.
74,83,84
In
Richardson and colleagues’ review of spirometric function
with different analgesic techniques post-thoracotomy,
8

/ Advanced Therapy in Thoracic Surgery
TABLE 1-6. Examples of Dosing Regimens for
Interpleural Analgesia
Study Intraoperative Regimen Postoperative Regimen
Tartiere et al, — 10 mL 0.25% bupivacaine
1991
81
q8h
Richardson et al, 20 mL 0.25% bupivacaine at 0.5% bupivacaine
1995
78
chest closure 0.1 mL/kg/h infusion
Stromskag et al, — 20 mL 0.375%
1990
90
bupivacaine prn
Schneider et al, — 30 mL 0.5% bupivacaine
1993
84
q4h
Mann et al, 1992
82
—20mL 0.25% bupivacaine
q4h
Silomon et al, — 20 mL 0.5% bupivacaine
2000
83
q4h
Raffin et al, 1994
85

0.15 mL/kg 2% lidocaine with 0.05 mL/kg/h 2%
1:200,000 epinephrine after lidocaine with
chest closure 1:200,000 epinephrine
infusion
prn = according to circumstances.
an overall 35% preservation of function (vs the preoper-
ative values) was noted for interpleural analgesia by 48
hours postoperatively.
8
This was lower than for all the
other techniques examined, including intercostal nerve
blocks, thoracic paravertebral, and epidural analgesia. In
two randomized studies comparing interpleural analgesia
and TPVB, analgesia for the two techniques was equiva-
lent, but patients receiving interpleural analgesia demon-
strated significantly worse FVC and FEV
1
values.
78,91
This
observation led to the suggestion that interpleural anal-
gesia may cause direct impairment of diaphragmatic and
intercostal muscle function, either by diffusion of local
anesthetic into the diaphragm and/or intercostal muscles,
with direct inhibition of their contractile function,
91
or
by blockade of the phrenic nerve as it travels through the
mediastinum and/or at its terminal branches innervating
the diaphragm. No studies to date have confirmed the

validity of either theory.
92
advantages and disadvantages
The primary advantage of interpleural analgesia for post-
thoracotomy pain is the ease with which the technique
can be performed. It is also relatively safe, and no special
monitoring is necessary for patients receiving this form
of analgesia.
77
The main disadvantage of interpleural analgesia is the
lack of consistent beneficial effects on pain relief and
pulmonary function in the post-thoracotomy patient.
Possible explanations for this have been discussed above.
adverse effects
The main adverse effects of interpleural analgesia for post-
thoracotomy analgesia include toxicity owing to excessive
systemic absorption of local anesthetic, blockade of the
thoracic sympathetic chain, and stellate ganglion blockade
(with an ipsilateral Horner syndrome).
93
Systemic local
anesthetic toxicity is rare because plasma concentrations
usually remain below levels associated with significant
toxicity.
81,94,95
When administered as a bolus dose, peak
blood levels occur 5 to 30 minutes after injection.
Similarly, blockade of the thoracic sympathetic chain
rarely produces clinically significant hypotension and
bradycardia. This lack of hemodynamic effects has tradi-

tionally been attributed to the unilateral nature of the
sympathetic block, although Ramajoli and De Amici have
convincingly demonstrated bilateral sympathetic blockade
of the thorax and abdomen with unilateral interpleural
instillation of both 0.25 and 0.5% bupivacaine.
96
Thus,
hemodynamic stability is probably due to incomplete
blockade of the upper thoracic ganglion, resulting in little
or no effect on the cardiac sympathetic fibers and allowing
compensatory vasoconstriction of the upper extremities.
contraindications
There are no absolute contraindications specifically
related to the technique of interpleural analgesia. Relative
contraindications include conditions in which there is an
anticipated lack of efficacy, such as with pleural fibrosis,
previous surgical or chemical pleurodesis, and bron-
chopleural fistula or empyema; and patients for whom
the effects of high systemic blood levels of local anes-
thetic may be particularly detrimental (as discussed
above under “Intercostal Nerve Block”).
Thoracic Paravertebral Nerve Block
definition and technique
After its first performance in 1905 by Hugo Sellheim,
TPVB enjoyed an initial period of popularity, followed by
a dramatic decline in use in the middle of the twentieth
century.
97
In the past two decades, however, there has
been a resurgence of interest in the technique, particu-

larly in Europe.
TPVB is a technique whereby local anesthetic is
injected into the paravertebral space in the thoracic
region. It has also been referred to as extrapleural,
extrapleural paravertebral, and extrapleural intercostal
analgesia. As depicted in Figure 1-2, the paravertebral
space is a wedge-shaped region adjacent to the thoracic
vertebrae in the vicinity where the spinal nerves emerge
from the intervertebral foramina. Its boundaries are as
follows: posteriorly, the superior costotransverse liga-
ment; laterally, the posterior intercostal membrane; ante-
riorly, the parietal pleura; and medially, the posterolateral
aspect of the vertebrae, intervertebral disk, and interver-
tebral foramen. The origin of the psoas muscle forms the
inferior boundary of the paravertebral space; thus, spread
of local anesthetic below T12 is uncommon. The cranial
boundary of the paravertebral space has not been
Postoperative Analgesia for Thoracotomy Patients: A Current Review
/
9
Subserous
fascia
Sympathetic chain
Interpleural
space
Extrapleural
compartment
Subendothoracic
compartment
Intercostal

nerve
Posterior
primary rami
Superior costotransverse ligament
Right
lung
Left
lung
Azygos
vein
Esophagus
Thoracic duct
Descending aorta
Pleura
Visceral
Parietal
Endothoracic
fascia
FIGURE 1-2. Anatomy of the thoracic paravertebral space.
Reproduced with permission from Karmaker MK.
98
defined, and radiocontrast dye has been observed in the
cervical region after thoracic paravertebral injection.
98
The thoracic paravertebral space is in continuity with the
epidural space medially via the intervertebral foramen,
the intercostal space laterally, and the contralateral
paravertebral space via the prevertebral and epidural
spaces.
98

The paravertebral space is traversed by the inter-
costal nerves, their dorsal rami, the rami communicantes,
and the sympathetic chain.
As with other techniques, TPVB may be performed by
direct injection through a needle or an indwelling
catheter, both of which may be introduced either percuta-
neously or under direct vision before the chest is closed.
Sabanathan and colleagues have described a technique for
use during thoracotomy that involves reflecting the pari-
etal pleura from the posterior wound margin onto the
vertebral bodies to form an extrapleural pocket.
99
A percu-
taneously placed catheter is then placed into this pocket
and positioned under direct vision so that it lies against
the angles of the exposed ribs. Richardson and Lonnqvist
have employed combined techniques whereby a percuta-
neously placed catheter is inserted before the surgery
begins and a bolus dose of local anesthetic is administered
to provide intraoperative anesthesia.
97
Before chest
closure, methylene blue is injected through the catheter,
and if the spread of dye is not optimal, the catheter is
reinserted by the surgeon. Video-assisted placement of a
paravertebral catheter during thoracoscopy has also been
reported.
100
Ta ble 1-7 presents various dosage regimens for TPVB.
Continuous infusion of local anesthetic through a

paravertebral catheter provides better pain control than
do intermittent bolus injections.
101
mechanism of action
TPVB produces analgesia by blockade not only of the
intercostal nerves but also of their dorsal rami and the
sympathetic chain. Owing to the continuous nature of
the paravertebral space, local anesthetic applied at one
level spreads to multiple contiguous dermatomes. Using
15 mL 0.5% bupivacaine, Cheema and colleagues
demonstrated a somatic sensory block extending for a
mean of 5 (range 1 to 9) dermatomes, and a sympathetic
block over an average of 8 (range 6 to 10) dermatomes.
102
However, the extent of spread is variable, as is evidenced
by these large ranges; thus, it may be necessary to
perform injections at more than one site to reliably anes-
thetize more than three to four segments. A small
amount of local anesthetic may also exit the interverte-
bral foramina to enter the epidural space, but whether
this contributes significantly to the analgesic effects of
TPVB is questionable.
98
efficacy
The efficacy of TPVB for post-thoracotomy pain control
has been well established. Lower pain score and opioid-
sparing effects have been noted in several studies compar-
ing TPVB with placebo and parenteral opioids,
103–106
although supplemental opioids were often still necessary.

In comparison to epidural blockade with local anesthetics
and/or opioids, TPVB has frequently demonstrated simi-
lar or better pain relief, accompanied by less nausea,
vomiting, hypotension, and urinary retention.
107–110
Most studies have demonstrated a significant improve-
ment of post-thoracotomy pulmonary dysfunction with
TPVB compared with placebo or parenteral opioids, as
demonstrated by higher FEV
1
,FVC, and/or PEFR
values.
104,105,106,111
In Richardson and colleagues’ review of
various techniques for post-thoracotomy analgesia, TPVB
demonstrated the best preservation of pulmonary func-
tion.
8
FEV
1
,FVC, and/or PEFR values had all returned to
approximately 75% of their preoperative value by 48 hours
postoperatively in patients who had received TPVB. When
TPVB has been compared directly with thoracic epidural
analgesia, most studies have demonstrated similar effects
on pulmonary function for the two techniques,
109,110
although TPVB was associated with higher values of PEFR
and oxygen saturation as measured by pulse oximetry
(SpO

2
) in one study by Richardson and colleagues’
group.
107
As noted previously (see “Interpleural
Analgesia”), TPVB has been demonstrated to produce
both better and similar effects on pulmonary function tests
when directly compared with interpleural analgesia.
70,112
Likewise, there is a limited quantity of evidence that
10
/ Advanced Therapy in Thoracic Surgery
TABLE 1-7. Examples of Dosage Regimens for Thoracic Paravertebral Blockade
Study Intraoperative Regimen Postoperative Regimen
Carabine et al, 1995
103
5 mL 0.25% bupivacaine after chest closure 0.25% bupivacaine 5 mL/h infusion
Catala et al, 1996
101
—20mL 0.375% bupivacaine q6h
or 15 mL 0.375% bupivacaine loading dose,
then 5 mL/h 0.375% bupivacaine infusion
Barron et al, 1999
105
0.3 mL/kg 1% lidocaine before chest closure or 0.1 mL/kg/h 1% lidocaine infusion or 0.1 mL/kg/h
0.3 mL/kg 0.25% bupivacaine before chest closure 0.25% bupivacaine infusion
Berrisford et al, 1990
111
20 mL 0.5% bupivacaine after chest closure Approximately 0.1 mL/kg/h 0.5% bupivacaine
Mathews and Govenden, 1989

108
10 mL 0.25% bupivacaine after chest closure 3–10 mL/h 0.25% bupivacaine
Richardson et al, 1999
107
20 mL 0.25% bupivacaine during chest closure 0.1 mL/kg/h 0.5% bupivacaine infusion
TPVB may decrease the risk of pulmonary complications
compared with placebo and parenteral opioids.
Sabanathan, Berrisford, and colleagues, in two separate
studies (with possibly overlapping subjects), have
reported fewer pulmonary complications in patients
receiving TPVB compared with placebo.
104,111
TPVB has also been shown to suppress the stress
response, as measured by serum cortisol and glucose
levels, and in this respect it functioned better than
thoracic epidural analgesia.
107
advantages and disadvantages
TPVB has been described as being quick and easy to
perform.
98,112,113
This statement should be interpreted
cautiously, however, as it was made by the main authors
regarding TPVB in the literature today, and their experi-
ences may not be applicable to other institutions. This
caution may be especially relevant for centers in North
America, where TPVB is rarely taught in the anesthesiol-
ogy and surgery training programs.
Other advantages of TPVB include the lack of urinary
retention and motor blockade of the lower extremities

owing to the thoracic and unilateral location of the
block.
102,114
As well, the unilateral nature of the block
results in little/no direct effects on hemodynamics,
102
and
the doses of local anesthetic are usually less than those
associated with systemic toxicity.
70
Even when higher
levels have occurred, there has been no evidence of
systemic toxicity.
45,110
Accordingly, no special monitoring
is necessary for patients with these blocks beyond the
usual postoperative care.
112
As TPVB is dependent on the
use of local anesthetics for postoperative use, opioid-
related risks are theoretically avoided. However, supple-
mentation with systemic opioids is often used; thus,
opioid adverse effects may be minimized but not absent.
The main disadvantage of this technique is that it is
more difficult to perform than the intercostal nerve and
interpleural blocks. As well, patients with a previous
thoracotomy are usually inappropriate candidates for the
block since the paravertebral space may be obliterated by
scar tissue. The technique may likewise be unsuitable for
patients undergoing a pleurectomy, although successful

use of TPVB has been reported, provided the parietal
pleura covering the vertebral bodies and a few centime-
ters distally is left intact.
106
adverse effects
The incidence of adverse effects with TPVB in the post-
thoracotomy population is 10% or lower.
112,115
The most
frequent adverse event is hypotension,
115
which has been
primarily attributed to the unmasking of relative hypo-
volemia as hypotension does not occur in well-hydrated
patients receiving TPVB for the treatment of chronic
pain syndromes.
98,102,112
Other complications, which occur
much less frequently, are inadvertent puncture of the
epidural or subarachnoid space owing to a faulty tech-
nique,
97
and unilateral Horner syndrome because of the
cephalad spread of anesthetic to the cervical sympathetic
structures. No fatality directly related to TPVB has been
reported in the literature.
98,112
contraindications
As alluded to above, a previous ipsilateral thoracotomy
would be a relative contraindication to the technique

because of a possible obliteration of the paravertebral
space. An empyema is not directly affected by manipula-
tions in the paravertebral space, but the accompanying
acidosis and hyperemia may limit the efficacy of the
TPVB and increase the risk of systemic absorption of
local anesthetic. Anticoagulation is a relative contraindi-
cation to the technique, but the paravertebral space is less
vascular than the epidural space; thus, the risk of venous
puncture is less than with epidural analgesia. As well, the
consequences of a unilateral paravertebral space hema-
toma are small compared with the potentially cata-
strophic consequences of an epidural hematoma.
112
Similarly, TPVB is relatively contraindicated in patients
with raised intracranial pressure because of the possibil-
ity of inadvertent dural puncture and subsequent brain-
stem herniation. However, the risk of puncture is less
than with epidural analgesia, so in this situation, TPVB
would be the best choice of the two techniques.
Epidural Analgesia
definition and technique
Epidural analgesia refers to the technique of injecting
analgesic medication into the epidural space, surround-
ing the spinal cord. As with most of the other regional
techniques discussed heretofore, epidural analgesia is
almost exclusively administered via an indwelling
catheter when used for post-thoracotomy pain relief.
Similar effects may be achieved by injecting analgesic
medication into the subarachnoid space (albeit with
lower doses),

116
but the technique is rarely used in the
United States because of concerns with introducing a
catheter into this space. The intimate proximity of the
subarachnoid space to the spinal cord poses a risk of
injury to the spinal cord, and an association between the
development of cauda equina syndrome and subarach-
noid microcatheters (also known as spinal micro-
catheters) has been suggested.
117
Local anesthetics and opioids are the two main classes
of drugs used for epidural analgesia in post-thoracotomy
patients. Other drugs that have been used in the epidural
space, either alone or as adjuncts, are discussed later (see
Postoperative Analgesia for Thoracotomy Patients: A Current Review
/
11
“Other Agents”). In the early 1980s, epidural morphine
was popular, primarily because of its hemodynamic
stability compared with epidural local anesthetics and its
relatively long duration of action.
5
The latter permitted
bolus dosing on an as-needed basis every 6 to 24 hours.
The risk of respiratory depression and slow onset of
action with epidural morphine promoted the search for
alternative opioids,
118
thus leading to the use of more
lipophilic epidural opioids such as fentanyl and its

analog, sufentanil. Owing to the short duration of action
of these opioids, continuous infusions are necessary.
Most recently the synergistic effects of combining
local anesthetics and opioids in the epidural space have
been recognized.
119
This synergism has been attributed to
the facilitation of opioid transport from the epidural
space to the subarachnoid space by local anesthetic,
120
and production of a conformational change in the spinal
␬ opioid receptor by local anesthetic agents, such that
opioid binding is facilitated.
121
Accordingly, continuous
infusions of opioid–local anesthetic combinations have
become popular, with the goal of providing similar or
improved analgesia with lower doses of both agents, so
that the incidence of adverse effects is reduced. Although
similar or improved analgesia has been achieved in
several studies,
122–126
a reduction in adverse effects has not
been universally accomplished (see “Effects Related to
Injection of Epidural Local Anesthetic–Opioid
Combinations,” below). Current literature suggests that
the combination of 10 to 12.5 µg/mL fentanyl (or
1 µg/mL sufentanil) and 0.1 to 0.125% bupivacaine is
closest to the ideal for post-thoracotomy patients,
producing a maximum of pain relief and minimum of

side effects.
6,127
Of interest, the addition of bupivacaine
does not seem to improve analgesia when added to
epidural meperidine.
128
This may be because meperidine
has significant local anesthetic properties itself and has
even been used as the sole anesthetic for lower abdomi-
nal surgery when administered in the subarachnoid
space.
129
Table 1-8 presents several examples of epidural
analgesia regimens.
There is controversy as to whether epidural catheters
should be inserted into the thoracic or lumbar region for
thoracotomy patients. Owing to the proximity of the
spinal cord to the epidural space in the thoracic region
and the greater technical difficulty of entering the
epidural space at this level of the spinal column, many
anesthesiologists are hesitant to insert a thoracic epidural
catheter. They are supported by evidence that equivalent
analgesia may be achieved by lumbar and thoracic
epidural injections in post-thoracotomy patients.
120,130–134
In contrast, advocates of thoracic epidural catheters
emphasize that higher volumes and/or higher doses of
epidural opioids and/or local anesthetics were needed
with the lumbar route to produce equivalent analgesia in
many of these studies, thereby suggesting that the lumbar

route may be acceptable but not optimal. As well, there is
no evidence that complication rates are higher with
thoracic than with lumbar epidural catheters,
135
and
many of the potential advantages of epidural analgesia
discussed below rely on blockade of the cardiac sympa-
thetic fibers at T1 to T5, which is more easily accom-
plished with a thoracic than with a lumbar epidural
catheter. With these considerations in mind, the
approach at our institution is to preferentially place a
thoracic epidural catheter; however, a high lumbar
catheter is used if this is unsuccessful.
mechanism of action
The mechanism of action of epidural opioids and local
anesthetics differs. Local anesthetics applied to the
epidural space act primarily by blockade of nerve
impulse conduction in the axonal membrane of the
spinal nerve roots as they traverse the epidural space.
136
Diffusion of local anesthetic into the long tracts of the
spinal cord may further contribute to the analgesia
produced by epidural local anesthetics. The various types
of nerve fibers exhibit differential sensitivity to local
anesthetics: sympathetic fibers are the most easily
blocked, and motor fibers are the most resistant.
137
Consequently, the concentration of local anesthetic is the
primary determinant of the depth of blockade, with
higher concentrations producing more motor blockade.

The actual extent of blockade along the spinal canal
12
/ Advanced Therapy in Thoracic Surgery
TABLE 1-8. Examples of Dosing Regimens for Epidural
Analgesia
Solution Infusion Rate Bolus Doses
Fentanyl 10 µg/mL 0.5–1 µg/kg/h 10–15 µg q10–15 min
prn
Sufentanil 1 µg/mL 0.1–0.2 µg/kg/h 5–7 µg q10–15 min
prn
Morphine — 3–6 mg q6–12h prn
Morphine 0.01% 0.5–0.8 mg/h 0.2–0.3 mg q10–15 min
prn
Hydromorphone — 0.8–1.5 mg q4–6h prn
Hydromorphone 0.005% 0.15–0.3 mg/h 0.15–0.3 mg q10–15 min
prn
Fentanyl 10 µg/mL + 6–8 mL/h 1–2 mL q10–15 min prn
bupivacaine 0.75–0.125%
Sufentanil 1 µg/mL + 6–8 mL/h 1–2 mL q10–15 min prn
bupivacaine 0.75–0.125%
Morphine 0.01% + 6–8 mL/h 1–2 mL q10–15 min prn
bupivacaine 0.75–0.125%
Hydromorphone 0.0025% 6–8 mL/h 1–3 mL q10–15 min prn
–0.005%+ bupivacaine
0.75–0.125%
Data from University of Texas M. D. Anderson Cancer Center protocol and
DeLeon-Casasola OA and Lema M.
154
prn = according to circumstances.
depends primarily on the volume administered, and

because of the greater sensitivity of the sympathetic
fibers, the extent of sympathetic blockade may be greater
than the somatic sensory block.
Epidural opioids exert their primary therapeutic
effects by binding to specific opioid receptors in the
substantia gelatinosa of the dorsal horn of the spinal cord
gray mater.
136,138
This region contains interneurons
involved in the ascending pain pathways (the spinothala-
mic and spinoreticular tracts). Opioid receptors are
located both presynaptically and postsynaptically, and
they function to inhibit the release of neurotransmitters
from primary sensory neurons and block the depolariza-
tion of post-synaptic neurons, respectively.
44
The term
selective spinal analgesia has been used to denote analge-
sia attributable to these spinal cord opioid receptors.
Before reaching the spinal cord, opioids injected into the
epidural space must first travel through the dura mater,
subdural space, arachnoid mater, subarachnoid space
(containing the cerebrospinal fluid), and pia mater. The
epidural space contains an abundance of fat tissue and an
extensive venous plexus, and 90 to 97% of an injected
dose is absorbed into these compartments,
139–141
thereby
never reaching the subarachnoid space.
Epidural opioids may also produce analgesia at a

supraspinal level (termed supraspinal analgesia) by bind-
ing to opioid receptors in the brain. Opioids gain access
to these sites via two main pathways: absorption into the
epidural veins and subsequent entry into the systemic
circulation, and rostral travel through the cerebrospinal
fluid to the brain. After a bolus injection of all epidural
opioids, plasma levels peak at approximately the same
time as with an intramuscular injection,
139,142,143
and in
some studies have achieved values high enough to
contribute to analgesia.
139,142,144–146
Plasma opioid levels fall
quickly, however, and are of little importance beyond the
first hour after epidural bolus administration for all
agents.
139,142,146
A different scenario arises when lipophilic agents
(such as fentanyl and sufentanil) are administered by
continuous epidural infusion or repeat bolus.
Continuing systemic absorption of these agents results
in accumulation, and some studies have recorded
systemic plasma levels within the usual therapeutic
range for these drugs, when administered by these meth-
ods.
123,143
Similarly, Miguel and colleagues and Sandler
and colleagues have demonstrated that epidural infu-
sions of fentanyl and sufentanil produce plasma levels

similar to those with intravenous infusion, when titrated
to equivalent analgesia.
147,148
This suggests that
supraspinal analgesia may be a major contributor to the
overall analgesic effect when lipophilic opioids are
administered in this manner.
Rostral travel through the cerebrospinal fluid of
opioids injected into the epidural space is most promi-
nent with morphine, as its relative hydrophilic properties
limit its diffusion out of the subarachnoid space, thereby
allowing greater quantities of morphine to be retained in
the cerebrospinal fluid for a prolonged period of time.
149
Morphine travels cranially via the slow process of cere-
brospinal fluid bulk flow, leading to peak levels of
morphine in the cervical cord region by 3 to 5 hours after
lumbar epidural injection.
136,150
Movement through the
cerebrospinal fluid for more lipophilic opioids may also
occur, especially with large bolus doses, but the quantities
of drug detected in the cervical cord and/or cisterna
magna have been small, and their contribution to the
analgesia achieved with these agents is unknown.
146,151
efficacy
The efficacy of epidural analgesia in providing pain
relief after thoracotomy depends on the drug(s) used.
Epidural analgesia with local anesthetics alone is more

effective in providing analgesia than are parenteral
opioids, but the concentrations needed to accomplish
this (eg, 0.5% bupivacaine) are accompanied by a signif-
icant risk of hypotension. When lower concentrations
have been used, supplemental parenteral opioids are
usually necessary.
70,107,152
The efficacy of epidural morphine in providing
post-thoracotomy analgesia is undisputed. It is consid-
ered the “gold standard” for epidural opioid analgesia.
Pain scores and/or the need for supplemental anal-
gesics are universally lower for epidural morphine than
for parenteral morphine, and these effects are accom-
plished using lower doses of epidural morphine, which
last longer than parenteral morphine.
5,152,153
The
lipophilic opioids are also effective in providing analge-
sia after thoracotomy when administered via the
epidural route. However, as discussed previously, there
is evidence that continuous epidural infusions of these
agents produce post-thoracotomy pain relief primarily
by the systemic absorption of the opioid and may offer
little advantage over the less complicated intravenous
route of administration.
154
The opioid–local anesthetic combinations popular
today are also very effective in providing pain relief after
thoracotomy. As combinations are relatively new tech-
niques and the efficacy of epidural analgesia for post-

thoracotomy pain has already been established, there has
been little interest in performing studies comparing the
efficacy of combinations to that of parenteral opioids or
placebos. Nevertheless, improved analgesia has been
noted with both epidural morphine–bupivacaine and
epidural fentanyl–bupivacaine infusions compared with
parental opioids.
152,155
Postoperative Analgesia for Thoracotomy Patients: A Current Review
/
13
Studies comparing epidural analgesia with other
modes of regional analgesia in post-thoracotomy patients
are few, and their interpretation has been confounded by
the use of a variety of different medications in the
epidural space. Three studies have used epidural local
anesthetics alone. Brockmeier and colleagues showed no
difference in analgesic efficacy between 0.375% epidural
bupivacaine and interpleural analgesia.
86
Richardson and
colleagues demonstrated better analgesia with TPVB
than with epidural analgesia, but the TPVB group
received 0.5% bupivacaine and the epidural group
received only 0.25% bupivacaine.
107
A final study
compared 0.25% epidural bupivacaine with 0.25% TPVB
bupivacaine and 0.5% interpleural bupivacaine.
70

All
techniques produced similar analgesia at rest, but the
intercostal nerve blocks group had better dynamic pain
relief for the first 4 hours after thoracotomy. In a study of
epidural analgesia using a combination of fentanyl and
bupivacaine, analgesia was superior to that produced by
TPVB,
114
although this effect did not persist beyond the
first postoperative day.
Evidence regarding the efficacy of epidural analgesia in
improving pulmonary function and decreasing pulmonary
morbidity in the post-thoracotomy patient is conflicting.
Many studies have revealed no difference in arterial blood
gas results, spirometry measurements, or pulmonary
complications when epidural analgesia has been compared
with parenteral opioids or other types of regional analgesia
in this population.
69,88,109,153,156–160
In Richardson and
colleagues’ review of different techniques for post-thoraco-
tomy analgesia discussed previously, epidural analgesia
with local anesthetics and/or opioids resulted in a moder-
ate preservation of pulmonary function.
8
By 48 hours after
surgery, FEV
1
,FVC and/or PEFR values had returned to
approximately 55% of their preoperative values in patients

who had received epidural analgesia, which was similar to
the results obtained with intercostal nerve blocks but
worse than the 75% values observed with TPVB.
For those studies that have shown an improvement in
pulmonary parameters, most have demonstrated
improvement in only some of the parameters measured.
For example, Guinard and colleagues demonstrated
higher FVC and FEV
1
values for thoracic epidural
fentanyl when compared with intravenous fentanyl, but
no difference in arterial blood gas results or the number
of patients with abnormalities on chest radiographs.
132
Salomaki and colleagues have shown lower PaCO
2
values
with epidural fentanyl but similar PaO
2
and incidences of
atelectasis compared with intravenous fentanyl.
161
Two
articles from Hasenbos and colleagues are the only stud-
ies that have found both improved arterial blood gases
(PaCO
2
less elevated above preoperative levels) and
reduced incidence of pulmonary complications.
162,163

However, these studies were not blinded, and the opioid
examined was nicomorphine, the 3,6-dinicotinoyl ester
of morphine, which is not available in North America. As
well, the sole analgesic in the nonepidural groups was
intramuscular nicomorphine, administered in as-needed
doses by the nursing staff. By providing parenteral opioid
in this manner, analgesic therapy in these groups may not
have been optimized.
A recent meta-analysis of the pulmonary effects of
various analgesic regimens in a wide variety of surgical
procedures (including but not restricted to thoraco-
tomies) revealed only a diminished incidence of atelecta-
sis with epidural opioids and a decreased incidence of
pulmonary infection and overall pulmonary complica-
tions, plus an increased PaO
2
with epidural local anes-
thetics.
164
Of interest, the authors emphasize the lack of
difference in spirometry results between the different
methods of analgesia and suggest that there is no ratio-
nale for using these surrogate measures of pulmonary
outcomes.
Epidural analgesia has little, if any, impact on modify-
ing the stress response to surgery in the post-thoracotomy
population.
107,165
This has been attributed to incomplete
blockade of the afferent sensory nervous input from the

site of surgery and the release of components of the stress
response, such as cytokines, directly into the bloodstream
from the site of tissue injury.
166
advantages and disadvantages
One major advantage of epidural analgesia is related to
the use of opioids in the epidural space. Systemic absorp-
tion and/or cephalad spread of epidural opioid may alle-
viate the shoulder pain commonly associated with
thoracotomies, and even neck incisions for esophagec-
tomies. In our institution, we do not routinely use supple-
mental parenteral opioids for pain in these two locations.
If necessary, NSAIDs and acetaminophen are almost
always sufficient adjuvants to our epidural analgesia.
Thoracic epidural analgesia with local anesthetics (alone
or in combination with opioids) may have unique advan-
tages in patients with coronary artery disease. Blockade of
the cardiac sympathetic fibers innervating the heart
(T1–T5) results in small reductions in heart rate, systemic
vascular resistance, and possibly cardiac output,
167,168
thereby
decreasing myocardial oxygen demand. At the same time,
myocardial oxygen supply may improve, particularly in
areas at most risk of ischemia. Thoracic epidural analgesia
with local anesthetic has been demonstrated to produce
dilatation of stenotic coronary arteries,
169
redistribution of
blood flow from the epicardium to endocardium,

170
and
redistribution of blood flow specifically toward ischemic
regions of the myocardium.
170
Maintaining the systemic
blood pressure close to the normal range (eg, mean arterial
14
/ Advanced Therapy in Thoracic Surgery
pressure < 20% below baseline) is necessary for these
effects to be most evident.
171
Another potential benefit of epidural analgesia in the
patient with coronary artery disease relates to coagulation.
Local anesthetic may be absorbed from the epidural space
in quantities sufficient to interfere with platelet aggrega-
tion,
172,173
thereby counteracting the hypercoagulable state
associated with major surgery and potentially diminishing
the risk of coronary artery thrombosis formation.
Despite the above observations, there have been no
properly conducted randomized controlled trials demon-
strating decreased risk of myocardial ischemia/infarction
through the use of epidural analgesia in any group of
patients postoperatively, let alone those having thoraco-
tomies. As well, there is concern that blockade of the
sensory innervation of the upper thoracic region may
simply obliterate the pain of myocardial ischemia, thus
removing an important warning signal of impending

myocardial infarction.
174
Epidural analgesia may also decrease the risk of postop-
erative arrhythmias. This is of particular relevance in the
post-thoracotomy situation as supraventricular arrhyth-
mias (especially atrial fibrillation) occur in approximately
15% of patients after lung surgery, and recurrent episodes
have been associated with increased perioperative mortal-
ity.
175
Animal studies suggest that thoracic epidural analge-
sia with local anesthetic may reduce the risk of ventricular
tachyarrhythmias and reentry supraventricular arrhyth-
mias,
176–178
an effect that has been attributed to cardiac
sympathetic blockade. In humans a retrospective review by
Groban and colleagues noted a significantly lower inci-
dence of atrial arrhythmias while thoracic epidural analge-
sia (with opioid or opioid plus local anesthetic) was in use
compared with the incidence after the epidural was
removed on the second or third postoperative day.
179
In a
prospective, randomized study comparing thoracic
epidural bupivacaine with thoracic epidural morphine,
Oka and colleagues demonstrated a lower incidence of
supraventricular tachyarrhythmias with epidural bupiva-
caine when administered for 3 days after thoracotomy.
180

The aforementioned cardiovascular benefits of
thoracic epidural analgesia with local anesthetics cannot
be extrapolated to the use of epidural opioids or to
epidural local anesthetics administered by the lumbar
route. In the former instance, there is no direct inhibition
of sympathetic input to the heart. In the latter, blockade
of T1 to T5 would require such an extensive blockade of
the sympathetic nervous system that the resultant
decrease in blood pressure would very likely counteract
any beneficial effects attributable to the blockade of the
cardiac sympathetic fibers.
The main disadvantage of epidural analgesia is that,
of the regional techniques described heretofore, it is
probably the most difficult to perform and is almost
exclusively performed by an anesthesiologist or nurse
anesthetist. Although many of these individuals have
had extensive training and/or experience in performing
epidurals for obstetric indications, and thus can facilely
insert an epidural in the lumbar region, thoracic epidu-
rals for analgesia after thoracotomy are different. Not
only is the thoracic epidural space more difficult to
identify owing to anatomic differences in the spinal
architecture of the thoracic region, but the majority of
thoracotomy patients are elderly, with calcified supra-
spinous and interspinous ligaments and compressed
intervertebral spaces, all of which add to the difficulty of
successfully inserting an epidural.
adverse effects
Effects Related to Insertion of a Needle or Catheter
into the Epidural Space. Adverse effects of epidural anal-

gesia related to the insertion of the needle and/or
catheter into the epidural space include inadvertent
spinal puncture, inability to insert a needle or catheter
into the epidural space, premature dislodgment of the
catheter from the epidural space, temporary back pain at
the insertion site, epidural hematoma, epidural abscess,
and permanent neurologic deficits. The most common of
these is an inadvertent spinal puncture, which occurs
with an incidence of approximately 0.3 to 5%.
136,181,182
Although rare, subdural hematoma and pneumocephalus
have been reported after spinal puncture.
182
More
commonly, a medication intended for the epidural space
is injected into the subarachnoid space instead, which
may have disastrous consequences. An epidural dose of
either local anesthetic or opioid would be clearly exces-
sive in the subarachnoid space, potentially producing
major motor blockade, hypotension and “total spinal
anesthesia” with the former class of drugs, and life-
threatening respiratory depression with opioids.
An inadvertent spinal puncture may also produce a
headache, which can be incapacitating. This postdural
puncture headache may be frontal and/or occipital,
usually develops 24 to 72 hours after the spinal puncture,
and is due to leakage of cerebrospinal fluid through the
hole in the subarachnoid membrane and subsequent
traction on pain-sensitive structures at the base of the
brainstem.

183
It may be associated with nausea/vomiting
and cranial nerve palsies and auditory disturbances,
184,185
and it is clearly differentiated from other causes of
headache by its prominent exacerbation with the upright
position and complete resolution with the supine posi-
tion. Therapy is important, not only from a humanitar-
ian point of view, but because the headache may
discourage the patient from coughing and assuming the
upright position, thereby potentially interfering with
Postoperative Analgesia for Thoracotomy Patients: A Current Review
/
15
recovery.In addition to nonopioid and opioid analgesics,
more specific therapy with oral or intravenous caffeine
and aggressive fluid intake instillation is usually success-
ful in alleviating the postdural puncture headache. The
latter is often undesirable in the post-thoracotomy
patient, however. When these measures fail, instillation of
10 to 30 mL of normal saline or 20 mL of freshly
obtained autologous blood (an “epidural blood patch”)
into the epidural space, is indicated.
186
The potentially catastrophic complications of epidural
needle or catheter insertion, epidural hematoma and
abscess, and permanent neurologic deficits are, fortu-
nately, very rare. Incidence rates have been estimated to be
≤ 1 in 150,000 to 190,000,
187,188

≤ 1 in 1,000 to 6,500,
189–191
and ≤ 1 in 3,000 to 4,500,
135,192
respectively. Permanent
neurologic deficits (usually paraplegia) may occur as a
consequence of cord compression and ischemia induced
by an epidural hematoma or abscess. Additionally, they
may be related to mechanical trauma from the epidural
needle or catheter, inadvertent injection of a neurotoxic
substance into the epidural space, or spinal cord ischemia
from other causes, such as epinephrine-induced vasocon-
striction of arteries supplying the cord, pressure effect
from the volume of epidural injectate, and hypotension
induced by the sympathetic block.
193
Epidural abscesses may arise from direct extension of
infection in the local area of the epidural insertion site,
or from infection at a remote part of the body, with
bacteremia and subsequent seeding of the epidural
space.
194,195
Factors associated with the occurrence of
epidural abscesses are duration of epidural catheteriza-
tion ≥ 3 days
190
;immunocompromise associated with one
or more complicating disease, such as cancer, acquired
immunodeficiency syndrome, diabetes, multiple trauma,
chronic renal failure, or chronic obstructive pulmonary

disease
190,195,196
;multiple attempts at inserting the epidural
needle/catheter
191
; and the use of low-dose unfractionated
or low molecular weight heparin.
190
The association with
the latter two factors may reflect the development of a
hematoma within the epidural space, which subsequently
acts as a nidus for infection.
Direct puncture of the extensive epidural venous plexus
during epidural needle or catheter insertion may result in
the development of an epidural hematoma. Although it
may initially be small and clinically unimportant, this
hematoma may later enlarge when the clot is disrupted by
a coagulation abnormality or direct trauma. The latter
may occur at any time while the catheter is being used as
epidural catheters are well-known to migrate within the
spinal canal.
182
However, a clot is most likely to be
disrupted when an epidural catheter is removed from the
patient. Approximately half of the epidural hematomas
attributed to epidural analgesia in Vandermeulen and
colleagues’ 1994 review of the literature occurred immedi-
ately upon removal of the epidural catheter.
197
Risk factors

associated with the development of an epidural hematoma
include increased age,
198
multiple attempts at inserting the
epidural needle or catheter,
198
and coagulation defects.
188,198
It is controversial whether the appearance of blood in the
needle or catheter during epidural insertion (known as a
“traumatic” needle/catheter insertion) is a risk factor for
the development of a significant epidural hematoma.
Given the extensive vascularity of the epidural space and
the 3 to 12% incidence of puncture of a blood vessel or
vessels during epidural catheter insertion,
182
there are obvi-
ously a large number of epidural hematomas that are too
small to attain clinical importance.
The association between epidural hematomas and
coagulation defects has been recognized for decades.
197
Defects in either the platelet-mediated or coagulation
factor–dependent phases of the coagulation system
enhance the possibility of epidural hematoma formation,
and combinations of defects increase the risk further.
198–200
Therapeutic anticoagulation with heparin, warfarin, and
antifibrinolytics are known offenders, as are therapeutic
and prophylactic doses of low molecular weight

heparin.
187,197,201
The use of NSAIDs and low-dose prophy-
lactic unfractionated heparin has not been associated
with a significantly increased risk of epidural hematoma
formation.
187,188,202
Effects Related to Epidural Injection of Local
Anesthetics. Adverse effects of local anesthetics injected
into the epidural space include hypotension, motor block-
ade, urinary retention, and systemic toxicity. These effects
are usually dose related, being most pronounced when
higher concentrations of local anesthetic are used.
Hypotension is a frequent occurrence as the sympathetic
blockade produces peripheral vasodilation and bradycar-
dia, and it is generally the limiting factor in the use of high
concentrations of local anesthetic. For example, El-Baz
and colleagues reported a 23% incidence of systolic blood
pressure < 60 mm Hg with heart rate < 60 beats per
minute in the first 24 hours after surgery, using 5 mL bolus
doses of 0.5% bupivacaine administered on an as-needed
basis through a thoracic epidural catheter.
4
Motor block-
ade of the legs interfering with ambulation is uncommon
if the epidural catheter is inserted in the thoracic region.
203
In contrast, weakness of the upper extremities may
develop with an epidural at this level and may be distress-
ing to patients.

4
Urinary retention should not occur with
thoracic epidurals if the volume of local anesthetic is
limited to that necessary for blockade of just the thoracic
dermatomes. Toxicity owing to systemic absorption is a
rare occurrence at the usual recommended doses.
Effects Related to Epidural Injection of Opioids.
Epidural opioid adverse effects are similar to those antici-
16
/ Advanced Therapy in Thoracic Surgery
pated with parenteral administration of this class of
drugs. The most frequent are nausea/vomiting, pruritus,
urinary retention, and intestinal hypomotility and
somnolence, and the most important is respiratory
depression. Many of these effects are dose related and
occur more frequently in patients who are opioid naive.
204
They are usually mediated by opioid receptors, such that
opioid antagonists should be effective in the prevention
and treatment of these effects.
205
Unfortunately, the doses
of antagonist needed for this purpose may overlap with
the doses that will antagonize the analgesic effects; there-
fore, other treatment modalities are usually employed
first, and opioid antagonists are reserved for instances
when they fail. Compared with parenteral opioid admin-
istration, the epidural route is associated with a greater
incidence of pruritus and urinary retention, a lower inci-
dence of somnolence, and an equivalent incidence of

nausea/vomiting and respiratory depression.
204
Pruritus,
nausea/vomiting, and urinary retention occur less
frequently when epidural morphine is administered as a
continuous infusion than as intermittent bolus injec-
tions.
4
Respiratory Depression. Respiratory depression is the
most feared complication of epidural opioids. Large series
have reported 0.1 to 3% incidences of “clinically signifi-
cant” respiratory depression,
118,189,203,206–208
defined as that
requiring intervention. These represent combined data
from patients having a wide variety of surgical procedures,
who have received different types of medication, adminis-
tered by varying protocols, through catheters inserted at
both lumbar and thoracic levels of the spinal column. The
incidence appears to be similar for most opioids,
209
with
the possible exception of an increased incidence with high
bolus doses of sufentanil.
210
After a single bolus dose of
epidural opioid, respiratory depression classically follows
two distinct patterns, which have been designated early
and late.
204

Early respiratory depression occurs within the
first 2 to 4 hours after administration of the epidural
opioid, has been observed with most opioids used during
epidural analgesia, correlates with high peak plasma levels,
and is thus thought to be primarily due to systemic
absorption of the opioid. Late depression occurs at > 2 to 4
hours after a dose of epidural opioid—most often at 6 to
12 hours
204,211
—but there have been reports of respiratory
depression persisting as long as 22 hours after administra-
tion of a bolus dose of epidural opioid.
205,212,213
This type of
respiratory depression has been evidenced almost exclu-
sively with morphine and is due to the rostral spread of
opioid through the cerebrospinal fluid to the respiratory
control centers in the brainstem. With the frequent use of
infusions in recent years, the concepts of early and late
have become obscured, and respiratory depression may
occur at any time.
Respiratory depression with epidural opioids usually
presents with a slow respiratory rate, although there have
been reports of severe hypercarbia with a normal respira-
tory rate.
214,215
In these examples, somnolence was present;
hence, there is a need for the assessment of the level of
consciousness as an indicator of respiratory depression.
Well-established risk factors for the development of

respiratory depression include older age, American
Society of Anesthesiologists physical status classes III to
IV, respiratory disease, sleep apnea syndrome, elevated
intrathoracic pressure, and concomitant use of systemic
opioids and/or other central nervous system depres-
sants.
118
More controversial risk factors are bolus injec-
tions, compared with continuous epidural infusions
154,216
;
and thoracic epidural catheters, in contrast to lumbar
epidurals.
118,130
The latter has been demonstrated only
with morphine.
Efforts to prevent postoperative respiratory depression
associated with epidural opioids have focused on using
the minimally effective dose of epidural opioid, limiting
the quantity of all opioids and sedatives used intraopera-
tively, and avoiding concomitant use of parenteral opioids
and other central nervous system depressants.
214
Frequent
monitoring of patients for evidence of respiratory depres-
sion is necessary, most often with intermittent assessment
of respiratory rate and level of consciousness every 0.5 to
2 hours, plus continuous pulse oximetry. Reliance on
pulse oximetry alone is not recommended as a decrease in
oxyhemoglobin saturation may be a late sign of respira-

tory depression when supplemental oxygen is used.
Arterial blood gases and/or continuous ventilatory moni-
tors may be considered for high-risk patients.
215
Monitoring should be applied throughout the course of
administration of the epidural opioids and continued for
4 to 6 hours after the last dose or after stopping an infu-
sion.
118,204
Morphine is the exception as the risk of delayed
respiratory depression mandates a more protracted
period of monitoring: 12 to 24 hours after the last dose
has been recommended.
118,182,204,205,214
The location of the
monitoring has changed over the last few years. In the
1980s it was recommended that all patients with epidural
opioids (with the possible exception of the obstetric
population) be observed in a setting such as an intensive
care unit or postanesthesia care unit.
118
More recently,
large series have demonstrated the apparent safety of
caring for these patients on a ward, provided the staff is
well educated and the aforementioned level of monitoring
is maintained.
189,203,208,217
Effects Related to Injection of Epidural Local
Anesthetic–Opioid Combinations. The currently popu-
lar technique of using combinations of opioids and local

anesthetics to decrease the dose of each may reduce the
incidence of drug-related adverse effects, although the
Postoperative Analgesia for Thoracotomy Patients: A Current Review
/
17
evidence for this varies between studies. Most consis-
tently, the incidence and severity of hypotension is less
than that associated with local anesthetic alone,
126,171,218
and the incidence of somnolence is lower than that asso-
ciated with epidural opioids alone.
123
At our institution
we usually initiate epidural analgesia therapy with a solu-
tion containing fentanyl 10 µg/mL and bupivacaine
0.075% and subsequently adjust the two drugs indepen-
dently, in accordance with the adverse effect profile of the
individual patient.
contraindications
Relative contraindications to the use of epidural analge-
sia include elevated intracranial pressure, preexisting
disease of the spinal cord or peripheral nervous system,
infection, and coagulopathy. Elevated intracranial pres-
sure is listed here because of the risk of inadvertent
dural puncture and subsequent brainstem herniation.
With neurologic disease, there is concern that the
epidural analgesia may exacerbate the underlying
disease, as has been suggested for demyelinating diseases
such as multiple sclerosis,
219

or that a coincidental deteri-
oration in neurologic function may be incorrectly attrib-
uted to the epidural.
Owing to the potential risk of epidural abscess forma-
tion, infection at the intended site of epidural insertion is
considered an absolute contraindication, and evidence of
infection at a more distant site is a relative contraindica-
tion to the use of epidural analgesia. Although no studies
have properly addressed this issue, epidural analgesia is
probably acceptable if the distant infection is completely
localized, but it is generally recommended that epidural
analgesia be avoided in the possible presence of
bacteremia, as evidenced by an elevated white blood cell
count or temperature. The situation becomes more
controversial if appropriate antibiotics have been started.
The literature also does not address the issue of epidural
analgesia in the patient with an empyema but no evidence
of systemic infection, but many anesthesiologists would
be reluctant to insert an epidural in this scenario. Further-
more, the question of whether the catheter should be
removed when an infection develops in a patient with an
indwelling epidural catheter also has not been discussed
in the literature. At our institution we approach each case
on an individual basis, taking into consideration such
factors as the duration of epidural use, whether the
patient appears to be benefiting from the epidural, and
whether appropriate antibiotics have been initiated.
To diminish the risk of epidural hematoma formation,
epidural analgesia is usually avoided in patients with a
preexisting coagulopathy. It has traditionally been taught

that the prothrombin time, activated partial thrombo-
plastin time (aPTT), and international normalized ratio
(INR) should all be within the normal range and that
platelets should number ≥ 100,000/mm
3
before an
epidural needle or catheter is inserted.
220
More recent
recommendations have suggested that epidural analgesia
may be safely considered with an INR up to 1.4 and
platelet counts as low as 80,000/mm
3
.
197
Bleeding times
are no longer advocated as a reliable method of deter-
mining platelet function.
187
If patients have been on any
medications effecting coagulation preoperatively, these
drugs should ideally be stopped before the epidural is
inserted, and the epidural catheter should be removed
before they are restarted. Guidelines for specific medica-
tions are presented in Table 1-9.
A more difficult situation arises when medications
interfering with coagulation are administered in the peri-
operative period. The most conservative approach is to
completely avoid epidural analgesia in these patients. In
institutions with the expertise to provide good post-

thoracotomy analgesia by other methods (especially TPVB
and continuous intercostal nerve blockade), this is a
reasonable approach. Postoperative use of NSAIDs and
subcutaneous unfractionated heparin appears to be safe
when used in conjunction with epidural analgesia, based
on the very small number of case reports of patients devel-
oping epidural hematomas in these circumstances and the
lack of hematoma development in the few larger studies
that have addressed this issue.
198,221
However, the response
to subcutaneous unfractionated heparin can be vari-
able,
222,223
and patients with cachexia and/or liver dysfunc-
18
/ Advanced Therapy in Thoracic Surgery
TABLE 1-9. Epidural Management in Patients Receiving Agents Affecting Coagulation Preoperatively
Agent Insertion Recommendations Laboratory Tests before Insertion
Subcutaneous unfractionated heparin (1,000 U q8–12h) Insert EP ≥ 4 h after last dose aPTT if cachectic or liver dysfunction; platelets if heparin
taken for > 4 d
LMWH Insert EP ≥ 12 h (ideally 24 h) after last dose None recommended
Intravenous heparin Insert EP ≥ 2–4 h after last dose aPTT; platelets if heparin taken for > 4 d
Warfarin Insert EP ≥ 4–7 d after last dose PT, INR
Thrombolytics and fibrinolytics (eg, streptokinase, t-PA) Insert EP ≥ 1–2 d after last dose Fibrinogen
Ticlopidine Insert ≥ 7 d None recommended
Data from Horlocker TT,
187
Vandermeulen EP et al,
197

Horlocker TT et al,
198
Tryba M,
201
Heit JA.
254
aPTT = activated partial thromboplastin time; EP = epidural; INR = international normalized ratio; LMWH = low molecular weight heparin; PT = prothrombin time;
t-PA = tissue plasminogen activator.
tion may be particularly sensitive to the anticoagulant
effects of the drug. As well, use of any form of heparin
beyond approximately 4 days may lead to thrombocytope-
nia.
201
It is therefore most prudent to monitor the aPTT
and platelet count regularly in these patients. Guidelines
for the use of other agents are summarized in Table 1-10.
If one decides to perform epidural analgesia in
patients at risk of developing an epidural hematoma or
abscess, frequent assessment of neurologic function
(optimally every 2 hours
187
) is essential. As well, the
concentrations of local anesthetics in the epidural solu-
tion should be minimized, or local anesthetics avoided
entirely, so that if a neurologic abnormality is detected,
there is no confusion between drug effect and actual
pathology. Immediate diagnosis of an epidural
hematoma is essential as permanent neurologic deficit is
more likely if surgical decompression is delayed beyond
the first 8 to 12 hours after presentation.

197
Although it is
controversial whether blood in the epidural needle or
catheter is a risk factor for the development of hema-
toma, the policy at many institutions is to cancel or delay
surgery for up to 24 hours if blood is noted during
needle or catheter insertion, and systemic heparinization
is planned.
187,197
Another approach, employed by Loik and
colleagues, for patients undergoing cardiac surgery has
been to routinely insert the epidural catheter the day
before surgery, thereby maximizing the time interval
between catheter insertion and heparinization.
224
duration
The optimal duration for epidural analgesia after thoraco-
tomy has not been established. Depending on the institu-
tion, epidural catheters may be removed at 48 to 72 hours
postoperatively or continued for up to 7 days, or even
longer. As much of the pain after thoracotomy is attribut-
able to the chest tubes, the general guideline at our insti-
tution is to maintain the epidural until these tubes are
removed. Thus, epidural catheters usually remain in place
for 3 to 7 days postoperatively. Pneumonectomy patients
are an exception to the “chest tube rule” as these tubes are
generally removed 24 hours postoperatively but epidural
analgesia is continued for at least 3 days. At the other
extreme, patients with esophagectomies often have their
chest tubes continued for more than a week. As epidural

medication requirements are usually minimal by 7 days
after this surgery, we generally remove the catheter on the
seventh operative day in these patients.
The only study that has addressed this issue is by
Nomori and colleagues, who performed a retrospective
review of data from patients having an anterior limited
thoracotomy who received epidural morphine by
continuous infusion for either 3 or 8 days postopera-
tively.
23
There were no differences between groups with
respect to pulmonary function tests or pain scores for
the first 7 postoperative days, but the day 8 group had
more pain than did the day 3 group on the eighth and
ninth postoperative days. As well, the pain scores on day
8 after the epidural was removed in the day 8 group were
significantly higher than the pain scores on the seventh
postoperative day. By contrast, the day 3 group experi-
enced no such “rebound” after their catheters were
removed. These observations suggest that, at least for an
anterior limited thoracotomy, extending the use of
epidural analgesia beyond the first 3 postoperative days
has no benefit and may even exert a negative impact on
overall pain control. Despite the limitations of the study
design, the results of this study are intriguing, and future
randomized controlled trials are warranted to establish
the optimal duration of epidural analgesia from a risk-
benefit perspective.
other agents
In addition to local anesthetics and opioids, many other

agents have been examined as potential candidates for
epidural analgesia. These include clonidine, opioid agonist-
antagonists, ketamine, verapamil, and methylprednisolone.
Epidural clonidine has been used for postoperative
analgesia in a variety of procedures. Its mechanism of
Postoperative Analgesia for Thoracotomy Patients: A Current Review
/
19
TABLE 1-10. Epidural Management in Patients to Receive Agents Affecting Coagulation Perioperatively*
Agent Initiation of Agent Removal of Epidural Catheter Laboratory Tests before Removing
Epidural Catheter
Subcutaneous unfractionated Start ≥ 1 h after EP insertion Remove ≥ 4 h after last dose aPTT if cachectic or liver dysfunction;
heparin (1,000 U q8–12h) platelets if heparin taken for > 4 d
LMWH Start ≥ 4 h after EP insertion Remove ≥ 12 h (ideally 24 h) after last dose None recommended
and wait ≥ 2 h after removal before
injecting next dose
Intravenous heparin Start ≥ 1 h after EP insertion Remove ≥ 2–4 h after last dose aPTT; platelets if heparin taken for > 4 d
Warfarin start ≤ 24 hours before EP insertion No specific recommendations PT, INR
Data from Horlocker TT,
187
Vandermeulen EP et al,
197
Horlocker TT et al,
198
Tryba M,
201
and Enneking FK, and Nenzon H.
255
aPTT = activated partial thromboplastin time; EP = epidural; INR = international normalized ratio; LMWH = low molecular weight heparin; PT = prothrombin time.
*The use of EP catheters in patients who will receive thrombolytics and fibrinolytics is strongly discouraged.

action is primarily by stimulation of ␣
2
-adrenergic recep-
tors in the dorsal horn of the spinal cord,
58
although
clonidine also produces direct blockade of conduction in
A delta and C nerve fibers. The main advantage of
epidural clonidine relates to its lack of most of the classic
opioid-related adverse effects, such as nausea/vomiting,
pruritus, and respiratory depression. However, epidural
clonidine may produce sedation, hypotension, and
bradycardia owing to stimulation of intracranial ␣
2
-
adrenergic receptors secondary to systemic absorption of
the drug. In nonthoracic surgery, clonidine is an effective
analgesic when administered alone in the epidural space,
but the doses required are high enough to produce a
significant incidence and severity of these clonidine-
related adverse effects.
225,226
Combinations of clonidine
and local anesthetics or opioids produce additive, and
possibly synergistic, analgesic effects, resulting in
improved analgesia with relatively low doses of cloni-
dine.
227,228
However, sedation and mild hypotension have
still been a problem in these studies. In the single investi-

gation focusing on post-thoracotomy patients, a single
bolus of epidural clonidine exhibited no effect on pain
relief compared with placebo.
229
Further studies are
necessary in this population.
Medications with opioid agonist-antagonist properties
have been used for epidural analgesia with the goal of
reducing the opioid-related side effects, especially respi-
ratory depression. In the only two studies focusing on
post-thoracotomy patients, lumbar epidural nalbuphine
provided significantly less analgesia than did lumbar
epidural morphine.
230,231
It is unknown whether a thoracic
approach would have produced different results. In a
group of 20 gynecologic patients, epidural pentazocine
produced good postoperative analgesia, with 16 patients
being completely pain free and the other 4 reporting mild
pain but requiring no additional analgesics.
232
A further
benefit in this study was the lack of urinary retention in
all 16 epidural pentazocine patients who did not have an
indwelling urinary catheter. Accordingly, this drug
appears to be promising but needs to be examined in the
post-thoracotomy population.
Discovery of the integral role of NMDA receptors in
processing nociceptive information in the spinal cord has
led to much interest in ketamine as an epidural analgesic

agent.
233
Ketamine is a potent, noncompetitive inhibitor
of the NMDA receptor and has the major clinical advan-
tage of exhibiting no respiratory depressant effects.
Epidural ketamine has not been studied in the post-
thoracotomy population, but for other types of surgery
ketamine, appears to have little or no analgesic efficacy
when used as a sole agent in the epidural space.
234–236
More
promising results have occurred when epidural ketamine
has been combined with epidural opioids and/or local
anesthetics. In many of these investigations, ketamine
potentiated the analgesic effects of the other agents.
237,238
A disadvantage of ketamine relates to its propensity to
cause psychomimetic effects, which have been reported
in up to 15% of patients receiving ketamine by the
epidural route.
239
These effects have been successfully
treated with discontinuation of the drug and/or with
systemic benzodiazepines.
Verapamil has been advocated as a possibly useful
epidural analgesic agent based on observations that
neurotransmitter release is mediated by calcium influx
into the synaptic terminals of neurons.
240
By interfering

with this influx, normal sensory processing in the spinal
cord is disrupted, and verapamil has been shown to
potentiate the antinociceptive effects of morphine at the
spinal cord level in an animal model.
239
In a preliminary
study of patients having lower abdominal surgery, vera-
pamil added to an epidural bupivacaine solution
decreased supplemental opioid requirements.
241
Further
investigations are necessary to establish the safety of
verapamil in the epidural space from a perspective of
neurotoxicity and to examine the analgesic efficacy of
epidural verapamil in the post-thoracotomy population.
Investigations of patients having spinal surgery have
demonstrated moderate effectiveness of epidural glucocor-
ticoids as analgesic agents.
241
This has been primarily
attributed to localized anti-inflammatory activity of these
drugs, but evidence that glucocorticoids may also influ-
ence synaptic transmission in the spinal cord has led to the
suggestion that epidural glucocorticoids may be useful for
other types of surgery as well.
242
Blanloeil and colleagues
examined the effects of a continuous infusion of epidural
methylprednisolone on pain relief after posterolateral
thoracotomy, but they found no difference in analgesia

between patients who received methylprednisolone and
those who received placebo.
243
Accordingly, there is no
evidence at present that epidural glucocorticoids will be
useful agents for post-thoracotomy analgesia.
Management of Pain
The management of postoperative pain in general has
long been the sole responsibility of the surgeon after the
acute phase in the postanesthesia care unit. Probably
concomitantly with the introduction of epidural analge-
sia, anesthesiologists have undertaken some shared
responsibility for the control of post-thoracotomy pain.
This has improved postoperative analgesia and arguably
improved intraoperative management. Whether a formal
“thoracic team,” which incorporates representatives from
thoracic surgery, anesthesiology, nursing, and pain
management, improves outcome is debatable. Improved
outcome has only been suggested for pediatric fellowship
20
/ Advanced Therapy in Thoracic Surgery
training,
244
and the mechanism of the improved outcome
still may just be due to more opportunity to maintain
skills.
245
It is likely, however, that the simple existence of a
group of identifiable individuals with an interest in pain
relief both during and after thoracic surgery would

enhance immediate feedback within the group. This
would predispose to rapid adoption of needed improve-
ments and facilitate adherence to the principles of
continuous quality improvement. Familiarity and repeti-
tion should increase the success rate of procedures and
the satisfaction felt by patients.
Certainly epidural anesthesia should be managed
solely by an anesthesia provider due to the specialized
knowledge required for implementing and safely provid-
ing this service. Most large hospitals have an acute pain
service or postoperative pain service in addition to the
anesthesiologists in the operating rooms. The postopera-
tive pain service not only helps manage the ongoing
needs of patients with epidural analgesia, but is also
available to manage or consult on other postoperative
analgesia–related dilemmas. In addition, almost all
medical communities have available chronic pain special-
ists or even a chronic pain service. Specialists in chronic
pain come from the disciplines of anesthesiology,
surgery, neurology, and others. They have undertaken
extensive training about pain, its causes, and its control,
and as such they represent a major resource for other
health care professionals.
At the University of Texas M. D. Anderson Cancer
Center, we are fortunate to have the availability of all
three above-mentioned components of pain manage-
ment, namely a thoracic team, postoperative pain service,
and chronic pain service. The management of an individ-
ual patient is strongly dependant on the root cause of the
pain and whether there was preexisting pain. Tolerance is

a phenomenon common to almost all drugs. Chronic
pain patients can be expected to have much increased
needs postoperatively. Optimum management is facili-
tated by early involvement of the chronic pain service
when indicated. Figure 1-3 shows the organization of
postoperative pain control and use of pain services at
M. D. Anderson Cancer Center.
Most commonly, patients undergoing thoracic surgery
are opioid naive. In our setting they receive an epidural
placed by a member of the thoracic team or postopera-
tive pain service, undergo surgery, and, after activation of
the epidural analgesia near the end of surgery, have their
pain managed by the postoperative pain service. The
postoperative pain service writes the epidural orders,
deals with complications, treats breakthrough pain, and
is proficient in relieving disaggregated pain. Each patient
is seen twice per day by a combination of pain service
nurses, rotating residents, and dedicated anesthesia
faculty member, either singly or together. Complete
around-the-clock coverage is provided, backed up, if
necessary, by the in-house anesthesiologist on call. At all
stages the thoracic surgeon is involved and consulted.
After the epidural is discontinued, usually at the time of
chest tube removal, the patient’s pain management
reverts completely to the attending thoracic surgeon. The
postoperative pain and chronic pain services are still
available in case of need.
Postoperative Analgesia for Thoracotomy Patients: A Current Review
/
21

Thoracotomy
Patient
PCEA by PPS
Until Epidural
Discontinued
IV – PCA by
Thoracic Surgery
Opiod
Naive
Successful
Good Pain
Relief
Discharge
PPS
Inadequate
Poor Pain Relief
Other Symptoms
Chronic Pain
on Narcotics
Preoperatively
Normal Chronic Pain
CPS
Discharge Discharge
PPS CPS
Discharge
Discharge
FIGURE 1-3. Organization of postoperative thoracic pain management at the University of Texas M. D. Anderson Cancer Center. CPS = chronic
pain service; IV-PCA = intravenous, patient-controlled analgesia; PCEA = patient-controlled epidural analgesia; PPS = postoperative pain service.
Patients with chronic pain, defined variously as being
on > 10 mg or the equivalent of morphine per day, are

equally common at M. D. Anderson. Their management
is similar until discontinuation of the epidural analgesia.
At this point the chronic pain service continues their
pain management. The chronic pain service is consulted
early in the postoperative period to facilitate changeover.
It has been noted that although chronic pain patients
require higher initial and continuing concentrations of
epidural narcotics, their pain relief can still be well
managed by epidural analgesia.
If epidural analgesia is impossible, then conventional
intravenous analgesia is employed and initial manage-
ment is by the operating room anesthesiologist. After the
patient’s time in the postanesthesia care unit, pain
management falls squarely on the thoracic surgeon. Only
if the patient’s pain is impossible to control does the
postoperative pain service become involved. Its staff may
be able to suggest different drug regimens or dosages.
Chronic pain patients are managed similarly, except that
when intravenous patient-controlled analgesia fails, the
chronic pain service is consulted first.
Pre-emptive Analgesia
Pre-emptive analgesia is a subject of endless fascination to
most anesthesiologists. It has been defined as the
phenomenon by which analgesia administered prior to a
painful event, such as a thoracotomy, decreases the later
intensity of perceived pain, even after the duration of
action of the initial analgesic.
246
More recently, the defini-
tion has been widened to include treatment that “prevents

the development of hyperexcitability, even if it takes place
after surgery.”
247
It must be distinguished from merely
improved analgesia following earlier administration of
analgesia compared with nonadministration of an anal-
gesic or lesser doses of the same analgesic. In a well-
designed study, Doyle and Bowler found that pre-emptive
intravenous morphine, intramuscular diclofenac, and
intercostal nerve blocks with bupivacaine only demon-
strated a decrease in VAS pain scores during a vital capac-
ity breath postoperatively.
248
No other measure of pain was
different between groups, and the long-term pain was
indistinguishable between groups. Early activation of
epidural analgesia might be expected to demonstrate pre-
emptive analgesia, but this expectation was shown to be
incorrect in a study using epidural bupivacaine.
249
Pre-
emptive analgesia has been suggested with the opioids
fentanyl and morphine in nonthoracic models,
250,251
raising
the suspicion that higher intraoperative opioid doses may
have a beneficial effect beyond the operative period, but
this has not been demonstrated for thoracotomy patients.
It is possible that the high-dose opioid employed for
cardiac surgery in the 1980s and 1990s, using a median

sternotomy approach, led to the oft-repeated observation
that median sternotomy is not as painful as the traditional
thoracotomy. With the current fast-track micromanage-
ment of cardiac anesthesia, post-sternotomy pain is
becoming a bigger issue for thoracic surgeons. It is not
clear how an appropriately blinded study could be
designed to investigate this intriguing possibility.
NSAIDs have also been investigated for pre-emptive
effects but, again, not in thoracic models. Using ketoro-
lac, Fletcher and colleagues demonstrated improved pain
relief in a hip-fracture model at the price of increased
blood loss,
252
and Norman and colleagues showed less
postoperative pain in an ankle fracture model.
253
The
selective COX-2 inhibitors may have a role to play in
postoperative, pre-emptive, and multimodal analgesia,
but so far, proof is lacking.
Summary
We have reviewed the provision of postoperative analge-
sia for patients who have undergone thoracotomy from
its humble beginnings to the current state of this art—
and an art it is, indeed, as the identical drugs and tech-
niques in different hands give quite different degrees of
success. The provision of pain relief after thoracotomy is
a complicated but still rewarding proposition. Newer
multimodal analgesia techniques show promise for
improving the overall experience in future patients. It is

likely that methods to ameliorate or even prevent the
development of chronic post-thoracotomy pain will be
elucidated. We must all continue to investigate, try differ-
ent strategies, improvise, and experiment to ensure
continued progress in this challenging field.
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