Phẫu Thuật Tạo Hình (Tập 1): Nguyên Lý Cơ Bản – Neligan (Ấn bản 4)

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CHAPTER 9 • Anesthesia and pain management in plastic surgery
Cardiovascular side effects include myocardial infarction,
particularly with underlying ischemic heart disease. This side
effect differs between drugs, with diclofenac posing the great­
est risk, and naproxen the least.
Contraindications for NSAIDs, both relative and absolute,
are numerous, and discretion must be used in patients with
comorbid conditions. However, they remain very effective
adjuncts to perioperative pain management. Their routine use
in plastic surgery procedures may be precluded due to the
minor increase in risk of bleeding and hematoma.13
COX-2 receptor inhibitors
Selective COX-2 inhibitors were developed in an effort to
reduce the GI side effects and bleeding associated with
NSAIDs. Coxibs reduce but do not eliminate the risk for GI
bleeding. They are effective in the management of postopera­
tive pain and have a low NNT, but their analgesic effect
has not been proven to be superior to traditional NSAIDs. A
major advantage of coxibs is their negligible effect on platelet
function. The risk of bleeding or hematoma formation is
negligible.13,19
The long-term use of coxibs is associated with potential risk
for cardiovascular and thromboembolic events. Due to the
risk of perioperative myocardial infarction, coxibs should be
avoided in patients with ischemic heart disease. There is no
difference in the incidence of renal side effects between
NSAIDs and coxibs. Overall, coxibs have a lower risk for
bleeding complications due to a negligible effect on platelet
function, and a lower risk of GI ulcers and bleeding compared
to NSAIDs.13
Acetaminophen, NSAIDs, and coxibs are effective agents
in multimodal perioperative pain management. Acetamino­
phen has minimal effect on platelet function and can be used
safely without any such risk for bleeding or hematoma. It can
be administered intravenously, and can reduce the need for
opioid analgesics. NSAIDs and coxibs are effective analgesics
and demonstrate an additive effect when combined with
acetaminophen. While NSAIDs affect platelet function and
Table 9.4  The selectivity of different NSAID and COX-2 inhibitors
on the COX-2 and COX-1 isoenzymes
Drug
COX-2/
COX-1 ratio
COX-1/
COX-2 ratio
Aspirin
167
3.1
Naproxen
0.6
1.7
Ketorolac
2
0.5
Diclofenac
2.2
1.4
Indomethacin
30
0.02
Ibuprofen
15
0.007
Piroxicam
33
0.04
Tenoxicam
15
0.62
Meloxicam
0.33
3
Etoricoxib
0.02
344
Celecoxib
0.03
30
Rofecoxib
0.003
272
increase the risk for bleeding and hematoma, coxibs have
minimal risk for bleeding and hematoma formation as well as
a lower risk for GI side effects and better tolerance in asthmat­
ics. However, the risk for thromboembolic side effects prevents
their use in patients with ischemic heart disease or a history
of thrombotic events. Acetaminophen and NSAID/coxib
agents in the perioperative period are well established in
clinical practice. The exact regimen can be tailored for each
individual patient based on risk/side-effect profile of these
agents. In combination with other non-opioid analgesics,
these drugs can be very effective in pain management in
plastic surgery.13
Opioids
Opioids are proven to be effective, reliable, and easily titrated
in the perioperative period. Current formulations are derived
from natural and synthetic sources, and prescriptions of this
class of medication are strictly controlled by the Drug Enforce­
ment Agency of the United States. Opioids act mainly on
opioid receptors in the spinal cord, medulla and cerebral
cortex modifying ascending pain signals and altering the
perception of pain. The bound opioid receptors are also
responsible for the adverse effects including constipation,
sedation, and pruritus.20
In an acute analgesic regimen, opioids may be administered
orally or parenterally. Rapidity of onset and predictable
plasma levels are advantages of parenteral administration,
though disadvantages of IV injection include rapid rise in
plasma concentration, and the need for skilled provider
administration and observation. Patient-controlled analgesia
(PCA) is a modality of delivering opioids that may improve
analgesia and patient satisfaction and reduce side effects by
decreasing total exposure. It has gained popularity due to an
increased safety margin, ease of administration, increased
efficacy of analgesia, and decreased provider workload.20 See
Table 9.5 for dosing. PCA dosing recommendations are out­
lined in Table 9.6. These doses may need to be reduced further
in patients who are at risk of opioid sensitivity (obesity,
obstructive sleep apnea, elderly).
Serious side effects are seen with opioid administration
including addiction, as illustrated by nearly 15 000 prescrip­
tion opioid-related overdose deaths in 2008.20,21 A significantly
increased risk of road trauma is seen with increasing opioid
dose.22 Chronic opioid therapy is also associated with a dose-
dependent increase in the severity of sleep-disordered breath­
ing.23 Furthermore, even short periods of exposure to opioids
are associated with the risk of opioid tolerance and hyperal­
gesia which can potentially lead to chronic pain.24,25
Avoiding adverse effects associated with opioids requires
implementation strategies for decreasing total opioid doses
while maintaining adequate analgesia. Adjuvant medications
as well as surgical anesthetic techniques are paramount to
dose reduction. Opioids prescribed in the immediate postop­
erative period should be emphasized as a short-term regimen
with transition to non-opioids as soon as appropriate.20 Risk
reduction strategies are shown in Table 9.7.
Specific patient populations may be at increased risk for
adverse effects with opioid therapy. These include patients
with obstructive sleep apnea (OSA) and obesity, elderly
patients, and patients on chronic opioid therapy. Obese

105
Opioids
Table 9.5  Opioid dosing
Agonist
Equipotent IV
dose (mg/kg)
Equipotent PO
dose (mg/kg)
Duration
(hr)
Oral
bioavailability
(%)
Comments
Morphine
0.1 (2–4 mg every
2–4 hrs PRN)
0.3
3–4
20–40
“Gold standard”, very inexpensive
Histamine release, vasodilation,
consider avoiding in asthmatics and
in circulatory compromise
Poor oral bioavailability; give 3–5 times
the IV dose
Meperidine
(Demerol®)
1
N/A
3–4
60–80
Catastrophic interactions with MAO
inhibitors
Tachycardia; negative inotrope
Metabolite normeperidine produces
seizures
12.5 mg effectively treats shivering
Not recommended for routine use
Hydromorphone
(Dilaudid®)
0.015–0.2
(0.2–0.5 mg
every 2–4 hrs
PRN)
0.05
3–4
50–70
Commonly used when morphine
produces too many undesirable
systemic side effects
No histamine release
Fentanyl
(Sublimaze®)
0.001 (25–50 mcg
every 5–15 min
in monitored
setting)
N/A
0.5–1
Very effective for short painful
procedures
Vagotonic and can cause bradycardia
Minimal hemodynamic alterations
Chest wall rigidity/glottis closure
Transmucosal dose 10–15 mcg/kg
Transdermal patch available for chronic
pain
Codeine
N/A
1.2 (15–60 mg
every 4–6 hrs
PRN)
3–4
40–70
PO only
“Prodrug” must be converted by
CYP2D6 to morphine to produce
analgesia (ultra-rapid metabolizers
can produce excessive amounts of
morphine, slow metabolizers no
analgesia)
Often combined with acetaminophen
No longer recommended
Contraindicated (“black box warning”)
in pediatric tonsillectomy patients
Hydrocodone
(Vicodin®,
Lortab®)
N/A
0.1 (15–60 mg
every 4–6 hrs
PRN)
3–4
60–80
PO only (liquid and tablet)
Only available in combination with
acetaminophen
DEA class 2 drug
Oxycodone
(Tylox®,
Percocet®,
Oxycontin®)
N/A
0.1 (5–10 mg
every 4–6 hrs
PRN)
3–4
60–80
PO only
Often prescribed with acetaminophen
but available as a single agent
Liquid formulation 1 mg/mL and 20 mg/
mL (potential for catastrophe with
wrong formulation)
Sustained release tablet available,
which cannot be crushed or chewed
(Oxycontin®)
High abuse potential in sustained
release formulation

106
CHAPTER 9 • Anesthesia and pain management in plastic surgery
side effects may contribute to increased all-cause mortality.
Furthermore, the elderly are at risk of long-lasting cognitive
dysfunction postoperatively from anesthesia independent of
postoperative opioid dosing with 17% of patients experienc­
ing dysfunction at 3 months.42 Opioid dosing has not been
found to have a direct link to cognitive dysfunction postop­
eratively. Side effects in conjunction with anesthesia increase
the risk for cognitive complications. Adjuvant anesthetics
play a key role and have been used with much success in
reducing opioid administration by 15–55% in the first 24
hours postoperatively. Adjunctive medications such as acet­
aminophen, NSAIDs, and α-2 agonists may be a mainstay in
therapy for the elderly population, lending to adequate anes­
thesia and limited exposure to opioids.42
It is not uncommon that patients who present for surgery
are taking opioids for various reasons. It is important to deter­
mine the drug, dose, frequency, and duration in developing
a postoperative pain regimen in such patients. Patients who
have been taking opioids for a period in excess of 6 months
are considered chronic opioid users and are likely to have
a tolerance to analgesia and some side effects.20 Additional
acute dosing above baseline chronic dosing must be consid­
ered while exercising caution because of dose-dependent side
effects. Furthermore, patients who have chronic pain and use
chronic opioids have more postoperative pain and resolve
pain more slowly than opioid-naïve patients.43 Chronic
nonmalignant pain is a complicated pathology that may be
managed best by consultation with a pain specialist.
Some chronic opioid users adhere to special regimens
or drugs including methadone or suboxone. Methadone is
used as a long-acting opioid, as well as a drug to facilitate
weaning from opioids.44 Larger doses may be used for with­
drawal prevention. It is essential to determine methadone
indications, and communication with the prescribing
physician to delineate the analgesic plan for the patient
postoperatively.20
Buprenorphine is a unique opioid that tightly binds the
opioid receptor, but elicits low activity.45 This agent can also
be used for chronic pain and opioid addiction. Similar to
methadone, discussion with the prescribing physician is
essential to allow tapering if indicated. Discussion with the
anesthesiologist is also imperative as standard opioid regi­
mens may not be effective immediately postoperatively. Close
monitoring is necessary as discontinuation of buprenorphine
can lead to increased sensitivity to opioids and the concurrent
adverse effects.20
patients have a higher incidence of OSA secondary to increased
soft tissue in and around the pharynx and larynx. This leads
to upper airway obstruction and the propensity for disordered
breathing during sleep. OSA is estimated to affect 9–24% of
middle-aged adults.26 Through a variety of mechanisms,
opioids may contribute to airway obstruction, apnea, and
hypoxemia. Opioids have a dose-dependent effect on genio­
glossus tone, which can contribute to airway obstruction.27
The sedative effect of opioids may also contribute to airway
closure28 while also altering the arousal thresholds that remain
critical in postapneic recovery. Furthermore, postoperative
lung volumes are reduced in OSA patients causing upward
movement of the diaphragm and carina.29 This reduction in
airway length is associated with increased propensity for
airway obstruction.30 Postoperative sleep-disordered breath­
ing is related to opioid dose, and some patients with OSA may
be more sensitive to opioids.31,32 While apneic episodes are
likely to be witnessed and corrected in the post-anesthesia
care unit, these episodes may go unrecognized on the ward
where the nurse-to-patient ratio is lower and patients are
monitored less closely.20 Postoperative desaturation is fairly
common among this population, and cardiorespiratory com­
plications occur with increased frequency.33–36 Cutting the
opioid dose in half or increasing the dosing interval with
prolonged observation may be prudent to avoid adverse
effects. Respiratory failure in OSA patients is transient and
ventilatory support is typically needed for 24 hours postop­
eratively.34 Early utilization of positive airway pressure
therapy in the postoperative period is associated with a sig­
nificant reduction in the incidence of respiratory failure,
intubation, and intensive care utilization.37–40 Recommenda­
tions for postoperative care in this group of patients includes
the use of continuous pulse oximetry, opioid restriction,
increased length of PACU observation, and early postopera­
tive positive airway pressure therapy.41
The aging surgical population necessitates an understand­
ing of the effect of opioid administration in these patients. The
pharmacokinetics and pharmacodynamics of all medications
including opioids may change significantly in the elderly
patient. Changing circulating plasma volume and changes in
body weight composition may lead to a variable effect.
Adverse effects that may be tolerated in younger patients may
have more profound effects in the elderly. The addition of
opioid side effects may increase the likelihood of falls in the
elderly, which can lead to multiple complications with a
higher degree of morbidity and mortality. Additional opioid
Table 9.6  PCA dosing guidelines
Drug
Continuous basal
infusion (mg/hr)
Demand
dose (mg)
Lockout interval
minutes (range)
Number of
demand doses/
hr (range)
4-hour limit
(mcg/kg)
Morphine
(standard 1 mg/mL)
0.5–1
Rare in adults
1
8
(6–15)
5
(1–10)
250
Fentanyl
0.025–0.05
Rare in adults
0.025
15
(6–15)
4
(1–10)
5
Hydromorphone
(standard 0.2 mg/mL)
0.2
Rare in adults
0.2
8
(6–15)
5
(1–10)
50

107
NMDA receptor antagonists and gabapentinoids
Table 9.7  Summary of adverse effect reduction strategies for opioids in special situations
Description
Risk modification
IV PCA
Opioid reduction strategies: intraoperative and postoperative strategies including adjuvant medications
(acetaminophen, ketamine, magnesium, NSAIDs, α2-agonists, gabapentinoids, and liposomal
bupivacaine) and techniques (surgical technique modification and regional and neuraxial anesthesia)
Limit/avoid other sedatives
Oral opioids
Limit postoperative prescription and close follow-up
Limit/avoid other sedatives
Patient education on adverse effects, warning signs
Adjuvant medications (acetaminophen, α2-agonists, gabapentinoids, NSAIDs, and liposomal bupivacaine)
Obesity, OSA
Preoperative screening for OSA
Preoperative consideration for polysomnography
Opioid reduction strategies: intraoperative and postoperative strategies including adjuvant medications
(acetaminophen, ketamine, magnesium, NSAIDs, α2-agonists, gabapentinoids, and liposomal
bupivacaine) and techniques (surgical technique modification and regional and neuraxial anesthesia)
Avoid other sedatives (anxiolytics and sleep aids)
Consider extended monitoring, although controversial
Early postoperative positive airway pressure therapy if significant desaturation occurs
Advise sitting or head up reclining posture when sleeping postoperatively
Elderly patients
Opioid reduction strategies: intraoperative and postoperative strategies including adjuvant medications
(acetaminophen, ketamine, magnesium, NSAIDs, α2-agonists, gabapentinoids, and liposomal
bupivacaine) and techniques (surgical technique modification and regional and neuraxial anesthesia)
Adjuvant analgesia (local, regional, or neuraxial anesthesia, modified surgical technique, and nonsedative
analgesics)
Avoid other sedatives
Opioid tolerant
Continue chronic opioids
High-dose opioid taper
Opioid reduction strategies: intraoperative and postoperative strategies including adjuvant medications
(acetaminophen, ketamine, magnesium, NSAIDs, α2-agonists, gabapentinoids, and liposomal
bupivacaine) and techniques (surgical technique modification and regional and neuraxial anesthesia)
Patient education and establish expectations
IV, intravenous; NSAID, nonsteroidal anti-inflammatory drug; OSA, obstructive sleep apnea.
From Momoh AO, Hilliard PE, Chung KC. Regional and neuraxial analgesia for plastic surgery: surgeon’s and anesthesiologist’s perspectives. Plast Reconstr Surg.
2014;134(4 Suppl 2):58S–68S.
NMDA receptor antagonists and
gabapentinoids
Ketamine
Ketamine works as a noncompetitive N-methyl-D-aspartate
(NMDA) receptor antagonist. The NMDA receptor is activated
with sustained and intense pain stimuli, and has been impli­
cated in both immediate hyperalgesia and long-term changes
in pain perception that may lead to chronic postsurgical pain
(CPSP).46,47 Ketamine has also been shown to downregulate
proinflammatory pathways, which may be the mechanisms
responsible for antihyperalgesia effects.47,48
Ketamine has a half-life of 180 minutes and is metabolized
in the liver, and its unique characteristics include the preser­
vation of respiratory drive and hemodynamic stability.47,49 The
favorable profile of ketamine as an anesthetic agent includes
continuous spontaneous breathing as it has minimal respira­
tory depressant effects and preserves upper airway muscle,
pharyngeal, and laryngeal tone. Further favorable character­
istics include a mild sympathomimetic effect that results from
catecholamine release, and an inhibition of noradrenaline
reuptake leading to an increase in heart rate, stroke volume,
and mean arterial pressures.46,50 This profile is favorable in
hemodynamically unstable patients.
Recent data have demonstrated that ketamine improves
analgesia and reduces opioid requirements in the periopera­
tive setting.51–54 Furthermore, evidence supports the intraop­
erative use of ketamine in patients with chronic pain and
those on chronic high-dose opioids. Reports demonstrate
reduced postoperative pain, as well as reduced opioid con­
sumption.55 The use of ketamine has also been associated
with a significant reduction of opioid-related side effects
including postoperative nausea and vomiting (PONV).51,52
Dose-dependent neuropsychiatric effects, including dyspho­
ria, hallucinations, vivid, unpleasant dreams, and catatonia or
psychoses are potential side effects of ketamine rendering it
unfavorable as a sole anesthetic agent. However, subanes­
thetic doses have a considerably lower incidence of these
adverse effects and seem to be well tolerated.49
There is a lack of data with regard to the use of ketamine
in plastic surgery patients; however, many conclusions can be
extrapolated from the literature and other patient popula­
tions. Low-dose ketamine as an adjunct is most beneficial in
surgeries where postoperative pain is expected to be high.51
The sympathomimetic effects in conjunction with decreased
intraoperative and postoperative opioid requirements may
help to preserve hemodynamic stability and decrease the

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CHAPTER 9 • Anesthesia and pain management in plastic surgery
need for perioperative vasopressor use. Decreasing the need
for perioperative vasopressor use would be ideal for flap
perfusion.49
At subanesthetic doses (0.5 mg/kg bolus or 0.1 mg/kg/h),
ketamine improves analgesia and reduces opioid require­
ments. This effect seems most significant in surgeries that are
expected to be painful and have a moderate and high degree
of pain. Furthermore, the sympathomimetic effects may be
beneficial in maintaining hemodynamic stability. Psychiatric
side effects such as dysphoria and hallucinations seem to be
far less common than with anesthetic doses of ketamine
(1–5 mg/kg), and are reported by multiple authors to be well
tolerated.49
Gabapentinoids
Gabapentin and pregabalin are alkylated analoges of gamma-
aminobutyric acid (GABA). Gabapentin was originally
developed as an anticonvulsant.46 Neither of these agents
exert their clinical effects by way of the GABA-A or GABA-B
receptors. Instead, they seem to bind voltage-gated calcium
channels of cortical and dorsal horn neurons, attenuating
the release of the neuropeptides glutamate, norepineph­
rine, and substance P.46,50 Furthermore, gabapentin may
activate descending inhibitory noradrenergic pathways that
regulate the neurotransmission of pain signals in the dorsal
horn.50,56
Gabapentin has been used successfully in several neuro­
pathic pain states including complex regional pain syndrome,
multiple sclerosis, and postherpetic neuralgia.57–61 Pregabalin
has also been found to be useful in diabetic neuropathy.62 Both
agents are only available as oral preparations and differ in
bioavailability.
Several studies have concluded that both gabapentin and
pregabalin reduce both postoperative pain and opioid use
postoperatively. Overall the gabapentinoids are well tolerated
with the most common transient adverse effects of somno­
lence, dizziness, headaches, balance problems, peripheral
edema, sweating, dry mouth, and nausea and vomiting.46,50,63,64
There remains some debate about the timing and dose of
administration. Higher preoperative doses seem to provide
better analgesia although sedation may be seen. The optimal
duration of postoperative administration remains to be deter­
mined. The overall risk–benefit ratio is likely to favor their use
in procedures that are expected to be painful or that might
cause acute neuropathic pain.49
Local anesthetics
Major improvements in local anesthetic injection and applica­
tion techniques have allowed surgeons more flexibility. Mini­
mizing pain with injection has led to an increase in convenience
while maintaining patient safety and comfort. The wide-
awake approach without sedation has proven to be effective
in hand surgery,65 cosmetic surgery,66 facial skin cancer recon­
struction,67 and adult cleft lip repair68 among others.
Minimizing pain with injection of local
anesthesia (Box 9.1)
Blunt-tipped cannulae have been shown to be effective for the
infiltration of HA fillers in sensitive areas with minimal pain.69
BOX 9.1  Tips for minimizing pain with injection of local anesthesia
• Create skin perforation with a 27-gauge needle
• Switch to a 30-gauge blunt-tipped cannula for injection when
possible
• To promote painless injection of local anesthesia with sharp
needles:
1. Buffer lidocaine and epinephrine with 8.4% sodium
bicarbonate
2. Warm the local anesthetic
3. Distract the patient or area of injection with pressure or soft
pinch near the point of injection
4. Use smaller 27- or 30-gauge needles
5. Stabilize the syringe with both hands to avoid movement of
the needle
6. Inject 0.5 cc perpendicular to the dermis, and subdermally,
followed by a pause until the patient reports no further
needle pain
7. Inject an additional 2 cc before moving the needle followed
by moving and injecting in an anterograde fashion slowly
with 1 cm of local anesthetic palpable or visible ahead of
the needle
8. Always reinsert needles within 1 cm of blanched areas
9. Have patients frequently provide feedback and pain scores
during the injection process
Following skin peforation with a 27-gauge needle, a fine
blunt-tipped 30-gauge cannula is introduced. This method
allows for the painless passing of cannulae beneath the skin
for injection of large areas with local anesthesia with little to
no pain. Furthermore, far less ecchymosis results without the
use of a sharp needle tip.70
Injecting local anesthesia with traditional sharp needles in
an almost painless manner is readily achievable.68,71 When
injecting with sharp needles, the pain of injection can be
mitigated by (1) buffering lidocaine and epinephrine with
8.4% sodium bicarbonate; (2) warming the local anesthetic;
(3) distracting the patient or the area of injection (pinch or
pressure near the injection point); (4) using smaller 27- or
30-gauge needles; (5) stabilizing the syringe with both hands
to avoid movement of the needle; (6) injecting 0.5 cc perpen­
dicularly subdermally followed by a pause until the patient
reports no further needle pain; (7) injecting an additional 2 cc
before moving the needle followed by moving and injecting
in an anterograde fashion very slowly with 1 cm of local
anesthetic palpable or visible ahead of the needle; (8) reinsert­
ing needles within 1 cm of blanched areas; and (9) having
patients provide feedback and scores by relaying pain during
the injection process.67
Liposomal delivery of local anesthetics
Liposomal bupivacaine offers long-lasting local anesthesia by
means of sustained, gradual delivery. With exposure over
time, the vesicular network opens successively thereby releas­
ing the local anesthetic content. With liposomal bupivacaine
in Exparel (Pacira Pharmaceuticals, Inc, San Diego, CA), 3%
of the bupivacaine is initially free at the time of injection for
an immediate effect as with traditional bupivacaine, while the

109
Local anesthetics
Tumescent analgesia in plastic surgery
Tumescent analgesia (TA) delivers a very dilute anesthetic
subcutaneously in a large volume of fluid. This form of local
anesthesia is used most commonly in liposuction, but may be
used in a variety of procedures to reduce intraoperative and
postoperative pain, and decrease the need for additional
anesthetics and narcotics. The added benefit of dilute epi­
nephrine causes vasoconstriction and significantly limits
blood loss.
TA was popularized in the 1990s by Klein for use during
liposuction.77 Currently, TA can be used alone or in conjunc­
tion with other forms of anesthesia. When used in conjunction
with other modalities, TA offers several of the ascribed advan­
tages of multimodal anesthesia.
Tumescent analgesia has been reported in a wide array of
surgical procedures including:
■ Liposuction
■ Subcutaneous mass excision and scar revisions
■ Excisional body contouring (abdominoplasty, body lifts,
brachioplasty, thigh lifts)
■ Breast augmentation, reduction, mastopexy,
gynecomastia, and capsular contracture revision
■ Mastectomy
■ Burn excision and skin grafting
■ Skin procedures (dermabrasion and laser resurfacing)
■ Face and neck lifts
■ Hair grafting
■ Lower extremity varicose vein stripping and
endovascular ablation
■ Lymph node dissections
remainder is contained within the vesicles for gradual deliv­
ery.70 While there is evidence purporting a potentially positive
early experience with liposomal bupivacaine for wound
infiltration, further evidence for its use in plastic surgery is
needed. In particular, it is not FDA-approved for epidural or
peripheral nerve block administration and these routes of
administration are currently being investigated.
Local anesthetic infiltration into operative
sites (wound infiltration)
The injection of bupivacaine into TRAM flap donor sites
decreases opiate requirements in the 72 hours postopera­
tively.72 In another study, patients who received bupivacaine
(0.375%) infused at 4 mL/h used less mean patient-controlled
anesthesia narcotic in the immediate 48 hours postoperatively,
and transitioned to oral narcotics earlier than control patients.
Overall pain satisfaction scores were significantly improved
in the continuous infusion group in comparison to the control
group.73 Furthermore, ropivacaine injection into cleft palate
incision sites demonstrated significantly improved postopera­
tive pain scores at all observational periods in comparison to
the control groups.74
Local anesthetic infiltration via a wound catheter and a
pain pump have shown favorable outcomes in other special­
ties.75 With respect to plastic surgery, there is evidence to show
that bupivacaine wound catheters reduce narcotic use, nausea
and vomiting, and increase overall pain satisfaction scores.73,76
Further studies are necessary to elucidate the advantages of
routine catheter usage in plastic surgery. Maximum dosing
recommendations for different anesthetic techniques are
outlined in Table 9.8.
Table 9.8  Maximum local anesthetic dosing guidelines
Amide drug (concentration range)* and
technique concentration range
Spinal
Caudal/lumbar
epidural
Peripheral
Subcutaneous
Lidocaine (0.5%–2.0%)
(0.5–1.0% infiltration)
(1–2% peripheral, epidural, subcutaneous)
(5% spinal)
1–2.5
5–7§
5–7§
5–7§
Bupivacaine (0.0625–0.5%)
(0.125–0.5% infiltration)
(0.25–0.5% peripheral, epidural,
subcutaneous)
0.3–0.5
2–3§
2–3§
2–3§
Ropivacaine (0.0625–0.5%)
(0.125–0.5% infiltration)
(0.2–0.5% peripheral, epidural, subcutaneous)
0.3–0.5
2–3§
2–3§
2–3§
Prilocaine
(0.5–1% infiltration)
(1–1.5% peripheral)
(2–3% epidural)
NR
5–7§#
5–7§#
5–7§#
Intra-arterial or intravenous injection of these doses may result in systemic toxicity or death.
*Concentrations are displayed in mg percent. Example, a 1% solution contains 10 mg/mL, a 2% solution contains 20 mg/mL.
§The higher dose is recommended only with the coadministration of epinephrine 1:200 000. Maximum epinephrine dose for adults under general anesthesia with volatile
agents is 2–3 mcg/kg.
#Total adult dose should not exceed 600 mg.

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CHAPTER 9 • Anesthesia and pain management in plastic surgery
depression, coma, respiratory depression, and cardiac arrest
may occur.80,86
In the event of local anesthetic toxicity, the following steps
must be taken:
1. Stop infusion of fluids with local anesthetic
2. Assure airway management and oxygenation
3. Call for help
4. Prepare for seizure suppression with benzodiazepines
5. Manage cardiac arrhythmias as per ACLS protocol but
do not use lidocaine
6. Administer 20% Intralipid 1.5 mL/kg (may need to
repeat up to 10 mL/kg) then infuse 0.25 mL/kg/h if
cardiac effects persist
7. Isolated neurologic events (seizures) can be treated with
benzodiazepines (midazolam, diazepam, or lorazepam)
or propofol. Propofol should NOT be used as a lipid
substitute for cardiac arrest.
High tumescent fluid injection volumes may lead to intra­
vascular fluid overload with cardiac and pulmonary conse­
quences. With high infusion volumes, administration of
other fluids must be titrated. In patients with cardiac, pul­
monary, or renal compromise who are at higher risk for
fluid overload, the volume of TA administration must be
limited.80
In large volume liposuction, mild hyponatremia and hypo­
kalemia may occur. This is rarely a clinical concern, but nev­
ertheless, one must be aware of this potential problem in large
volume liposuction.87 Furthermore, large volumes of room
temperature tumescent fluid may lower body temperature.
Therefore, in cases prone to hypothermia, such as large
volume, and large surface area, tumescent fluid should be
warmed to 37°C, in addition to other warming measures to
avoid hypothermia.80
Regional and neuraxial analgesia
in plastic surgery
Regional analgesic modalities deliver local anesthetics to
groups of peripheral nerves outside the central nervous
system, thereby blocking sensation to specific dermatomes.
Neuraxial techniques deliver local anesthetic and analgesic
agents directly or indirectly to the spinal cord or neuraxis.
The benefits of regional and neuraxial techniques parallel
those of multimodal anesthesia and include improved pain
control, decreased narcotic use, and narcotic-associated side
effects, shorter hospital stays, and better patient-reported
outcomes.88
Paravertebral block
The paravertebral block (PVB) involves the injection of a local
anesthetic into the paravertebral space. The thoracic paraver­
tebral space is triangular in shape and is bordered anteriorly
by the parietal pleura, medially by the vertebral column, and
posteriorly by the superior costotransverse ligament. The
nerve root divides into dorsal and ventral rami as it exits the
neuroforamen. Ventral rami become the intercostal nerves
that provide sensation to the abdomen and chest wall. This
targets the nerve root as it emerges from the neuraxis (Fig.
9.1), thereby providing ipsilateral analgesia in the specific
■ Thyroidectomy
■ Hernia repair
Fluid composition
Several TA fluid formulas have been described77–79 and are
based on either 1000 mL of 0.9% saline or Lactated Ringer’s
solution.80 Lidocaine is the most frequently used local anes­
thetic in tumescent fluid, however various local anesthetics
have been used. A combination of lidocaine and bupivacaine
has been described in abdominoplasty combined with lipo­
suction without any complications.81 In patients with liver
dysfunction, care should be taken with dosing as the amide
agents (lidocaine, bupivacaine, ropivacaine) are metabolized
by the liver. Furthermore, while lidocaine and bupivacaine
can safely be used in combination, there is little guidance
with respect to the upper limits of dosing when used in
combination.80
The reported dose limitation for lidocaine with epinephrine
is 7 mg/kg; however, doses of 35 mg/kg are frequently used
during liposuction,77 and up to 55 mg/kg have been reported
without complications.82 Peak lidocaine blood levels occur
10–14 hours following infiltration.83 In highly vascularized
areas, such as above the clavicle, plasma lidocaine levels peak
at approximately 6 hours after injection.84 Due to peak plasma
concentrations occurring several hours following injection,
patients may experience toxicity well after the procedure has
been completed and following discharge.
Epinephrine in tumescent analgesia
The maximal hemostatic effects of epinephrine occur 25
minutes after administration rather than the commonly held
belief that this occurs at 7–10 minutes.85 However, only a
minimal improvement in the hemostatic effect is achieved
after 15 minutes. Epinephrine has a 2–3 minute half-life, and
therefore there are no clear dosing guidelines when used in
TA. An upper limit of 10 mcg/kg has been suggested but this
depends on cofactors like the co-administration of volatile
anesthetic agents. Arrhythmias can develop in adults under
general anesthesia with isoflurane, sevoflurane or desflurane
with as little as 2–3 mcg/kg. Pediatric patients appear to toler­
ate 10 mcg/kg under volatile anesthesia without arrhythmias.
Epinephrine should be avoided in patients with pheochro­
mocytoma, hyperthyroidism, severe hypertension, cardiac
disease, or peripheral vascular disease.86
Complications of tumescent anesthesia
Though complications are rare, one must be aware of possible
complications particularly in high volume tumescent infil­
tration. Lidocaine is commonly used in doses of 35–55 mg/
kg and this is considered safe in TA. Cardiac monitoring is
suggested with doses over 35 mg/kg as lidocaine toxicity
can cause cardiac and neurologic complications. In cases of
high volume infiltration, extended monitoring is suggested
due to peak plasma levels occurring 10–14 hours after admin­
istration. Signs and symptoms of lidocaine toxicity include
restlessness, drowsiness, light-headedness, metallic taste in
the mouth, tinnitus, slurred speech, and peri-oral numbness
and tingling. At higher plasma levels, shivering, muscle
twitching, tremors, convulsions, central nervous system

111
Local anesthetics
reason for the limited use of PVBs in outpatient plastic surgery
procedures. Use of ultrasound guidance helps avoid this
complication. Additional complications include epidural
spread, hypotension, bradycardia, and intravascular injec­
tions may cause toxicity.88
Transversus abdominis plane block
The transversus abdominis plane (TAP) block places a long-
acting local anesthetic in the fascial plane between the trans­
versus abdominis and the internal oblique (Fig. 9.2). This
technique blunts the afferent sensory component of the termi­
nal branches of intercostal nerves resulting in analgesia of the
abdominal wall. In the traditional TAP block, the tenth
thoracic (T10) through first lumbar (L1) terminal branches are
the nerves typically targeted. The fascial plane between the
dermatomal segments.88 In contrast to neuraxial analgesic
techniques, the central nervous system is usually avoided
along with the associated complications such as hypotension,
urinary retention and bradycardia.
Long-lasting analgesia can be achieved by inserting a
catheter into the paravertebral space to provide continuous
infusion of local anesthetic in the early postoperative
period.89,90 Depending on the location of the block, this tech­
nique can be used in breast, thoracic, and abdominal proce­
dures. Indications and contraindications for paravertebral
and neuraxial blocks are outlined in Table 9.9. While PVBs
facilitate outpatient surgical management and early discharge
by providing long-lasting analgesia with few side effects, this
technique poses a risk for pneumothorax due to the proximity
of the lung to the paravertebral space. Although this risk is
less than 1%, this potential complication is likely a major
Fig. 9.1  Paravertebral anatomy. (Adapted from Momoh
AO, Hilliard PE, Chung KC. Regional and neuraxial
analgesia for plastic surgery: surgeon’s and
anesthesiologist’s perspectives. Plast Reconstr Surg.
2014;134(4 Suppl 2):58S–68S.)
Rib
Vertebral
body
Transverse
process
Paravertebral
space
Lung
Parietal
pleura
Fig. 9.2  Transversus abdominis plane block anatomy. EO,
external oblique; IL, longissimus iliocostalis; IO, internal
oblique; LD, latissimus dorsi; LV, lumbar vertebra; MM,
multifidus muscle; PM, psoas major; QL, quadratus
lumborum; ST, subcutaneous tissue; TA, transversus
abdominis muscle. (Adapted from Momoh AO, Hilliard PE,
Chung KC. Regional and neuraxial analgesia for plastic
surgery: surgeon’s and anesthesiologist’s perspectives. Plast
Reconstr Surg. 2014;134(4 Suppl 2):58S–68S.)
Needle
US probe
TA
IO
LD
IL
QL
PM
LV
MM
ST
EO

112
CHAPTER 9 • Anesthesia and pain management in plastic surgery
Table 9.9  Indications and contraindications for regional and neuraxial techniques
Technique
Performed by
Indications
Contraindications
Paravertebral
block
Anesthesiologist
Thoracic and abdominal surgical procedures
Use as primary anesthetic or as adjunct to
primary anesthetic
Inpatient and ambulatory surgery procedures
Rescue analgesia after failure of oral or
parenteral analgesia
Early postoperative mobilization desired
Patient refusal
Coagulopathy or bleeding diathesis
Localized infection at injection site
Allergy to local anesthetics
Prophylactic anticoagulation therapy*
Inability to communicate with patient*
Transversus
abdominis
block
Anesthesiologist or
surgeon
Lower abdominal surgical procedures
Adjunct to primary anesthetic
Inpatient and ambulatory procedures
Early postoperative mobilization desired
Patient refusal
Localized infection at injection site
Allergy to local anesthetics
Epidural
Anesthesiologist
Thoracic, abdominal, and lower extremity
surgical procedures
Use as primary anesthetic or as adjunct to
primary anesthetic
Indwelling catheter for postoperative analgesia
limited to inpatient procedures only
Patient refusal
Coagulopathy or bleeding diathesis
Localized infection at injection site
Systemic infection
Allergy to local anesthetics
Elevated intracranial pressure
Severe hypovolemia
Severe aortic or mitral stenosis
Prior back surgery at injection site*
Prophylactic anticoagulation therapy*
Inability to communicate with patient*
*Relative contraindication
From Momoh AO, Hilliard PE, Chung KC. Regional and neuraxial analgesia for plastic surgery: surgeon’s and anesthesiologist’s perspectives. Plast Reconstr Surg.
2014;134(4 Suppl 2):58S–68S.
transversus abdominis and internal oblique is a relatively
avascular plane and this may account for the slow drug clear­
ance and subsequent prolonged duration of analgesia.91,92 The
TAP block can be performed intraoperatively by anesthesiolo­
gists or surgeons with ultrasound guidance percutaneously
or directly through exposed fascia (Fig. 9.3). The TAP block is
typically used in combination with other anesthetic modali­
ties as its primary analgesic effects are within the abdominal
wall and may not address visceral pain associated with intra-
abdominal procedures.88
The ultrasound probe is placed within the lumbar triangle
of Petit, the boundaries of which are the costal margin supe­
riorly, the iliac crest inferiorly, the external oblique anteriorly,
and the latissimus dorsi posteriorly. Local anesthetic is then
infiltrated in the fascial plane between the internal oblique
and transversus abdominis. Catheters may be placed for
continuous or intermittent infusion. A subcostal approach to
the TAP block is also possible and provides analgesia to the
supraumbilical abdomen (T7–T9). The subcostal TAP block is
unlikely to be used alone as most abdominal procedures in
plastic surgery also involve the lower abdomen.88
Though complications are rare with the TAP block, they
include hematoma and intraperitoneal injection with injury to
intra-abdominal organs.93–95
Neuraxial analgesia
Spinal and epidural anesthesia
Spinal anesthesia is a neuraxial blockade of spinal nerve roots
as they travel through the subarachnoid space. This type of
Fig. 9.3  (A) Intraoperative, ultrasound-guided delivery of TAP block. Note
concurrent inset of flap in background. (B) Ultrasound scan of transversus
abdominis plane (TAP) block. EOM, external oblique muscle; IOM, internal oblique
muscle; TAM, transversus abdominis muscle. (A, from Whebl GAC, Tan EKH.
Transversus abdominis plane block in autologous breast reconstruction: a UK
hospital experience. J Plast Reconstr Aesth Surg. 2013;66(12):1665–1670.
© British Association of Plastic, Reconstructive and Aesthetic Surgeons 2013. B,
from Ross AK, Bryskin RB. Regional anesthesia. In: Davis PJ, Cladis FP, Motoyama
EK (eds). Smith’s Anesthesia for Infants and Children. 2011;452–510. © Mosby
2011.)
A
Subcutaneous fat
EOM
IOM
TAM
Peritoneum
Anterior
Posterior
B

113
Local anesthetics
Cardiovascular sequelae are primarily due to efferent sympa­
thetic blockade leading to an uncompensated decrease in
systemic vascular resistance. A decrease in preload in conjunc­
tion with an unopposed vagal influence leads to a decreased
heart rate and cardiac output.97 Hypotension and bradycardia
are usually mild and readily respond to treatment.88
Respiratory complications typically occur as a result of
blockade of the intercostal and abdominal muscles needed
for forceful exhalation. Inhalation remains unaffected as the
diaphragmatic innervation is spared. While accessory muscles
are not essential for expiration in healthy patients, those with
pulmonary disease such as asthma or COPD may be prone
to complications. Therefore, careful patient selection is
crucial, as is the preparedness to manage these potential
complications.88
The majority of regional and neuraxial techniques are better
established in other surgical fields including general surgery,
urologic surgery, and gynecologic surgery. However, applica­
tions in plastic surgery are increasing. These techniques are
best implemented in collaboration with anesthesiologists.88
block is also frequently referred to as a subarachnoid block,
or intrathecal injection. This technique provides rapid and
deep anesthesia below the level of the block, and is generally
confined to shorter procedures of the lower extremities or
pelvis, therefore limiting its utility in a large portion of plastic
surgery procedures.
Epidural anesthesia blocks the spinal nerve roots outside
of the subarachnoid space (Fig. 9.4). It has a wide range
of applications including operative anesthesia, obstetric and
postoperative analgesia, and chronic pain management. The
epidural technique is advantageous because it allows a cath­
eter to be placed in the epidural space anywhere along the
neuraxis to provide continual analgesia via infusion. Thoracic
epidurals may spare motor nerves to the lower extremities as
well as micturition pathways, thereby allowing for early
ambulation and the avoidance of prolonged urinary catheter
use. An epidural may be used as the primary anesthetic for
surgery, but typically this requires high doses of local anes­
thetic and is often combined with other modalities.88 The
epidural is an excellent form of analgesia for surgery involv­
ing the lower extremities, particularly reconstruction with
microvascular work. The sympathectomy may provide an
advantage by enhancing blood flow to the extremity.
Lumbar neuraxial procedures are performed with the
patient in the seated position (Fig. 9.5). Full neck and back
flexion overcomes lumbar lordosis by widening the gap
between adjacent lumbar spinous processes. This opens the
interlaminar space and facilitates access to the neuraxis. The
L3/L4, L4/L5, or L5/S1 interspaces are frequently chosen for
analgesia of the pelvis and lower extremities. It is prudent to
place a Foley catheter and implement fall precautions when
epidurals are used in the postoperative period.88
Complications of the epidural blocks are typically related
to technique or physiologic effects of the neuraxial injection.
Complications related to technique include spinal headaches,
transient paresthesias, peripheral neuropathy, epidural
abscesses, and epidural hematomas. Physiologic complica­
tions include cardiovascular, respiratory, thermoregulatory,
and urogenital sequelae.
Cardiovascular effects are not uncommon and typically
include hypotension with an incidence as high as 33%.96
Fig. 9.4  Needle placement for medication delivery in spinal and epidural anesthesia. (Adapted from Momoh AO, Hilliard PE, Chung KC. Regional and neuraxial analgesia for
plastic surgery: surgeon’s and anesthesiologist’s perspectives. Plast Reconstr Surg. 2014;134(4 Suppl 2):58S–68S.)
Supraspinous ligament
Interspinous ligament
Ligamentum flavum
Dura mater
Spinal space
(subarachnoid space)
containing
cerebrospinal fluid
Epidural block
Spinal block
LV
LIV
Cauda equina
Epidural space
Fig. 9.5  Placement of a thoracic epidural block for postoperative pain control.
(From Barrington MJ, Scott DA. Do we need to justify epidural analgesia beyond
pain relief? 2008;372:514–516. © Lancet 2008.)

114
CHAPTER 9 • Anesthesia and pain management in plastic surgery
Summary
One of the most common concerns reported by patients prior
to surgery is the presence of postoperative pain.2 Evidence
reveals that adequate postoperative analgesia is only achieved
in a minority of patients.98 Furthermore, reports in the United
States reveal that 86% of adult surgical patients experienced
pain after surgery, of which 75% had moderate-to-severe pain
in the immediate postoperative period, and 74% experienced
similar levels of pain after being discharged home.99 These
findings reveal that advances in surgical and analgesic tech­
niques have had minimal clinical effect on postoperative pain
management.100
It is well established that unrelieved postoperative pain is
linked to adverse physiologic changes that may increase
adverse postoperative outcomes including morbidity and
mortality.3 Furthermore, limitations in movement secondary
to pain can prolong rehabilitation, reduce health-related
quality of life, and delay return to normal daily activities.5,100–103
Increased cost of care, prolonged hospital length of stay,
readmissions, or unexpected admissions, and patient dissat­
isfaction are common consequences of these adverse
outcomes.104–106
The concept of multimodal analgesia was developed with
the understanding that postoperative pain is a complex and
multifactorial phenomenon. As such, combinations of analge­
sics of different classes acting upon various target sites may
provide superior pain relief with a lower incidence of adverse
effects.107–109 The goal of multimodal analgesia is to improve
pain relief while reducing opioid requirements and the
adverse effects of opioids or any other single agent.
Future considerations include establishing sufficient evi­
dence for multimodal analgesia in plastic surgery while
optimizing analgesic regimens. Use of patient-specific and
procedure-specific pain management strategies should
improve pain control, and perioperative outcomes including
rehabilitation and return to activities of daily living.
24. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative
systematic review. Anesthesiology. 2006;104:570–587. Evidence
suggests that opioid-induced hyperalgesia does develop in humans.
Previous or ongoing exposure to opioids, and high intraoperative opioid
use appear to increase postoperative opioid requirements. In the animal
model this hyperalgesia may last for hours to days. The opioid receptor
appears to be an important site for this process.
32. Brown KA, Laferriere A, Moss IR. Recurrent hypoxemia in
young children with obstructive sleep apnea is associated with
reduced opioid requirement for analgesia. Anesthesiology.
2004;100:806–810. Recurrent hypoxemia in children increases their
sensitivity to opioids. Children with severe OSA require half as much
opioid after tonsillectomy as children without OSA. This implies that
pediatric patients with severe OSA will require significantly less opioid
in the postoperative period.
55. Loftus RW, Yeager MP, Clark JA, et al. Intraoperative ketamine
reduces perioperative opiate consumption in opiate-dependent
patients with chronic back pain undergoing back surgery.
Anesthesiology. 2010;113:639–646. In a randomized controlled trial,
intraoperative administration of ketamine (0.5 mg/kg load with 10 mcg/
kg/min infusion) reduced opioid consumption after spine surgery in these
patients with chronic pain who are opioid-tolerant.
89. Ilfeld BM, Madison SJ, Suresh PJ, et al. Treatment of
postmastectomy pain with ambulatory continuous paravertebral
nerve blocks: a randomized, triple-masked, placebo-controlled
study. Reg Anesth Pain Med. 2014;39:89–96. For mastectomy, adding a
multiple-day, ambulatory, continuous ropivacaine infusion to a
single-injection ropivacaine paravertebral nerve block results in improved
analgesia and less functional deficit during the infusion.
91. McDonnell JG, O’Donnell B, Curley G, et al. The analgesic
efficacy of transversus abdominis plane block after abdominal
surgery: a prospective randomized controlled trial. Anesth Analg.
2007;104:193–197. A single injection (bilateral) TAP block resulted in
lower VAS pain scores and lower opioid requirements 24 hours after
bowel surgery in adults.
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Surg. 2014;134:69S–82S.
50. Schmidt PC, Ruchelli G, Mackey SC, Carroll IR. Perioperative
gabapentinoids: choice of agent, dose, timing, and effects
on chronic postsurgical pain. Anesthesiology. 2013;119:
1215–1221.
51. Laskowski K, Stirling A, McKay WP, Lim HJ. A systematic review
of intravenous ketamine for postoperative analgesia. Can J Anaesth.
2011;58:911–923.
52. Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for
acute postoperative pain. Cochrane Database Syst Rev.
2006;(1):CD004603.
53. Elia N, Tramer MR. Ketamine and postoperative pain–a
quantitative systematic review of randomised trials. Pain.
2005;113:61–70.
54. McCartney CJ, Sinha A, Katz J. A qualitative systematic review of
the role of N-methyl-D-aspartate receptor antagonists in
preventive analgesia. Anesth Analg. 2004;98:1385–1400.
55. Loftus RW, Yeager MP, Clark JA, et al. Intraoperative ketamine
reduces perioperative opiate consumption in opiate-dependent
patients with chronic back pain undergoing back surgery.
Anesthesiology. 2010;113:639–646. In a randomized controlled trial,
intraoperative administration of ketamine (0.5 mg/kg load with 10 mcg/
kg/min infusion) reduced opioid consumption after spine surgery in these
patients with chronic pain who are opioid-tolerant.
56. Hayashida K, DeGoes S, Curry R, Eisenach JC. Gabapentin
activates spinal noradrenergic activity in rats and humans and
reduces hypersensitivity after surgery. Anesthesiology.
2007;106:557–562.
57. Rosner H, Rubin L, Kestenbaum A. Gabapentin adjunctive therapy
in neuropathic pain states. Clin J Pain. 1996;12:56–58.
58. Mellick GA, Mellick LB. Reflex sympathetic dystrophy treated
with gabapentin. Arch Phys Med Rehabil. 1997;78:98–105.
59. Houtchens MK, Richert JR, Sami A, Rose JW. Open label
gabapentin treatment for pain in multiple sclerosis. Mult Scler.
1997;3:250–253.
60. Rice AS, Maton S. Gabapentin in postherpetic neuralgia: a
randomised, double blind, placebo controlled study. Pain.
2001;94:215–224.
61. Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the
treatment of postherpetic neuralgia: a randomized controlled trial.
JAMA. 1998;280:1837–1842.
62. Lesser H, Sharma U, LaMoreaux L, Poole RM. Pregabalin relieves
symptoms of painful diabetic neuropathy: a randomized
controlled trial. Neurology. 2004;63:2104–2110.
63. Ho KY, Gan TJ, Habib AS. Gabapentin and postoperative pain–a
systematic review of randomized controlled trials. Pain.
2006;126:91–101.
64. Gajraj NM. Pregabalin: its pharmacology and use in pain
management. Anesth Analg. 2007;105:1805–1815.
65. Lalonde DH. Reconstruction of the hand with wide awake surgery.
Clin Plast Surg. 2011;38:761–769.
66. Mustoe TA, Buck DW 2nd, Lalonde DH. The safe management of
anesthesia, sedation, and pain in plastic surgery. Plast Reconstr
Surg. 2010;126:165e–176e.
67. Strazar AR, Leynes PG, Lalonde DH. Minimizing the pain of local
anesthesia injection. Plast Reconstr Surg. 2013;132:675–684.
68. Lalonde DH, Price C, Wong AL, Chokotho T. Minimally painful
local anesthetic injection for cleft lip/nasal repair in grown
patients. Plast Reconstr Surg Glob Open. 2014;2:e171.
69. Berros P, Braz AV, Trevidic P, et al. Evolution in technique: use of
hyalurostructure for lips rejuvenation as an alternative to needle
injection without troncular anesthesia. J Cosmet Laser Ther.
2013;15:279–285.
70. Lalonde D, Wong A. Local anesthetics: what’s new in minimal
pain injection and best evidence in pain control. Plast Reconstr
Surg. 2014;134:40S–49S.
71. Farhangkhoee H, Lalonde J, Lalonde DH. Teaching medical
students and residents how to inject local anesthesia almost
painlessly. Can J Plast Surg. 2012;20:169–172.
72. Utvoll J, Beausang-Linder M, Mesic H, Raeder J. Brief
report: improved pain relief using intermittent bupivacaine
injections at the donor site after breast reconstruction with
deep inferior epigastric perforator flap. Anesth Analg.
2010;110:1191–1194.
73. Heller L, Kowalski AM, Wei C, Butler CE. Prospective,
randomized, double-blind trial of local anesthetic infusion and
intravenous narcotic patient-controlled anesthesia pump for pain
management after free TRAM flap breast reconstruction. Plast
Reconstr Surg. 2008;122:1010–1018.
74. Coban YK, Senoglu N, Oksuz H. Effects of preoperative local
ropivacaine infiltration on postoperative pain scores in infants and
small children undergoing elective cleft palate repair. J Craniofac
Surg. 2008;19:1221–1224.
75. Liu SS, Richman JM, Thirlby RC, Wu CL. Efficacy of continuous
wound catheters delivering local anesthetic for postoperative
analgesia: a quantitative and qualitative systematic review of
randomized controlled trials. J Am Coll Surg. 2006;203:914–932.
76. Rawlani V, Kryger ZB, Lu L, Fine NA. A local anesthetic pump
reduces postoperative pain and narcotic and antiemetic use in
breast reconstruction surgery: a randomized controlled trial. Plast
Reconstr Surg. 2008;122:39–52.
77. Klein JA. Tumescent technique for local anesthesia improves
safety in large-volume liposuction. Plast Reconstr Surg.
1993;92:1085–1098.
78. Nagy MW, Vanek PF Jr. A multicenter, prospective, randomized,
single-blind, controlled clinical trial comparing VASER-assisted
lipoplasty and suction-assisted lipoplasty. Plast Reconstr Surg.
2012;129:681e–689e.
79. Prado A, Andrades P, Danilla S, et al. A prospective, randomized,
double-blind, controlled clinical trial comparing laser-assisted
lipoplasty with suction-assisted lipoplasty. Plast Reconstr Surg.
2006;118:1032–1045.
80. Gutowski KA. Tumescent analgesia in plastic surgery. Plast
Reconstr Surg. 2014;134:50S–57S.
81. Swanson E. Prospective study of lidocaine, bupivacaine, and
epinephrine levels and blood loss in patients undergoing
liposuction and abdominoplasty. Plast Reconstr Surg.
2012;130:702–722.
82. Ostad A, Kageyama N, Moy RL. Tumescent anesthesia with a
lidocaine dose of 55 mg/kg is safe for liposuction. Dermatol Surg.
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83. Klein JA. Tumescent technique for regional anesthesia permits
lidocaine doses of 35 mg/kg for liposuction. J Dermatol Surg Oncol.
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114.e3
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85. McKee DE, Lalonde DH, Thoma A, et al. Optimal time delay
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88. Momoh AO, Hilliard PE, Chung KC. Regional and neuraxial
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89. Ilfeld BM, Madison SJ, Suresh PJ, et al. Treatment of
postmastectomy pain with ambulatory continuous paravertebral
nerve blocks: a randomized, triple-masked, placebo-controlled
study. Reg Anesth Pain Med. 2014;39:89–96. For mastectomy, adding a
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single-injection ropivacaine paravertebral nerve block results in improved
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90. Jüttner T, Werdehausen R, Hermanns H, et al. The paravertebral
lamina technique: a new regional anesthesia approach for breast
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91. McDonnell JG, O’Donnell B, Curley G, et al. The analgesic efficacy
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lower VAS pain scores and lower opioid requirements 24 hours after
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92. McDonnell JG, Curley G, Carney J, et al. The analgesic efficacy of
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10 
Evidence-based medicine and health
services research in plastic surgery
Claudia R. Albornoz, Carolyn L. Kerrigan, E. Dale Collins Vidal, Andrea L. Pusic, and
Amy K. Alderman
SYNOPSIS
The key take-home messages from this chapter are how to:
■ Gather existing evidence on outcomes
■ Interpret evidence on outcomes
■ Design new studies to add evidence on outcomes
■ Identify and analyze existing sources of data to create new evidence
on outcomes
■ Capture the patients’ perspective on outcomes
■ Recognize the importance of an essential dimension of evidence: the
patients’ perspective
■ Consider the cost dimension in achieving outcomes
■ Understand the challenges and approaches in translating good
evidence into daily clinical practice.
Physicians must make complex decisions in situations of
uncertainty – often with incomplete, inaccurate, or outdated
information. The goal of outcomes research is to improve the
information available to make these complex decisions. It is
important to understand that measuring outcomes is not just
about the final result of our interventions. More importantly,
it is a means by which we gather evidence to improve
decision-making, the processes of care, and the systems in
which we work. Maximizing patient care and surgical out­
comes requires continuous efforts to identify information
needs and to produce the best evidence to fulfill these needs.
The best evidence – where do we
find it?
There are two ways to obtain best evidence for decision-
making to improve quality of care (Fig. 10.1). The first is to
evaluate existing data and identify those reports that are
convincing based on a good study design and clinically mean­
ingful outcomes. When the current evidence is inadequate, the
second choice is to produce new credible evidence. This section
will describe a structure for evaluating existing evidence and
then introduce methods for producing best evidence.
Evaluating existing literature
Best evidence requires three things: (1) a good study design;
(2) an appropriate statistical analysis; and (3) clinically mean­
ingful outcome measures. In a thorough review, Offer and
Perks1 have enumerated the challenges that plastic surgeons
face when trying to practice evidence-based medicine. They
cite the lack of quality evidence in our literature as a major
factor. Even a superficial perusal of our journals makes it clear
that they are replete with descriptions of procedures by indi­
vidual surgeons and the “outcomes” of those procedures in
that surgeon’s hands. These studies, known as case reports or
case series, have limited applicability to other practices, and
are not structured, not compared, and not randomized. This
is not only weak evidence on which to make medical deci­
sions, but it is not an acceptable way to make such decisions
in this era of healthcare reform and pay for performance
(P4P).2 As shown in Fig. 10.1, the stronger the evidence, the
better the care one is able to deliver.
Literature search strategies
Practicing evidence-based medicine involves searching for
the best available research, appraising the relevant studies for
validity, and then translating the evidence to optimize patient
care.3 Many clinical questions remain unanswered because of
problems formulating relevant questions, insufficient access
to information resources, and a lack of search skills.4 Today,
there are a variety of strategies and web-based resources that
allow searches of the relevant literature to answer many clini­
cal questions. Some examples are provided below.
PubMed
The US National Library of Medicine provides access to more
than 16 million citations through PubMed, accessing refer­
ences from MEDLINE and directly from journals. Information

116
CHAPTER 10 • Evidence-based medicine and health services research in plastic surgery
Meta-analysis has some disadvantages. First, meta-analysis
has been criticized for both overly broad inclusion criteria and,
conversely, for overly strict inclusion criteria. Either may result
in degradation of the results. Inclusion criteria that are overly
broad may lead to inclusion of studies of lesser quality or with
less reliable results. Very strict inclusion criteria may mean
that the studies that are included have limited generalizability.
Another disadvantage is that meta-analyses are costly and
require a significant time commitment from the research team.
The technique of meta-analysis may have limited applica­
bility in plastic surgery, where there are few randomized trials
and the metrics from one study to another may vary consider­
ably. An example of a meta-analysis can be seen in Fig. 10.2.6
This figure demonstrates an analysis of randomized trials
evaluating the impact of tamoxifen on survival. As the reader
can observe, there are multiple studies, with the findings of
each plotted on a central axis. The summary analysis, which
incorporates data from these studies, appears at the bottom
of the vertical axis and suggests a benefit for the use of tamoxi­
fen in early breast cancer. As can be seen, the 95% confidence
interval for that summary measure is quite narrow. This
implies a better point estimate of the true benefit of tamoxifen.
Also note that the quality of the individual study is used to
determine its weight in computing the summary score.
More recently, researchers conducted a meta-analysis of
randomized controlled trials comparing rates of capsular
contracture using either smooth or textured implants. These
authors identified seven randomized controlled trials that
addressed this issue. Individually four of the seven studies
did not find a statistically significant decrease in the rate
of contracture with textured implants. However, when the
results of the studies were pooled, the meta-analysis sug­
gested that textured implants had lower rates of contracture.7
To see further examples of good-quality meta-analyses, the
reader is referred to the online Cochrane reviews.8
Systematic reviews
Systematic reviews are evaluations of the literature conducted
according to clearly stated, scientific research methods that
are designed to minimize the risk of bias and the errors associ­
ated with traditional literature reviews. The review process
includes a comprehensive search based on defined criteria
and includes a thorough evaluation of the quality and validity
of the studies identified in the search process.9
The best-known source for systematic reviews is the
Cochrane Database of Systematic Reviews, which contains
over 3600 completed reviews.8 The Cochrane Group also
provides a handbook for systematic reviews of interventions
which prescribes seven steps for preparing a review:
1. Structuring the question
2. Identifying possible studies for inclusion
3. Evaluating selected studies
4. Data collection and synthesis
5. Analyzing results
6. Discussing the findings
7. Updating reviews
Systematic reviews are influential tools in supporting
evidence-based practice and some consider them to provide
stronger evidence than randomized controlled trials. More­
over, they are essential for summarizing existing data, thereby
Fig. 10.1  Improved care is linked to better evidence.
Produce
evidence
Identify
needs
Outcomes
research
Improving
care
from PubMed searches has been shown to improve both
patient care and health outcomes significantly.4
Clinical Queries
Clinical Queries is a feature of PubMed that can help identify
citations with the study design of interest. It is able to link the
type of question (e.g., intervention, diagnosis, natural history,
and outcome) to a search strategy that specifies the desired
study design.4
PICO
The critical first step in the pursuit of evidence-based medicine
is to ask a well-formulated question. Without sufficient focus
and specificity, an otherwise relevant and important clinical
question can be mired in irrelevant evidence. When the PICO
framework is used with the PubMed Clinical Queries (see
above), it has been shown to improve the efficiency of the
literature search. The acronym PICO stands for patient
problem, intervention, comparison, and outcome, and is a
strategy to pose a well-formulated question.4 In a literature
search for evidence in plastic surgery, for example, a question
framed using the PICO approach might be expressed this
way: In patients undergoing breast reduction (P), preopera­
tive antibiotic prophylaxis (I) versus no prophylaxis (C), what
is the rate of postoperative infections (O)?
Meta-analysis
Conceptually, a meta-analysis is the summation of multiple
qualitative studies in order to increase the sample size, thus
strengthening the conclusions over that which can be drawn
from an individual article. This analysis allows researchers to
reach a more reliable conclusion when there are conflicting
results from multiple studies.5 Ideally, a meta-analysis is con­
ducted using the highest level of evidence, such as randomized
controlled clinical trials. Although meta-analysis can also be
conducted on cohort studies and even case series, the quality
of the evidence and, therefore, the conclusions are weaker.

117
Study design and levels of evidence
Fig. 10.2  Meta-analysis of
randomized controlled trials
evaluating the impact of adjuvant
tamoxifen on survival risk among
women with early breast cancer.
(Early Breast Cancer Trialists’
Collaborative Group. Tamoxifen
for early breast cancer. Cochrane
Database of Systematic Reviews.
2001:4.) Multiple studies have
been included, with the findings
of each plotted on the central
axis. Data are represented as an
odds ratio. (Odds ratio, similar to
relative risk, reports the
proportion of an occurrence to a
nonoccurrence.) The summary
analysis, which incorporates data
from these studies, appears at the
bottom of the vertical axis and
suggests a benefit for the use of
adjuvant tamoxifen in early breast
cancer.
Study
Tamoxifen
Control
Peto Odds Ratio 99% CI Weight %
Peto Odds Ratio 99% CI
03 Tamoxifen for average of 3 or more (median: 5) years

CRFB Caen 002
33 / 250
38 / 244

0.6
0.85 [0.46, 1.58]

CRFB Caen C5 post
57 / 89
64 / 90

0.9
0.82 [0.50, 1.34]

FASG GFEA 02
68 / 375
104 / 368

1.3
0.61 [0.41, 0.92]

GROCTA I Italy ER+
57 / 171
86 / 168

1 .1
0.51 [0.33, 0.80]

Marseille post
15 / 37
8 / 34

0.2
1.94 [0.63, 5.93]

NSABP B-14 N- ER+
248 / 1439
278 / 1453

4.2
0.88 [0.70, 1.11]

Osaka
10 / 53
12 / 55

0.2
0.82 [0.27, 2.47]

Scottish
305 / 666
354 / 657

4.9
0.74 [0.60, 0.91]

Stockholm B post (5)
263 / 1104
300 / 1096

4.4
0.84 [0.67, 1.05]
Subtotal (95% CI)
1056 / 4184
1244 / 4165

17.7
0.78 [0.72, 0.85]
Test for heterogeneity chi-square = 15.86 df = 8 p = 0.0445


Test for overall effect Z = -5.68 p = 0.00
Total (95% CI)
6346 / 18565
7030 / 18534

100.0
0.85 [0.82, 0.89]
Test for heterogeneity chi-square = 55.88 df = 54 p = 0.4041
Test for overall effect Z = -8.69 p = 0.00
Review:
Tamoxifen for early breast cancer
Comparison: 01 Adjuvant tamoxifen versus control
Outcome:
02 Mortality (death from any cause)
Tamoxifen better
Tamoxifen worse
0.2
0.5
1
5
2
avoiding the wasted effort that would result from unneces­
sary duplication of previous studies.9 To see further examples
of good-quality systematic reviews, the reader is referred to
the online Cochrane reviews.
Study design and levels of evidence
Broadly, study designs can be divided into experimental and
observational studies. Experimental studies, which include
randomized controlled clinical trials, patient preference trials,
and large, multicenter trials, test a hypothesis by examining
the impact of an intervention on the outcome. In contrast,
observational studies, which include cohort studies, case–
control studies, case series, and case reports, describe the
natural history or incidence of disease or analyze associations
between risk factors and the outcomes of interest. As one
might expect, there is generally a direct correlation between
the complexity of a study design and the quality of the result­
ing data (Table 10.1).
Experimental studies
Randomized controlled clinical trials
The randomized controlled clinical trial is perhaps the most
complex of the experimental study designs and is the standard
to which all others must be held. The design of the random­
ized controlled trial evolved over the course of many years
and each component of the design attempts to minimize the
influence of study bias and confounders on the results. The
ultimate goal is to create a sample population that is truly
representative of the whole. In this way, the results of a limited
trial can be generalized to the population at large with
confidence.
According to the National Institutes of Health, clinical
trials are conducted in four phases, each serving a different
purpose and helping researchers answer different questions
(Table 10.2). In phase I, researchers evaluate an experimental
drug or intervention in a small number of test subjects (20–80)
to evaluate its safety, determine a dose–response curve, and
identify potential side-effects. In phase II, the experimental
drug or intervention is given to a larger group of subjects
(100–300) to test its effectiveness and further evaluate its
safety profile. In phase III, the experimental drug or interven­
tion is given to a much larger group of subjects (1000–3000)
in order to “confirm its effectiveness, monitor side effects,
compare it to commonly used treatments, and collect informa­
tion that will allow the experimental drug or treatment to
be used safely”. In phase IV, post-marketing surveillance is
continued to identify additional information on the risks,
benefits, and optimal use of the intervention.10
Unfortunately, randomized controlled trials are expensive
and often impractical to answer questions that compare one
surgical intervention to another.11,12 While patients are often
willing to be randomized to take a pill versus a placebo, few
are willing to be randomized to one of two surgical procedures
or to a sham procedure. Further, surgeons often have a strong
preference for one type of surgery over another and are
therefore unwilling to randomize patients.13
Although the randomized controlled clinical trial is consid­
ered the “gold standard”, it is not without limitations. For
example, the underlying assumptions of randomized con­
trolled clinical trials may be invalid. The preferable treatment
between two alternatives may be unclear; evidence of treat­
ment effects from other sources may be insufficient; only
specific effects resulting from the intervention are therapeuti­
cally valid; and only when the trial’s inclusion and exclusion
criteria match the characteristics of an individual patient can

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CHAPTER 10 • Evidence-based medicine and health services research in plastic surgery
Table 10.2  Four phases of clinical trials
Phase
Purpose
I
To test an experimental drug or treatment in 20–80
people to evaluate safety, determine a safe dosage
range, and identify side effects
II
To test the experimental drug or treatment in 100–300
people to determine effectiveness and evaluate its
safety
III
To test the experimental drug or treatment in 1000–
3000 people to confirm effectiveness, monitor side
effects, compare it to commonly used treatments,
and collect information to allow for its safe use
IV
Postmarketing studies to learn more about the drug’s
or treatment’s risks, benefits, and optimal use
Table 10.1  Levels of evidence
Level of evidence
Type of study
Key features
Level I
Randomized
controlled trial
Two randomly selected groups, one serving as a control, with a blinded comparison of
outcomes of an intervention
Level II
Prospective and
retrospective
cohort studies
A single group followed over time and evaluated for risk factors relative to outcome or
incidence of disease
Level III
Case–control study
Two groups, one with and one without disease, with a comparison of risk factors relative to
outcomes
Well-designed
clinical study
Experimental study design with an intervention and a control arm compared for outcomes
Level IV
Cross-sectional
cohort study
A single group evaluated at a single point in time for disease prevalence or risk factors
Case series
A single group of consecutive cases identified by a disease or condition and followed over
time
Level V
Expert opinion
Opinion based on experience and review of literature
Case reports
A small group identified by a disease or condition and followed over time
(Adapted from the American Society of Clinical Oncology.)
their preferred treatment while patients without a preference
are randomized.16–18 Thus both randomized and nonrandom­
ized patients are studied together under the same protocol
other than the treatment assignment.
There are a range of opinions as to the validity and useful­
ness of this study design. Some researchers believe they
complement, rather than replace, randomized controlled
clinical trials. Preference trials have been criticized for results
that may not be generalizable due to the inherent bias in
allowing patients with a strong preference to select their own
treatment. Patients who prefer a specific treatment may be
more compliant than others who have no such preference.
This, and other potential impacts of a patient’s preference on
actual outcome, is not yet a well-understood bias that can be
accounted for. In addition, particularly in small studies, there
is the inability to control fully for potential confounders that
may differ significantly between treatment groups.17 Propo­
nents of preference trials believe that subjects who choose
their treatment may be more representative of patients in
actual clinical practice and that they can provide insights into
the patient decision-making process.16
Large multicenter trials
When an insufficient number of patients are enrolled in a
randomized controlled clinical trial, researchers may choose
to use large multicenter trials to increase the sample size.16 A
multicenter controlled clinical trial carries the same require­
ments as a single-center trial and each site must follow the
same protocol, with identical inclusion and exclusion criteria,
randomization strategies, interventions, and methods for col­
lecting and evaluating the outcomes.14 Nevertheless, some
researchers have found variability in surgery and surgical
techniques in multicenter trials.16
Observational studies
Given the difficulty of executing a randomized controlled
trial, the next best level of evidence is produced by a good
experimental study or well-designed cohort study, with the
the outcome of the study be fully transferred to clinical prac­
tice.11 In addition, randomized controlled clinical trials are
inadequate to study infrequent or delayed adverse events;
they are difficult, if not impossible, to conduct for the study
of rare diseases; and although the benefits and harms of an
intervention may be well recognized, its extent or significance
is not always well assessed.12
Alternatives to randomized controlled clinical trials
In practice, randomized controlled clinical trials often pose
logistical challenges and ethical problems, which limit sample
sizes.14,15 Therefore, alternatives to randomized controlled
clinical trials are needed.
Patient preference trials
When patients or surgeons have strong treatment preferences
and refuse randomization, patients may be willing to partici­
pate in a preference trial. A preference trial is a trial in which
the patient is offered the treatment options rather than random
assignment. Patients who have a clear preference are given

119
Study design and levels of evidence
done by subject recall or chart analysis, both of which are
flawed when compared to prospective data collection. Data
collected in this manner are more likely to be incomplete,
inaccurate, inconsistent, or subject to recall bias. On the other
hand, the major advantages of retrospective studies are that
they can be done in a relatively short timeframe and are much
less costly than prospective studies.
Case–control studies
Case–control studies (Fig. 10.5) differ from cohort studies in
that two distinct groups of subjects are investigated. The first
group (case) is selected by the presence of disease and the
second (control) by its absence. In contrast, a single popula­
tion at risk for disease is studied in a cohort design. Like
cohort studies, the case–control design may be prospective or
retrospective. The major strength of the case–control study is
in the investigation of rare conditions or outcomes. Its weak­
ness lies in the inability to assess incidence or prevalence of
disease and its increased susceptibility to bias. Controls may
be concurrent or historic, matched (on key variables such as
age and sex) or unmatched.
Case series and case reports
As defined above, cases are simply a collection of subjects that
have been identified by the presence of a disease or condition.
In our literature, these are frequently reported based on a
specific intervention. If the collection of subjects is large and
former having some, but not all, the features of a randomized
controlled trial. Although there is widespread belief that
observational studies are less valid, often overestimating the
magnitude of treatment effects, there are at least several
reports suggesting that good observational studies can
provide the same level of internal validity as randomized
trials.19,20
Cohort studies
Cohort studies evaluate a group or cohort at risk for disease.
The evaluation may occur over time or at a single point in
time. The latter is further described as a cross-sectional cohort
study and is often used to collect data on the prevalence of
disease. The second common use of cohort studies is to
analyze the exposures that put subjects at risk for disease or
interventions that reduce that risk. This requires an evaluation
of the cohort at a minimum of two points in time. The study
may be designed prospectively (Fig. 10.3) or retrospectively
(Fig. 10.4). In the prospective cohort study, the investigator
develops a hypothesis about variables that may impact the
outcome under investigation, collects data about those risk
factors, and then follows the cohort for development of the
outcome of interest. For example, when the association
between smoking and lung cancer was suspected, a prospec­
tive study design increased the strength of that causal
association.
While prospective studies lend credence to causal associa­
tions, they are expensive and generally require years of
follow-up. Retrospective studies have similar goals, but iden­
tify the cohort at risk in the present and investigate the risk
factors or exposures that occurred in the past. This is often
Fig. 10.3  In the prospective cohort study, the investigator develops a hypothesis
about variables that may impact the outcome under investigation, collects data
about those risk factors, and then follows the cohort for development of the
outcome of interest. For example, when the association between smoking and lung
cancer was suspected, a prospective study design increased the strength of that
causal association. While prospective studies lend credence to causal associations,
they are expensive and generally require years of follow-up.
Present
Time
Risk factor absent (e.g., smoking)
Risk factor present (e.g., smoking)
Cases of lung cancer
Study cohort
Future
Risk factors
collected
Outcomes
assessed
Cohort at risk
Cohort with
outcomes identified
Fig. 10.4  In the retrospective cohort study, the investigator identifies a cohort,
collects data about those exposures or risk factors that occurred in the past, and
then examines the association between risk factors and outcomes. For example,
when the association between smoking and lung cancer was suspected, a
retrospective study design supported the hypothesis but failed to show a causal
association. In retrospective studies, data collection is often done by subject recall
or chart analysis, both of which are flawed when compared to prospective data
collection. The major advantages of retrospective studies are that they can be done
in a relatively short timeframe and are much less costly than prospective studies.
Past
Time
Risk factor absent (e.g., smoking)
Risk factor present (e.g., smoking)
Cases of lung cancer
Study cohort
Present
Cohort at risk
Cohort with
outcomes identified
Prior risk factors
collected & analyzed
Population at risk &
disease status identified

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CHAPTER 10 • Evidence-based medicine and health services research in plastic surgery
consecutive (case series), it may provide valuable information
about indications and contraindications for surgery and
expected outcomes. If the cases are nonconsecutive (case
reports), it raises concerns about sampling bias, such as patient
self-selection or surgeon’s recall bias, that may dilute the
ability of the study to capture the true indications and out­
comes. The value of case reports lies in their ability to present
a new idea, a new surgical approach, and refinement of exist­
ing surgical techniques and to communicate rare adverse
events.
Large-database analysis
Population-based research
Effectiveness versus efficacy
Evaluating surgical outcomes is necessary in order to provide
high-quality care, patient safety, and informed patient choice.
Surgeons must have up-to-date reliable information about
surgical risks and outcomes that can be transferable to their
own patient population. Surgical outcomes data from single-
surgeon or single-center studies demonstrate the efficacy of a
procedure performed by a particular surgeon but do not
provide data on the effectiveness of a procedure performed
by different surgeons in diverse patient populations.
Clinicians need to have information on an intervention’s
outcomes under real-world conditions, not just in the optimal
setting.21,22 As we discussed in the prior section, case series
and clinical trials performed across a few academic centers are
at risk for selection bias, and the results represent outcomes
under optimal conditions. National databases, on the other
Fig. 10.5  Case–control studies differ from cohort studies in that two distinct
groups of subjects are investigated. The first group (case) is selected by the
presence of disease and the second (control) by its absence. Like cohort studies,
the case–control design may be prospective or retrospective. The major strength of
the case–control study is in the investigation of rare conditions or outcomes. Its
weakness lies in the inability to assess incidence or prevalence of disease and its
increased susceptibility to bias.
Cases of lung cancer and controls
with proportion smoking identified
Cases of lung cancer and
controls identified
Risk factor absent (e.g., smoking)
Risk factor present (e.g., smoking)
Cases of lung cancer
Controls
Time
Risk factors
identified
Data collected
and analyzed
Fig. 10.6  Mortality rates following carotid endarterectomy in patients enrolled in a
randomized controlled trial (trial hospitals) compared to those not enrolled in a
study and operated on at hospitals with high, medium, and low volumes of
endarterectomy cases. (Adapted from Wennberg DE, Lucas FL, Birkmeyer JD, et al.
Variation in carotid endarterectomy mortality in the Medicare population: trial
hospitals, volume and patient characteristics. JAMA. 1998;279:1278–1281.)
High volume
Medium volume
Low volume
Trial hospitals
30-day mortality rate
3.5
0
Adjusted
Crude
0.5
1
1.5
2
2.5
3
hand, include patients and physicians from all types of health­
care settings, allowing assessment of outcomes in the “real
world”. This was demonstrated with the randomized clinical
trials for carotid endarterectomy procedures (Fig. 10.6).22 The
clinical trials reported a very low mortality rate for these
procedures. However, after the clinical trials concluded, the
mortality following carotid endarterectomy was substantially
higher than that reported in the trials, even among those
institutions that participated in the randomized studies.
Mortality with carotid endarterectomy was also found to be
inversely proportional to a center’s volume. Thus, clinical
trials generally do not represent real-world surgical out­
comes.22 An alternative, research using a national database, is
a population-based approach that provides information on a
procedure’s effectiveness under real-world conditions rather
than just its efficacy in ideal situations.
The importance of power
Adequate sample size is another key component to outcomes
research. True differences in outcomes can only be detected
when research studies are adequately powered through a
large-enough sample size.23,24 Plastic surgery faces the chal­
lenge of being a relatively low-volume group of providers
compared to other specialties, such as those treating cardio­
vascular disease. Outcomes studies with small patient samples
are often underpowered and at risk for a type II, or B, error.
This statistical error happens when a study does not find a
statistically significant difference between treatment groups
when a difference truly exists (lack of statistical power).25
Chung et al. found more than 80% of “negative studies” in the
Journal of Hand Surgery had powers of less than 0.80 to detect
a 25% difference between treatment groups. There was a
greater than 20% risk of missing a true difference between
treatment groups when a study had less than 0.80 power. The
primary reason for the low power among these studies was
insufficient sample size.26 Large-database analyses can provide
sufficient sample size to avoid an underpowered study.
Table 10.3 illustrates the importance of an adequate sample
size in outcomes research. In this theoretical example, imagine

121
Large-database analysis
patients. Researchers should be aware of the potential limita­
tions of data sources. For example, the SEER registries only
capture information within the first 4 months of initial treat­
ment, and the TOPS database relies on voluntary physician-
reported data. However, a recent study supports the validity
of the TOPS database.27
Administrative claims data
Administrative data, also known as “claims data” or “dis­
charge data”, are collected for billing purposes and lack
detailed patient information found in clinical registries. The
data are available from several different sources, including
hospitals, states, and payers. The content usually represents
only one episode of care, unlike a clinical registry. The data
are commonly in a uniform format called a hospital discharge
abstract, which includes: a patient identifier, hospital identi­
fier, demographic information (age, gender, race, payer),
admission acuity (emergent, urgent, elective), length of stay,
hospital charges, discharge status (death, transfer, extended
care, home), primary/secondary diagnoses and procedures.
Outcomes data from administrative sources are generally
limited to mortality, length of stay, and charges. Data accuracy
is better for primary procedure codes, diagnosis codes, demo­
graphics, and outcomes and less accurate for secondary
diagnoses, which makes risk adjustment difficult.
It is not possible to use claims data to evaluate cosmetic
procedures since these procedures are self-pay. Researchers
have used information from CosmetAssure to evaluate cos­
metic surgery outcomes.27 CosmetAssure is an insurance
policy sold nationally that covers medical and surgical com­
plications from cosmetic surgery. There is a financial incentive
to report a covered complication. However, clinical outcomes
collected in the database are limited and patient-reported
outcomes are not included.
How to use large databases for research
Administrative data can be a good starting point for a research
project since the data are readily available and often inexpen­
sive. The data source can also provide a large sample size that
can help when studying a rare event or condition. The research
question must take advantage of the strengths of the data for
the project to be successful. Advantages of administrative
data include population-based data that can be used to assess
regional variations in care, real-world outcomes, and epide­
miological trends.
Small-area variation
Prior to the 1970s, the rate of surgery for a population could
not be determined, and data were limited to the number of
cases performed at a given institution or by a specific surgeon.
In 1973, Wennberg and Gittelsohn published a method for
estimating the population served by a medical center, which
allowed for the first time the calculation of procedure rates
(e.g., the number of tonsillectomies per 100 000 people
served).28,29 We now know that certain surgical procedures
demonstrate wide and unexplained variations in regional and
national rates (e.g., hysterectomy, prostatectomy, caesarean
section) whereas other procedures are performed at similar
rates (e.g., appendectomy, cholecystectomy). In general, those
procedures whose risks and benefits are well established
a large group of physicians having performed a cosmetic
procedure on 48 500 patients with 1500 complications (3%
complication rate). Imagine a small group of plastic surgeons
having performed the same procedure on 46 patients, and 4
had a complication (8% complication rate). This is not a sta­
tistically significant difference due to the small number of
procedures performed by the plastic surgeons. Imagine, in a
similar example, the complication rate for the large group of
physicians remains at 3% (1500 patients with a complication)
and, due to a slight change in sampling, the plastic surgeons
had no complications on 46 patients (0% complication rate).
This is also not a statistically significant difference because the
study was underpowered in regard to the number of patients
treated by plastic surgeons. In fact, the study sample could
increase to 100 patients for the plastic surgeons with no
complications and still there would not have been a statisti­
cally significant difference between provider groups.
Data sources
Clinical registries
Large databases in healthcare can be generally described as
either a clinical registry or administrative claims data (Table
10.4). Clinical registries are designed for the purpose of col­
lecting clinical data and have the advantage of providing
detailed patient and treatment information. Many national
clinical registries are disease-specific, such as the Surveillance
Epidemiology and End Results (SEER) registry and the
National Comprehensive Cancer Network (NCCN) that
monitor outcomes in cancer patients. Plastic surgery has a
national clinical registry called Tracking Operations and
Outcomes for Plastic Surgeons (TOPS), which is supported by
the American Society of Plastic Surgeons and the American
Board of Plastic Surgery. The primary purpose of TOPS is to
facilitate monitoring the quality of surgical care in plastic
surgery. These types of clinical registries can be invaluable to
researchers who are interested in studying patient popula­
tions that may not be captured in claims data, such as younger
patients not captured in Medicare or self-pay cosmetic
Table 10.3  Understanding the relationship between sample size
and statistics
Sample
size
Number of
complications
Complication
rate (%)
Large physician
group
48 500
1500
3
Plastic surgeons
46
4
8
Difference is not statistically significant
Large physician
group
48 500
1500
3
Plastic surgeons
46
0
0
Difference is not statistically significant
Large physician
group
48 500
1500
3
Plastic surgeons
100
0
0
Difference is not statistically significant

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CHAPTER 10 • Evidence-based medicine and health services research in plastic surgery
Table 10.4  Examples of clinical registries and administrative claims data
Data source
Description
Clinical registries
Surveillance, Epidemiology and End
Results (SEER) registry
Sponsored by the National Cancer Institute and collects data on cancer incidence and
survival for approximately 26% of the US population ()
National Comprehensive Cancer
Network (NCCN)
Alliance of the leading cancer centers in the US that are dedicated to improving the quality
of cancer care ()
National Surgical Quality Improvement
Program (NSQIP)
Program is sponsored by the American College of Surgeons and includes academic and
private-sector hospitals which desire to participate. Data include inpatient and outpatient
visits among patients undergoing major surgical procedures (
quality-programs/acs-nsqip)
Tracking Operations and Outcomes
for Plastic Surgeons (TOPS)
Program is sponsored by the American Society of Plastic Surgeons, the Plastic Surgery
Educational Foundation, and the American Board of Plastic Surgery. Board-certified
plastic surgeons may participate. Inpatient and outpatient data are collected (https://
tops.plasticsurgery.org)
Administrative claims data
State–federal partnerships
State healthcare organizations submit datasets to the Agency for Healthcare and Research
Quality ()
  State Inpatient Database
  Nationwide Inpatient Sample
  Kids Inpatient Database
  State Ambulatory Surgery Database
Medicare150
  Part A
Inpatient hospital discharge abstracts
  Part B
Outpatient claims data
Veterans Affairs (VA) data
  Patient Treatment File (PTF)
Inpatient hospital discharge abstracts
  Outpatient Care Files (OCF)
Outpatient visits at VA-based clinics
CosmetAssure151
Insurance company that covers complications related to cosmetic surgery
exhibit the least variability. Procedures with high variability
suggest that the optimum management has yet to be estab­
lished or adopted. Although small-area variations allow us to
make observations about differences in procedure rates, they
do not help explain these variations or tell us which rate is
right. What it does suggest is that a more definitive evaluation
needs to be undertaken to identify the optimal treatment
strategy.30 The Dartmouth Atlas of Health Care is one of the
best examples of how to use administrative data to examine
variations in the rates of surgery in the US using data from
the national Medicare database, provider files, and American
Hospital Association.31
Volume–outcome analysis
Another field of investigation that falls under the broad
heading of large-database analysis is the area of volume–
outcome studies. There is growing evidence to suggest that
surgical outcomes are better at high-volume institutions.32
The reason may in part be due to the skill of the surgeon but
also reflects the hospital and systems that support a given
population of patients. A landmark paper by Birkmeyer
et al.33 described a significant correlation between surgeon
volume and operative mortality in the US using Medicare
data. Another example is the work by Roohan et al.34 on the
5-year survival of patients with breast cancer treated at low-,
moderate-, and high-volume centers (Table 10.5). This work
shows that there is as much as a 30% difference in the
5-year survival between low- and high-volume hospitals. In
plastic surgery, the volume–outcome relationship has been
analyzed for autologous breast reconstruction, identifying
that centers with higher volumes have lower likelihood of
complications.35–37
Table 10.5  Volume–outcome association for 5-year survival after
breast cancer treatment
Hospital
volume
Breast cancer
cases/year
5-year survival
risk ratio
Very low
1–10
1.60
Low
11–50
1.30
Moderate
51–150
1.19
High
>150
1.00
(Adapted from Roohan PJ, Bickell NA, Baptiste MS, et al. Hospital volume
differences and five-year survival from breast cancer. Am J Public Health.
1998;88:454–457.)

123
Patient-reported outcomes research
NCCN database has been used to evaluate the association
between postmastectomy breast reconstruction and the deliv­
ery of adjuvant chemotherapy for breast cancer patients.47 The
authors found that immediate postmastectomy breast recon­
struction does not appear to lead to omission of chemotherapy,
but it is associated with a modest, but statistically significant,
delay in initiating treatment. Breast reconstruction trends
have been investigated using the NIS database. The authors
identified increasing use of immediate reconstruction after the
passage of the WHCRA in 1998, especially using implants.
The increased use of implant-based reconstructions was
associated with increasing bilateral mastectomies, especially
for contralateral prophylactic mastectomies.41,48 Additional
aspects of breast reconstruction have been studied, such as the
association of sociodemographic variables with the method
of breast reconstruction, the relationship between hospital
volume and outcome for autologous reconstruction, and the
economic implications of the use of microsurgery and bilateral
flaps.35,49,50 Regarding cosmetic procedures, the TOPS and
CosmetAssure databases have been used to assess outcomes
with abdominoplasty and breast augmentation procedures.27
The low complication rates found in this study support the
safety of these procedures when performed by plastic sur­
geons. However, the authors stress that surgeons should be
aware of the overall higher complication rates associated with
combining breast augmentation with other procedures (Fig.
10.7). In summary, these represent just a few examples of the
potential use of large databases in plastic surgery research.
Patient-reported outcomes research
Definition of terms
In plastic surgery research, attention is increasingly being
placed on understanding the patient’s perception of the surgi­
cal result and the impact that surgery has on quality of life
(QoL). To appraise and demonstrate the benefits of a chosen
surgical technique or alternate treatment adequately, it is
important for plastic surgeons to understand the available
approaches to measurement of patient-reported outcomes
(PRO).
Large cohort studies
Large-database analysis has played a key role in cohort
studies. This allows relatively rare events to be analyzed with
a large sample size, giving greater statistical significance and
power to the analysis. It often involves linking multiple
databases to examine risk factors or exposures relative to
outcomes. The outcomes measured most often are mortality
and cancer, as both are frequently tracked through various
regional and national registries.
Epidemiology
Large databases are also useful tools to evaluate trends over
time in surgical utilization and outcomes for a population. For
example, the Nationwide Inpatient Sample (NIS) was used to
document a dramatic increase in the use of bariatric surgery
in the US.38 The national SEER database has been used to
assess sociodemographic differences in receipt of postmastec­
tomy breast reconstruction39 and assess trends in the use of
breast reconstruction after the Women’s Health and Cancer
Rights Act.40 Initial studies found that the overall use of breast
reconstruction across the US was low, and that race/ethnicity
is a significant predictor of receipt of postmastectomy recon­
struction. More recent studies, using the NIS database, have
shown that the rate of immediate breast reconstruction
increased from 20 to 38% from 1998 to 2010, with a shift in the
method of reconstruction from autologous to implant.41
Examples of large-database analyses
in plastic surgery
Many large national and state databases have had limited
applications for plastic surgeons.42,43 The most obvious reason
is that many of the procedures performed by plastic surgeons
are not captured in these databases. For example, the Medicare
database captures only patients older than 65 years who use
Medicare as the primary payment mechanism.
Several authors have used these databases to garner infor­
mation useful to plastic surgeons. Gittelsohn and Powe used
data from the state of Maryland to compare rates of elective
surgery, such as septoplasty, rhinoplasty, reduction mammo­
plasty, and blepharoplasty.44 Significant variations were noted
in rates of surgery. Explanatory variables were explored, and
the authors concluded that income and race were significant
predictors of surgery. Keller et al. have looked at variations in
the rate of surgery for carpal tunnel syndrome in the state of
Maine.45 They were able to identify a 3.5-fold difference in
rates, and the authors concluded that the major driving factor
is physician decision-making. We do not know the “right”
rate of carpal tunnel surgery, but the data provided by studies
such as this will enable us to begin to ask the appropriate
questions.
Large databases have provided the source for cohort inves­
tigations on the relationship between breast reduction and a
reduced risk for development of breast cancer. Boice et al.46
identified breast reduction patients in Sweden using hospital
discharge data linked with Swedish registries for cancer,
death and emigration, and compared results with expected
breast cancer incidence in the general population using the
Swedish Nationwide Cancer Registry. The investigators found
that women 7.5 years after reduction mammoplasty were
at a statistically significant 28% decreased risk of cancer. The
Fig. 10.7  The graph displays differences in overall complications for breast
augmentation between single and combined procedures in the Tracking Operations
and Outcomes for Plastic Surgeons database. Complications for combined
procedures represent overall rates of a complication and cannot be assigned to a
particular procedure. The rates of all the complications between single and
combined procedures were significantly different (P < 0.01) using Pearson
chi-square. DVT, deep venous thrombosis; PE, pulmonary embolism.
0.6
0.8
0.3
1.2
0.02
0.1
Infection
DVT/PE
Hematoma
% with complication
1.4
0
0.2
0.4
0.6
0.8
1
1.2
Single
Combined

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CHAPTER 10 • Evidence-based medicine and health services research in plastic surgery
development of new plastic surgery-specific questionnaires.
As an example, the BRAVO study,61 which evaluated the
effectiveness of breast reduction surgery, was conducted in
2001 using the Breast Reduction Symptoms Questionnaire.
This questionnaire only provided an evaluation of symptom
relief. Since then, the science of PRO measurement has evolved
and new measures, such as the BREAST-Q,62 provide a
comprehensive appraisal, including satisfaction with breast
appearance and psychosocial well-being.
Essential elements for PROMs
PROMs must be clinically meaningful and scientifically
sound. A questionnaire that is clinically meaningful addresses
those issues considered important to patients and their sur­
geons. Scientific soundness refers to the demonstration of
reliable, valid, and responsive measurement of the outcome
of interest. A reliable measure yields consistent and reproduc­
ible results of the same measure. Reliability is an important
property of a PROM because it is essential to establish that
any changes observed between patient groups are due to the
intervention or disease, and not to problems in the measure
(Fig. 10.8). Test–retest reliability may be evaluated by having
individuals complete questionnaires on more than one occa­
sion over a time period when no changes in outcome are
expected to have occurred. The degree to which individual
responses remain the same is reported statistically as Cron­
bach’s alpha63 and intraclass correlation coefficients.64
Validity is the ability of an instrument to measure what we
intend it to measure (see Fig. 10.8). The distinction between
reliability and validity is important because, just as reliability
does not imply validity, the inverse is also true. That is, a
reliable measure will always yield the same score, but it may
not be valid, as it may not necessarily measure what it is
meant to measure. Establishment of validity may be consid­
ered an ongoing process. The measure is looked at from
various perspectives, including an assessment of the develop­
ment process, consideration of known group differences,
evaluation of internal consistency and of convergent and
discriminant validity relative to other existing measures.
Patient satisfaction and QoL may be measured using spe­
cially designed questionnaires, known as PRO measures or
PROMs. This term applies specifically to a questionnaire used
in a clinical or research setting where responses are collected
directly from patients. These questionnaires quantify QoL
and/or significant outcome variables (e.g., patient satisfac­
tion, symptoms) from the patient’s perspective. PROMs
provide a means of gaining insight into the way patients
perceive their health and the impact treatments have on their
QoL. A good PROM should evaluate the impact of disease,
trauma, surgical or nonsurgical intervention on various
aspects of a patient’s day-to-day life in a manner that is sci­
entifically sound and clinically meaningful.51
In plastic surgery research, many of the PROMs frequently
employed in studies to evaluate surgical outcomes have
not been developed and validated using acknowledged
guidelines.51–54 Such PROMs are considered ad hoc question­
naires, and although they may pose clinically reasonable
questions, one cannot be confident about their reliability
(ability to produce consistent and reproducible scores) or
validity (ability to measure what is intended to be measured).
The use of such measures, however, has been extensive in
plastic surgery. As an example, in a systematic review to
identify PROMs developed for use with breast surgery
patients, our team identified 65 ad hoc measures.52 PROMs that
can be used in any patient group regardless of their health
condition are called “generic questionnaires”, which allow
direct comparisons across disease groups, or between sick and
healthy groups. These measures can provide important infor­
mation for health policy decisions. For example, research
using the Short Form 36 (SF-36) – the most widely used
generic measure in the world55– with breast reduction patients
shows that women report clinically important differences in
QoL compared with women in the general population.56–59 In
the US, breast reduction is a procedure for which health insur­
ance companies frequently dispute payment; it is thus useful
to place the health burden experienced by women with breast
hypertrophy into the context of patients with other medical
conditions (e.g., women with hip or knee osteoarthritis
seeking joint replacement).
However, there are limitations associated with the use of
generic measures. Given their generic nature, they sometimes
lack sensitivity to the particular concerns of a patient group.
For instance, the SF-36, which measures physical, emotional,
and social functioning, does not include questions about sexu­
ality, body image, or satisfaction with breast appearance, which
are clearly important concerns of breast reduction patients.60
Generic measures, like the SF-36, may then not evaluate the
most important issue for a particular patient group. Disease-
or condition-specific questionnaires address problems specific
to a single disease or treatment group. Such measures, when
developed through in-depth patient interviews, can help to
identify issues of importance to a specific group of patients. As
these measures include content areas that are more relevant to
a given patient group, they are more likely than generic mea­
sures to be sensitive to measuring changes in specific aspects
of health. However, in general they cannot be used to make
comparisons across different patient groups.
An additional challenge is that, in plastic surgery, there are
many areas for which condition-specific instruments have
been either inadequately developed or not developed at
all.52–54 This situation is rapidly being remedied with the
Fig. 10.8  Reliability and validity. The quality of any standardized survey is judged
by its reliability and validity. The reliability is traditionally measured by test–retest;
the validity is a measure of accuracy. Looking at it simplistically, reliability is the
ability to hit the same spot repeatedly on the target, whereas validity is the ability to
hit the bull’s eye repeatedly.
Validity
Reliability

125
Patient-reported outcomes research
considered. The process completes questionnaire develop­
ment and provides the first evidence of validation.
In the third step, further psychometric evaluation and vali­
dation is performed. This step involves the administration
of the item-reduced questionnaire to a large population of
patients to determine acceptability, reliability, validity, and
responsiveness.
The fourth and final step involves the ongoing modifica­
tion and improvement of the instrument. As an example,
building upon the existing four modules of the BREAST-Q, a
new procedure-specific module was recently developed for
breast-conserving therapy (BCT) patients. This module facili­
tates comparisons between treatment groups (e.g., BCT versus
mastectomy and reconstruction) and evaluations of new
surgical approaches (e.g., oncoplastic surgery, fat grafting).
Our research group’s development of the BREAST-Q illus­
trates how new PROM can be constructed. In phase I, a con­
ceptual framework to understand patient satisfaction and
QoL in breast surgery patients was developed and included
six domains: satisfaction with breasts, overall outcome, and
process of care, and psychosocial, physical, and sexual well-
being. Our team developed this conceptual framework and
set of items to measure each component of the framework
using in-depth interviews and focus groups with patients,
expert panels with plastic surgeons, and a review of the litera­
ture.62 We then performed pilot testing and cognitive debrief­
ing to ensure that our PROM addressed all relevant issues and
that the items were acceptable to patients and easily under­
stood. In phase II, we performed an extensive multicenter
field test with 1950 patients. Based on these data, item reduc­
tion and scale development were performed using modern
psychometric methods. In this process, approximately 60% of
the items were deleted. In phase III, the item-reduced measure
Responsiveness is defined as the ability of a measure to
detect significant change accurately. If a PROM is used
to evaluate changes as the result of a surgical procedure or to
follow patients over time, the measure must be sensitive
to change. Responsiveness is examined by measuring out­
comes, before and after an intervention, and by evaluating the
measure’s sensitivity to change.
Overview of PROM development
To choose a QoL measure for use in a study or in clinical
practice, prospective users should take into account the
process used to develop PROMs. Knowing how a PROM was
developed is crucial to choosing an appropriate measure. Not
infrequently, researchers choose questionnaires based simply
on whether or not they have been “validated” and ask few
questions about how the items for the questionnaire were
constructed and tested. A poorly constructed or ad hoc ques­
tionnaire may be deemed “validated” simply because it has
been used in various studies and some basic statistical evi­
dence has been supplied. Frequent use of a questionnaire does
not equate with quality nor improve its psychometric proper­
ties. Rather, to ensure that a PROM will ultimately prove to
be a reliable, responsive, and valid measure, a rigorous step-
by-step development process is essential. During the develop­
ment process, careful qualitative work is necessary to
conceptualize, map out, and operationalize the variables most
relevant to patients. PROMs that are developed based on
expert opinion alone cannot be expected to address all satis­
faction and QoL issues that patients find relevant. Thus, while
expert opinion is clearly valuable, patient interviews and
focus groups are essential sources of information.
Since the early 1990s, there has been increasing interna­
tional consensus regarding appropriate methods for the
development and validation of QoL measures, culminating
with the 2002 report by the Scientific Advisory Committee of
the Medical Outcomes Trust65 and more recently with the US
Food and Drug Administration recommendations.66 Cano
et al.51 summarized these guidelines in a three-step approach
to PRO measure development that involves procedures for
item generation, item reduction, and psychometric evalua­
tion. We have added a fourth step representing the ongoing
process of instrument improvement (Fig. 10.9).
In the first step, the conceptual model to be measured is
formally defined, and a pool of items is generated. These
items for a PRO measure are developed through the following
three sources: review of the literature, qualitative patient
interviews, and expert opinion. The item pool is developed
into a questionnaire which is pretested or pilot-tested on a
small sample of patients in order to clarify ambiguities in item
wording, confirm appropriateness, and determine accept­
ability and completion time.
In the second step, the PRO measure is field-tested using a
large sample of patients. The questions that represent the best
indicators of outcome are then retained in a shortened version
of the PRO measure based on their performance against a
standardized set of psychometric criteria. The research team’s
objective is to choose the best items from the field test measure
for inclusion in the final measure. Items are eliminated accord­
ing to tests of item redundancy, endorsement frequencies,
missing data, factor analysis, and scaling assumptions.
Acceptability, reliability, validity, and responsiveness are also
Fig. 10.9  Four steps of patient-reported outcome (PRO) measure development.

• Field-testing of the preliminary PRO instrument
in a large heterogeneous population
• Revision and elimination of items
• Completion of the new PRO instrument
STEP 2 - ITEM REDUCTION
• Evaluation of the new PRO instrument with
respect to validity, reliability, and responsiveness
STEP 3 - PSYCHOMETRIC EVALUATION
• Clinical studies using the developed PRO instrument
• Ongoing modification and improvement of the
PRO instrument
• Development of a conceptual framework and
preliminary items from patient interviews, expert
panels and available literature
• Pilot testing of the draft PRO instrument in a
small sample of subjects
STEP 1 - ITEM GENERATION
STEP 4 - ENHANCEMENT OF PRO INSTRUMENT
(ONGOING PROCESS)

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CHAPTER 10 • Evidence-based medicine and health services research in plastic surgery
conditions of uncertainty (standard gamble method).74 Hence,
a value or utility is a measure of preference for a particular
health state or health service: the more preferable an outcome,
the more value or utility is associated with it. The most
common preference metric used is quality-adjusted life years
(QALYs).
QALYs represent a measure of the dollar cost of a year of
life if a person suffers one or more limitations of various kinds
and degrees, taking into account both QoL and life expec­
tancy.75 QALYs can be estimated using a variety of evaluation
tools such as the standard gamble, the time trade-off, or visual
analog scales.75,76 Preference-based measures incorporate the
strength of patients’ preference for the condition or disease,
and the units of measurement range from 0.0 (i.e., death) to
1.0 (i.e., perfect health), the idea being that a year in perfect
health is worth more to the patient than a year spent with a
disability (Fig. 10.10). Importantly, some health states may be
considered worse than death and thus have negative scores.
Preference-based instruments thus take into account values
and/or utilities in addition to QoL, and can be used in eco­
nomic evaluations to aid resource allocation decisions.77
There are two general approaches to measuring values and
utilities. The first involves use of preference classification
systems in which responses to a generic health status instru­
ment are converted to a value or utility. This conversion is
computed by an algorithm developed from population-based
responses. Widely used preference classification systems
include the Quality of Well-Being Scale,78,79 the McMaster
Health Utilities Index,80–82 and EuroQol.83,84 Whereas prefer­
ence classification systems are useful to study general health
status and population health, they may not capture adequate
(BREAST-Q) was completed by another large sample of breast
surgery patients and the data were examined to determine
how the measure performed. More specifically, targeting,
reliability, convergent validity, discriminant validity, and
responsiveness were examined.67
Modern psychometric methods
The science underpinning the testing of the attributes of reli­
ability, validity, and responsiveness is known as psychomet­
rics. The most commonly used form of scale evaluation, and
the one most familiar to surgeons, is based on traditional
psychometric methods.65 However, in recent times, research­
ers have become aware of the limitations of these methods
and are now moving to newer techniques. As such, modern
psychometric methods such as Rasch measurement68 and item
response theory (IRT)69 are increasingly being used in the
development of PRO measures. Rasch and IRT methods were
first developed for use in educational testing. While tradi­
tional psychometric techniques provide ordinal-level data,
Rasch analysis provides interval-level data.68 Ordinal-level
data provides only a rank order (e.g., first, second, third). In
contrast, with interval-level data, one unit on the scale repre­
sents the same magnitude measured across the whole range
of the scale (e.g., degrees Celsius). This improves the accuracy
with which we can measure clinical change. In addition, these
methods provide estimates for patients (and items) that are
independent of the sampling distribution of items (and
patients). Among other benefits, this allows for accurate
estimates suitable for individual-person measurement. This
can help to inform patient monitoring, management, and
treatment directly. Other advantages include item banking,
scale equating, computerized scale administration, and the
handling of missing data.70,71
In the coming years, one may expect that these newer, more
clinically amenable techniques will supersede traditional
approaches to developing and testing PROM. Additionally in
the near future, one may anticipate that electronic capture of
PRO data will become widespread. As web access has become
more prevalent throughout the world, it is possible for patients
to complete questionnaires via the internet and even smart­
phones, which allow for real-time reports to both clinicians as
well as patients.72,73 This has important implications for how
PRO data may be used to inform clinical care. For research
studies, the collection of ePRO data is also attractive as costs
per patient are potentially reduced.
Utilities and preference-based measures
Key concepts
While PRO measures can provide valuable information on the
way patients perceive their health and the impact treatments
have on their QoL and other significant outcome variables,
these measures do not incorporate patient preferences in their
scoring systems.
“Preference” is a broad term used to describe the concept
of desirability of a set of outcomes. Values and utilities are
two different types of preferences, depending on which
method is utilized to measure the preferences: values are
measured under conditions of certainty (rating scale, time
trade-off method), whereas utilities are measured under
Fig. 10.10  Comparison of health states on a common utility scale. Utilities range
from 0 to 1, where 0 represents death and 1 represents perfect health. Utilities differ
from standard questionnaires in that they quantify quality of life with a single
measure that encompasses the physical, psychological, and cultural preferences of
the patient. This permits comparison between patients and across different diseases
on a common scale.
1.0
0.0
Moderate angina
Arthritis of the knee
Breast hypertrophy = 0.86
Hospital dialysis
Blind or deaf
Perfect health
Death

127
Comparative effectiveness analysis
evidence that compares the benefits and harms of alternative
methods to prevent, diagnose, treat and monitor a clinical
condition, or to improve the delivery of care. The purpose of
comparative effectiveness research is to assist consumers,
clinicians, purchasers, and policy makers to make informed
decisions that will improve healthcare at both the individual
and population levels.”91 The analytic tools for data collection
can include systematic reviews of evidence, modeling, retro­
spective analyses of databases, and prospective trials. Contro­
versy surrounds the use of randomized controlled trials for
CER because the research setting should demonstrate an
intervention’s outcome under “real-world” situations rather
than under optimal conditions (as demonstrated in Fig. 10.6).90
However, the Institute of Medicine’s definition of CER does
not reject the inclusion of randomized controlled trials.90,92
National research priority
Reforming the national health system is a top priority for
health policy leaders and the key aim is to control healthcare
costs without impairing quality. Regional variations in treat­
ment patterns and cost growth support the need for more
informed medical decision-making.92 Many believe that this
goal will only be reached if we have better evidence to inform
healthcare decisions. Better evidence can improve quality,
safety, and the effectiveness of healthcare by providing both
patients and providers with the information needed to
make healthcare choices.92,93 PCORI (Patient-Centered Out­
comes Research Institute) was created in 2010 as an indepen­
dent nongovernmental, nonprofit organization, to fund
comparative clinical effectiveness research that addresses
questions and concerns more relevant to patients.94
Complexities
Whose perspective to take?
A variety of perspectives can be taken when examining the
value of a healthcare procedure, ranging from the individual
to society. The four most common perspectives evaluated are
societal, patient, employer, and payer.90 The societal perspec­
tive includes all of the benefits and costs associated with a
treatment for the whole of society, rather than for just one
individual patient. This type of analysis includes societal
components such as work productivity and caregiver costs.
The patient perspective only includes the costs and benefits
of a treatment that impact the individual patient. Any
increased productivity that would benefit a company or
workplace situation would not be included. Productivity that
directly benefited the individual would be counted. Costs
included would be those paid out of pocket by the individual
and costs related to travel and time off work.90,95
An employer perspective only includes the benefits and
costs of a treatment that impacts the employer. Any benefit
from increased productivity by the employee is included. In
addition, any tangential increased productivity is included,
such as decreased sick leave from the other employees as a
result of a vaccination. Costs included are out-of-pocket costs
for the employer and lost productivity as a result of employee
absenteeism.90,95
The payer perspective includes the benefits and costs of a
treatment that impact a payer only. Benefits to the individual
information about specific conditions or individual patient
preferences.
The second approach to measuring values and utilities is
to assess them directly. Several techniques may be used,
including a visual analog scale, time trade-off, and standard
gamble.76 The standard gamble is considered to adhere most
closely to the von Neumann–Morganstern utility theory. In
this technique, patients are asked to make a choice between
two alternatives. One alternative is to remain in their current
health state, and the other is to accept a gamble with a chance
of success or failure (Fig. 10.11). The chances of success and
failure are varied systematically until the point of indifference
between the two choices is reached. The probability of success
at this point of indifference represents the value or utility
estimate. Typically, the worse the perceived health of the
patient is, the lower the value or utility score (see Fig. 10.10).
Whereas the concept of preference assessment holds great
promise for plastic surgery,85,86 measurement of values and
utilities is an evolving science. Controversy exists as to the
gold-standard technique for measurement, and alternative
techniques may give slightly different results.87,88
Comparative effectiveness analysis
Definition
The primary purpose of comparative effectiveness research
(CER) is to facilitate value-based medicine, which is the
practice of medicine based on the value conferred by a health­
care intervention. Depending on the definition used, CER
may or may not have a cost component in the analysis. There
is no standard definition for CER and study design may vary
depending on whose perspective is taken: patient, payer,
societal.89 The total value or utility gained is measured in
QALYs and calculated by multiplying the years of utility gain
by years of benefit duration. This total gain, or comparative
effectiveness, can be compared with that of any healthcare
intervention, no matter how disparate. The concept of CER in
healthcare is similar to the consumer rating reports by Zagats
for restaurants and consumer reports for cars.90
There is currently no standard definition for CER. Most
researchers use the following definition for comparative
effectiveness by the Institute of Medicine: “Comparative
effectiveness research is the generation and synthesis of
Fig. 10.11  Utility assessment with the standard gamble technique. In standard
gambles, patients are asked to make a choice between two alternatives. One
alternative is to remain in their current health, and the other is to accept a gamble
with a chance of success and failure. The chances of success and failure are varied
systematically until the point of indifference between the two choices is reached.
The probability of success at this point of indifference is the utility value. Typically,
the worse the perceived health of the patient, the lower the utility.
CHOICE
A (present condition)
B (gamble)
Perfect health
Death
p
1-p

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CHAPTER 10 • Evidence-based medicine and health services research in plastic surgery
reconstruction, all things considered, was a cost-effective
option compared to implants when the expected lifespan of a
patient was long (i.e., young women or early-stage breast
cancer).100
Study design
As previously discussed, there are two broad categories of
research design: experimental and observational studies.
Observational research has many advantages, such as speed,
real-world decision, large sample sizes, and low cost. Experi­
mental studies, such as randomized clinical trials, can
overcome some of the limitations of observational studies
by randomly assigning patients to different interventions,
thereby controlling for known and unknown confounding
factors. The Institute of Medicine’s recommendations are for
the national CER program to develop large-scale, clinical and
administrative data networks to facilitate the use of observa­
tional and experimental data to inform CER.93
Limitations
There are several potential limitations to the implementation
of CER in healthcare. For one, there is no standard definition
for comparative effectiveness. It is also unclear what impact
this type of research will have on healthcare since many
providers do not incorporate this type of information into
medical decision-making. Population-based study results
may not be applicable to individual patient needs. For
example, autologous breast reconstruction may be cost-
effective compared to implants but the final decision of the
method of breast reconstruction needs to be made by the
patient. Patient treatment self-selection may also affect com­
parative effectiveness results. A study that finds no statisti­
cally significant difference in treatment outcomes does not
necessarily mean that there is no difference in outcomes. The
lack of statistical significance may be due to flaws in the study
design, such as an underpowered study. Furthermore, differ­
ent perspectives such as societal, patient, and employer may
have different results. It is important to understand that CER
helps to inform a medical decision but does not provide a
simple “one size fits all” answer.90
Summary
The primary reason for the interest by patients, providers, and
health policy leaders in CER is the belief that better informa­
tion will translate into better decisions and improved health
outcomes. The long-term impact of these efforts will depend
on healthcare reform legislation, the medical profession’s
ability to encourage physicians to change practices, and
patients’ willingness to participate in shared medical
decision-making.93
Future trends
Multicenter clinical trials network
When choosing a treatment option for their patients, plastic
surgeons use many sources of information to determine best
practice. Understandably, surgeons tend to rely in large part
on their training and personal experience. Outcome studies
are not included. Increased productivity to the individual or
society is not included. The time horizon used to calculate the
benefits and costs is the expected length that the individual
will participate in the insurance plan.90,95
Types of economic studies
CER may or may not include cost when comparing treat­
ments. However, there are five primary economic analyses in
healthcare that compare treatments by costs and outcomes
and differ primarily by how outcomes are measured. Firstly,
cost–benefit analysis compares the net costs and net benefits
of two treatments. Outcomes must be converted to monetary
units, such as willingness to pay. The results are typically
expressed as dollars expended for dollars gained.95,96 Secondly,
cost-effectiveness analysis (CEA) measures the cost associated
with two or more medical interventions for a given health
state to determine the relative value of one intervention over
the other. With CEA, the healthcare provider is looking to
answer the following question: “What are the costs associated
with the different treatment options available to achieve this
goal?”75 In a CEA, the health effects are measured in natural
units directly related to the goal of interest associated with the
intervention. For example, the measure of primary effective­
ness can be expressed in terms of “cost per unit of effect”,
where the effect can be the cost of life-years saved by kidney
transplantation compared to dialysis,90,95,96 the average blood
pressure decrease in mmHg, or the number of successful
replantations.97 Thirdly, cost–utility analysis (CUA) was
developed to address the limitations of CEA. It has emerged
in recent years as the preferred method for economic evalua­
tions in healthcare because both the QoL and length of life
must be assessed.75,90,95–98 Overall, CUA and CEA share simi­
larities from the cost analysis perspective. However, they
differ in terms of outcomes: in CEA, outcomes are single and
specific to the medical intervention under study; in CUA,
outcomes can be single or multiple, and, most importantly,
consider the notion of preference.74 The analysis produces a
cost per QALY for the intervention that can be compared to
other procedures. Fourthly, cost consequence analysis does
not convert outcomes to a common metric but instead lists all
of the consequences of the treatment.90,95 Lastly, cost minimi­
zation analysis is used to compare the costs of procedures
when the outcomes are identical. This approach is rarely
performed because two procedures usually have something
different in regard to issues such as complication rates, pain,
and time of recovery.90,95,96
A controversial issue is whether costs are appropriate
outcomes in CER. The primary justification for including
costs is that the overall value of an intervention can be
easily understood in economic terms.92 However, CER may
conclude that the more expensive treatment has the best
value. An example is breast cancer screening in patients
with BRCA genetic mutations. In a study by Plevritis et al.,
magnetic resonance imaging screening was found to be
cost-effective relative to mammography.99 CER looks at the
benefits, not just the costs, and therefore identifies the treat­
ment with the best value, not necessarily the one with the
lowest cost.92 A cost-effectiveness analysis in breast recon­
struction used the BREAST-Q as the effectiveness measure to
analyze whether implants or autologous reconstructions were
more cost-effective from the payer perspective. Autologous

129
Future trends
The Canadian Institutes for Health Research (CIHR) is
responsible for coining the relatively new term “knowledge
translation” (KT) and defines it as “a dynamic and iterative
process that includes synthesis, dissemination, exchange
and ethically sound application of knowledge to improve
the health, provide more effective health services and
products and strengthen the health care system.”103 KT has
been proposed as a solution to reduce care gaps, ensuring
collaboration between the public, patients, clinicians, manag­
ers, and policy-makers to inform health-related policy and
practice.104,105
A model for understanding KT
The CIHR elaborated a Knowledge To Action model, further
subdividing KT into two categories: (1) end-of-grant KT and
(2) integrated KT.104,106 In end-of-grant KT, strategies are devel­
oped to match research findings to the needs of the appropriate
individuals and organizations after research activity is com­
pleted. This approach is also known as diffusion and dissemi­
nation of research findings. Conversely, integrated KT engages
individuals and organizations in every step of the research
process, from establishing the research question to interpreta­
tion and dissemination of the findings. The goal of this
approach is to produce research findings that are more likely
to be relevant to, and used by, the stakeholders, including
patients, clinicians, managers, and policy-makers.107,108
A variety of models exist to improve quality of healthcare
through KT. One of the most common is the 4T model. The
first strategy, referred to as T1 (translation 1), focuses on
transforming basic science findings into translational research.
Next, T2 (translation 2) comprises all activities directed at
producing clinical studies based on translational research
findings. Activities under T3 (translation 3) center on the dis­
semination and delivery of healthcare interventions to all
patients, in every setting of care. Finally, T4 (translation 4)
activities focus on translating dissemination experiences into
new basic science investigations.
Barriers to uptake
The healthcare system currently falls short in its ability to
translate knowledge into clinical practice. A study comparing
medical care in the US with established national guidelines,
medical literature, and existing indicators of quality dem­
onstrated that, overall, patients received 54.9% of recom­
mended care.109 In fact, it takes an average of 17 years for
new knowledge generated by research, such as randomized
controlled trials, to be integrated into widespread practice.110,111
In a systematic review of the literature by Cabana et al., the
sequence of behavior change in a physician’s clinical practice
has been divided into three domains: knowledge, attitude,
and behavior.112 Each domain may encounter opposing forces
to the application of evidence-based knowledge. Firstly, phy­
sician knowledge acquisition may encounter barriers such
as lack of familiarity and lack of awareness (e.g., increasing
volume of new literature, time invested to stay informed).
Secondly, physician attitudes that favor behavior change may
be deterred by the lack of outcome expectancy, self-efficacy,
and motivation (e.g., mistrust regarding the validity of clini­
cal research, skepticism about the applicability of evidence
to clinical practice, discomfort regarding modification of
previous practice). Lastly, factors hindering the practical
reporting “single-surgeon experience” have traditionally
predominated in the plastic surgery literature. While such
series are of value, their findings are not necessarily generaliz­
able to other settings (e.g., lower-volume practices).
One of the more powerful forces in shaping best practice
is the randomized clinical trial. However, in certain settings,
single-center trials may be difficult to conduct because of
limitations in sample size and resources. One way of pre­
serving the clinical relevance of a trial is to have multiple
institutions enroll, treat, and follow patients under a common
study protocol. This approach also increases the heterogene­
ity of the population, which may ultimately lead to study
findings that are more generalizable and relevant. This het­
erogeneity may however make it more difficult to detect
treatment differences. Compared to a single-center trial, a
treatment effect may be more difficult to detect in a multi­
center trial. However, those effects that are detected are
likely to be more convincing than those found in a single,
homogeneous population.
To facilitate such studies, the Plastic Surgery Education
Foundation established the Clinical Trials Network. This ini­
tiative has provided a mechanism by which plastic surgeons
across the country may collaborate and contribute to the
advancement of clinical knowledge. One compelling example
of the value of multicenter clinical trials in plastic surgery is
the Venous Thromboembolism Prevention Study. In this
study, performed under the direction of the Network, five
high-volume plastic surgery centers have adopted a common
protocol for perioperative chemoprophylaxis of deep venous
thrombosis. The incidence of venous thromboembolism is
being prospectively evaluated and will be compared with the
incidence of events occurring in a retrospective cohort of
patients who did not receive prophylaxis. Data from this
study will inform national recommendations for chemopro­
phylaxis, support the practice of evidence-based medicine
and, ultimately, improve patient safety. One important barrier
to multicenter trials in plastic surgery is the cost. Multicenter
registries may be a more “cost-effective” form to evaluate
outcomes and measure quality.
Knowledge translation
As clinical research in plastic surgery continues to advance
rapidly, information overload is a constant challenge for sur­
geons. Incorporation of research findings into plastic surgery
practice currently relies on publications in peer-reviewed
journals and educational activities such as continuing medical
education (CME) and continuing professional development
(CPD). Because of their passive nature, CME and CPD have
had limited effects on modifying physicians’ practice. Dis­
crepancies or care gaps remain between what is recognized as
evidence-based practice and the care provided in everyday
plastic surgery practice. Moreover, patients may be receiving
potentially harmful or unproven medical and surgical inter­
ventions. In a 2001 report entitled, Crossing the Quality Chasm:
A New Health System for the 21st Century,101 the Institute of
Medicine identified three main gaps in quality of care: medical
error, overuse, and underuse. As an example, despite evidence
that the risk of deep venous thrombosis is particularly high
for patients undergoing combined abdominoplasty and lipo­
suction, only 60% of plastic surgeons report use of thrombo­
prophylaxis all the time.102

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CHAPTER 10 • Evidence-based medicine and health services research in plastic surgery
surgery community is that a high percentage of surgeons
practice alone in a private practice setting and may lack the
resources needed to participate in such endeavors. In addi­
tion, the practice of plastic surgery takes place in a highly
competitive marketplace where a culture of collaboration,
rather than competition, may be a difficult, but not impossi­
ble, shift to enable. It is possible that outside forces such as
changing reimbursement strategies will nudge our commu­
nity towards recognizing the value in collaborative learning
and improvement.
Role of electronic medical records/
integrating data collection into flow of usual
care versus research
To have truly effective KT and continuous improvement in
the quality, safety, and value of healthcare, an infrastructure
that supports data use in clinically intelligent ways is para­
mount. Current systems are limited by use of paper and by
lack of interoperability, even when electronic data are avail­
able, thus making the majority of clinical data relatively
inaccessible in practical terms. Where clinical data are cur­
rently used, e.g., Surgical Care Improvement Project (SCIP)129
measures and National Surgical Quality Improvement
Program (NSQIP)130, full-time employees must be hired to
abstract data manually from paper or electronic records and
re-enter them in a different format for submission. Due to
these high labor costs, only a small sample of surgical cases
and data points can be included. When clinical research trials
are performed, much of the data collection is done on paper,
duplicating information already present in the medical record,
which again represents a very labor-intense process. Further­
more, when patient-reported data are collected, patients may
be asked to answer questions similar to those already asked
during the clinical encounter, thus adding significant redun­
dancy to patients as well. In addition, it can be challenging or
even impossible to score paper-based questionnaires at the
bedside, thus depriving the patient–provider relationship of
data that could otherwise have a significant impact on their
decision-making.
Several specialty societies, including the American Society
of Plastic Surgeons, have hired consultants to design data
collection websites such as TOPS. However, this typically
requires practitioners to abstract data manually and re-enter
it into the national database, thus creating a significant barrier
to participation by many. Few groups, other than the Cancer
Trialists Collaborative Group, which receives national funding,
have been successful at carrying out and sustaining such
efforts.
Possible solutions: generic
With the evolution of computer technology and the internet,
the feasibility of turning data into meaningful information for
activities such as decision-making at the bedside, physician
feedback, benchmarking, improvement of care, credentialing,
certification, and research is becoming much more affordable,
practical, and realistic. Although information technology has
much to offer in enabling the transformation of healthcare
delivery, it has been slow in adoption and effectiveness com­
pared to other industries. To stimulate growth, the federal
application of behavior change reflecting new research-based
knowledge may be external (e.g., patient refusal, conflict­
ing research evidence, lack of resources, organizational
constraints).112,113 Other factors influencing successful imple­
mentation of evidence-based interventions include miscom­
munication between the organization and the healthcare
providers, preventing identification of factors hindering
compliance with recommended practices. Successful imple­
mentation of evidence-based practice has thus far depended
on the adoption of a comprehensive program that incorporates
methods to improve culture, teamwork, and communica­
tion.114,115 There is now a burgeoning field called the science
of healthcare delivery.116–118
Learning collaboratives
In a quest to improve healthcare delivery, the Institute for
Healthcare Improvement developed a learning collaborative
model in 1995, called the Breakthrough Series model. It is an
ongoing learning process in which groups of practitioners
from different healthcare organizations work in a structured
environment to improve a chosen area of their practice.119
While clinical trials networks are designed to test an
intervention (e.g., drug, surgical procedure, medical device,
screening approach), quality improvement learning collabora­
tives focus on the best way to adopt, implement, and adapt
evidence-based practice to real-life environments. These
collaboratives often identify ways to improve quality and
reliability and to decrease healthcare costs by meticulous
comparisons of variation in care processes, culture, and
systems between organizations.120 Many successful collabora­
tives have come together around diverse health conditions
such as cardiac care,121 cystic fibrosis,122 infant care,123 central
line infection,114 and a whole host of topics sponsored by the
Institute for Healthcare Improvement.124
In collaborative endeavors, the ultimate goal is to promote
the dissemination and adoption of evidence-based practice to
help organizations and healthcare professionals close the gap
between actual and best practice in healthcare. Using adult
learning principles, learning collaboratives allow practitioners
to collaborate and learn from their collective experience and
challenges. By bridging together practitioners with different
roles in the same organization114 and from different organiza­
tions,125 information is shared on best practices, quality
methods, and experiences while implementing systematic
improvements to the overall system of care.
In their systematic review, Schouten et al.126 reported on the
impact of quality improvement collaboratives, and concluded
that the evidence is “positive but limited” and that further
study is warranted to understand the most effective models.
Hospitals or providers with worse outcomes could learn best
practices of those with better outcomes. An example of this is
the Michigan regional collaborative improvement program,
funded by a private insurance carrier, that decreased surgi­
cally related complications in general, and vascular surgery
in particular by 2.6% (2500 patients) with savings of approxi­
mately $20 million.127
What does this mean for plastic surgeons? Within plastic
surgery, a pilot learning collaborative has been launched
using TOPS as a central data repository.128 The collaborative’s
focus is on sharing practices around abdominal procedures
and resultant seroma rates. A challenge for the plastic

131
What do we do with the outcomes?
tracking the effect of a particular treatment. Likewise, the
BREAST-Q62 has been developed to provide useful bedside
information as well as valuable research information.
At Dartmouth, we have been able to integrate electronic
patient-reported intake and outcomes into routine care for
the purpose of improving the quality and efficiency of care,
reporting, and research. This has been operationalized across
30 clinical conditions including comprehensive breast care
(BREAST-Q) and hand care (Quick Disabilities of Arm,
Shoulder and Hand, Boston Carpal Tunnel Questionnaire).
At Memorial Sloan-Kettering, the BREAST-Q is routinely
administered at the point of care allowing for the clinical use
of this information and implementation of interventions
when needed. Plastic surgeons participating in TOPS can
sign up to have the BREAST-Q sent to their breast patients
for longitudinal postoperative tracking. A common senti­
ment expressed by practitioners who have access to these
measures at the time of an encounter is that they cannot
imagine ever returning to a practice style where this infor­
mation was not available.
As we become more sophisticated at measurement, it
becomes important that, as a community, we endorse and use
the same measurement tools so that we can make meaningful
comparison of the data through our national registry. There is
no doubt that these measures will continue to improve
through an ongoing iterative process. The more plastic sur­
geons participate, the more they can help shape the design of
these data systems to make them even more practical at the
bedside, and more effective at answering important clinical
questions through well-designed research studies and learn­
ing collaboratives. The ICHOM (International Consortium
for Health Outcomes Measurements)134 organizes groups of
physicians, researchers and patient advocates to define a
standard set of outcomes measures, advocating for global
adoption so providers can compare, learn and improve. This
may promote international collaboration and decrease health­
care costs. Currently, they have 12 completed datasets (includ­
ing cleft palate) but aim to have 50 by 2017.
What do we do with the outcomes?
EMRs and HIT have the potential to improve the quality of
healthcare and support the transformation of the way medi­
cine is practiced and provided to patients. Computerized
continuous quality assessment from data found in EMRs
should facilitate ongoing monitoring and improvement of
healthcare quality as well as clinical decision-making. Numer­
ous national initiatives are currently assessing ways to
measure care systems with the goal of collecting and compar­
ing data on the structure of healthcare systems, care interven­
tions, and patient outcomes. These data are valuable to
many stakeholders: patients, providers, healthcare payers,
and government agencies. Thus, there is currently an unprec­
edented focus on quantifying healthcare value, because
improving the outcomes of care at a more affordable price is
an important and pressing challenge.
The first model summarizing factors influencing patient
outcomes was developed by Donabedian in 1966.136 This
framework is still relevant today, and hypothesizes that care
structures (e.g., dedicated microsurgical care team) and care
processes (e.g., standard limb replantation care pathway) play
government has developed a 5-year plan to phase in and define
“meaningful use” of electronic medical records (EMRs).131,132
The hope is that this will increase meaningful adoption of
health information technology (HIT) by both providers and
hospitals. The Medicare and Medicaid incentive program will
provide incentive payments to hospitals or providers that
implement, upgrade or demonstrate EMR technology. There is
a three-stage plan for implementing the meaningful use of
EMR from 2011 to 2016: data capture and sharing, advance
clinical processes, and improved outcomes.132
Standards for PROMs have not yet been included in the
current and future proposed definitions of “meaningful use”.
However, decision support rules and best practice alerts may
well benefit from inclusion of these measures. For instance, a
PRO instrument for depression could generate a best-practice
alert for referral to a mental health professional.133 Likewise,
a PRO measure for domestic abuse could generate a best-
practice alert for referral to social services professionals.
Having such PRO measures integrated into the flow of care
electronically, thus enabling immediate scoring and reporting
to the healthcare team, advances our ability to provide high-
quality care. This reaches beyond what we have been able to
achieve in the past with paper-based and research measures
administered and scored well after an office encounter, and
often never reported back to the care team. For example, the
International Consortium of Health Outcomes Measurement
is a nonprofit organization that aims to transform healthcare
by standardizing the way to measure outcomes. Their recom­
mendations for measuring the value of care for individuals
with cleft lip and palate include 9 dimensions of outcomes,
four of which are captured with CleftQ.134
The gradual adoption of EMRs by more and more health
systems, practices, and individual practitioners provides a
growing opportunity to capture structured data at the point
of care. Not only can these systems facilitate the systematic
capture of data, but they also allow systematic analysis and
reporting. This reporting can be done with several purposes
in mind, such as instantly providing decision support and
best-practice evidence to providers at the time of patient
encounter. The reporting can be “rolled” up to a cohort of
patients with similar health conditions (e.g., all breast cancer
patients), similar procedures (e.g., all free flaps), or on a pro­
vider’s panel (e.g., all surgical cases performed by the same
surgeon). These reports could also be aggregated at the prac­
tice level, departmental level, or at the national level.
Possible solutions: plastic surgery and PROMs
It is often a challenge for plastic surgeons to mobilize the
resources within their clinical environment to develop and
program the tools to collect field-defined data specific to the
specialty. However, several innovative centers have begun to
do just that with PROM. Just as we have easy access to timely
and standardized laboratory results, so should we have
similar availability of timely and standardized PRO at the
bedside. In many cases, particularly in the specialty of plastic
surgery, PROM may provide us with better decision-making
information, or may add an important dimension to more
traditional biometric measures. For instance, the Levine
score135 for carpal tunnel patients, when available during an
encounter, is very helpful to individual patients and their
surgeons in quantifying the impact of the symptoms and in

132
CHAPTER 10 • Evidence-based medicine and health services research in plastic surgery
complications. The withholding of a pro-rated Medicare
payment was used as a financial incentive to guarantee par­
ticipation in SCIP. However, at present, studies evaluating the
effect of SCIP process measures following colorectal surgery
on surgical site infection rates have mixed results.144,145 Of
note, these studies have relatively small sample size at each
participating institution. Furthermore, SCIP measures of
performance target a limited set of surgical procedures, none
of which pertains to plastic surgery. Such measures are pri­
marily useful at the organizational level, but not at the level
of the individual provider. However, collection of SCIP mea­
sures from a data-rich EMR will make reporting at the indi­
vidual provider level much more feasible.
The American College of Surgeons’ National Surgi­
cal Quality Improvement Program (NSQIP)130 is another
initiative that is gaining increased traction amongst surgi­
cal specialties and hospitals to track and improve surgical
outcomes. For participating hospitals, and the surgeons
they represent, clinical data rather than administrative data
can be used to compare outcomes across organizations
and support improvement efforts. One of the flaws is that
outcomes are reported only for the first 30 days, leaving
insufficient time to analyze outcomes in some plastic surgery
procedures.146
To date, two studies addressing performance measures in
plastic surgery have been conducted in the UK. The British
Association of Plastic Surgeons, following a requirement of
National Health Service clinicians to take part in clinical
audits, has taken the initiative to identify surgical procedures
that could be used as markers of performance across
the specialty.147 In their pilot study, a national performance
assessment for pedicled and free-flap survival was completed.
When comparing four plastic surgery units, the overall
outcome achieved was 89% total flap survival. In 2011, the
National Mastectomy and Breast Reconstruction Audit
reported outcomes in more than 8000 women with mastec­
tomy and reconstruction in the UK. The Breast-Q was chosen
as one of the outcome measures. This study was useful to
determine benchmarks, analyze level of satisfaction in patients
with breast reconstruction, and identify providers with better
and worse outcomes, amongst others.148 The multicentre
MROC study (Mastectomy Reconstruction Outcomes Consor­
tium) is currently enrolling patients in 11 centers in the US,
and it was designed to explore patients’ experiences after
reconstruction regarding aspects such as satisfaction with
breasts, psychosocial well-being, postoperative pain, etc.
Patient questionnaires are administered at several points
(preoperative, one week, three months, one year and eighteen
months), and the study is projected to close accrual in 2016.
This important study will shed light on the patient’s point of
view regarding breast reconstruction method, timing, but also
costs with the different procedures.149
The Maintenance of Certification Program of the American
Board of Plastic Surgery has ventured into this arena of physi­
cian performance measurement. Their Practice Assessment in
Plastic Surgery (PA-PS) modules include 20 of the most
common plastic surgical procedures. Some data analysis from
this system has already found use.150 Although far from being
as robust as what will be needed in the future, these modules
will likely undergo frequent upgrades to improve their useful­
ness to the practicing clinician and will undoubtedly include
PRO in the future.
a role in patient outcomes. In this type of model, outcomes
can take any form appropriate to one’s practice: for example,
mortality, health status, functional status, satisfaction, QoL,
and cost.
The creation of clinical practice guidelines has become a
strategy frequently used to improve healthcare quality and
outcomes. They represent a way of outlining evidence-based
practices through a review and synthesis of the literature in
an attempt to guide patient care better. However, although
extremely useful, guidelines alone are not sufficient to produce
improvements in the quality of care. The strategy of publica­
tion and dissemination of practice guidelines has failed to
guarantee their implementation, and there may be physician
resistance as clinicians feel their autonomy is compromised.
Also, clinical guidelines do not account for patient variability,
but need to be updated very often since medical knowledge
is continually changing. An alternative to clinical guidelines
is standardized clinical assessment and management plans
(SCAMPS): flexible and continuously improving care guide­
lines created by physicians, with the aims of decreasing
practice variability, optimizing use of healthcare resources
and improving patient care. SCAMPs allow physicians to
adapt clinical pathways to individual patient needs by incor­
porating current scientific evidence but also including patient
characteristics into the pathway. Since 2009, more than 12 000
patients have been enrolled in 49 adult and pediatric SCAMPs
in nineteen institutions, with reduction of practice variability
and improved patient outcomes.137
Performance measures
In the process of facilitating the measurement of healthcare
quality, performance improvement measures serve as a
vehicle for translating the strongest clinical evidence into
practice more rapidly. Measures typically go through many
iterations before they are widely endorsed as being mean­
ingful and reliable. In the earlier stages of maturation, it
has been proposed that the measures be called “quality
metrics”.138 These metrics can be used to assist providers,
hospitals, or the healthcare system in self-assessment,
enhancing both the quality of care and patient outcomes.
With repeated improvements in the measures themselves,
they may rise to the exacting standards of organizations
such as the National Quality Forum139 and be endorsed as
formal “performance metrics”138 and used for public report­
ing, comparison of care between institutions or healthcare
providers, P4P initiatives, and for meaningful use initiatives.
The credentialing and financial incentives behind compli­
ance with performance metrics encourage healthcare provid­
ers and organizations to offer the strongest evidence-based
quality of care.
One of the main examples of a process-driven quality
initiative is SCIP.129,140,141 This national quality partnership
of organizations was initially a voluntary collaborative to
improve surgical care by reducing surgical complications. It
transitioned to a mandatory, publicly reported system in
2005.142 The ultimate goal of this program was to reduce the
incidence of preventable surgical morbidity and mortality
nationally by 25% by the year 2010 through collaborative
efforts. This program has four preventable complication
modules: (1) surgical site infections;129 (2) venous thromboem­
bolism;143 (3) cardiovascular events; and (4) respiratory

133
What do we do with the outcomes?
homogeneous study samples may not be generalizable to all
patients.154 Besides, outcomes in daily practice are influenced
by various amalgamations of patient and treatment variables,
which are seldom replicable in randomized controlled trials.
In addition, many of the studies that failed to demonstrate an
improvement in outcomes did not assess outcomes occurring
at longer intervals after the delivery of the process of care to
the patient. Moreover, the present burden of comprehensive
data collection limits investigators’ ability to capture patient
information between care settings over time. Data collection
should be facilitated by the widespread use of electronic
medical records, allowing researchers to evaluate long-term
outcomes readily.153
Decision aids for patients
Making an informed decision about the best treatment can be
difficult for patients, especially when there is more than one
medically reasonable option. Over the last 30 years, the field
of evidence-based decision-making in healthcare has grown
rapidly. Patient decision aids aim to support this process and
help patients arrive at informed value-based choices. Accord­
ing to the International Patient Decision Aids Standards col­
laboration, decision aids are evidence-based tools designed to
prepare patients to contribute actively to the decision-making
process when choosing among healthcare options, according
to their preferences and values.164–166 They differ from conven­
tional patient education materials in that they are more
detailed, specific, and deliberated, and they provide a more
personalized focus on options and outcomes, with the goal of
helping patients make informed choices. Decision aids for
patients do not replace the patient–physician encounter;
instead, they supplement the provider’s counseling about
healthcare options.164 They can be used before, during, or after
an interaction with a practitioner.
A recent Cochrane systematic review of patient decision
aids reported that they improve patients’ knowledge regard­
ing their options, and reduce decisional conflicts from feeling
uninformed or confused about personal values.164 After using
decision aids, fewer patients are ambivalent about their treat­
ment choice. Importantly, more patients participate actively
in the decision process. However, randomized controlled
trials have failed to demonstrate that these tools improve
patient outcomes such as decision uncertainty, satisfaction,
anxiety, or QoL.167 Moreover, there is scarce evidence on the
effects of decision aids on patient compliance with treatment,
decisional regret, litigation rates, healthcare costs, and
resource use.164
Evidence supporting the use of decision aids in clinical
practice is substantial.164,167,168 A good decision aid should meet
the needs of its target population, and be acceptable to both
patients and providers who wish to incorporate them in their
clinical practice. Barriers to successful implementation are the
lack of effective systems for delivering decision support.
Further research is needed to assess the effects of decision aids
on congruence between patients’ values and their chosen
options.
Designing and building high-quality decision aids is
greatly enhanced when the available evidence base, includ­
ing patient-reported outcomes, is robust. There is much
opportunity for the plastic surgery community to add to this
evidence base.
On another front, the Joint Commission that accredits
healthcare organizations has created a standard around evalu­
ation of professional practice at the individual provider
level.151 Like other initiatives, preliminary measures will be
derived largely from process data and perhaps surgical com­
plications and we will await future iterations to integrate
patient-reported outcomes.
Public reporting and P4P
Despite limited evidence on their benefits, public reporting of
hospital quality data and P4P are the two most advocated
strategies to accelerate improvements in healthcare quality
and safety.152 Measuring and publishing information about
quality of hospitals, health plans, and physicians are driving
P4P programs. Public accountability of quality measures has
proved an excellent motivator for healthcare providers and
hospitals to invest efforts in quality activities, as performance
measures are open to the public for review.153,154
P4P is a compensation model used by private payers that
links financial incentives to the quality of healthcare pro­
vided.155 While the P4P concept is gaining momentum as a
means of improving overall quality of care by reducing gaps
between clinical practice and evidence-based guidelines,
it is also viewed as a way of encouraging efficient use of
healthcare resources. P4P initiatives can take various forms,
encompassing different payment models, various stakehold­
ers (e.g., hospitals, group practices, private practitioners),
and diverse clinical conditions. The available evidence
regarding the impacts of P4P has been mixed.156–158 Some
large-scale studies report moderate enhancements in process-
of-care measures, but to date, no impact has been reported
on patient outcomes or efficiency of care.152,159–161 Pay for
performance (value-based purchasing) is an important
part of the Affordable Care Act, intended to financially
incentivize hospital/provider performance. Scores reflect
achievement compared to other hospitals, as well as yearly
improvement. Value-based incentive payments will be given
to providers who deliver higher-value care (e.g., fewer
complications) and meet certain performance standards, as
evaluated by different outcomes measures.162 Additionally,
the US federal government has introduced its own Pay
for Reporting (P4R) program: the Physician Quality Report­
ing Initiative. This initiative offers financial incentives to
Medicare providers who participate in quality reporting.
Unlike P4P programs, the P4R model compensates physi­
cians regardless of their performance on process and
outcome measures.163
In 2002 and 2003, a natural experiment occurred, involving
thousands of American hospitals participating in a national
public reporting initiative, with more than 200 organizations
engaged in a simultaneous P4P initiative. Lindenauer et al.152
observed that hospitals participating in both public reporting
and P4P programs showed modestly greater improvements
in healthcare quality than hospitals engaged in public report­
ing alone.
Some critics argue that little evidence links performance
measures to patient outcomes.154 One explanation for this may
be found in the realization that current measures focus on a
very small number of processes of care out of the total inter­
ventions that characterize the patient’s experience in the
hospital.153 Also, results of randomized controlled trials with

134
CHAPTER 10 • Evidence-based medicine and health services research in plastic surgery
care that is underdeveloped and underutilized. Measuring
outcomes is not just about the final result of our interventions
but a means by which we gather evidence to improve decision-
making, the processes of care, and the systems in which we
work. Collaborative data collection through clinical trials and
quality improvement initiatives is essential to the generation
of clinically meaningful information in our specialty. Our
decisions need to be based on the highest-quality evidence
and not the accumulated experience of a single surgeon,
even if that surgeon is truly expert in the field. Equally
important to generating clinically meaningful information
is to translate that information into practice by providing
surgeons with mechanisms to implement and monitor new
standards.
Conclusions
This chapter would be incomplete without emphasizing the
key take-home messages. A clinician cannot make good deci­
sions without good evidence and cannot generate good evi­
dence without good study design and good data. Maximizing
patient care and surgical outcomes will require continuous
efforts to identify information needs and to produce the best
evidence to fulfill these needs. Outcomes research offers a
broad spectrum of methods by which to obtain good evi­
dence, and these have been insufficiently leveraged by our
specialty. In particular, measuring the patients’ perspective
on outcomes is a crucial dimension of research and clinical
11. Walach H, Falkenberg T, Fonnebo V, et al. Circular instead of
hierarchical: methodological principles for the evaluation of
complex interventions. BMC Med Res Methodol. 2006;6:29. Walach
and co-authors discuss the widely held assumption around the hierarchy
of evidence which places randomized controlled trials (RCTs) at the top
– which are in turn trumped only by meta-analyses of multiple RCTs.
However, this hierarchy is based on a pharmacological model of therapy.
When generalized to other interventions such as integrative medical
management, wound healing, and surgery, the hierarchical model is
valid for limited questions of efficacy. RCTs are strong in the arena of
internal validity (minimization of bias), but not as much so in regard to
external validity or generalizability of the findings. Rather than an
“evidence hierarchy”, they propose a “circular model” of evidence that
would include multiple methods, with different research designs,
balancing strengths and weaknesses to arrive at the best clinical
evidence.
22. Wennberg DE, Lucas FL, Birkmeyer JD, et al. Variation in carotid
endarterectomy mortality in the Medicare population: trial
hospitals, volume, and patient characteristics. JAMA.
1998;279:1278–1281. This paper assessed the perioperative mortality
among Medicare patients undergoing carotid endarterectomy (CEA). The
study found that the risk of preoperative mortality following CEA was
significantly higher than reported in the clinical trials, even among the
institutions that participated in the trials. This study demonstrates the
caution that one should have when translating the efficacy of clinical
trials to effectiveness in everyday practice.
26. Chung KC, Kalliainen LK, Hayward RA. Type II (beta) errors in
the hand literature: the importance of power. J Hand Surg Am.
1998;23:20–25. This manuscript describes how many papers in the
Journal of Hand Surgery had insignificant sample size and power to
provide an adequate assessment of therapeutic efficacy. The authors found
that 82% of “negative” studies had a power less than 0.80 to detect a
25% treatment effect. Researchers and clinicians should be aware of the
importance of adequate sample size and statistical power in order to
avoid making a type 2 or beta error, which is the erroneous conclusion
that the null hypothesis is correct.
51. Cano SJ, Klassen A, Pusic AL. The science behind quality-of-life
measurement: a primer for plastic surgeons. Plast Reconstr Surg.
2009;123:98e–106e. The authors provide an overview of the key
principles underlying the development of patient-reported outcomes
instruments. They provide definitions of the terminology pertaining to
this field of study, along with explanations of relevant concepts. The
authors also provide a description of the essential elements to assess the
quality of an instrument, along with a summary of the latest
developments in psychometric methods of quality-of-life measurement.
120. Ayers LR, Beyea SC, Godfrey MM, et al. Quality improvement
learning collaboratives. Qual Manag Health Care. 2005;14:234–247.
The authors interviewed individuals who had developed and implemented
highly successful learning collaboratives and describe the key
characteristics that made these initiatives successful and sustainable. For
those interested in knowing how to succeed, the authors’ description of
the importance of building trust, appreciating and dealing with
differences in organizational cultures and rallying around a passion for
quality improvement are very helpful.
Access the complete reference list online at

134.e1
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11 
Principles of cancer management
Evan Matros, Tomer Avraham, and Babak J. Mehrara
SYNOPSIS
■ There has been a gradual progression from radical to more
conservative resections of many cancers.
■ Neoadjuvant therapies have facilitated resectability and even down-
staging of some tumors.
■ A better understanding of immunology has led to the development of
biologic therapies.
■ Targeted therapies represent a new paradigm in the treatment of
cancer aiming to combine efficacy and decreased toxicity.
■ Rational, evidenced approaches to tumor ablation should aim to
improve oncologic outcomes, reduce morbidity, and facilitate
reconstruction.
Background
The introduction of reconstruction after extirpation was a
major advance in cancer management. Plastic surgical tech­
niques have facilitated large-scale resections by enabling
immediate closure of surgical defects. Furthermore, develop­
ment of microsurgical techniques enabled transfer of highly
vascularized flaps from distant donor sites, thereby increasing
the versatility of the reconstructive techniques and obviating
the need for time-consuming surgical delay procedures or
waltzing flaps.
Improved understanding of tumor pathobiology and
prognostic factors has led to a gradual paradigm shift in
cancer treatment from a “one size fits all” approach to tailored
oncologic therapy. This chapter provides background for the
current rationale behind modern treatment of tumors.
History of cancer treatment
While surgery remains the most successful single modality
treatment for solid tumors, the past century has demonstrated
an increased role for multimodality therapy. The goal of
current treatment for solid tumors is to minimize the defor­
mity of wide-scale surgical extirpation, with assistance of
neoadjuvant and adjuvant chemoradiation, to provide the
greatest likelihood for cure.
Neoadjuvant treatment is the term used to describe either
chemotherapy and/or radiation that are administered prior
to tumor excision. Neoadjuvant therapy is used to shrink
unresectable tumors rendering them resectable, or to decrease
the magnitude of the ablation necessary to achieve negative
margins.1 Patients may undergo a complete response with
total preoperative tumor eradication, or a partial response to
neoadjuvant therapy. The response to neoadjuvant chemo­
therapy is an important predictor of outcome and can deter­
mine which chemotherapy is used postoperatively.2 Clinically
neoadjuvant therapy is a common part of treatment algo­
rithms for many solid tumors. For example, randomized trials
demonstrate lower recurrence rates for T3 and T4 rectal
tumors when chemoradiation is delivered preoperatively as
compared to postoperatively.3 Furthermore, for distal tumors
lying near the anus, neoadjuvant therapy facilitates sphincter
preservation by converting cases that potentially require
abdominoperineal resection to low anterior resections.4
Neoadjuvant chemotherapy has come to play a significant
role in the management of breast cancer, with significant
impact on reconstructive decision-making for the plastic
surgeon. Traditional indications for neoadjuvant chemother­
apy include large tumor size, N2 nodal status, and inflamma­
tory component. More recently it has been advocated for
tumor down-staging and to facilitate breast conservation.5
Increased use of neoadjuvant therapy in breast cancer has
resulted in recognition of pathologic complete response,
whereas no tumor is identified on surgical specimen follow­
ing completion of chemotherapy. Further study is required to
determine if the need for ablative surgery is obviated in this
setting.6
Disadvantages of neoadjuvant therapy include the possi­
bility for disease progression prior to surgical resection and
increased rates of surgical complications due to side effects of
chemoradiotherapy. For example, in a review of nearly 1200

136
CHAPTER 11 • Principles of cancer management
unthinkable and today is being utilized with ever increasing
indications. Modern surgical therapy uses insight gained
from clinical trials to minimize the scope of resection with an
eye on preserving form and function (Fig. 11.1). Radical
approaches are reserved for only the most advanced cancers
with extensive local invasion.
While the utility of primary tumor excision has been estab­
lished, the role of surgery in management of metastatic disease
is less clear. The majority of patients with metastasis receive
palliative treatment with radiation to achieve local control
and chemotherapy for disseminated disease. However, if
thorough evaluation reveals isolated or a limited number of
metastases in a patient with a good prognosis, both cure and
extended survival have been achieved with surgical “metas­
tectomies”. Patients with extremity sarcomas who undergo
pulmonary resections have 5-year survival rates up to 25%.12
Similarly, hepatic lobectomy for colorectal metastasis is asso­
ciated with 25–40% 5-year survivorship in selected patients.13
Finally, surgeons may be called upon to obtain tissue for
diagnosis of a new mass. Depending on tumor size, either
incisional or excisional biopsies are performed as a precursor
to definitive resection or to establish a diagnosis for cancers
treated nonsurgically. Incisional biopsies should always be
oriented in a direction that facilitates future wide surgical
excision.
Radiation
Ionizing radiation is defined as energy sufficient to release
electron(s) from an atom or molecule. Most radiation agents
use either photons or electrons to cause ionization. The quan­
tity of ionization produced in air by a beam of radiation is
termed the exposure and is measured in units of roentgens.
The more clinically relevant measure is the absorbed dose,
which is a calculation of the amount of energy absorbed per
unit mass. This is quantified in joules per kilogram, or gray
units (Gy). Upon entering tissues, the ionizing agent dose
increases, but then degrades exponentially as its distance
from the source increases in accordance with the inverse-
square law.14
The mechanism whereby ionizing radiation achieves tumor
cell kill is not completely understood. Ionizing radiation
causes cellular damage directly through release of electrons
microsurgical breast reconstructions, Mehrara et al. demon­
strated that neoadjuvant chemotherapy was an independent
risk factor for postoperative complications in breast cancer
patients undergoing microvascular breast reconstruction
resulting in increased rates of wound complications if surgery
was performed less than 6 weeks after completion of
chemotherapy.7
In the adjuvant or postablative setting, chemotherapy or
radiation is implemented to decrease locoregional recurrence
or systemic disease by treating microscopic tumor deposits or
metastases that are not detectable at the time of surgery. It is
important to emphasize, however, that even if radiation or
chemotherapy is planned postoperatively, all attempts should
be made (if surgically feasible) to obtain microscopically nega­
tive tumor margins at the time of surgical resection. This
concept is based on the fact that negative tumor margins are
an important predictor of local or regional metastases in most
solid tumors.8
Surgery
The earliest treatment for tumors was fulguration using
electrocautery, application of toxic materials, or surgical
extirpation. Due to the high local recurrence rates seen after
tumor excision, surgical management at the turn of the 20th
century developed into a “bigger is better” approach with
wide margins. The best-known example is the Halsted radical
mastectomy for invasive breast cancer advocating the removal
of the pectoralis major muscle, all of the breast tissue and
axillary nodes.9 Similarly, head and neck malignancies were
treated with internal jugular vein ligation, sternocleidomas­
toid muscle resection, and spinal accessory nerve sacrifice.
Such aggressive approaches to tumor control have subse­
quently been shown to be unnecessary for many cancers.
Instead, the efficacy of limited anatomic resections has been
proven in studies which: (1) demonstrate equivalency with
more radical approaches, or (2) combine surgery with multi­
modality therapy. For example, margins greater than 2 cm
have shown no benefit in the treatment of cutaneous mela­
noma.10 Additionally, effective treatment of breast cancer no
longer mandates mastectomy if lumpectomy is combined
with postoperative radiotherapy.11 Nipple areola-sparing
mastectomy would have at some time been considered
Fig. 11.1  Superiority of lesser resections to radical surgery. (A) This patient had a less aggressive surgical approach with a nipple-sparing mastectomy followed by
immediate autologous tissue reconstruction. (B) The second patient had a more aggressive modified radical mastectomy, followed by radiation and delayed reconstruction.
Note that while both patients have acceptably cosmetic reconstruction, the outcome of the patient shown in (B) is inferior to that of the patient shown in (A). In part due to
the extensive nature of her surgery, she has more extensive and noticeable scarring, as well as skin color mismatch.
A
B

137
History of cancer treatment
Although the increased rates of wound-healing complica­
tions following surgery in irradiated tissues have been thought
to be related to the harmful effects of radiation on the local
blood supply, the exact cause(s) of this increased risk remains
unknown.21 In fact, studies have suggested that radiation
injury causes depletion of local tissue stem cells and that
restitution of these cells with stem cell injections can improve
tissue healing.22 Interestingly, recent studies have called into
question the ability of radiation to improve survival, and as
such suggest the need for more nuanced patient selection and
risk stratification.23
Concerns about toxicity and tissue injury after radiation
have led to the development of a number of modalities aiming
to increase the precision of radiation delivery. Intensity-
modulated radiation therapy (IMRT) is an example of this
approach combining 3D CT scans and computer software to
optimize radiation simulation and delivery. During treatment,
the intensity of the radiation beam is modulated by computer­
ized X-ray accelerators enabling delivery of radiation to three
dimensional tumor shapes thereby minimizing injury to the
surrounding regions. For these reasons, IMRT has gained
favor in the treatment of prostate, lung, head and neck, and
brain lesions. In addition, recent studies have shown that
IMRT can decrease cardiac and pulmonary toxicity in left-
sided breast cancers. Recent studies have focused on demon­
strating survival benefits to IMRT and decreasing long-term
complication rates of radiation.24–26
Proton beam therapy is a type of radiation therapy in
which a beam of protons (rather than electrons) is used to
deliver radiation to the tumor bed. Because these particles are
bigger than conventional radiation therapy, the delivery of the
treatment dose can be more precisely controlled limiting
surrounding tissue and exit dose delivery. These radiation
delivery treatments are more complex than conventional
therapy since a particle accelerator is required to generate the
proton beam. The use of different particle sizes enables radia­
tion oncologists to target tumors at different depths delivering
the maximum peak of radiation (called Bragg Peak) at a
precise point. The use of multiple photons generated from
multiple particles (with variable penetration capacity) enables
peak radiation delivery to the entire tumor bed.27,28
Brachytherapy is radiation therapy that is delivered inter­
nally to the wound bed after tumor extirpation. In some cases,
the radiation source can be placed without tumor extirpation
or within the tumor itself to increase radiation dose delivery.
This approach enables radiation oncologists to place the
radiation source in very close approximation to the tumor bed
thereby limiting radiation injury to surrounding tissues or
external skin. In this manner, radiation therapy can be deliv­
ered safely in some cases even in patients who have been
previously treated with external beam radiotherapy.29,30
Chemotherapy
The goals of chemotherapy are similar to those of radiation,
namely preferentially to kill cancer cells relative to normal
tissues while minimizing toxicity. The success of chemo­
therapy is due to the fact that normal cells have improved
ability to repair damaged DNA and survive relative to cancer
cells. For chemotherapy to be successful, complete eradication
of all tumor cells is essential. Agents that kill 99.99% of 109
tumor cells, the approximate number of cells in a 1-cm mass,
or indirectly by producing free radicals from water. Since
oxygen increases the half-life of reactive radical species, radia­
tion is most effective in oxygen-rich environments. When
electrons or free radicals come into contact with biologically
important molecules, such as DNA, detrimental effects occur.
Although cells efficiently repair single-strand DNA breaks,
double-strand breaks are less easily handled by cellular
machinery. If sufficient DNA damage accumulates prior to the
next mitotic cycle the cell is overwhelmed, leading to cell
killing. When the interval between successive doses of radia­
tion is increased, greater numbers of cells can repair DNA
strand breaks. This principle is termed sublethal damage and
provides the rationale for radiation delivery in fractionated
daily doses ranging from 1.8 to 2.5 Gy. The success of radiation
therapy is predicated on the fact that normal cells have a
greater ability to repair sublethal damage between radiation
fractions than tumor cells. Radiation therapy is most com­
monly delivered at a distance from the tumor called external-
beam radiotherapy or teletherapy; however, it can also be
administered as brachytherapy with high doses given directly
into a specified area.14
Clinical use of radiation therapy began in the 1940s and
1950s after early pioneers in the field were able to minimize
local complications such as radiation burns and secondary
skin cancers. Although uncommon, radiation can be used as
monotherapy for radiosensitive tumors such as Hodgkin’s
disease.15 For other tumor types equivalency between surgical
excision and radiation therapy has been demonstrated. For
example, treatment of T1/T2 prostate cancer with either
radical prostatectomy or external-beam radiotherapy has
comparable survivorship, but with different risk profiles for
each therapy.16,17 Choice of treatment is based on patient
preference and surgical risk factors as assessed by the treating
urologist. Similarly, aerodigestive tumors of less than 2 cm
respond equally well to either radiation or surgery. In the case
of laryngeal neoplasms, radiotherapy is preferred due to its
ability for organ preservation.18
Surgeons most commonly use radiation as part of neoad­
juvant or adjuvant regimens in combination with extirpation
for solid tumors. These two modalities complement each
other to improve locoregional control. While surgery fails at
tumor margins where cell counts are low or microscopic,
radiation works best at the periphery where oxygenation
levels are highest. Radiation is least effective in the avascular
center of necrotic tumor masses where oxygen tension is
poor.19
The efficacy of radiation therapy in reducing local recur­
rence has led to an increase in use of this modality for many
cancer types. This increase is amplified by trends towards
minimization of surgical extirpation and the use of neoadju­
vant chemotherapy with resultant tumor down-staging. The
increased role of radiation therapy in cancer management has
led to refinements in its delivery. In the past, radiation was
administered in the neoadjuvant setting with the goal of
rendering microscopic tumor deposits, spilled inadvertently
at the time of resection, incapable of cell division. However,
technical difficulties and increased complication rates, such as
wound breakdown and infection associated with this schedule
of radiation, have led to its preferred use in the adjuvant
setting for many cancers. Additionally radiation is a known
independent risk factor for the development of postsurgical
lymphedema as well as secondary skin malignancies.20

138
CHAPTER 11 • Principles of cancer management
allow a tumor burden of 105 cells to remain. Since agents are
unlikely to kill every tumor cell in a single administration,
chemotherapies are delivered in several rounds to achieve
maximal cell killing. Administration of chemotherapy in
fractions takes advantage of the fact that some agents are
effective only in certain stages of the cell cycle (termed
kinetic resistance) and minimizes toxicity at each time point
by allowing decreased dosing.31 Furthermore, combination
chemotherapy using agents with different mechanisms of
action and toxicities allows maximal tumor killing while
minimizing host side effects. Recognition of chemotherapy
toxicity has led to modifications such as regional administra­
tion, which allows for increased drug doses with reduced
systemic side effects. Examples of this application include
isolated limb perfusion for patients with melanoma in-transit
metastases or hepatic artery infusion pumps for colorectal liver
metastasis.32,33
Chemotherapeutic agents such as nitrogen mustard and
methotrexate were first introduced in the 1940s with the inten­
tion of avoiding surgery altogether. While effectiveness of
chemotherapeutics as single-modality treatment for hemato­
logic malignancies such as leukemia and lymphoma has been
demonstrated, their efficacy in primary treatment of solid
tumors has not been borne out in most cases. Exceptions
include chemotherapy for subtypes of testicular cancer and
combined chemoradiotherapy such as the Nigro protocol for
anal cancer.34,35 A common indication for chemotherapy in the
management of solid tumors is for palliation of patients with
metastatic disease who are ineligible for curative surgery. In
such cases, chemotherapy is administered with the intent of
prolonging survival and improving quality of life.
Surgeons most frequently encounter chemotherapy as part
of neoadjuvant or adjuvant treatment in combination with
tumor excision. Examples of tumors commonly treated in this
manner include breast, colon, and head and neck cancers.
Synergy between surgery and chemotherapy is exemplified
in the case of extremity sarcomas. Previously patients with
osteosarcomas were treated with amputation; however, the
introduction of neoadjuvant chemotherapy has increased rates
of limb preservation with equivalent long-term survival.36
Immunotherapy and biologics
Passive and active immunotherapies are newer forms of
cancer treatment that use immune mechanisms to kill tumor
cells. In passive immunotherapy the host immune system
remains quiescent while therapeutic agents are introduced to
eradicate tumor cells. The most common application of this
treatment is delivery of monoclonal antibodies against specific
tumor antigens (Fig. 11.2). Advantages of this approach
are the highly specific nature of therapy that theoretically
decreases both side effects and toxicity. A widely used
agent is trastuzumab, a monoclonal antibody that binds to
the extracellular segment of the HER2/neu receptor, over-
expressed in approximately 25% of breast cancers.37,38 Biolog­
ics such as trastuzumab and pertuzumab are commonly used
as components of neoadjuvant regimens.39
Adoptive immunotherapy is an alternative form of passive
immunotherapy wherein cells with antitumor activity are
introduced into the host (Fig. 11.3). An example would be
ex vivo manipulation of host autologous tumor-infiltrating
lymphocytes, which have a naturally occurring reactivity to
Fig. 11.2  Passive immunotherapy with monoclonal antibodies (mAb).
(A) Monoclonal antibodies can act by binding a cell surface molecule that acts as
a signal transducer. Antibody binding to this molecule inhibits its ability to
transduce signals and activate downstream pathways that confer the malignant
phenotypes of cell cycle dysregulation, cellular survival, and metastatic potential
(e.g., trastuzumab). (B) Monoclonal antibodies can contribute to immunotherapy by
cytotoxic effects (e.g., rituximab). Antibody binding to tumor-specific antigen can
lead to complement fixation and activation, with ultimate formation of the
membrane attack complex that punches pores in the tumor cell membrane.
Antibody binding may also cause the activation of cytotoxic natural killer cells or
phagocytic macrophages. (C) Finally, monoclonal antibodies can bind and block
the activity of growth factors that are necessary for tumor maintenance. An example
of this is bevacizumab, which binds vascular endothelial growth factor (VEGF) and
therefore inhibits tumor angiogenesis.
A
B
C
Proliferation
Survival
Invasion
Malignant
characteristics
Intracellular
signalling domain
Transmembrane
signalling domain
Functional
activation
Monoclonal antibody
e.g., trastuzumab
Macrophage
Macrophage activation
and phagocytosis
Activation of cytotoxic
natural killer (NK) cell
Blockade of growth factors (e.g., bevacizumab)
Tumor angiogenesis
and growth
VEGF
Complement
activation
Passive immunity
Tumor-specific
antigen
Membrane attack
complex (MAC)
Cytotoxic mAb
e.g., rituximab
NK cell
Pore

139
History of cancer treatment
cancer, in the presence of IL-2 to increase cytolytic potential or
tumor antigen recognition.40 Studies are currently evaluating
the utility of this therapy for the treatment of melanoma.41
Active immunotherapy describes protocols in which the
host immune system is directly stimulated by presentation of
antigenic materials. If the antigenic material causes general­
ized stimulation of the immune system, it is considered
nonspecific stimulation (Fig. 11.4). The best-known immuno­
stimulant agent is bacillus Calmette–Guérin (BCG), an attenu­
ated form of bovine tuberculosis bacillus. Although its
mechanism of action is unclear, it has proven benefit in the
treatment of superficial bladder cancers, with less promising
results as a therapy for melanoma.42 Infusions with cytokines
are another nonspecific form of active immunotherapy. For
example, melanoma is a frequent target for agents such as
interleukin-2 and interferon-alpha because it is the tumor
with the most immunogenic response.43,44
Agents that elicit a targeted response to either tumor anti­
gens or effector cells are considered specific (Fig. 11.5). The
best example of specific active immunotherapy is develop­
ment of vaccines derived from antigens expressed on patients’
cancer cells. The highly specific nature of this therapeutic
approach underscores its limitations. For example, multiple
patients’ tumors may express different peptide antigens or
alternatively different subclonal populations may exist within
a single individual.
The latest generation of antineoplastic agents, called biolog­
ics, targets molecular pathways identified from basic science
tumor biology. In contrast to traditional methods, which
develop drugs through trial-and-error testing, drug creation
in this manner is referred to as rational design since targets
are specified a priori. Since many biologics are antibodies, they
may be considered as forms of passive immunotherapy. The
earliest example, imatinib (Gleevec), was designed to block
the abnormal gene product of the Philadelphia chromosome,
Fig. 11.3  Adoptive transfer of autologous tumor-infiltrating lymphocytes.
Lymphocytes are obtained and cultured from tumor specimen. Lymphocyte
proliferation is stimulated with interleukin-2 (IL-2). Cells with specificity are isolated
and expanded. Patient myeloablation is achieved with chemotherapy and radiation.
The expanded antitumor lymphocytes are readministered, often along with IL-2.
Culture and
select
lymphocytes
Select and
expand cells
with tumor
specificity
Stimulate with
interleukin-2 (IL-2)
Sample or
resect tumor
Lymphocyte
Administer along
with IL-2
Fig. 11.4  Active immunotherapy with a nonspecific agent such as bacillus
Calmette–Guérin (BCG). Administration of the agent causes a nonspecific
inflammatory reaction with attendant cytokine release. This results in activation of
neutrophils, natural killer (NK) cells, and macrophages. These cells in turn release
various cytokines, including interleukin-2 (IL-2), tumor necrosis factor-alpha
(TNF-α), and interferon gamma (IFN-γ). These cytokines in turn lead to activation
of lymphocytes and resultant tumor cell killing.
Activation of
macrophage
Activation of
lymphocytes
T cell
B cell
IL-2
TNF-α
IFN-γ
Nonspecific
inflammation
and cytokine
release
Activation
of neutrophils
and NK cells
NK cell
BCG
Cuboidal epithelium
Neutrophil
Fig. 11.5  Active immunotherapy with tumor vaccination. A variety of approaches to
tumor vaccination have been applied, with variable results. An approach that has
been advocated recently utilizes ex vivo activation of the antigen-presenting
dendritic cell (DC). Immature DCs are expanded ex vivo. They are then exposed to a
tumor-specific antigen and stimulated. The resultant mature DCs are administered to
the patient. These cells act as antigen presenters, leading to activation of T cells
with specific antitumor activity.
Ex vivo immature
dendritic cell
Exposure
to tumor
antigen
Administer
to patient
Mature
dendritic cell
T cell activation
and cytotoxicity
after antigen
presentation by
DC leads to
tumor-specific
immunity
the constitutively active Bcr-Abl tyrosine kinase.45 Clinical
efficacy with imatinib has led to targeting of other oncogenes
such as vascular endothelial growth factor with bevacizumab
(Avastin) and CD20 with rituximab (Rituxan). As the newest
class of antineoplastic agents, the role of biologics in the
chemotherapeutic armamentarium is under investigation.

140
CHAPTER 11 • Principles of cancer management
identification of these cells can be challenging and may require
more sensitive measures such as immunohistochemistry (to
label tumor antigens). Even these more sensitive measures
may miss small foci of cancer metastases, therefore resulting
in false negative diagnosis. Accurate diagnosis of surgical
margins and biopsy specimens is critical since false nega­
tive findings can have a significant effect on diagnosis and
treatment.
Clinical findings illustrate this concept. For example,
patients with head and neck squamous cell cancers who
undergo prophylactic lymphadenectomy have significant
rates of local recurrences despite absence of tumor cells on
final pathology.52 A second example can be seen in rectal
cancers with negative margins on initial resection. Evalua­
tion of patients with locally recurrent disease shows that 50%
occur at the suture line despite negative histology.53 Tumor
recurrence in these scenarios may be attributable to micro­
scopic tumor deposits not detected on pathologic evaluation.
Laboratory studies have also demonstrated the presence of
microscopic tumor cells. Examples exist in both head and
neck and melanoma specimens where cancer cells cannot be
detected in routine histology, but have been successfully
grown in vitro.54,55 More recently, molecular biology techniques
such as polymerase chain reaction and immunohistochemis­
try have been used to perform molecular ultrastaging of
histologically node-negative patients for identification of
microscopically invisible tumor deposits. Whether such small
tumor burdens are clinically significant is the subject of further
investigation.56
The aforementioned examples provide justification for
multimodality treatment of solid tumors managed primarily
with surgical extirpation. Although margins are frequently
reported as “negative”, recurrences often occur. Chemo­
therapy or, more commonly, radiation is used in these settings
to treat potentially viable occult tumor cells. Alternatively, it
should be noted that the immune system has the potential
to eradicate residual tumor cells remaining after extirpation.
Review of patients with positive margins of basal cell cancer
demonstrate recurrence rates of only 20–30%, suggesting the
body’s capacity to destroy small numbers of cancerous cells.57
Ideally the goal of cancer diagnosis is to identify patients
accurately with microscopic spread of tumor to avoid unnec­
essary delivery of adjuvant agents that have untoward side
effects and toxicities.
Classification
Tumor classification can be based on a number of different
factors, including morphology, degree of differentiation, and
histologic cell type. Classification schemes differ for each
tumor type since factors that determine behavior are variable.
Retrospective studies have identified tumor characteristics
that may be used to predict the clinical behavior of the tumor
type. For example, sarcoma behavior correlates with the
number of mitoses identified per high-power field or histo­
logic subtype.58–60 In contrast, prognosticators for breast cancer
include tumor size, lymph node status, and hormone receptor
expression.61–64 The principal goal of classification schemes is
to substratify tumors to predict clinical behavior more accu­
rately and guide therapy. Although recent advances have
been made in this field, the quest for more accurate diagnosis
and prognostication of tumor behavior is a major source of
With widespread availability and use, plastic surgeons will
increasingly operate on patients who receive them. Few data
are available about surgery in this setting, but case reports
suggest angiogenesis inhibitors such as bevacizumab contrib­
ute to wound breakdown since neovascularization is a key
component of normal wound healing.46
Photodynamic therapy
Photoradiation uses light within the visible spectrum to
produce energy within cells. The most widely known applica­
tion of photoradiation is lasers. Chemicals called photosensi­
tizers, which are preferentially taken up by cancer cells relative
to normal tissues, respond to light by producing free radicals.
When light is shone on these cells, accumulation of energy
leads to thermal damage and cell killing.47
Since photodynamic therapy requires light to be activated,
its utility is limited to superficial tumors. Photodynamic
therapy is currently being used for the treatment of advanced
esophageal and non-small cell lung tumors and is under
investigation for oral, skin, and other cancers.48,49
Pathobiology
Understanding of tumor cell biology provides a foundation
for current clinical management of cancers.
Critical mass
Normal cells tend not to overcrowd one another and align
themselves in an orderly fashion. In contrast, tumors cells lose
this propensity and grow by overlapping each other. Tumor
cells grow in a logarithmic fashion, quantified as the doubling
time. Each tumor grows at a different rate so doubling times
can vary between 2 and 200 days.50,51 Tumors are generally not
detectable until they reach approximately 1 cm in diameter.
Depending upon the doubling time, a tumor may be present
in a patient for years before it becomes palpable. Understand­
ing this concept affords the oncologic team sufficient time to
evaluate newly diagnosed patients properly and thoroughly
without rushing therapy. The first step, when technically
feasible, is to obtain a biopsy of a tumor mass to establish the
cell type and correct diagnosis. Excisional, incisional, or
needle biopsies are performed depending on the size and
location of the tumor. In some cases, for example, renal cell
cancer, needle biopsy or incisional biopsies may be contrain­
dicated as these procedures can cause peritoneal seeding.
Tissue diagnosis is usually correlated with imaging studies
such as computed tomography scans or magnetic resonance
imaging to identify distant and regional tumor spread. Sup­
plied with this information, informed decisions can be made
with the patient about the best treatment and timing of
adjunctive therapies relative to surgery.
Tumor margins
Variability in the distribution of tumor cells within a given
tissue sample can hamper the identification of malignant cells
in tissue sections. For example, if 10% of cells in a speci­
men have a malignant phenotype they are easily visualized
using a microscope. However, if the number of malignant
cells decreases to 0.1% or 1 in 1000, unless clustered together,

141
Management
comprehensive oncologic team about the risks and benefits of
each therapy with informed decision-making by the patient.
Furthermore, the availability of highly effective autologous
and implant-based breast reconstruction techniques may
further influence the decision to proceed with simple mas­
tectomy. Similarly, limb preservation for osteosarcomas has
only become possible through use of neoadjuvant chemo­
therapy and functional reconstructions with allografts or
endoprostheses. These examples highlight a paradigm shift
in ablative strategies over the last century from a “Halstead
approach” to modern treatment that relies on advances in both
multimodality therapy and reconstruction to manage solid
tumors.
Beyond primary tumor mass excision, the treatment of
draining lymph nodes is an important part of solid tumor
management. Since carcinomas drain through regional nodal
basins, in contrast to sarcomas that spread hematogenously,
removal of regional lymph nodes is crucial for these malig­
nancies. Regional lymphadenectomy is routinely performed
as part of staging to determine prognosis and for its potential
therapeutic value.70–74
For patients with clinically palpable nodes at the time of
tumor resection, removal of involved nodes is generally per­
formed to achieve regional control by preventing mass effect
and skin breakdown. In cases with no clinical evidence of
lymph node involvement either on examination or radio­
graphically, the timing of lymphadenectomy is controversial.
Lymph node dissection can be performed either at the time of
initial tumor extirpation, termed prophylactic or elective
lymph node dissection (ELND), or when the tumor subse­
quently recurs in a nodal basin (therapeutic lymph node
dissection, or TLND). ELND is not routinely recommended
for two reasons. First, regional lymphadenectomy leads to
increased morbidity such as extremity lymphedema or com­
plications of surgical dissection such as nerve damage. Second,
ELND has not clearly demonstrated improved survival com­
pared to TLND for malignancies such as melanoma.75 Ideally,
ELND should be restricted to cases with high probability of
occult regional tumor spread such as head and neck cancers
with a large primary tumor.76
The introduction of the sentinel lymph node concept
by Morton et al. has further altered surgical management
of clinically negative regional lymph node basins.77 The
sentinel node concept is based on the fact that tissues drain
into regional nodes in a reproducible and orderly fashion.
After injection of either radioactive colloid or blue dye into
the tumor, the first or sentinel node draining the basin is
excised to be examined for tumor involvement. The status
of the sentinel node is representative of the entire regional
nodal chain, suggesting whether or not ELND should be
performed. Through careful intraoperative identification
of the sentinel node and thorough histologic analysis, false
negative rates for sentinel node biopsy now range from 0
to 11%.78,79 A subset of patients with negative sentinel nodes
on hematoxylin and eosin stain will have micrometastatic
disease present on immunohistochemistry. The consequence
of such small tumor deposits is unclear since these patients
have similar survivorship to controls.80 An additional benefit
of sentinel node mapping is that, since only a single node is
harvested, more thorough histologic and pathologic evalua­
tion is performed of the specimen for improved nodal staging
accuracy.
current research. In the future, the goal is to identify tumors
based on “genetic signatures” that enable not only more
accurate diagnosis, but also targeted treatment.
The oldest classification system is based on clinical find­
ings. Here, staging is based on degree of tumor spread, pres­
ence of lymph node involvement, and presence of distant
metastasis by either radiography or biopsy. The widely used
TNM system expounded on clinical classification systems in
an attempt to stratify patients further into prognostic groups.
In this system, tumor (T) represents the extent of the primary
tumor as measured in size, depth of invasion, or degree of
anatomic involvement. Node (N) enumerates involvement of
lymph nodes, such as the number of affected nodes or node
size. Metastasis (M) reflects the involvement of distant organs.
Other classification systems rely on tumor morphology as
the basis for prognosis. For example, Lund’s classification
for basal cell carcinomas is based upon descriptive features
of the tumor such as nodular (well-defined margins), ulcer­
ative, morphea and sclerosing patterns (indistinct margins).
In this system, the presence of either morphea or sclerosing
features is associated with a more aggressive and problematic
course.65 A second example is the morphologic classification
established by Clark for melanoma, which includes lentigo
maligna, superficial spreading, nodular, acral, and desmo­
plastic variants.66
Histologic classification systems use histologic cell type or
category to stratify clinical outcomes. Examples of histologic
grading systems include salivary gland tumors, which are
separated into mucoepidermoid, adenoid cystic, acinic cell,
and squamous cell subtypes.67 Clark’s histologic system cat­
egorized melanomas by level of invasion into the papillary
and reticular dermis and subcutaneous fat.66 Using this
approach, determination of the depth of invasion was subjec­
tive with poor interrater reliability. Subsequently, Breslow’s
system was developed which more objectively quantitated
tumor thickness by measurement with a micrometer attached
to the microscope field.68
More recently, molecular biology concepts have been
applied to tumor classification. Knowledge of the transcrip­
tome and proteasome of tumors has led to identification of
unique molecular signatures for each tumor that predict clini­
cal behavior. An example is the reproducible and highly
specific molecular signature of the clinically aggressive triple-
negative (absent for ER/PR/HER2 receptors) breast tumors.69
Through use of basic science techniques, investigators aim to
subclassify tumors on a molecular level to refine staging
schemes and provide tailored therapy.
Management
The oncologist’s goal is to apply available treatment options,
both surgical and nonsurgical, to minimize morbidity while
enabling patient cure. In addition, the relative value of recon­
struction in restoration of organ function and cosmesis is not
equivalent in all scenarios and may play a role in choosing an
oncologic regimen. For example, laryngeal cancer treatment
with radiotherapy is strongly preferred over laryngectomy
since current methods of voice reconstruction are inadequate.
In contrast, many breast cancers are treated equally well
with either lumpectomy and radiotherapy or mastectomy
alone. These situations require detailed consultation with a

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CHAPTER 11 • Principles of cancer management
Theoretically, sentinel node mapping should decrease the
number of unnecessary regional lymphadenectomies per­
formed with associated morbidity. Rates of extremity lymph­
edema with sentinel node mapping have decreased to 5%
compared with 35% for complete lymphadenectomies.81,82
Currently sentinel node mapping is performed for breast
cancer and melanoma while reliability of the concept in head
and neck, lung, and uterine cancers is under investigation.83–85
A second major issue to consider when performing lymph­
adenectomy is the extent of dissection. Arguments supporting
extended or radical lymphadenectomy are that greater node
removal more accurately stages disease and failure to remove
these nodes leaves residual cancer cells behind. For example,
colon cancer guidelines recommend that at least 12 nodes
be evaluated histologically to avoid a false-negative nodal
status.86 Arguments against routine use of extended lymph­
adenectomy include increased morbidity of dissection and
lack of a survival benefit compared to limited dissections in
randomized trials.
A comprehensive discussion of cancer surveillance is
beyond the scope of this chapter, though some points are
worth mentioning. Although the premise behind surveillance
is to improve outcome through early detection, few protocols
demonstrate an actual survival benefit. For example, head
and neck patients with asymptomatic recurrences identified
through screening methods demonstrate no survival differ­
ence compared to patients who presented with symptoms.87
Concerns have also been raised that reconstruction may
obscure recurrence detection, but data do not support this
contention. Maxillectomy defects reconstructed with flaps, as
opposed to obturators, demonstrate statistically comparable
times to recurrence.88 Similarly, for breast cancer neither
implant nor autologous reconstruction has been associated
with a delay in diagnosis of recurrent disease.89,90 Recurrences
after transverse rectus abdominis myocutaneous flap recon­
struction can be successfully managed with local excision and
flap salvage in 80% of cases. Regardless of the type of breast
reconstruction performed, recurrent disease is detectable on
physical exam, not mammography.
Conclusion
Today, the most common treatment for solid tumors remains
surgical excision; however, the last century has demon­
strated the advantages of multimodality therapy using
chemoradiation. Refined staging and increased knowledge
of pathobiology have allowed individualized tumor man­
agement with development of targeted treatment regimens.
It is incumbent upon plastic surgeons to understand the
principles of cancer management in order to perform recon­
structions that minimize postsurgical complications, thereby
allowing patients to receive adjunctive therapy in a timely
manner.
1. Trimble EL, Ungerleider RS, Abrams JA, et al. Neoadjuvant
therapy in cancer treatment. Cancer. 1993;72:3515–3524.
3. Improved survival with preoperative radiotherapy in resectable
rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med.
1997;336:980–987. Large trial which unequivocally demonstrated
improved outcomes in patients receiving neoadjuvant radiotherapy for
rectal cancer. This paradigm is now in use, or being explored in a variety
of cancers, including breast and lung. There may be significant
implications for reconstructive options.
9. Halsted WS. I. The results of operations for the cure of cancer of
the breast performed at the Johns Hopkins Hospital from June,
1889, to January, 1894. Ann Surg. 1894;20:497–555. Seminal
manuscript demonstrating the widely held 19th-century belief that wide
tumor excision based on anatomic principles provides the greatest chance
for cure.
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Mastectomy is no longer considered mandatory and is reserved for select
patients.
23. Whelan TJ, Olivotto IA, Parulekar WR, et al. Regional nodal
irradiation in early-stage breast cancer. N Engl J Med.
2015;373:307–316.
35. Nigro ND, Vaitkevicius VK, Buroker T, et al. Combined therapy
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Seminal study which demonstrated curative management of a “solid”
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protocol now spares many patients from highly morbid abdominoperineal
resection (APR).
56. Damle S, Teal CB. Can axillary lymph node dissection be safely
omitted for early-stage breast cancer patients with sentinel lymph
node micrometastasis? Ann Surg Oncol. 2009;16:3215–3216.
68. Breslow A. Thickness, cross-sectional areas and depth of invasion
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908. Study which demonstrated the biology of melanoma is dictated by
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77. Morton DL, Wen DR, Wong JH, et al. Technical details of
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lymph node dissection, this procedure reduces patient morbidity,
including lymphedema, and length of stay.
78. Veronesi U, Viale G, Paganelli G, et al. Sentinel lymph node biopsy
in breast cancer: ten-year results of a randomized controlled study.
Ann Surg. 2010;251:595–600.
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